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  • GCVRZ Forum 919 comments
    Oct 17, 2013 4:58 PM | about stocks: SNY

    Welcome to the GCVRZ Forum. Please use the comment section for any questions or answers. Investors -- both long and short -- are welcome as are potential investors. Additionally, I am particularly interested in the views of professional physicians and medical researchers and the experiences of patients with direct experiences with Lemtrada.

    From one anonymous doctor:

    (click to enlarge)

    Themes: GCVRZ, Lemtrada, Alemtuzumab Stocks: SNY
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Comments (919)
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  • Author’s reply » To start things off, I would like to raise the topic of the impact on disability over time. Other MS drugs have slowed the rate of worsening disability or had no effect. What does Alemtuzumab do to disability over time? How will this impact the FDA decision and how will it impact sales?
    17 Oct 2013, 05:06 PM Reply Like
  • Saw this the other day from the EU: http://bit.ly/1i05f93
    "Latest data from the CARE-MS II extension study show that alemtuzumab (Lemtrada, Genzyme/Sanofi) has a durable effect on disability in multiple sclerosis (MS), with the mean Expanded Disability Status Scale (EDSS) score at 3 years still below that at baseline."
    and this is a good meta site: http://bit.ly/1i05hO8

     

    I'm not a Dr. I happen to be long the CVR and think this is a fascinating drug that shows promise based on my limited research for a terrible disease. How crazy that an 'old' drug can be recycled for treatment of a new disease?

     

    Chris, I'm on the free side of the paywall. Any thoughts on the valuation of the CVR with the new (small but unexpected) hurdle of the panel in November?

     

    It may sound self-interested but it's a shame this drug is off the market one day longer than absolutely necessary. AT.
    17 Oct 2013, 05:27 PM Reply Like
  • Author’s reply » I think that it is reasonable to expect approval, but I am not confident in the impact of the panel. Hopefully others can opine.
    17 Oct 2013, 06:12 PM Reply Like
  • If you don't mind me interjecting, I don't look at the the advisory panel as a hurdle. To me it means FDA attention is on it that much sooner. The clock is ticking. March 2014 is not that far away.
    17 Oct 2013, 07:42 PM Reply Like
  • Could you post the news article about the November Panel requirement? Thanks. I was taken by surprise on the 10% drop.
    17 Oct 2013, 10:37 PM Reply Like
  • Author’s reply » November 13, 2013: Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement -- http://1.usa.gov/H7xXJo
    18 Oct 2013, 06:42 AM Reply Like
  • Related news from 1 week ago:
    http://bit.ly/19bT9I5
    17 Oct 2013, 05:44 PM Reply Like
  • Author’s reply » I'm no expert, but that appears to be quite positive.
    17 Oct 2013, 06:13 PM Reply Like
  • Another recent medical news article:

     

    http://bit.ly/19QcN9f

     

    Seems some physicians are negative about the drug:

     

    "Medical director at the Providence Multiple Sclerosis Center in Portland, Oregon, Stanley Cohan, MD, said, “I don’t think this drug will be approved, but if it were available, I wouldn’t use it.” The authors of the study, Alasdair Coles, PhD, from Cambridge University in the United Kingdom acknowledged that many of his colleagues do not agree with the idea of using alemtuzumab in multiple sclerosis."

     

    http://bit.ly/H0T40o

     

    I read the story of David Sturt who has MS and has not suffered a relapse after being treated with Campath (Lemtrada) 10 years ago:

     

    http://bit.ly/H0T6oZ

     

    This was pulled from a forum of patient experiences with Lemtrada/Campath:

     

    http://bit.ly/H0T6p1
    17 Oct 2013, 11:32 PM Reply Like
  • I wish the folks at greenliveforever.com could compose in English. So there are 38 people in the study, and there were 64 thyroid events, 6 cases of thrombocytopenic purpura, graves opthalmopathy, a surgical decompression, breast and cervical cancer, Burkitt’s lymphoma, thyroid papillary carcinoma, and basal cell carcinoma?

     

    Are they saying these were all caused by the drug?
    19 Oct 2013, 02:34 PM Reply Like
  • The doctor quoted on the greenliveforever.com website was a quote made back in 2010. Dr. Cohan was reacting to the first phase III trial results. I find it interesting that a physician who was involved in clinical trials for Tysabri would have anything negative to say about other alternative therapies. PML, induced by Tysabri, has killed more patients than any other MS therapy. It is now four years later and his opinion may have changed over time. Here is the medscape article from which he was quoted:

     

    http://bit.ly/16j7TH4
    19 Oct 2013, 05:07 PM Reply Like
  • Thanks for your various feedbacks, rootbeer. That's incredible that you've found no RRMS drug has been rejected by the FDA in 10 years.

     

    There are about 95,000 patients on Tysabri currently and 59 have died from PML (271 have PML). If we divide these two to get a crude risk of mortality measure we have 0.25%. Which is in the ballpark of reported PML risks (0.4%-2%) multiplied by PML mortality rate (20%). But note for PML: "all survivors had additional disability, often severe."

     

    Sources:
    http://bit.ly/15SPG0y
    http://bit.ly/15SPG0C

     

    As far as I am aware, in Phase 2 and 3 trials, Alemtuzumab has had 1 death from ITP and 1 from sepsis, out of 334 (Phase 2), 581 (CARE MS-1), and 657 (CARE MS-II) patients, respectively, for a bit lower back-of-envelope mortality of 0.13%. It seems my math on risks agrees with your sentiment about Tysabri being worse, although not significantly worse.

     

    My main concerns for approval are the FDA may not believe the safety procedures for early detection of ITP, or may not like the risks of abnormal thyroid function, or may consider the mortality risks as being too high. And of course approval could be delayed past the GCVRZ approval deadline of March 31, 2014. Actually delay is much better for us than the binary outcome of rejection since the other CVR payouts are still available. It is encouraging that you believe the FDA gives more latitude for RRMS drugs and can delay in the interests of safety if needed.

     

    Some people were asking about the payout conditions of the CVR. They are available from the SEC. All investors should read them:

     

    http://1.usa.gov/V5QIkF

     

    Finally, this situation was discussed by "longtermvalue" in 2011. His highest probability guess was estimating that the production milestone would be hit but it was missed. He estimated Lemtrada approval at 70%.

     

    http://bit.ly/15SPIpm
    19 Oct 2013, 08:20 PM Reply Like
  • Great idea Chris. I do hope you do this more on some of your other articles that end up behind the pay wall. Sometimes the best information comes out in the discourse.
    17 Oct 2013, 06:49 PM Reply Like
  • Author’s reply » I'm glad you like it. That is my intent.
    17 Oct 2013, 07:20 PM Reply Like
  • It is reasonable to think that the sell off was due to the panel announcement. The panel rec could be pos or neg (I think pos) but either way that there is a panel shouldn't have moved the stock. The deadline for $1 CVR approval is March 31,2014. The panel rec is mid NOV so the FDA approval could have better odds (even though still small) of going past April fools day. And that would mean no $1 for approval. I bought more at 1.81 today
    17 Oct 2013, 08:12 PM Reply Like
  • Author’s reply » Brainstorm (and might be a stupid one): maybe it is a combination of the panel as well as the AMRN news, which reminds the market of the potency of the FDA.
    17 Oct 2013, 08:21 PM Reply Like
  • Am I correct that even if the 3/31/2014 approval deadline is missed, that $1 can still be forthcoming if the first revenue target is hit?
    17 Oct 2013, 08:40 PM Reply Like
  • AMRN did cross my mind, but I don't think the potential benefits of Vascepa to lower triglycerides compares to that of Lemtrada for a debilitating disease like MS. I'm guessing some people are worried about the approval timeframe due to the panel. Someone on the GCVRZ Yahoo board stated "There were 8 cases of advisory committee meetings at the end of last year (10/16/12-12/20/12). All but one were resolved by 2/4/13. (The outlier took 7 months, and seems to have nothing to do with holidays, etc.)". I haven't verified this, but if the statement is true that gives me more confidence.
    17 Oct 2013, 08:46 PM Reply Like
  • Author’s reply » Yes. Correct.
    17 Oct 2013, 08:54 PM Reply Like
  • The $1 will still be paid if the 2nd sales milestone is met.
    17 Oct 2013, 09:58 PM Reply Like
  • No I think it has to hit the second target... no payout for first target if I understood correctly
    23 Oct 2013, 02:32 AM Reply Like
  • FDA says No a lot. And Yes a lot. AMRN denial could have scared some holders of both...Interesting thought.
    This is likely to be quite volatile the next month....Limit orders may catch attractive prices for those who are willing to risk the binary event (FDA approval not panel rec)
    17 Oct 2013, 09:01 PM Reply Like
  • I was glad for the recent selloff, as I've been shy about pulling the trigger on this until today. I agree that that the standards for treating a serious debilitating disease are different that for treating a risk factor like high tri-g's which can be lowered with diet and exercise.
    17 Oct 2013, 09:23 PM Reply Like
  • Two questions, I was not aware there was a hard date on the Lemtrada approval March 31, 2014. Has anyone done an analysis on the probability of approval but AFTER that date? I don't believe Chris mentioned this risk in his write up of the investment thesis.

     

    Secondarily, is this panel a "out of normal" activity prior to approval? Why does this pose additional risk? Or why does the market view it that way?
    17 Oct 2013, 10:23 PM Reply Like
  • people are using that date as a last date to get it done for it to qualify for the first payment on the CVR. There is a second chance for it to payoff for approval though as long as the second sales milestone is hit.
    17 Oct 2013, 11:11 PM Reply Like
  • I welcome anyone to propose a short thesis on GCVRZ. It is my highest conviction position and I will use any short thesis to reassess my reasoning for owning the security. I follow several different companies involved in neurodegenerative diseases. I like to look for companies that have a novel medication that will have high impact on a disease, that is transformative, and that has a strong moat, leading to a virtual monopoly. GCVRZ is not a company but it represents a medication that is transformative. The British neurologists call it a step change. It will be a monopoly in the sense that it will be the only medication that is an induction therapy. Induction of what? Induction of a durable remission of 4-6 years or induction of a cure? That is the million dollar question.

     

    MS is a long, lousy disease. If you have MS, even when you think nothing is going on, the brain of a patient with MS is being systematically shredded slowly and silently and it progresses from the relapsing, remitting phase into the secondary progressive phase. We talk incessantly about the medications for RRMS but we never hear any mention of a medication to slow down secondary progressive MS. Why? Because there is nothing available. The patient who evolves into SPMS is more or less set adrift. The pharmaceutical companies collect their billions of dollars from patients who have RRMS but have nothing to offer them when they reach the secondary progressive phase of the disease. It takes about twenty years for this process to evolve. The end result is unemployment, divorce, loneliness, paralysis, numbness, loss of vision, incontinence, and severe dementia followed by death. I won't even talk about the patient who presents with primary progressive MS. That is a quicker path to death.

     

    So when we say that there is no cure, we mean that there is no way for us to prevent progression from RRMS to SPMS. And if we have a medication that induces a remission, we won't know if it is actually a cure until twenty years from now. Nothing in life is one hundred percent other than death. But if a medication can result in a durable remission and/or cure for about fifty or sixty percent of the patients that take it, isn't the chance of developing hyperthyroidism worth the benefit of a possible durable remission (or cure)?

     

    Should we wait twenty years to find out? Just let everybody with RRMS slowly progress into SPMS so that the pharmaceutical companies can collect their billions of dollars from patients that are on some form of maintenance therapy? Or can we find some way to offer alemtuzumab to patients, while managing the risk of developing hyperthyroidism (30%) and ITP (1%)?

     

    The thirty member countries that make up CHMP thought about this question and said, yes. We can manage the risk and we want to offer alemtuzumab to the patients in Europe rather than wait twenty years to find out whether or not it is a cure. Even if it only cures ten percent of the patients that take the drug, but results in a durable remission in the other sixty or seventy percent of patients, that benefit of slowing down this deadly, relentless disease is worth the risk of developing hyperthyroidism (which is curable).

     

    While we wait for the advisory committee meeting, a question has been raised regarding the three year history of neurologic drug approvals and rejections (complete response letter). The worry is that there is an overall negative trend in the approval of neurologic medications. I am willing to address this theory but, felt compelled to spell out the question that will be addressed by the advisory committee, one that has already been addressed by 30 member countries in CHMP, using the same data that is now up for review in the FDA.

     

    To be continued...
    18 Oct 2013, 07:25 AM Reply Like
  • I sent a message to you on Chris's article's comments, also posted it above, asking about negative response by some doctors regarding what appears to be a wide array of side effects. Not a short thesis but perhaps you can give some insight on that. I agree, I want to see a thorough short thesis.
    19 Oct 2013, 02:41 PM Reply Like
  • Minor point on terminology. You refer to MS as a "neuro-degenerative" disease, which is true from a linguistic point of view, and many neurologists and neuro-scientists favor this term, especially when the destruction of axons and loss of grey matter sets in. However, I prefer to reserve the term "neuro-degenerative" for diseases like Parkinson's, Alzheimer's, ALS and others which are primarily caused by the death of neurons, usually due to the intra-cellular accumulation of toxic mis-folded proteins. I find it most useful to categorize MS as an auto-immune disorder, a category which focuses our attention on the etiology of MS and its treatments, which all involve modulation of the immune system. In these ways, MS patients are more similar to patients treated by rheumatologists than to patients treated by neurologists for other diseases.
    22 Dec 2013, 01:47 PM Reply Like
  • I agree more or less with what you say. Regarding rheumatoid arthritis vs MS, it appears that rheumatoid patients can avail themselves of multiple disease modifying agents more readily than MS patients. When patients, who were on Avonex, were also placed on Tysabri, it had disastrous consequences. There is a reluctance to place MS patients on multiple different disease modifying agents because they are all, more or less, immunosupressive agents. Immunosuppressive agents lead to a higher risk of PML in the MS patient population.
    23 Dec 2013, 10:41 AM Reply Like
  • Are you aware of any promising remylenation therapy or new MS treatment as opposed to another disease modifying therapy?

     

    Thanks,
    23 Dec 2013, 11:09 AM Reply Like
  • rootbeer, thank you once again for your analysis. you are extremely helpful in describing in terms a layman can understand.
    18 Oct 2013, 08:00 AM Reply Like
  • Author’s reply » “Lemtrada FDA Panel Signals Near-Term U.S. Action on Application… The November timing of an advisory panel meeting on Sanofi's Lemtrada for use in multiple sclerosis may secure FDA action on the application before year-end. While some panels, such as the one for Amarin's Vascepa, result in significant obstacles, many result in approval after the panel gives label and monitoring recommendations. U.S. approval before March 31 would trigger a $1 payout to holders of CRVs from Sanofi's buyout of Genzyme.”

     

    - Andrew Berens and Thomas Smith, Bloomberg Biotech Team
    18 Oct 2013, 09:41 AM Reply Like
  • GCVRZ is at about the same price as it was before the CHMP approval. I would submit that it is significantly more valuable now than it was before. Much of the risk has been removed. Furthermore, it is quite possible that many of the potential US sales will happen in EUR if the US does not approve. People all over the work who can scrape up the money will be going there for treatment.
    18 Oct 2013, 10:00 AM Reply Like
  • Here is a link to a video interview, conducted by one of my former colleagues, of two well respected neurologists at the conclusion of ECTRIMS. This video provides further color on the lack of available treatment for progressive MS, the increasing incidence of MS, vitamin D, and deleterious effects of smoking on MS.

     

    http://bit.ly/16mxVnA
    19 Oct 2013, 09:49 AM Reply Like
  • Thank you, initially Chris and now so many others, for highlighting this opportunity. There is something satisfying about taking a position in GCVRZ due to the security's "inherents" (I should say, characteristics) but also the potential benefits it may yet bring to patients in Europe and hopefully the USA (and elsewhere, obviously).

     

    Although I call myself Biological, I am no biologist. I have had exposure to biotech, both via funds and individual companies, in the past. I see a very remote parallel between investors in GCVRZ and what was then CRA (Celera Genomics, the folks in Maryland who decoded the human genome). I made much money on CRA only to lose it all back...I hung on to it out of emotion like, I think, people are hanging on to TSLA today, perhaps. At the time, CRA made a good scientific case for infinite returns.

     

    GCVRZ is clearly different but I tell story just to highlight what emotions did to me, back then. Investing requires serious fortitude and clarity. I lacked it then but I believe I have learned.

     

    I added to GCVRZ yesterday because the analysis and commentary to date seems to indicate a better proposition than initially highlighted by Chris. Way better and, in my case, at a better price. At that time, we were looking at a potential binary situation...yeah or nay. Fine, kind of unusual payout situation but - well - better understood than, say, I can understand longs in Z or TSLA. Today, we have approval in Europe to fall back on, do we not? We have greater knowledge, Europe approval and a fixed date for FDA review.

     

    Now, I recognize that Lemtrada could be transformative but this is where emotions can run wilder than logic. I wish it be so transformative, surely, for those who suffer and for my own profit, but no one will really know what the future will hold. Don't let that drive your investment - you do not need to. I still think Chris' original proposition is the best guide. At that time, the security seemed undervalued in light of greater uncertainty and without the benefit of so much information (which now points to transformative type of upside). That original proposition, I think, is still indicating a 50%+ bargain (with all the caveats) regardless of the revenues that GCVRZ may yet produce.
    19 Oct 2013, 10:13 AM Reply Like
  • Is there a negative trend in recommendations for approval from the FDA advisory committee and should an investor in GCVRZ consider this record before investing? You be the judge.

     

    - 5/22/2013: Suvorexant, complete response letter
    This was an insomnia drug that received a CRL due to safety concerns. FDA Indicated that the drug was definitely efficacious and could be reconsidered when a 10 mg tablet was available for marketing. FDA felt that the higher doses (20 mg and 40 mg tablets) may be unsafe for certain patient populations.
    http://bit.ly/17Aokd8

     

    Comment: people are not dying from insomnia. FDA, therefore, places higher emphasis on safety.

     

    - 5/24/2012: Vyndaqel, complete response letter
    This drug was submitted for approval by Pfizer for use in transthyretin familial amyloid poly neuropathy.
    http://bit.ly/17Aokd9
    Although in the past, drug approval depended on positive results from at least 2 trials, a drug can now be considered for approval with a single adequate and well-controlled clinical investigation, along with confirmatory evidence. Findings are expected to be robust. The two primary endpoints of this single trial had P values of 0.12 and 0.07.

     

    Comment: for a trial endpoint (trial result) to be deemed clinically significant, it must have a P value < 0.05 or less than 5% probability that the results achieved, were simply due to chance. Drug was rejected due to lack of proven efficacy. I guess that Pfizer spent a ton of money on developing this drug and had nothing to lose by submitting it for approval. This was like trying to throw a ninety five yard touchdown pass from your own 5 yard line with 5 seconds remaining in the game.

     

    - 10/17/2011: Azilect, complete response letter
    This is a drug used in Parkinson's Disease and is already approved for use in Parkinson's Disease. In this meeting, TEVA was seeking support for a label expansion. The company claimed that the drug not only effectively treats symptoms of PD, but is DISEASE MODIFYING. Two phase III studies were submitted in support of this application. One phase III study (ADAGIO) showed opposite results for the 2 doses used in the study. Findings from the double-blind study suggest the 1-mg dose may afford a disease-modifying effect in early Parkinson's, whereas the 2-mg dose does not. It is a contradiction the researchers were unable to explain. The puzzling results were published in the New England Journal of Medicine in September 2009. The committee rejected the new indication and said that the data was not robust. Everyone agreed, however, that the drug was quite useful for treating symptoms of PD and the drug continues to be marketed for this indication. (Trade name, Rasagiline)
    http://bit.ly/17Aon8R

     

    Comment: TEVA markets Copaxone which has been responsible for about 50% of the company's profits. This drug comes off patent in 2014 and TEVA is apparently not averse to begging the FDA for label expansion of already approved drugs in order to maintain revenue.

     

    - 3/10/2011: Lamicital XR (new indication), approved

     

    - 1/21/2011: Gadobutrol, approved

     

    - 1/20/2011: Florbetapir, complete response letter
    This is a diagnostic imaging agent called Amyvid, useful for, but not diagnostic of Alzheimer's Disease. I am a radiologist, have used it, and I know it quite well. Experience is necessary in interpreting the images. "It is an extremely attractive agent being proposed," Britt Anderson, MD, Peripheral and Central Nervous System Drugs Advisory Committee chair, said during an interview. "We would like to see some structured training and evidence of consistency among readers," explained Dr. Anderson, who is from the University of Waterloo in Toronto, Ontario, Canada.

     

    Comment: A negative Amyvid scan is helpful in ruling out Alzheimer's Disease. A positive scan has overlap in patients with other dementias.
    There is a need to find a diagnostic scan that is highly sensitive for EARLY detection of Alzheimer's. This diagnostic imaging agent does not do that, and since the positive study overlaps with other dementias, it is of limited clinical value in differentiating Alzheimer's from other dementias.
    http://bit.ly/17Aon8S

     

    - 8/11/2010: Potiga, complete response letter
    This is a medication used for a seizure disorder. The advisory committee actually unanimously recommended approval but the FDA delayed approval. This overwhelmingly positive vote was despite concerns the drug has been linked to toxic effects not usually seen with other antiepileptic drugs. The FDA's chief concern was urinary retention that has been reported with Potiga. However, the advisory committee concluded this risk could be mitigated with monitoring. The FDA sought a change in label language and risk mitigation strategies to prevent urinary retention. The drug was approved by the FDA on 6/10/11 for use in partial seizures.
    http://bit.ly/17Aonp7

     

    Comment: the recurring theme in the FDA is one of emphasizing safety when there are other alternative therapeutic options in non lethal diseases. Strict adherence to safety concerns resulted in a delay of approval but, not a rejection.

     

    - 6/10/2010: Gilenia (Gilenya), approved

     

    - 5/6/2010: Acthar, approved

     

    SUMMARY:
    In my opinion, the advisory committee has been quite reasonable and predictable in both recommending drugs for approval and/or delaying/rejecting drugs. It is misleading to look at the record and then conclude that the committee has a negative bias toward drug approval. One should understand that a pharmaceutical company spends an enormous amount of money in phase I, II, and III trials. The pharmaceutical companies have nothing to lose by requesting a review. This skews the record toward a negative trend.

     

    I think that it is more instructive to look at the record of approvals and rejections for drugs used in RRMS. No proposed drug for RRMS has ever been rejected by the FDA in the last 10 years (that I am aware of).

     

    Cladribine, a drug approved for use in Leukemia, owned by Merck, and tested in a phase III trial for RRMS, was withdrawn from consideration after feedback from the FDA. The FDA did not dispute efficacy. The FDA was concerned with the known toxic side effects (resulting in death) and wanted another phase III trial. The patent expiration would not have allowed Merck to recover the development costs and the drug was withdrawn from all marketing applications.

     

    There is an unmet need as I have explained in prior posts. People are slowly succumbing to the disease even while on a disease modifying therapy such as the injectables, Tysabri, and the newer oral medications. In this situation, the safety concerns have to be muted in an attempt to offer patients some chance of slowing disease progression.

     

    Regarding safety of Alemtuzumab, risk mitigating strategies have already been included in the NDA.

     

    The FDA had previously approved alemtuzumab when it was marketed as Campath and used in CLL. Alemtuzumab resulted in one death due to brain hemorrhage due to development of ITP during the trials for MS. The risk mitigation strategy is to monitor the platelet count and initiate therapy for ITP if it develops. (The risk is only 1%.)

     

    The reader is encouraged to search my prior posts regarding the risks of PML while on Tysabri for some perspective on how much latitude the FDA is willing to grant the pharmaceutical companies in approving drugs for RRMS.
    19 Oct 2013, 11:08 AM Reply Like
  • Excellent post. I would only add that the FDA may have been mistaken about Azilect. It may be truly disease-modifying (although weakly so), with an inverted U-shaped response optimized at the 1 mg per day dose, i.e. 2 mg is too much of a good thing.
    23 Dec 2013, 10:57 AM Reply Like
  • Not sure if everybody knows that even if Lemtrada get approved past 3/31/14 there is still a way to get the $1 for approval. A friend pointed this out to me...see below

     

    3) Product Sales Milestone #2: CVR holders are entitled to receive $3 per CVR in the
    event global net sales for Lemtrada total $1.8 billion during any 4 consecutive calendar
    quarters. Any quarters used in the achievement of this sales milestone cannot be used
    again for the achievement of any subsequent milestones. In addition, if this Product
    Sales Milestone #2 is achieved despite U.S. FDA approval of Lemtrada for treatment of
    multiple sclerosis not having occurred on or before March 31, 2014 (and so the Approval
    Milestone Payment was not made), CVR holders will be entitled to receive an additional
    $1 per CVR for Product Sales Milestone #2.
    19 Oct 2013, 10:11 PM Reply Like
  • And one would conclude that the upcoming FDA decision is not the binary event that everyone makes it into.
    19 Oct 2013, 10:54 PM Reply Like
  • Though it still is ... after all if the FDA doesn't approve then the award for milestone 1 (ostensibly the easiest to achieve) goes out the window. So failure to get approval by the March deadline has a big impact on the potential future value of the CVR.
    20 Oct 2013, 04:42 AM Reply Like
  • No, milestone 3 stays in effect until 2020 and when annual sales reach 1.8 billion the CVR holder is paid $4 instead of $3 if milestone 2 was not paid out. For someone to consider 3/31/14, the last possible day to receive $1 is mistaken.

     

    It is also a mistake to think that the FDA will reject the medication based on efficacy and demand a new trial. Perhaps the discussion results in a request to change the label language, resulting in a delay but, the CHMP did not request this. To postulate that SNY receives a CRL, withdraws the request for marketing approval, and markets alemtuzumab in the rest of the world, holds no merit. This leaves US MS patients with no option, other than to travel to Europe if they want a chance at durable remission. And where does this situation leave patients with CLL? They no longer have access to a medication that is given in a dose up to 90 mg per week for approximately 12 consecutive weeks. SNY agreed to make the medication available for free to the European patients with CLL in exchange for the right to market the medication as Lemtrada, rather than Campath. I presume the same for the US. Outright rejection of the medication is a rejection for the MS patients and the patients with CLL since the medication has been withdrawn from the market. Not a tenable thesis and 3/31/14 has no real bearing on the CVR payments.
    20 Oct 2013, 09:09 AM Reply Like
  • Rootbeer,
    To your point if a FDA decision doesn't come by 3/31/14 it could setup the mother of all buying opportunities. Should the concerns that some have mentioned like end of year bureaucratic slowdown help to push this past the deadline the CVR could plunge. And longterm not much would have changed...only somewhat of a less chance for the $1.But I bet the market initially wouldn't take it like that.
    20 Oct 2013, 10:45 AM Reply Like
  • @Special Situation: I didn't even notice that point about Milestone #2. Thanks for pointing that out! But also keep in mind the right that Sanofi has to redeem the CVR if market price is <= $0.5, 3 years since Lemtrada launch, and sales in last 4 quarters are less than $1 billion.

     

    So rejection is still the main binary outcome to be concerned about at this stage, but delay isn't necessarily that bad.

     

    @rootbeer, Be careful when judging odds as 100% in investment. Those are bet your life sort of odds. Always having some doubt prevents over-aggressive sizing mistakes.
    20 Oct 2013, 01:58 PM Reply Like
  • Addendum: I should rephrase the last post. 3/31/14 is a significant date for the owner of this CVR and a delay beyond this date for approval would be a disappoinment and a setback.
    1. probability of delay due to lack of efficacy resulting in a request for another phase III trial: zero
    2. probability of delay due to safety concerns requiring another trial: almost zero.
    3. probability of delay due to disagreement over labeling lanquage: remote but possible. It became even more remote after CHMP issued the recommendation for approval.

     

    These are the reason that I own the CVR.
    20 Oct 2013, 04:03 PM Reply Like
  • Good point. I agree.
    20 Oct 2013, 04:16 PM Reply Like
  • I agree. I should tone down my fervor and welcome the comment.
    20 Oct 2013, 04:20 PM Reply Like
  • @Rootbeer: What about a FDA delay/Cladribine-like thesis?

     

    4 people died in the Cladribine study so that is not so different in numbers than the people who died in Alemtuzumab phase 2 and 3 studies. If the FDA requires an additional Phase 3 trial, well, the last one took 2 years, so it might be January 2016 before that is complete. But the U.S. patents expire in September 2017. So it seems possible Sanofi might not want to pay for an additional Phase 3 trial (under that scenario). Then there might just be the E.U. sales until 2014 when the E.U. patents expire (I was not able to find when in 2014 they expire -- does anyone know?). With a pessimistic 60-70% chance of hitting that milestone the value would be $1.2-1.4.

     

    But I have no particularly good insight in that scenario. In the event of delay what do you think is the most likely outcome?
    26 Oct 2013, 01:26 PM Reply Like
  • Cladribine phase III trial:
    http://bit.ly/16FNGLP

     

    Two doses of cladribine were compared against placebo. There were a total of four deaths in the two cladribine arms and two deaths in the placebo arm. The cladribine arms had a heart attack, cardiac arrest related to tuberculosis, a drowning, and death due to metastatic pancreatic carcinoma. The two deaths in the placebo arm were a suicide and a stroke.

     

    Cladribine is an antineoplastic approved for use in Hairy Cell Leukemia. But in the MS population, it causes fairly frequent severe infections and had caused multiple neoplasms that were both benign and malignant. It did receive a complete response letter from the FDA in March of 2011, citing safety concerns. (Please accept my apology for a post made in the past in which I said that I was not aware of any FDA rejection of a MS medication in the past ten years.). This would have been an oral induction therapy if it had been approved. Merck could have done another trial at the lower dose. With the proper patient selection, and utilizing risk management strategies, this could have been a useful medication. Patent considerations apparently kept Merck from pursuing an additional phase III trial.
    For some other thoughts please read this link:

     

    http://bit.ly/16FNJqT
    Interestingly, one of the lead investigators in this trial, Gavin Giovannoni, is a vocal advocate of alemtuzumab in the UK.

     

    Phase II trial of alemtuzumab in comparison to Rebif:
    http://bit.ly/16FNGLT

     

    This study compared two different doses of alemtuzumab to Rebif, was begun in 2002, and was suspended in 2005 after three cases of ITP were reported. Idiopathic thrombocytopenic purpura is a disease in which there is a severe deficiency of platelets. Platelets are necessary for clot formation. These patients are prone to severe bleeding anywhere in the body. One patient died after developing a hemorrhagic stroke. (He bled into the brain.) A risk management strategy consisting of monthly blood counts was implemented. The trial resumed and ultimately, there were a total of two deaths, one from pre existing cardiovascular disease and one from the stroke due to ITP in patients who were on alemtuzumab. No death from ITP occurred after implementation of the monthly blood count. (ITP is treatable. Platelets are administered along with IV steroids and gamma globulin.)

     

    CARE MS I:
    http://bit.ly/16FNH29

     

    In this phase III trial, alemtuzumab was compared to Rebif. As a result of the phase II trial, Risk mitigation strategies were implememted for the phase III trial. Patients received acyclovir as prophylaxis for herpes skin infections. The risk of ITP was previously defined as 1%. Monthly blood counts were performed to detect developing ITP, and if detected, conventional therapy was instituted. The risk of hyperthyroidism was previously defined at about 15-20%. Blood samples were taken every three months to screen for developing hyperthyroidism and if detected, conventional therapy was instituted.

     

    One patient died in the alemtuzumab group due to an automobile accident during the study. One additional alemtuzumab patient died after the study due to sepsis.

     

    After 22 months, three patients developed ITP and all were successfully treated with conventional therapy.

     

    Infections occurred in 45% of the Rebif patients and in 67% of the alemtuzumab patients. No infection led to discontinuation of treatment during the study and no infection was life threatening.

     

    Regarding thyroid disorders, 6% of patients on Rebif developed a thyroid disorder and 18% of patients on alemtuzumab developed a thyroid disorder.

     

    Regarding cancer, 2 out of 376 alemtuzumab patients developed thyroid cancer. None of the 187 Rebif patients developed cancer. (The vast majority of thyroid cancers can be treated with excellent long term results.)

     

    Overall, and most importantly, adverse events (including relapse of disease) led to a discontinuation of therapy in 12 % of the Rebif patients and in 3.7% of the alemtuzumab patients.

     

    Conclusion:
    Cladribine could have addressed the safety concerns raised by the FDA in another phase III trial but patent considerations for a small molecule, antineoplastic that had been on the market for many years, prevailed. Merck could not recoup its expenses in another phase III trail without market exclusivity.

     

    Alemtuzumab is entitled to 12 years of data exclusivity from the date of FDA approval (similar in Europe). If FDA rejects alemtuzumab and requests a third phase III study, Sanofi could theoretically complete this and still have effective exclusive rights. I view this as extremely unlikely. FDA has already approved Tysabri knowing that it could cause a serious rare complication called PML. There are now 400 reported cases due to Tysabri. PML carries a mortality rate of 25% in the MS population. Please see my prior posts on Tysabri and PML for more detail.

     

    There have been no lethal complications reported with alemtuzumab following adoption of the risk management strategies discussed above. Although any immunosupressive agent can theoretically induce PML, it has never been reported with alemtuzumab in the MS population.

     

    Here is a link that discusses the ramifications of data exclusivity:
    http://bit.ly/16FNH2b
    28 Oct 2013, 11:13 PM Reply Like
  • @Rootbeer: Thanks for the extensive discussion and comparison. That's very interesting about data exclusivity -- I've some patents, but I had never heard about data exclusivity.
    29 Oct 2013, 07:06 PM Reply Like
  • Per the author's request, I'm posting a private message I sent to him. It was a pm because it questions the prudence of making an even larger bet on GCVRZ shares than I already have--not a very conservative approach. I was going to send a similar message to rootbeer but here it is in case anyone else is interested in weighing in:

     

    "I have about 20% of my (small) portfolio in GCVRZ rights. I'm quite comfortable with that... it amounts to half of the profits from a recent windfall from buying puts on LRN a few weeks before it plummeted by 36%, so if I suffer a loss I'm still way up for the year.

     

    Since the LRN win I have kicked myself a few times for not putting more money on the table. It was almost certain they would miss earnings in October, and if I'd bought 10X more puts I still could have sold them the day after earnings if there had been no surprise.

     

    I'm looking at GVCRZ as a similar situation: a near-certain win. The risk is higher in that if there is a delay past March, the rights will immediately decline by probably 50% or (much) more and will not recover for a couple of years at best, whereas LRN puts would have declined by only 20% (the bid-ask spread). If Lemtrada is approved by March, however, the combined market value of the rights and the reward payout immediately increase from my cost of $1.95 to about $5-6 for a 3X return.

     

    The question is whether and to what degree we can expect a March approval? Dr. Robbins (rootbeer) is certain Lemtrada will be approved, and perhaps for that reason we can be equally confident that eventually at least a couple of the milestones will be reached and the $1 'approval reward' paid out eventually. If it is not approved by March, of course, it will take years and not months to see a profit on the investment... years during which I could take advantage of many other arb/special situations.

     

    Needless to say, I'm not asking you what to do. I am trying to put a number on the probability of a March approval, however. I also want to discern what the likely downside would be in the case of a delay. Is this something you'd like to look into with me?

     

    I'm sending this to you privately because my appetite for risk is quite high and I wouldn't suggest that anyone else contemplate some of the asymmetrical bets I make."

     

    Chris's response, which I tend to agree with, is that there is a 90% probability of approval by March 31. Chris considers the rights to be worth zero in the case of a delay (for sizing purposes, not as a prediction); I assume they will drop to .25 or .50 at best and languish until sales show definite promise.

     

    I'm very interested in others' perspectives on the probability of a delay.
    31 Oct 2013, 05:15 AM Reply Like
  • Author’s reply » Thanks for posting; I look forward to reading others' answers.
    31 Oct 2013, 05:28 AM Reply Like
  • I think if you are this concerned about the probability of delay, then you should probably not put any more money into GCVRZ. Unlike most securities, this is one of those trades where you have to be willing to LOSE whatever you to put in (making it closer to a bet than a trade). You seem to be at a comfortable allocation because you are playing with house money, and I see no reason to further stress yourself out by adding 10-20% allocation.

     

    Whenever I miss out on a good trade by selling too early or having too small a position, I am quick to remind myself of how greed can easily destroy my account. While I could quickly rattle off 10-15 names ($FB for instance) in which I would be MUCH farther ahead if I had held on.. I can also think of a handful of names that went bust and would have taken me down with them if I hadn't taken profits/cut losses ($PMI is one of my worst). Remember, at the end of the day, you need cash to play this game, which is why capital preservation is equally as important as capital appreciation.

     

    My .02 on delay is that it seems unlikely. Rootbeer seemed to nail it on the head when he said that delay would only come from issues about safety. But, even that seems unlikely, as the safety concerns are well-known and don't seem to have changed through the trials. I suspect the Advisory Panel will want to hear about patient monitoring programs and will base its decision on their opinion of the effectiveness of this monitoring.

     

    I try to remind myself that, in considering any drug for approval, the FDA is performing a risk-benefit test. Even a drug with significant risks (like Lemtrada) can be approved if it offers enough benefits to outweigh those risks. I think these benefits have been demonstrated in the various trials, and also with the CHMP recommendation:

     

    "The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for Lemtrada and therefore recommends the granting of the marketing authorisation."

     

    http://bit.ly/16PieFF
    31 Oct 2013, 09:18 AM Reply Like
  • I am not so sure about the tripling of the market price of the CVR upon FDA approval before March 31, 2014.

     

    If the first milestone is not met then there will be an opportunity. Then the market might price the CVR at 0.5 or so, but that's below the real value. As Rootbeer pointed out the value will then be at least the discount of 2, let's say 1.8 since the second milestone will still be met.

     

    If the FDA rejects the drug completely then that's all, the other milestones won't be met. Extremely unlikely though.

     

    If the approval is just delayed, let's say by 3 months, then the second sales milestone will still be met paying an extra dollar for the late approval, and the value will be around $5, at least.
    2 Nov 2013, 11:18 AM Reply Like
  • I have not seen one single credible short thesis. C'mon. How about using alemtuzumab in women who are planning on becoming pregnant? Worst or best choice? Here's your answer:

     

    http://bit.ly/16nDX7s
    19 Oct 2013, 10:58 PM Reply Like
  • I like to remind myself that FDA only gave "standard" review status which implies FDA believes cost/benefit is only marginally better than existing therapies. However, if we believe this, I think that the improvement in EDSS scores and the fact that Alemtuzumab represents a more aggressive treatment (as you and Chris have explained) are very compelling reasons for this compound to be another alternative available to physicians/patients.

     

    Make sense?
    20 Oct 2013, 10:20 AM Reply Like
  • Yes, it makes sense. I can provide some additional data on improvement in the EDSS scores in a future post. Regarding cost/benefit, who can really say? It would depend on the percentage of patients who experience a durable remission without requiring a follow up booster infusion. The four and five year follow up data on the phase III patients will give some insight on this question.
    20 Oct 2013, 04:14 PM Reply Like
  • Great. Looking forward to your next post.

     

    Thx,
    21 Oct 2013, 06:52 AM Reply Like
  • Do we know anything about the roll-out plans for Europe?
    20 Oct 2013, 11:29 AM Reply Like
  • Chris and others - I came upon this notice at clinical trials.government: NCT01020370. This is the identifier. I found it by searching MS. Its on the second group of studies (#25) marked "completed". Its titled, "Exploratory Study to Investigate the Reparative and Regenerative Potential of Alemtuzumab in Relapsing-Remitting Multiple Sclerosis Patients Participating in the CARE MS I and MS II Studies".

     

    I noted that the record was just posted on October 17th.
    20 Oct 2013, 11:44 PM Reply Like
  • Author’s reply » Great find; thanks for posting. Here is the link: http://1.usa.gov/18BOpw7
    21 Oct 2013, 06:48 AM Reply Like
  • Regarding the Wayne State Study: Is this a Sonofi sponsored study, or could it be sponsored by someone trying to knock down the Lemtrada application? I note no results are posted. Is the timing coincident?
    27 Oct 2013, 10:39 PM Reply Like
  • It doesn't look to be a Sanofi sponsored study, but some interesting results are turned up when doing a Google search for "wayne state Alemtuzumab."

     

    I discovered that Dr. Omar Kahn, the neurologist who performed the previously linked to survey, is the principal investigator for the Peripheral and Central Nervous System Drugs Advisory Committee (as of 2011, cannot confirm presently). There are several articles readily available on Google showing Dr. Kahn's praise for the drug.

     

    http://bit.ly/1akjmqR - "Alemtuzumab could be the first definitive treatment that may eliminate active disease in MS patients, meaning no further relapses, no disease progression and no new lesions in the brain,” he said. “While it may not cure the disease, it may give hope to millions of patients that early intervention with Alemtuzumab may prevent the fear and stigma of the disease in the form of crippling disability and being in a wheelchair. It has been a very rewarding 10-year effort to see this happen with WSU’s participation and leadership.”

     

    http://bit.ly/1akjo26 - "The data from this second of two such studies, Dr. Khan said, are the “best ever efficacy data in any MS trial in the last 20 years.” Alemtuzumab, he said, significantly reduced the rate of sustained accumulation of disability compared to treatment with interferon beta-1a. “With the completion of this study, we are now looking at FDA registration and approval in 2012,” said Dr. Khan. “As we speculated, which is now substantiated by this study, Alemtuzumab presents with the best data and sets a new benchmark of efficacy. This is clearly a major breakthrough in the treatment of MS.”

     

    Obviously, here we are in late 2013 and the drug is still not approved, so maybe Kahn is a bit optimistic. I was able to find this article - http://bit.ly/1akjo28 - which is a bit more recent and talks about concerns regarding thyroid side effects (which has been discussed at length in this forum and Chris' original post). Here's the relevant quotes that from article:

     

    "In an interview, Robert Lisak, MD, professor of neurology, Wayne State University School of Medicine, Detroit, Michigan, pointed out that side effects of the drug have encompassed potentially serious autoimmune diseases, including thyroid disorders and immune thrombocytopenia, both of which require careful monitoring and management...This drug, in phase 2 trials especially, and to some degree in phase 3, did look like a bit of a game changer," said Dr. Lisak. "But it doesn't look like it's that way for every patient anymore."

     

    Hope that this is helpful.
    28 Oct 2013, 10:29 AM Reply Like
  • Thank you for your detailed information on the Wayne State Study. Your info leads me to believe that we are going to receive several labeling "recommendations" from the study group. I believe we are approaching a 90% certainty of approval and an 80% chance of gaining it before March end, 2014.
    29 Oct 2013, 03:29 AM Reply Like
  • I recently started looking at GCVRZ and am by no means comprehensively up to speed on FDA protocol with regards to drug approval. I just want to clarify what is definitively known here regarding the Nov. 13th panel and how it relates to potential approval (and by extension that 2nd milestone payout) by year-end or 1Q14:

     

    1. The panel results/outcome will NOT be an official approval or rejection of Lemtrada, nor will any official date be announced for approval if sentiments at the meeting are positive. However we will have a high level of confidence aftewards as to whether it will be approved or not before the milestone date.

     

    2. For brand new drugs, advisory panel recommendations for approval typically take about 2-3 months before the actual PDUFA date. However since Lemtrada is/was already on the market as Campath, this lag period will likely not be as log. Hence that is why numerous links point to the PDUFA date occurring before year-end.

     

    3. Upon announcement of the advisory panel review last week, the 10% drop in GCVRZ price was likely attributed to an increased probability in the drug receiving a negative recommendation for no other reason besides the fact that a panel was convening, an not due to any recent negative press regarding the drug

     

    My question is, do all drugs typically have advisory panels like this one between Phase III and FDA approval? Or is this a special situation for drugs that are 50:50?

     

    Appreciate if anyone can confirm or clarify these thoughts and answer my questions at the end, thanks
    21 Oct 2013, 01:02 PM Reply Like
  • FDA wants a robust discussion of risk benefits from a variety of stakeholders including physicians, government, industry, and the public.
    21 Oct 2013, 02:33 PM Reply Like
  • Rootbeer,

     

    Are you familiar with the way Tysabri is prescribed? Apparently it is administered only through the TOUCH program which allows FDA to monitor patients and outcomes. Only authorized prescribers/infusion centers and registered patients have access to Tysabri.

     

    I am thinking perhaps FDA called the advisory committee seeking guidance re the potential need for a robust monitoring program similar to TOUCH.

     

    One could argue that Alemtuzumab is not as dangerous as Tysabri, but it does have numerous side effects that need to be monitored.

     

    I don't see how FDA could have significant questions re efficacy or safety.
    21 Oct 2013, 11:50 PM Reply Like
  • I agree with everything you said. There is a page on the FDA website called REMS. Risk Evaluation and Management Strategy. Tysabri is on this page with a variety of other medications. Tysabri was pulled from the market due to all the cases of PML and then had a REMS developed before it was placed back on the market. Lemtrada will probably end up on this same page. It is much better to be on this page prospectively, before marketing, rather than later. Investors should not dread this.
    http://1.usa.gov/1bd92gX
    22 Oct 2013, 10:49 PM Reply Like
  • FDA powerpoint: A Brief Overview of Risk Evaluation & Mitigation Strategies (REMS)
    http://1.usa.gov/HrciwT

     

    “Some drugs would not be able to be approved, or be able to stay on the market, unless a REMS with ETASU was required to ensure that their benefits outweigh their risks.”

     

    ETASU - Elements To Assure Safe Use
    29 Oct 2013, 07:40 PM Reply Like
  • Author’s reply » I would like to address a matter that has been of some concern regarding next month’s meeting on Lemtrada. Bloomberg noted that it is unusual for the FDA to announce meetings outside of the Federal Register. There is not any significance to the fact that the Lemtrada meeting was announced outside of the Federal Register, according to a knowledgeable FDA source. During the government shutdown, the Office of the Federal Register was not publishing Federal Register Notices for advisory committee meeting announcements. In order to provide the earliest possible notice to the public of upcoming advisory committee meetings, the FDA published meeting announcements on its public website. Since the government shutdown has ended, Federal Register Notices announcing advisory committee meetings will once again be published in the Federal Register.
    22 Oct 2013, 11:50 AM Reply Like
  • Interesting. I thought the announcement seemed discrete.

     

    3 weeks from tomorrow.
    22 Oct 2013, 12:02 PM Reply Like
  • I am very familiar with how Tysabri is prescribed. The TOUCH program allowed Biogen to collect antibody titers to the JC Virus while following the patients who had no choice, but to stay on Tysabri due to having failed all other therapies. By following all patients, they could relate the level of antibody titers to the patients who developed PML. Using the information gleaned from the antibody titers, they are attempting a new risk management that would allow patients to stratify the risks of developing PML. Biogen reasons that if a patient knows that the risk of developing PML is, for example, 1 in 1000, a patient can start Tysabri as first line therapy. If a patient has no alternative, then this information is useful to give peace of mind. If, however, people start to use it as first line therapy, they need to realize that there is no realistic way of detecting PML until it is too late. The symptoms of neurodegenerative disease due to PML are essentially indistinguishable from worsening symptoms due to worsening MS. The diagnosis is made in retrospect by looking at the MRI of the brain for the pattern of PML. Then what.? As a physician, you fight like hell to save this person's life now that you realize that he or she has PML instead of worsening MS. One out of four die and the others have a significant amount of brain damage/disability resulting from the PML plus, continuing disease progression from MS.

     

    At the end of the day, hyperthyroidism is just not a big deal. I have personally treated many patients with hyperthyroidism. You take a radioactive iodine pill with a glass of water and go on with your life like nothing ever really happened.

     

    Lemtrada/hyperthyroidism vs Tysabri/PML :
    I would choose Lemtrada if I have the choice. If I have NO choice, then I would choose Tysabri.
    22 Oct 2013, 10:30 PM Reply Like
  • That is excellent color! Thanks for explaining. Very much appreciated.
    22 Oct 2013, 11:04 PM Reply Like
  • This is probably the best MS blog in the world. It is a great place to see physician, researcher, and patient comments. Alemtuzumab is discussed frequently.

     

    http://bit.ly/1a6TIpE
    23 Oct 2013, 07:17 AM Reply Like
  • Professor Giovannoni seems to be a great resource here.

     

    http://bit.ly/1f3huSK
    30 Oct 2013, 04:29 AM Reply Like
  • Playing devil's advocate here, it looks like Biogen is having much success with its MS drugs Tecfidera and Tysabri.

     

    Biogen Idec Total Revenues Increased 32% to $1.8 Billion in Third Quarter;
    Company Raises 2013 Financial Guidance
    --TECFIDERA® now the leading oral MS therapy in the United States --
    http://bit.ly/1dD3SQ7

     

    Biogen's new MS drug tops expectations; ups 2013 forecast
    http://reut.rs/16jHzuf
    29 Oct 2013, 03:44 PM Reply Like
  • based on what we have learned here thus far it would seem very auspicious that Tysabri is meeting with success despite its risks, i.e., if Alemtuzumab is more efficacious and less risky
    30 Oct 2013, 10:59 AM Reply Like
  • Author’s reply » Here is a new article on GCVRZ that I recommend reading: Genzyme Contingent Value Right: A Great Bet On The Most Efficacious MS Drug -- http://seekingalpha.co...
    29 Oct 2013, 04:38 PM Reply Like
  • CUMULATIVE PROBABILITY OF DISEASE PROGRESSION

     

    Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. It is a generally held belief that relapses result in sustained worsening of disability over time.

     

    The majority of MS patients (80–90%) initially experience a relapsing−remitting disease course (RRMS), with alternating phases of clinical worsening, remission and stability. Over time, approximately half of MS patients convert from a relapsing−remitting to a secondary progressive disease course (SPMS), with continuous clinical worsening independent from relapses. In 10–20% of patients, the disorder presents with a primary progressive course (PPMS) with continuous clinical worsening, with and without additional relapses from the disease onset.

     

    The overall rate of age related brain atrophy in normal adults is approximately 0.3% per year. In MS patients, the rate is 0.6% per year. So time is brain and the more time spent on a less efficacious drug, the higher the rate of relapses, and the higher the rate of acquiring sustained disability.

     

    The benefit of long-term treatment with interferon beta (IFNB) preparations for RRMS remains unproven. Randomized controlled trials of these agents provide evidence of benefit only for the relatively short duration (generally two years) of the trials.

     

    Copaxone (daily 20mg sc) the cumulative probability of disease progression was 22% and 40% for placebo at 35 months (1)

     

    Avonex (30mg, injection) the cumulative probability of disease progression was 22% and 35% for placebo at 24 months (2)

     

    Betaseron (250mcg, injection) the cumulative probability of disease progression was 35% and 46% for placebo in the 60 month follow up study (3)

     

    Rebif (injection) cumulative probability of disease progression is not available due to the fact that the randomized clinical trials did not use sustained accumulation of disability as an endpoint.

     

    Peginterferon (injection) cumulative probability of disease progression is not available

     

    Gilenya (0.5mg oral) The cumulative probability of disease progression was 12.5% and 19.0% for placebo during the 24 month study. FREEDOMS Trial (4)

     

    Tysabri (300mg IV) The cumulative probability of disease progression was 17% vs 29% in the placebo group after 24 months. (5)

     

    Tecfidera (240 mg, oral, twice per day) CONFIRM (6) trial showed no significant difference in the probability of disease progression when compared to placebo. DEFINE (7) trial showed that after 24 months 16% of patients showed progression of disability compared to 27% for placebo.

     

    From NEJM editorial after publishing CONFIRM and DEFINE trials:
    To put the oral drugs in context: the interferons that ignited the field of treatment for multiple sclerosis have served well for 25 years to reduce relapses by approximately one third, but they have only minimally influenced progression of the disease and disability. Although there have been few direct comparisons between oral and parenteral treatments, the interferons and a second parenteral compound, glatiramer acetate, (copaxone) have now been equaled or surpassed in reducing relapses by some of the new orally administered drugs. None have quite attained the suppression of disease activity shown with monthly intravenous natalizumab, but the risk of progressive multifocal leukoencephalopathy (PML), albeit low, has restrained the application of that agent. (8)

     

    Aubagio (7 mg, oral once per day) The cumulative probability of disease progression after two years was 21.7% for Aubagio and 27.3% for placebo. TEMSO trial (9).

     

    Lemtrada (12 mg, IV, induction therapy given as 5 daily infusions in month one and 3 daily infusions in month twelve.) CARE MS II, a phase 3 trial, compared Lemtrada to Rebif. The cumulative probability of sustained disability was 13% for Lemtrada and 20% for Rebif. This was a risk reduction of 42% with a P value of .0084.

     

    http://1.usa.gov/1cq0nNc

     

    2. http://1.usa.gov/1cq0okq

     

    3. http://1.usa.gov/1cq0oks

     

    4. http://bit.ly/1cq0oku

     

    5. http://bit.ly/1cq0oAI

     

    6. http://bit.ly/1cq0nNe

     

    7. http://bit.ly/1cq0oAK

     

    8. http://bit.ly/1cq0nNf

     

    9. http://bit.ly/1cq0oAM

     

    10. http://bit.ly/1cq0nNg
    COMMENT:
    With the exception of the Lemtrada trials, all of the reported phase 3 (and phase 2) trials
    were compared to a placebo. The reader should understand that no clinical trial is directly comparable due to different stages of disease at entry into a clinical trial. Having said that, Lemtrada was compared to what was considered first line therapy (rebif) in head to head competition and was found to be better by a significant margin.

     

    It is relatively easy for a drug to look good when it is compared against...nothing.
    29 Oct 2013, 11:50 PM Reply Like
  • Author’s reply » Sanofi Q3 2013 – Interview with CFO Jerome Contamine: When it comes to Lemtrada, we… got approval in Europe with a very good indication…” http://bit.ly/1aT0k5V (under “Genzyme” section)
    30 Oct 2013, 07:28 AM Reply Like
  • Notice that he first says something like "we got approval in Europe with a very good indication" and then "in the US the outcome is planned on November 13th". Does he mean that he expects Lemtrada to be approved already on November 13?
    31 Oct 2013, 08:24 AM Reply Like
  • Author’s reply » My interpretation is that he expects to know more when the panel meets. We'll see. I'll be there and plan on reporting back with what I learn.
    31 Oct 2013, 08:25 AM Reply Like
  • Author’s reply » "In September, the European Commission granted marketing authorization for Lemtrada™ (alemtuzumab, being developed in multiple sclerosis in collaboration with Bayer HealthCare) which is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis with active disease defined by clinical or imaging features." - http://bit.ly/1aT0yKn
    30 Oct 2013, 07:31 AM Reply Like
  • what's up with the volume today? Is this a bad sign?
    30 Oct 2013, 05:42 PM Reply Like
  • I have been asked to comment on the possible delay of approval and the effect that this would have on the CVR. A delay would presumably result from safety concerns and not efficacy. There is class 3 evidence of superiority of alemtuzumab over B interferon (Rebif). In regards to safety, what has not been vetted already? The two biggest risks are hyperthyroidism and ITP. The risk mitigation strategies are included in the NDA. PML? It hasn't been seen in the MS population. And it wasn't seen in the CLL population when it was known as Campath. Papillary thyroid cancer? If you are going to get a cancer, this is the one you want to get. You will most likely die of something else. Herpes skin infections? They are put on acyclovir to protect against this.

     

    But, for the sake of argument let us say that they ask for more data on safety. They want four years of follow up on the phase 3 patients to see if there is any further cases of hyperthyroidism, a treatable disease.

     

    Is it really all or none in this investment? It is none if SNY decides to walk away from the US market. But not likely, since SNY needs this medication to help reinvigorate growth of revenue.

     

    So, the downside is not zero. But, there would clearly have to be a reassessment of the value of the CVR. The value depends on the likelihood of reaching all the milestones. The delay would result in a possible competitive therapy appearing on the market just as sales are beginning to ramp up in 2017-2018. The drug is called ocrelizumab and is owned by Roche.

     

    I think that there would be an eventual payout of $4 on reaching 1.8 billion in sales. It would probably not reach the other milestones of 2.3 billion and 2.8 billion in sales unless there is a breakthrough in predicting who will develop autoimmune thyroid disease.
    30 Oct 2013, 11:08 PM Reply Like
  • Rootbeer, I find your comment very important. It means that due to competition of ocrelizumab Sanofi will try to develop the market for Lemtrada as soon as possible. And it also means that the fourth and the fifth milestone are now less likely to be met?

     

    Has any phase 3 trial started for ocrelizumab on MS patients? And how long would such a trial take? I think at least 2 years. If this trial starts next year and it takes a year to approve it then ocrelizumab could be on the market in 2017.

     

    Note that ocrelizumab requires an injection twice a year, so more often than Lemtrada.
    31 Oct 2013, 07:37 AM Reply Like
  • http://bit.ly/17ztObG

     

    I was, more or less, asked to come up with a worst case scenario. And I pointed out that the worst case scenario is not all or nothing. It is all or something. Alemtuzumab has already been approved in Europe and will be approved very shortly in the US because it is a step change. It is a step change because it is an induction therapy that induces a durable response and possibly, a cure in some people.
    Regarding Ocrelizumab, it is another monoclonal antibody that is also an induction therapy. I expect that it could be on the market in the 2017-2018 time frame. I cannot make any predictions other than to say that the future of MS therapy is with induction therapies, not with oral maintenance therapies. They will probably play a lesser role.

     

    Regarding monoclonal antibodies, I expect that Tysabri will fall hard due to the risk of PML. Alemtuzumab will compete with Ocrelizumab if the latter makes it through the phase 3 trials.

     

    For now, I am confident that the $2 that I invested will be returned to me.
    31 Oct 2013, 10:55 AM Reply Like
  • There has been some speculation as to whether Sanofi might try to delay approval so as to duck some payout obligations to GVCRZ holders.

     

    I think this is highly unlikely.

     

    1. GVCRZ rights were issued to Genzyme shareholders upon the merger with SNY.

     

    2. Genzyme is running the Lemtrada show, so incentive lies with the major actors (Genzyme employees=GVCRZ shareholders) to get the approval in time.

     

    3. Any attempt by Sanofi to delay approval would cause severe discontent within the organization.

     

    4. Sanofi up this point gets Lemtrada for free, don't they? Broadly speaking that is. Making the payouts is just a way of compensating Genzyme for R&D. It shouldn't be met by any resistance by Sanofi since it represents a normal cost of doing business.
    31 Oct 2013, 05:27 AM Reply Like
  • At this stage, how can they delay FDA approval?
    31 Oct 2013, 06:20 AM Reply Like
  • Zero Tolerance For Disease Activity in RRMS

     

    One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.

     

    “Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”

     

    Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.

     

    “On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.

     

    “In our clinic, we’re now trying to actually improve patient function over time,” noted Dr. Vollmer. “We expect them to get better, particularly if they exercise and take some of the more highly effective therapies. Particularly for patients with the earlier phase disease, we’re looking for full disease remission, including remission of fatigue and depression symptoms.” (1)

     

    1. 2013;21(2):9 Neurology Reviews
    31 Oct 2013, 06:49 AM Reply Like
  • Does Having JCV Affect The Choice of Staying on Tysabri?

     

    http://bit.ly/1gg7V5U

     

    The aim of this study was to examine treatment decisions regarding whether or not patients were willing to stay on Tysabri and whether or not the patients were willing to use levels of antibody titers to guide this decision. If your level of antibody titers to the JC virus (JCV) is low, you presumably have a relatively low risk of developing PML which is about 1 in 1000. But there is no real legitimate way to detect the development of PML until it is in full swing, wreaking havoc on the brain.

     

    RESULTS:JCv antibody status was available in 112 Tysabri patients. Mean Tysabri duration was 27.4 months (2-72). Antibodies were detected in 55 patients (49.1%): 2 (3.6%) stopped due to JCv+ alone, 14 (25.5%) due to prolonged therapy (>2years), 1 (1.8%) due to prolonged therapy and past immuosuppression, 3 (5.5%) disability progression, 1 (1.8%) to conceive. (12.3% of JCv negative patients stopped due to prolonged therapy). No significant difference in mean Tysabri duration or disease-modifying therapy history between JCv Ab+ and Ab- groups (p>0.05). Other PML risks (>2 years, past immunosuppression) did not differ significantly between JCv+ patients who opted to continue compared to those choosing to stop (p>0.05).

     

    COMMENT: Most JCV positive patients want to get off of this drug after two years and 12.3% of JCV negative patients stopped after two years. This study confirms what I have said about Tysabri in prior posts.

     

    Biogen Idec Inc (BIIB) Management Discusses Q2 2013 Results - Earnings Call Transcript:

     

    Moving to TYSABRI. Second quarter global in-market sales decreased by 2% versus the prior year. As I mentioned, in the U.S., a significant number of higher-risk TYSABRI patients transitioned to TECFIDERA, which slowed TYSABRI growth despite the fact that we believe we are continuing to generate solid demand.

     

    During the quarter, approximately 2/3 of the patients who discontinued TYSABRI stayed within our franchise and started TECFIDERA. This creates another issue that we are well aware of and prepared for. Given that well over 1,000 higher-risk patients have transitioned from TYSABRI to TECFIDERA, we expect to see a number of cases of PML in these patients, just as has been observed in TYSABRI patients who have switched to other therapies. We believe that our competition will try to make an issue out of this, but we believe the physician community expects it. Our Medical Affairs team is having discussions with physicians, and we believe we are ready.

     

    COMMENT: The reader should understand from prior posts that there is a low but, significant risk of developing PML, the longer a patient stays on therapy. Many patients elect to come off Tysabri after two years of therapy. Not only is a patient exposed to the risk of developing PML while on Tysabri but, the patient is also exposed to developing PML when withdrawing from therapy. ( Here in the US, we say, "Damned if you do and damned if you don't!") Withdrawal can lead to a rebound reactivation of disease within three to six months after stopping Tysabri. This rebound reactivation of disease can trigger PML in patients who have tested positive to JCV.

     

    As I have said previously, if there is an alternative powerful therapy such as alemtuzumab, why would any neurologist recommend Tysabri to a patient? In this new era of oral therapies and alemtuzumab, the neurologist will probably reserve Tysabri for JCV negative patients or JCV positive patients who have failed just about everything else.

     

    CONCLUSION: The study discussed above confirms that patients do not want to stay on Tysabri unless they have to. Biogen management is aware of the problem and wants to "help" patients stay on the medication by offering titers. Most patients understandably, are not listening to the Biogen management team.
    1 Nov 2013, 12:18 AM Reply Like
  • QUESTION TIME

     

    (1) Tecfidera shows good efficacy and safety, and is doing very well in sales. Do you have any comments about Tecfidera as a competitor?

     

    (2) In the event of FDA totally rejecting the drug, even though that is very remote, couldn't European sales count towards the first sales milestone? Others seem to have interpreted the value of the CVR as $0 in this case, but my interpretation would not find this to be $0. Who's right?

     

    1. Tecfidera is a competitor. But in the future people will have to decide whether they want to be on an induction therapy such as alemtuzumab or on an oral maintenance therapy such as tecfidera. Alemtuzumab will start out as second line therapy, reserved for people who fail on the orals and injectables. Phase 3 studies show that one out of 6 people suffer a relapse per year while on tecfidera and more so, on injectables. In the era of zero tolerance, that is enough patients to meet at least the milestone of 1.8 billuion in sales. Eventually, it will be used as first line. But ocrelizumab will be coming up and this is the drug which will compete with alemtuzumab for induction therapy. That is why I cannot really predict what will happen beyond 2017-2018.

     

    2. Milestones stipulate worldwide sales. Failuire to gain FDA approval causes a loss of $1in milestone payments. If you believe that SNY will not agressively seek FDA approval up through 2020, then you also probably believed that there was a real chance that the US government would have defaulted on the US debt.
    2 Nov 2013, 09:56 AM Reply Like
  • NEJM perspective on MS and alemtuzumab following publication of phase 2 CAMMS223 trial in 2008 which is still valid today:

     

    Multiple sclerosis is a cruel disease. It strikes young adults, runs a chronic, unpredictable course, and is eventually disabling for many patients.

     

    Multiple sclerosis is one of the great unsolved mysteries in modern medicine, with a number of striking epidemiologic features, including an increasing global frequency, an inverse relationship between serum 25-hydroxyvitamin D levels and disease risk, and a tantalizing association with Epstein–Barr virus infection.

     

    Multiple sclerosis usually begins as a relapsing–remitting disease, but in most patients a steadily progressive neurologic disorder ultimately ensues. As a general rule, the relapsing phase of the disease is mediated by focal bursts of inflammation in white matter in the brain and spinal cord, whereas axonal and neuronal loss predominates during the progressive phase. (In other words, it destroys your gray matter which explains the ongoing, accelerated brain atrophy that occurs in MS patients despite being on a disease modifying therapy.)

     

    For any given patient with relapsing–remitting multiple sclerosis, there is an annual risk of 2 to 3% for transition to the chronic, progressive form..

     

    The consequences of inflammation in multiple sclerosis — demyelination, incomplete remyelination, and gliosis (scarring) — appear to sensitize surviving axons to additional insults, which in effect shortens their life span. Stated another way, a disease flare in 2008 may increase the risk of progressive multiple sclerosis many years later.

     

    Although some permanent disability occurs as a consequence of relapses, chronic and progressive disease is the overwhelming cause of loss of ambulation. The prevention of inflammation during the relapsing–remitting phase appears to delay, or perhaps even prevent, the later development of secondary progression. Unfortunately, currently available first-line agents (including the beta interferons and glatiramer acetate), although effective in some patients, reduce the clinical relapse rate by only one third. The relatively modest clinical benefits of these drugs highlight the need for more effective therapies against the early inflammatory phase of the disease.

     

    In this issue of the Journal, Coles et al. report on the remarkable outcomes of a clinical trial of alemtuzumab, a monoclonal antibody that produces sustained depletion (lasting many months to a year or longer) of CD52-expressing cells, including CD4 and CD8 T cells, natural killer cells, and monocytes. Circulating B cells are only transiently depleted and may increase from baseline levels within a few months after treatment, perhaps contributing to autoimmune complications. Dramatic reductions in clinical relapses, the development of new disability, and the lessening of focal inflammatory activity were observed in patients who were treated with once-yearly administration of alemtuzumab...

     

    It is evident that protection by alemtuzumab against relapse comes at a substantial price. Thyroid autoimmunity was one expected complication, since it had been reported in earlier preliminary studies of anti-CD52 therapy. In the current study by Coles et al., thyroid autoimmunity occurred in nearly one quarter of treated patients. Although Graves' disease is well described as a complication of alemtuzumab treatment for other underlying diseases and is possibly attributable to an immune reconstitution syndrome, the very high prevalence of this complication in patients with multiple sclerosis suggests a special, unique predisposition in this population...

     

    Another open question relates to the significance of the improvement in the progression of sustained disability associated with alemtuzumab, as compared with interferon beta-1a, in this trial. Such improvement was almost certainly due to a reduction in disability resulting from relapses and not from any effect on secondary progression. However, given the magnitude of the effects observed in relapsing–remitting disease, one would be optimistic that with longer durations of therapy, an effect on the risk of chronic, progressive multiple sclerosis might also be found.

     

    For many years, therapy to prevent progressive disease has been the holy grail of research in multiple sclerosis. Alemtuzumab may in fact have this characteristic; however, if long-term therapy is required to sustain the clinical benefit, would the risk of toxicity then outweigh the benefit? A more hopeful scenario might presume that a relatively short course of alemtuzumab can restore immune homeostasis, which would eliminate the need for retreatment for many years. Indeed, there is suggestive evidence that an increase in the number of regulatory T cells, which are deficient in active multiple sclerosis, may occur during the early recovery period after therapy with alemtuzumab.

     

    COMMENT: This editorial gives one the proper perspective on MS and current disease modifying therapies. Current DMT's have variable beneficial, effects on relapse rates but they don't have much effect on altering the course into the chronic progressive phase. If an induction therapy can induce a durable remission, will it be able to delay the eventual development of the chronic progressive phase of the disease? Do we have to wait another twenty years to find out? Or can the FDA release this medication to the MS population, manage the risks, and give them a chance? That is the question.

     

    We have multiple maintenance therapies. Do we have a relatively safe induction therapy? We do in Europe.

     

    Please note that there will be a hiatus in entering any further posts.

     

    To be continued in 2-3 weeks.
    2 Nov 2013, 12:47 PM Reply Like
  • Author’s reply » Thyroid disease with Alemtuzumab: http://bit.ly/HAx7pu
    3 Nov 2013, 03:21 PM Reply Like
  • I will continue to being you content that is not my own for the next several weeks. From my favorite blog on one of my favorite topics,
    "Why should a patient with benign MS be treated with alemtuzumab?"The response is long but the content is excellent. MS has been divided by some experts into three arbitrary types. Benign, intermediate, and rapidly progressive. Benign MS just means that the lesions hit in areas of the brain that are not critical to everyday function. But, sooner or later, the lesions add up to big long term trouble.

     

    This dialogue speaks to the revolution that is going on. To stay invested in GCVRZ, you need the confidence and knowledge that this medication is truly transformational. It is an induction therapy and the only one in existence, at least in Europe.

     

    http://bit.ly/184MP2n
    4 Nov 2013, 01:18 PM Reply Like
  • I'm disappointed that Bloomberg would put out such an unsubstantiated, unattributed, unresearched article such as this.

     

    Sanofi’s Lemtrada Drug May Be Too Risky, FDA Staff Says
    http://bloom.bg/HCJXDg
    8 Nov 2013, 08:55 AM Reply Like
  • Agreed.
    8 Nov 2013, 09:02 AM Reply Like
  • Why do you consider this unsubstantiated? I read what I could of the staff doc. Looks pretty damning. Am I missing something? I am long, hurting, and picking at stock pre market hoping that this is sloppy trading. Please if you have an opinion that this is not damning I want to hear it.
    8 Nov 2013, 09:09 AM Reply Like
  • Sorry the article was very limited. Did not see the full report.
    8 Nov 2013, 09:23 AM Reply Like
  • Anyone have more info about these comments from the FDA?
    8 Nov 2013, 09:14 AM Reply Like
  • From http://1.usa.gov/1bdb9Du

     

    Multiple serious and potentially fatal safety issues have been reported in patients treated with
    alemtuzumab for MS. The Sponsor has proposed a Risk Evaluation and Mitigation Strategy
    (REMS), components of which will be discussed with the relevant safety sections of this review.
    In addition, Genzyme plans to submit, post-approval, a protocol for a long-term safety study to
    determine the incidence of adverse events of special interest, specifically ITP, autoimmune
    cytopenias, nephropathy, serious infections, serious thyroid disorders, and malignancies in a
    “real-world” setting. However, because of the serious and potentially fatal safety issues, unless
    alemtuzumab shows substantial clinical benefit, this reviewer recommends that FDA not approve
    Genzyme’s application to market alemtuzumab for relapsing forms of MS.
    8 Nov 2013, 09:18 AM Reply Like
  • Comments Here: http://1.usa.gov/1bdb9Du
    8 Nov 2013, 09:19 AM Reply Like
  • Rights brutally clubbed this AM. Down to $.58 at open.
    8 Nov 2013, 09:40 AM Reply Like
  • Can anyone give insight into the chances of the panel disregarding the staff comments? Would seem unlikely, but any informed comments would be welcomed.
    8 Nov 2013, 09:45 AM Reply Like
  • In addition to the EU and FDA, is there any country or regulator that is reviewing or has approved Lemtrada?
    8 Nov 2013, 09:50 AM Reply Like
  • Per Bloomberg:

     

    In emailed statement, Sanofi says Lemtrada follow-up data consistent with trials:

     

    * Sanofi says double-blind trial not possible b/c of drug differences
    * Sanofi says Lemtrada offers important step forward
    * Sanofi says Lemtrada used "high-bar" for efficacy
    8 Nov 2013, 09:51 AM Reply Like
  • If we get a CRL and Sanofi shows a willingness to move forward, than I beliex=ve there is substantial upside from here (.60), IMHO. I can not see them shutting this down. This was the centerpiece of a $20 billion acquisition.
    8 Nov 2013, 09:53 AM Reply Like
  • Wow look at the panic! The comments copied and pasted by Logic Wins at first glance appear damning. However this sentence:

     

    "However, because of the serious and potentially fatal safety issues, unless
    alemtuzumab shows substantial clinical benefit, this reviewer recommends that FDA not approve
    Genzyme’s application to market alemtuzumab for relapsing forms of MS."

     

    certainly sounds like the staff member hasn't even reviewed it completely. And it's just one guy, all is not lost.... I'm probably buying more.
    8 Nov 2013, 09:56 AM Reply Like
  • I agree there's panic. But why do you suggest the review may not have been complete? it was a 370 page document.
    8 Nov 2013, 09:57 AM Reply Like
  • After reviewing the actual document, he was assigned to do the risk assessment without seeing the actual results of the entire study so as to provide an unbiased opinion.
    8 Nov 2013, 10:42 AM Reply Like
  • I haven't read the report, but if that's the case it's an important distinction and explains why they write 'unless alemtuzumab shows substantial clinical benefit'. We all know Lemtrada is not without risks, but from the articles I've read it does in fact provide 'substantial clinical benefits' for many MS patients.
    8 Nov 2013, 01:53 PM Reply Like
  • Down 60% at 9:30!
    8 Nov 2013, 10:00 AM Reply Like
  • The second document on REMS:

     

    http://1.usa.gov/17j4Xe3

     

    This looks complicated.
    8 Nov 2013, 10:00 AM Reply Like
  • There are some historical data on FDA advisory committee meetings. > 50% chance of approval even if data presented is not fully positive.

     

    Here's a good article on what the review process means. Usually it means that there is greater than 50% chance of approval for drugs. http://bit.ly/1auvDmF
    8 Nov 2013, 10:01 AM Reply Like
  • Interesting thanks.
    8 Nov 2013, 10:06 AM Reply Like
  • So it sells $400M in EUR, that is worth a dollar. Good chance of that.
    8 Nov 2013, 10:16 AM Reply Like
  • For anyone who has followed Rootbeer's insightful contributions to the forum, the Lemtrada CVR seems to be worth at least $2.
    8 Nov 2013, 10:34 AM Reply Like
  • Opened a small position at 0.63 this morning. I tend to shy away from Bio stocks in general due to the short-term binary nature of them but this is a quite interesting play now - $0.63 downside and $12.37 upside still. I'm no expert but it seems to me that even if the short-term payouts aren't received that the chance of hitting some of the other payout milestones down the road (or simply the fact that they will be in play for awhile) more than compensate the potential short-term downside.
    8 Nov 2013, 10:36 AM Reply Like
  • So where is Mr. DeMuth Jr. now? I am surprised he hasn't posted anything yet today. I have just lost a large amount of capital by listening to his Lemtrada recommendation...........
    8 Nov 2013, 10:52 AM Reply Like
  • No offense Kelliots - but he's likely doing what you should be doing. Reading the 200+ page FDA meeting summary.
    8 Nov 2013, 10:56 AM Reply Like
  • Author’s reply » Reading and assimilating as much data as quickly as I can and then thinking about the best course of action.
    8 Nov 2013, 10:58 AM Reply Like
  • Is that how you lost $$$? Listening to someone? Did you do all you could researching, confirming, running expected value reports, ... before you invested? or did you just listen to someone on a message board.
    8 Nov 2013, 11:00 AM Reply Like
  • Chris, Mr Market is also digesting the data and seems to think that folks might have over-reacted at the open this morning. Up to .84 after dipping to .57. I too will try to plow through the document before reacting to headlines.
    8 Nov 2013, 11:18 AM Reply Like
  • This is a pretty wimpy comment, Kelliots. Everyone knew this was a highly speculative play. What research did you do? How much did you risk? Have you liquidated? Sounds like you're blaming others for the decision you made to go long.
    8 Nov 2013, 11:20 AM Reply Like
  • Kelliots, you are pathetic. DeMuth, Rootbeer and others have done an incredible amount of research and presented it for FREE. And you slap them in the face for it? You are clearly the type of guy who doesn't do any of his own homework, and when things go wrong you point fingers and cry. I took a bath today, but I did tons of my own research and understood the risks I'm enormously thankful to Demuth, Rootbeer and others for helping me understand the situation..
    8 Nov 2013, 11:42 AM Reply Like
  • Bud, his recommedation was an "idea". You should always do you own work and understand your upside and downside and size appropriately. The timeline, possible outcomes, and timeline were all reasonably defined here. Thanks to Chris and others for posting the original idea.
    8 Nov 2013, 12:16 PM Reply Like
  • Kelli,

     

    Chris has posted dozens of ideas and most will take time to mature and prosper. I think this one is indeed a winner despite yesterdays actions (as most of his ideas are in the long run).

     

    However investing is not a game for the impatient. Yet if you do some DD on this name you may decide this is a buying opportunity. Good luck no matter how you play this going forward.
    9 Nov 2013, 06:29 AM Reply Like
  • Kelliots you didn't lose capital listening to someone else, you lost capital making up your own mind and taking action based on what you thought was best. If you can't live with it at least refrain from trying to blame someone else.
    10 Nov 2013, 10:28 AM Reply Like
  • Page 7 of the FDA report has draft points to consider that are interesting. I found the preceding pages with summaries from the 3 parts of the report also very useful. Clinical safety, Clinical Efficacy, and Statistics are discussed. The report reads pretty negative, but I get the feeling that they are supposed to be very careful.

     

    If this is a coin flip(and I dont have the experience to say it is), these represent a great risk reward. Sorry to the longs stuck into this gap, I hope it ends up working out for you.
    8 Nov 2013, 11:05 AM Reply Like
  • Was able to increase my position by more than 50% b/c I had kept powder dry and used modest position sizing due to the binary-type risks. So, I am hoping too that it works out very well for longs!
    8 Nov 2013, 11:08 AM Reply Like
  • My first panic reaction this morning was, probably like most, to sell and move on. But, I actually think longs would be better off holding than selling here, and here's why:

     

    (1) Chances of FDA Approval are not zero. They may be pretty close, but they aren't zero. Unfortunately, I don't have enough experience to put a % on approval after the FDA letter. Hopefully others will provide color on this.

     

    (2) Remember the $2 payout for $400M in global sales. Here's the exact language:

     

    "Product Sales Milestone #1: CVR holders are entitled to receive $2 per CVR in the event net sales for Lemtrada total $400 million or more on a global basis during specified periods following product launch."

     

    "For the United States of America, the United Kingdom, Germany, France, Italy and Spain, sales achieved in the 4 calendar quarters immediately following the quarter in which Lemtrada is first sold in that country (after receipt of marketing approval in that country, including pricing and reimbursement approval, if necessary) are counted toward the $400 million sales milestone."

     

    So, even without FDA approval, I think this is the best chance to recoup your capital. I also couldn't give you a probability of this being reached without being completely disingenuous, but I do think that it's high enough that it's worthwhile to hold on.

     

    GL all
    8 Nov 2013, 11:16 AM Reply Like
  • It's catching a pretty firm bid now - up to 84. My early read is headline is scarier than the odds. Here is Sanofi's full statement:

     

    "Our company is confident that Lemtrada offers an important step forward in the way physicians and patients will think about treating multiple sclerosis. Given the importance of addressing unmet medical need, Genzyme decided to introduce a high bar to the demonstration of efficacy by comparing Lemtrada to the standard
    of care, which at the time of the study initiation was interferon beta-1a. Given the differences in how the drugs are administered – injections versus infusion regimens – and dosing schedules (thrice-weekly versus annually) a double-blinded study was not feasible. However, the interpretation of relapses and the interpretation physical disability were performed by independent
    experts who were blinded to the therapy of the patients. Furthermore, five-year follow-up data for patients in the phase II studies and three-year follow-up data of patients in phase III demonstrate findings that are consistent with results from the clinical studies years after dosing.

     

    These are, of course, issues that will be considered by the Advisory Committee and we look forward to our discussion with them."

     

    I took a deep breath and added a bit. My gut is still for approval especially as it's a second-line therapy. But still reviewing...

     

    People should be grateful that Chris has shared his views and provided this forum, in my opinion.
    8 Nov 2013, 11:20 AM Reply Like
  • "However, the interpretation of relapses and the interpretation physical disability were performed by independent experts who were blinded to the therapy of the patients."

     

    I think this is important. The outcomes assessor was blind.

     

    And the patients in this trial had severe MS that had not responded well to treatment. Would it be ethical to give these folks a placebo?
    8 Nov 2013, 11:36 AM Reply Like
  • I agree with that last statement. No one should be on here kicking Chris around because of this news. A lot of us have been tracking this drug for many months and no one saw this coming. In fact, several people begged for a short thesis to counter the data we collected so that we could have the full investment picture and not just the long argument. You take a chance with any investment and this one is no different.

     

    8 Nov 2013, 11:43 AM Reply Like
  • If the FDA had already made their decision, they wouldn't have called for the advisory committee. These are valid concerns. But, they seem subjective to me.

     

    Sanofi's presentation will need to address these concerns.

     

    “Some patients who received the drug in the earlier phase 2 trial in 2004 and 2005 have not needed further treatment of any kind since,”
    http://bit.ly/1akjo28
    8 Nov 2013, 12:09 PM Reply Like
  • Was looking back at some of the history of the GCVRZs and noticed that Sanofi did a dutch tender auction back in 2012 that netted them appx 14% of the outstanding rights at $1.75. Any thoughts on whether they may try something like this again? At this price it could be a nice hedge for them against future milestone payments on international sales even if it didn't receive domestic approval.
    8 Nov 2013, 12:19 PM Reply Like
  • No time for a tender but I wouldn't be surprised if they are buying in the market. They did this previously but launched the tender as the price started to un.
    8 Nov 2013, 12:33 PM Reply Like
  • Here's a thought:

     

    Suppose I hire a lawyer to review a contract. If the lawyer comes back and says, 'it's great, sign it,' how do I know the lawyer even looked at it? So the lawyer will say something such as, clause 3 in paragraph 5 needs to change. The provision in subparagraph i is untenable, etc.

     

    If I hire a statistician, MD, etc to review a drug app, I don't want them to come back and say that there are no issue with the new drug app; I want them to do their best to tear it apart. That way, I know we are 'stress testing' the app and will do our best job in determining whether to approve.
    8 Nov 2013, 12:21 PM Reply Like
  • You are absolutely correct. This is a stress test for alemtuzumab. The tone is serious but, intentionally serious and meant to draw out a full vetting of the risks. We know the benefits. It is twice as good at reducing relapses and delaying disability when compared to the most widely used MS medications in the world. (Rebif, and by proxy, all the injectables-CRAB)

     

    A careful examination of the document would lead one to conclude that the FDA would like an in depth dialogue and guidance regarding the REMS, submitted by Genzyme. The Tysabri REMS is specifically referenced and the onus is on this advisory committee to ensure that all aspects of the proposed REMS for Lemtrada is not only water tight, but, air tight. This is being done to help ensure that Lemtrada is not pulled from the market at a later date, as happened to Tysabri.

     

    Regulators are concerned with what could happen to a patient who is induced and then drops out. Are there mechanisms in place to ensure that this patient is tracked for the next five years? It is known from the trials that autoimmune thyroid disease can develop at some point, out to four years following induction.

     

    The reaction in the market is overdone to an extreme. If you were successfully stopped out at a higher level or you have additional capital to deploy, this is an opportunity for you.

     

    My opinion on the probability of approval has not changed and I am long GCVRZ,
    8 Nov 2013, 02:04 PM Reply Like
  • At the end of the document the statistical results are discussed. What's your opinion on the criticism on the statistics? What are SAD events and how about the difference between EU results and results from Eastern Europe?
    8 Nov 2013, 02:15 PM Reply Like
  • rootbeer,

     

    Thanks!

     

    "The reaction in the market is overdone to an extreme. If you were successfully stopped out at a higher level or you have additional capital to deploy, this is an opportunity for you."

     

    Actually, I doubled my position this morning.
    8 Nov 2013, 02:25 PM Reply Like
  • This changed my opinion because I now think due to the previous FDA complaints that the study design should have been improved -- they should've worked hard to make it double-blind. I think now FDA delay or rejection is likely because the placebo effect is so strong. I'm currently thinking through what the value should be in the case of a Europe only rollout. I feel it's about $1ish. Obviously I'm not willing to sell below that value. But any opinions on that scenario are welcome! See also my comments on the other article:

     

    http://bit.ly/1begri0

     

    In the future I probably won't do such exciting investing -- it's kind of distracting, not to mention difficult! I prefer watching grass grow.
    8 Nov 2013, 02:48 PM Reply Like
  • With all due respect, it is not possible to design a fool proof double blind study when one medication is given subcutaneously three times per week and the other is given five times in month one, then three times in month 12, intravenously. Regarding "placebo effect", what placebo effect is there when you are not taking anything on the alemtuzumab arm, following induction?
    8 Nov 2013, 03:47 PM Reply Like
  • I think he is arguing that they should have done alemtuzmab vs. a placebo and not alemtuzmab vs. standard of care (interferon).
    8 Nov 2013, 03:54 PM Reply Like
  • I am no expert. But many past MS studies compared with a placebo instead of an active comparator, such as interferon beta-1a:

     

    http://1.usa.gov/195z5Uv

     

    They didn't get these concerns about the placebo effect from the FDA. That design may have been a better choice for the study. At the least I should have noticed this downside risk before it became "significant news" and the market sold off.

     

    I do not have the background to estimate the magnitude of the placebo effect in this situation.
    8 Nov 2013, 03:59 PM Reply Like
  • Gilenya was compared to interferon as well. I suppose it had similar drop out rates in the trial?
    8 Nov 2013, 04:57 PM Reply Like
  • OK, the phase 2 and phase 3 studies were compared against the most widely used class of drugs that the MS patients used then and even now. The result is that we know that Alemtuzumab is twice as good as the injectables in decreasing the relapse rate per year and twice as good in delaying worsening of disability. This is a much stronger set of data than comparing alemtuzumab against a placebo. The bar was set much higher in these phase 3 trials than in any other preceeding trial for any other MS medication.
    8 Nov 2013, 06:09 PM Reply Like
  • The report talks about this to some extent. They say that if 10-15% of the participants in one of the studies had benefited from PE, then the study stops being statistically significant. That's pretty weak evidence. :(
    8 Nov 2013, 06:58 PM Reply Like
  • I hope you don't get whip-sawed out. I actually think the risk/reward here is more favorable then ever and worthy of a larger stake. I'm glade I hadn't moved into this with force up until this point. Not a grass growing type investment but the reward can be lushess. I think many people will find themselves with a multi-bagger if they buy below 80 cents.
    9 Nov 2013, 06:22 AM Reply Like
  • Describing this as an opportunity is irresponsible, imo. You know as well as anyone that the risk of a negative panel increased many times over. The selling is not necessarily overdone and many I've talked that know the process well describe these documents as the kiss of death. I got kicked in the teeth when i bought more on a similar "opportunity" after aveo's briefing documents were released. A stock, if i remember correctly, you were long as well. The fact that the fda doesnt like the study design scares the living hell out of me. Its the one thing they dont seem to budge on, ever. And they especially dont budge when they basically told sny to not run an unblinded study prior to phase 3.

     

    So the guy two below doubled his position? Is it ethical to champion that. Anyone adding now has to be aware the chances of approval have gone from a near certainty to < 20% once those briefing docs were released. I think an argument could be made that the cvr is actually overpriced.
    9 Nov 2013, 10:15 AM Reply Like
  • Good thoughts. I added slightly after the drop but am fully prepared for this to be a zero and sized accordingly. Pretty hard to handicap but my gut us we are in 50/50 land now.

     

    I am not an expert but based on my reading and talking to people I *think* there was no possibility of a double-blind study unless a placebo was used (due to the huge differences in how and whn Rebif and Lemtrada are administered). So while double-blind is the gold standard, counterbalancing this is that rather than the baseline being no treatment at all (a placebo), the comparison is a very-well studied and effective treatment (Rebif/interferon) - so it is powerful to show that if you are significantly better than Rebif, and Rebif is significantly better than nothing/placebo, then it is a good thing.

     

    I also put a fair amount of weight on the EU approval - different experts and different eyes but presumably the same issues were raised.

     

    Finally the fact that it was on the market as Campath for a long period gives a lot of understanding about safety, side effects, etc.

     

    Having said that all bets are off when dealing with bureaucracy.

     

    Reading through the FDA paper as well as Sanofi's submission yesterday I feel like there is at least a 50/50 shot here.

     

    If approved I think $3 of payouts are pretty achievable (perhaps more but I have always assumed $3). So at 75 cents you have 75 cents of downside and $2.25 of upside. Ignoring time value of money (we are in a ZIRP world after all...) the market is kind of saying there is a 25% chance this thing gets approved. I don't mind those odds given my feeling is more like 50/50. But of course I am a bagholder now so probably can't think straight, so haircut what I think by 50% and it's priced about right!

     

    Have I captured the essence of it?
    9 Nov 2013, 10:40 AM Reply Like
  • If the non - US approval sales milestone($2 payment) is not only achievable but likely, does it not make sense to lower your cost basis to well below the expected payout? At this point it must be looked at as an arbitrage. The ace in the hole is and always has been prior approval in the Eurozone. Most are looking at this as a complete wash which it is most likely not. My plan is to be patient, lower my cost basis significantly(which I have), and take the $2 payout. Anything above and beyond that $2 payment is icing on the cake.
    9 Nov 2013, 10:55 AM Reply Like
  • What do you make of the fact that one of the last lines of the efficacy sections is: "Collectively, the two studies rendered more evidence of ineffectiveness than effectiveness of aletuzumab on disability."
    9 Nov 2013, 11:45 AM Reply Like
  • No question these two doctors barfed all over it. Could be worse - they could be on the panel :)
    9 Nov 2013, 11:55 AM Reply Like
  • I am not banking on the FDA at all, only global sales at this point. There is clearly a difference of opinion between the EU FDA equivalent and the FDA. If I am only banking on the first non-US sales milestone and subsequent payment, why does it matter what the FDA does? If they approve it, great. If they do not, so what. My cost basis is significantly below the $2 threshold.

     

    Reference your question, the reviewers are clearly hung up on the fact that Genzyme did not conduct a double blind study. This view taints the rest of their opinions. Perhaps the actual panel will be more forgiving or Sanofi/Genzyme will present a great rebuttal. I will count on neither.
    9 Nov 2013, 02:02 PM Reply Like
  • Increased holding by 40%, if I'm going down, I'm going down swinging! lol Still think the benefits outwiegh the risks as far as the drug goes in my opinion. Furthermore, as a reminder, it is already approved in the Eurozone. Chances of getting invested capital back is probably 60-70%.
    8 Nov 2013, 12:48 PM Reply Like
  • Not to mention it is approved for leukemia here in the US. I think many are forgetting this. If it shows significant efficacy for MS this will be nothing but a great buying opportunity. I think that rootbeer's and other's have shown that efficacy is not an issue.
    8 Nov 2013, 01:23 PM Reply Like
  • From S&P Capital IQ:

     

    "a likely delay in the launch of Lemtrada multiple sclerosis drug due to recent disclosure of certain side effects. We are pushing back our expectation for FDA approval of Lemtrada by one year to the end of 2014."
    8 Nov 2013, 01:23 PM Reply Like
  • Not shooting the messenger, but I love it when analysts pile on just trying to look smart. All of these side effects were already known for the most part. He's reacting to a headline when it would be advisable to sit on his hands.
    8 Nov 2013, 01:41 PM Reply Like
  • The problem is, I think, the FDA's attack on the statistical results. I can not judge the criticism. However it's weird that this criticism was not revealed earlier, during the EU approval process or as comments on the Lancet articles.

     

    I hope someone like Rootbeer will comment on the section discussing the statistical results at the end of the FDA document.
    8 Nov 2013, 01:49 PM Reply Like
  • Author’s reply » The FDA staff is doing their job in preparing for next week’s advisory committee meeting. This is what they do with advisory committees. Sanofi’s management is all in favor of a strong REMS program. That would not bother them. They have been meeting with the FDA in preparation for the FDA decision to approve or reject Lemtrada. The decision remains scheduled for the latter half of December 2013. The FDA is going through the data – including the consistent results in Genzyme’s 5-year follow up. The staff raised questions on trial design. Sanofi believes that they have answers. For one specific example, it was clear that a double blind study was not feasible. The companies are preparing for the panel and can now do so with the staff’s questions. All of the questions have answers. Sanofi is not backing off of their support for this drug and does not appear to be discouraged by the staff’s background package.

     

    Lemtrada is twice as good as what most people take today. There are real risks. Safety issues need to be discussed, but also need to be put into perspective. What is the magnitude of the risks and – importantly – how do they compare to MS? The FDA decision centers around safety and how risk can be mitigated. Staff concerns are fairly reasonable. They want an in depth discussion and will get one. For more on FDA advisory committees:

     

    http://bit.ly/1aw5YKu.

     

    What would a robust REMS program look like? It would probably look like the program devised for Tysabri after it was pulled from the market. The FDA is concerned with designing an effective REMS and ensuring compliance with the monitoring requirements. Doctors administering the drug will register with Genzyme in order to track patients for complications. Next week, the advisory committee with probably make recommendations for further strengthening the REMS program as well as enforcing compliance. Biogen is tracking all serious adverse events associated with Tysabri. According to the most currently available data, there have been 401 cases of Tysabri-induced progressive multifocal leukoencephalopathy (PML) as well as 88 deaths. A REMS works for Tysabri and a REMS would work for Lemtrada, which is the safer of the two drugs.
    8 Nov 2013, 02:19 PM Reply Like
  • Thanks to you and rootbeer for your comments. Days like these it helps to have some reassurance.
    8 Nov 2013, 02:29 PM Reply Like
  • “These are the times that try men's souls. The summer soldier and the sunshine patriot will, in this crisis, shrink from the service of their country; but he that stands it now, deserves the love and thanks of man and woman. Tyranny, like hell, is not easily conquered; yet we have this consolation with us, that the harder the conflict, the more glorious the triumph. What we obtain too cheap, we esteem too lightly: it is dearness only that gives everything its value.”
    8 Nov 2013, 02:52 PM Reply Like
  • I don't think the Reuters article gives an accurate overview of the FDA report. For me the interesting bit starts at page 300 of this pdf. From there the most important results are those of the 323 trial, of patient within an early phase.

     

    One if the complaints of the reviewer is the higher drop out rate for those patients on interferon.

     

    "The sponsor attributes this difference in dropout rate to subjects who had previously failed interferon treatment refusing further treatment with the same drug.", on page 306

     

    But this argument is not valid for the 323 trial involving only patient not on any MS medication before.

     

    Still reading...
    8 Nov 2013, 03:48 PM Reply Like
  • Author’s reply » And for the defense... Sanofi (SNY) presents their advisory committee briefing document:

     

    http://1.usa.gov/1awgIZh
    8 Nov 2013, 04:27 PM Reply Like
  • Chris, when did this report become available? I'm just wondering if it was priced in today already.

     

    Just started reading it, but my initial impression is very good. I don't see any way that placebo affect and rater bias can cause the following results (page 17):

     

    • A significant reduction in in the number of patients with new gadolinium enhancing lesions and new or enlarging T2-hyperintense lesions which are associated with acute
    inflammatory disease activity;
    • A significant reduction in the number of patients with new T1-hypointense lesions which are associated with axonal injury; and
    • A significant slowing in the rate of brain volume loss as determined by brain parenchymal fraction (BPF), a measure of brain atrophy.
    8 Nov 2013, 04:56 PM Reply Like
  • Author’s reply » It just popped up at the end of the day.

     

    The drug is effective.
    8 Nov 2013, 05:00 PM Reply Like
  • Interesting pages in the FDA report: 314, 319, 320(esp point 5), 321, 322.

     

    On page 314 a table with MRI outcomes.

     

    The criticism is that self-injection with Rebif is so unpleasant that more people stop this medication. And the trial offers them other treatment if their MS worsens. This introduces a bias for extra relapses with Rebif in the trial.

     

    On page 324 there is a quoted comment from the Lancet paper complaining about another bias and telling us that in the trial the lapse rate on Rebif was low as well.

     

    The efficacy reviewer does acknowledge de reduced relapse rate.

     

    On page 339 the statistical review starts. Also this reviewer does confirm the reduced relapse rate.

     

    Both reviewers concluded that the 323 and 324 trials fail on time to sustained accumulation of disability (SAD).
    8 Nov 2013, 04:54 PM Reply Like
  • Ii wonder who the big seller was today. The top three holders are
    -Abrams Capital
    -Dalton Investments
    -Whitebox Advisors

     

    We should know soon when the November SEC filings come out.
    8 Nov 2013, 05:10 PM Reply Like
  • FWIW, its interesting that sanofi took a pretty big hit on the report, and then almost completely recovered. Now, obviously, Sanofi is much less leveraged to this particular approval outcome than these special rights are, and there are other things besides a change of heart about this drug that could have caused the turnaround.

     

    but the bigger boys who play in the big pond seem to have decided, by the end of the day, that this was a wash.
    8 Nov 2013, 05:39 PM Reply Like
  • Author’s reply » Today’s staff document was a precursor to a precursor to next month’s FDA decision on whether or not to approve Lemtrada. The FDA advisory panels frequently make recommendations that do not side with the FDA staff. Additionally, the FDA final decision does not always side with the advisory panel. They usually coincide, but not always.
    8 Nov 2013, 05:42 PM Reply Like
  • Well: I've looked over the document myself now, finally. I have to admit its not very encouraging.

     

    the bottom line take home message seems to be

     

    1. There is one study that shows effectiveness on subjective measures, but it is subject to placebo effect. There is another study that shows lack of effectiveness on subjective measures. combined this evidence is weak.

     

    2. Neither study shows effectiveness on objective measures. This is more informative than the above.

     

    3. "Collectively, the two studies rendered more evidence of ineffectiveness than effectiveness of
    aletuzumab on disability."

     

    4."adequately designed and well controlled blinded studies need to be conducted in order to establish the possible efficacy for aletuzumab."
    8 Nov 2013, 06:39 PM Reply Like
  • The briefing suggests a very poorly (perhaps fraudulently) designed and executed set of trials from which efficacy conclusions can't be drawn. There's a solid case to be made that Sanofi management should have known this and mislead investors by misrepresenting Lemtrada's potential. Looks like Pomerantz has already filed a class action suit. Might be a decent payout, as unlike most situations the defendant (Sanofi) still has plenty of dough. Something to consider.
    9 Nov 2013, 01:01 AM Reply Like
  • Still digging into this...
    It seems that they had an unusual low occurrence of SAD in the interferon patients in the 323 trial, and because of that the difference between interferon and alemtuzumab is not significant.
    9 Nov 2013, 08:27 AM Reply Like
  • Apologizes to Chris DeMuth, it was not my intent to castigize or assign blame. I am just frustrated over this extremely negative development. However, even without FDA approval there is a chance to eke out a profit even though it may take several years now.
    9 Nov 2013, 10:19 AM Reply Like
  • I've seen summary CHMP documents and the EPAR for Lemtrada in the EU but not a detailed document about the trial design - has anyone looked at this or know where to find it? Could be useful in comparing their views of trial design and statistical significance to those raised by the two doctors in the FDA report.
    9 Nov 2013, 12:08 PM Reply Like
  • Author’s reply » Great idea; please post what you have and we'll see if others can fill in anything missing.
    9 Nov 2013, 12:10 PM Reply Like
  • http://bit.ly/1aeSTsn

     

    http://bit.ly/1aeSW7l
    9 Nov 2013, 12:48 PM Reply Like
  • nothing hugely informative in that.

     

    there does seem to be a greater focus on number of relapses than there is on progression of disability in the EU doc, and more of the opposite in the US staff report.

     

    If anyone can site past examples of staff reports that negative that have resulted in positive panel recommendations, I would be all ears.

     

    Also: does anyone know if the UK NHS will pay for lemtrada treatment for MS?
    9 Nov 2013, 01:02 PM Reply Like
  • Exactly - I'm looking for the backup material that would have been provided in advance of these meetings - the equivalent of the 370-page FDA doc. Not sure if they do that in the EU.
    9 Nov 2013, 01:19 PM Reply Like
  • Note the Gilenya briefing http://goo.gl/jxsCG . Save as PDF and go to page 305 to see how they did study vs. interferon. They actually gave patients weekly placebo injections. So it certainly could have been possible for Sanofi to do a double-blind test vs. interferon, with placebo infusions and injections. Problem was apparently the proprietary pre-filled Rebif (interferon) syringe that Sanofi says precluded them from doing a double blind properly. If that's true, they should have chosen the lower-dose Rebif (without the proprietary syringe) or another interferon as the comparator.

     

    It's also instructive to compare the clinical/statistical reviews for Gilenya vs. Lemtrada overall, the highlighted study weaknesses and overall recommendations are night and day. On page 321 of the PDF'd Lemtrada briefing see "Table of 323 and 324 Protocol features that may have increased biased reporting" with a lot of simple things that should have been fixed. Also note page 304 Table 14 "Completion rates..."

     

    Imagine it's 2009, when the Phase 3 studies were being recruited. The only approved treatment options at that time were the platforms (interferon and Copaxone, all with similar efficacy) and Tysabri (approved 2004, then pulled from market and re-approved in 2006 with severe side effect warnings). You have MS and you haven't responded to interferon treatment, so you beg your doctor to get you into this test for Lemtrada that has shown amazing published phase 2 results (maybe a cure!!!). When you join the study and find out you got picked for more interferon and not the miracle drug, you either drop out immediately or fake a relapse to get put on a potentially better drug. If you got picked for Lemtrada and know that showing severe relapse might get you taken off of it, you downplay your symptoms.

     

    Excerpts from the briefing that are particularly worrisome:

     

    "In the key 324 trial there were two groups of patients. One group took alemtuzumab once per year in five- and three-day courses of intravenous infusions in a clinical setting. This group received a drug that the patients in both treatment arms would view as more likely to be effective because of the widely known results of an open label phase 2 trial and because they have already continued to have relapses on the active comparator drug. Furthermore, the consent form suggests that they will have to stop taking the preferred drug if they provide evidence that their disease is worsening. The other group were required to inject themselves three times weekly with Rebif, a drug that could cause disfiguring skin changes at the injection site and flu-like symptoms in as many as 60% of the subjects. They also took yearly courses of methylprednisolone infusion corresponding to the infusions given the alemtuzumab group. This group also knew that the Rebif had failed to work for them before and that if they report worsening of their condition they may be able to stop taking the Rebif and switch to another treatment."

     

    "In the 323 and 324 trials, any placebo effect may have been magnified by the unblinding of the patients and treating physicians. Patients who know they are on the preferred drug will be more likely to have a positive placebo effect. Patients who know they are on the drug that is poorly tolerated and has failed before are more likely to have a negative placebo effect."

     

    "It is troublesome to see that so many patients were not assessed for baseline and were not treated until weeks after the randomization. Such delaying not only allowed patients to drop out before receiving any treatment and assessments when assigned treatment was undesired but also effectively invalidated the baseline scores. When screening EDSS score was used as baseline, the SAD events went down by more than 10% in all IFNB-1a groups and went up by more than 10% in all aletuzumab groups in the two studies, resulted a p-value of 0.2010 for treatment difference
    (Table 15). The results suggest that possible unblinding might not be limited to patients."
    9 Nov 2013, 01:38 PM Reply Like
  • Note that last paragraph especially. The very strong implication is that the RATERS weren't blinded, and in fact gave artificially low baseline EDSS scores to the interferon group and artificially high baseline EDSS scores to the Lemtrada group. Thus the interferon group had much higher EDSS deterioration vs. the Lemtrada group.

     

    There's your evidence of fraud right there, straight from the FDA. Lawsuit!!!

     

    A preview of the 11-13 FDA meeting: http://goo.gl/BWZ6wz
    9 Nov 2013, 08:09 PM Reply Like
  • Jeffries 11-8-2013 research report pegs odds of approval at 20-30%. Quotes below:

     

    "The issue is whether the risk of extra adverse events versus comparators can be justified given that the FDA analysis of the data suggests the efficacy is not necessarily distinct from Rebif (especially on disability measures)."

     

    "Remember Xarelto: We would like to remind investors regarding the Xarelto (anticoagulant) FDA briefing documents, in which the FDA reviewer recommended a CRL for Xarelto in stroke prevention. This was based on the concern that Xarelto had not shown efficacy versus its comparator (warfarin) due to the clinical trial design (time in therapeutic range was too low). The AdCom panel then gave a positive vote for approval two days later (Yes 9, No 2, 1 abstain). The drug was subsequently approved at first pass, and has become a very successful product. As was seen in the Xarelto AdCom, the AdCom panel contains clinicians who are "on the ground" treating patients, and may be more likely to look through the fine detail of the statistics and be more inclined to opine on the benefit of the product for the patient. In Lemtrada's case, it is likely that there are panel members who have prescribed alemtuzumab off-label for many years, under the firm belief that it gives benefit to patients."
    9 Nov 2013, 01:49 PM Reply Like
  • FWIW the last PCNS Adcom had Dr. Jeffrey Cohen as a voting member (goo.gl/7SFn0Z). In the Lemtrada materials, he's still listed as on the committee (goo.gl/xgpoIN), but not on the meeting roster (goo.gl/dVKBao) which suggests that he's recusing himself because of his involvement in the Lemtrada trials (goo.gl/xdlOCg see first 2 listed studies).

     

    Dr. Cohen is a big proponent of Lemtrada and hitting MS early and hard (see Cohen's quotes from Rootbeer's post above "Zero Tolerance For Disease Activity in RRMS"). I was hoping he would help sway the committee, but it's not clear he'll be able to do that now though. Googling through the other Adcom members, I don't see anyone with a ton of MS expertise or with quotes suggesting they agree an aggressive early approach to treatment.
    9 Nov 2013, 01:56 PM Reply Like
  • Great stuff here thanks. This is such a difficult situation to handicap and this data is very helpful. Although probably unlikely, an "Xarelto" situation would be welcomed with open arms by many CVR holders.
    9 Nov 2013, 02:24 PM Reply Like
  • Also worth noting the example of Vyndaqel. The EU approved in 11/17/2012, and the FDA held an Adcom meeting on 5/24/2012. The FDA issued a complete response letter requiring another study to substantiate efficacy.

     

    I think this will almost certainly be the outcome for Lemtrada. Plenty of new MS drug alternatives recently including Gilenya (52% reduction in ARR vs. interferon Avonex vs. Lemtrada's claimed 49-55% reduction vs. interferon Rebif). Plenty of new treatments being tested. I don't see the FDA overlooking shoddy/biased drug trials and setting a bad precedent.

     

    Vyndaqel Briefing: http://goo.gl/KyvjHs
    Complete Response Letter: http://goo.gl/wG4HIG
    9 Nov 2013, 02:35 PM Reply Like
  • A couple quotes from Bloomberg's Biotech Analysts:

     

    "There are 143,000 relapsing-remitting MS patients in the EU5 (Germany, France, Italy, Spain and the U.K.), FosterRosenblatt estimates. Assuming 50% are treated with drugs at a $60,000 first-year cost (equivalent to German pricing), 10% market share would be needed to achieve $400 million in aggregate first-year sales. Achieving 10% share in the first year is ambitious for any new drug, particularly in a disease where doctors are more cautious about new therapies."

     

    "Novartis's Gilenya captured about 14% of European drug-treated multiple sclerosis patients, analysis of the first 12 months of sales ($293 million) shows. At $30,000 per patient, that equates to almost 10,000 patients on Gilenya outside the U.S. While Gilenya had some safety concerns and restrictive monitoring, it was the first oral MS drug. If Lemtrada matches this trajectory, it could achieve the first CVR milestone of $400 million in sales, even without U.S. approval."

     

    "The EMA approved Sanofi's Lemtrada in June and the product has launched in Germany and Finland. While the FDA and EMA operate autonomously and these markets are independent, a strong, unexpected opinion by one agency can affect a product's commercial viability in other regions. For example, Pfizer's Xeljanz received U.S. approval, yet was not approved in the EU, where questions about efficacy and safety led to lackluster uptake in the U.S. market."

     

    "Briefing documents released ahead of the Nov. 13 FDA panel for Sanofi's Lemtrada reveal an FDA decision is expected by Dec. 27 (PDUFA date). This is an update vs. [Bloomberg]'s previously expected "mid-to-late December"".
    9 Nov 2013, 02:51 PM Reply Like
  • Quotes from BofA 11-8-2013 research:

     

    "Overall, documents are very negative, citing both safety concerns and inadequate demonstration of efficacy, given poorly conducted clinical trials. We currently forecast risk-adjusted peak sales of Eur950m, with cEur500m in the US (Lemtrada has already received EUapproval). A recommendation against approval, therefore, represents only c1-2% EPS risk [to Sanofi's income statement]".

     

    "While the FDA acknowledges that clinical trials have shown a relapse rate benefit, it notes: 1) This cannot definitely be ascribed to Lemtrada, given that the study was not blinded and due to the subjective nature of the relapse rate endpoint. The FDA specifically states “The clinical trials lacked required procedures to ensure that relapse event reporting was uniform in the two treatment groups”; 2) Evidence on improvement in disability is “weak”, given a benefit shown in only one of the two studies. The FDA also questions the extent of benefit in the single study that did demonstrate a disability improvement (after correcting for placebo effect and bias); 3) The most unbiased finding in the clinical studies was MRI lesion volume, on which Lemtrada failed to show a benefit."

     

    "As described above, the FDA briefing documents are clearly cautious and suggest a recommendation against approval is most likely. However, within its questions, the FDA leaves open the option for a restricted approval as a last-line agent, with a potentially onerous REMS (largely what is assumed in forecasts anyhow).
    Specifically, the FDA’s last two questions focus on line of therapy for approval and a discussion of what may be an appropriate REMS. The FDA recommends safety monitoring for 4 years, with an annual global disability assessment, as well as regular blood monitoring."
    9 Nov 2013, 02:59 PM Reply Like
  • I am confused how this drug went from a quantum leap in MS treatment to a sloppy trial with unclear results in a matter of days?
    9 Nov 2013, 06:39 PM Reply Like
  • EJT, I don't mean to be rude but the previous 183 posts might make the picture a little bit more clear. The 370 page FDA report makes for a good bedtime read....
    9 Nov 2013, 07:00 PM Reply Like
  • It was impossible to know that the trials were shoddy without having the data given to the FDA. It's almost unfathomable that Sanofi would go through the time and expense of the trials without being sure they were done properly, but that's exactly what happened. Based on all the publicly available data, GCVRZ was a very solid bet on superior efficacy vs. manageable safety risk. Demuth, Rootbeer and others did an excellent job of showing that. But the efficacy stats go out the window if the trials weren't done properly. It's truly an out-of-left-field event. A great example of why risk controls and diversification are so important, as there's only so much you can ever know. I don't kick myself for losing money on this, it was a very good bet with a low-probability outcome as a result. I would like a lawsuit to reveal exactly how much Sanofi (and the physicians, and the raters) knew about the trial biases. Betcha there's a few interesting e-mails somewhere about it.
    9 Nov 2013, 07:23 PM Reply Like
  • @Dog, really good commentary. Thanks very much for parsing and posting.

     

    I'm grateful I cut my position in half about 4 months ago, just for reasons of risk reduction. It could have been worse.
    9 Nov 2013, 11:07 PM Reply Like
  • I would like to solicit people's view of the value of the CVR if lemtrada approval is

     

    a) rejected
    b) sent back for a new phase III trial with proper double-blinding.
    9 Nov 2013, 06:51 PM Reply Like
  • Root beer, what makes no sense is that why would Genzyme do the tender at $1.75 if they did any due diligence when issuing the CVR and prior to the Sanofi acquisition. You would think massive due diligence was done. If the work was that shoddy I would think someone on the deal team would point it out. I am playing devils advocate and my guess is that this drug will be approved. Drugs at this level always have major issues- look at standard chemo drugs - they basically kill you to save you. Mark me down as a contrarian approval.
    9 Nov 2013, 08:29 PM Reply Like
  • I don't think Sanofi will do another trial if the FDA requests it. So if the FDA disapproves it will be game over for this medicin in the US. I wonder if Sanofi will then continue to supply Campath free of charge.

     

    Because of the irreversible side effects I think it is appropriate, ethical, to inform patients and doctors about the type of treatment. Genzyme took big risks in the trial set up but they did not have good alternatives either.

     

    See the document that Genzyme wrote. It seems that the equity analysts haven't read it yet.

     

    The main reason for the lack of efficacy is the trial 323, where the Rebif patients fared exceptionally well, much better than in the literature. I would think that this contradicts the perception of a bias towards alemtuzumab. It might be attributed to the selection of patients, in the initial stages of MS, where clinical differences are difficult to detect.

     

    In the Genzyme doc I also read that the T2 lesion volume is statistically significantly less for alemtuzumab, but only after the first year. This can be inferred from the FDA document as well. The idea is apparently that it takes a while to see the effects of alemtuzumab.

     

    It would be interesting to see how the adcom reacts on this defense from Genzyme, and how they react on the results of the extensions of the trials and what the Genzyme defense is to the implicit accusations that something is wrong with the data from Eastern-Europe and Israel.
    10 Nov 2013, 02:54 AM Reply Like
  • Unfortunately, I did not see the drop until after 11 am so missed an opportunity to buy below 0.65. The current price does not offer enough benefit for the risk. I’m a practicing neurologist with a large MS population who is generally an early adopter of new treatments and have been involved in clinical trials (though not for alemtuzumab).. Also, I know several of the CAMMS investigators. I currently do not own GCVRZ.

     

    My bottom line, up front, is that the shares will probably only payout $1 in 2020 as I believe the drug will be approved, but sales milestones will not be met. Therefore with 6% time value of money, the fair price is 0.65 cents today. If US approval is not met in time, meeting sales milestones will be near impossible and the ultimate price will be 0.00 but post PDUFA price might still be 0.20 allowing an exit. If approval on time is met, the ultimate price, IMO, will be 1.00, but there could be a spike >1.50, allowing for a successful exit. I believe the chance of approval is 60%, but before the documents felt the chance was 80-90%. My change in opinion comes from the efficacy concerns raised in the documents. I still think its very effective, but will they prove it to the FDA?

     

    The AdCom has to discuss and answer the 5 questions on page 7, so I’ll leave my two cents…

     

    1. Has substantial effectiveness been shown in adequate and well controlled trials for RRMS? Primary outcomes were reduction in annualized relapse rates (ARR) and time to sustained accumulation of disability (SAD)--- if these are not satisfactory, then the other endpoints really don’t matter. In retrospect, IMO, the sponsors should have picked one dose of alemtuzumab (12 mg) to carry forward from phase 2 to 3 and have done study one (naïve) vs. placebo and study two vs. Rebif. This would have improved the statistical power and have presented data against placebo. Dr. Marler and Yan present arguments that these endpoints may not really have been met. Some arguments are against the lack of patient blinding. Of course the FDA knew that all along and were ok with it. Blinding alemtuzumab would be very difficult as there are mild infusion reactions that would tell a patient they were definitely on drug. I believe blinding concerns are adequately addressed in the Sanofi response. Marler and Yan raise concern about 12.6% dropout from patients in CAMMS324 who were randomized to receive Rebif (MS patients who had tried and failed an IFN probably were not interested in retrying a similar or same drug). Free choice is a cornerstone of any drug trial. As these patient would likely have done same or worse during the 2 year study, I don’t see a problem (it actually biases the other way). Of course dropout rates were higher with Rebif than alem (p.66); the alem patients just did 5 days and 3 days and then just needed required follow-up, Rebif patients still needed to actively treat. Effectiveness: Graphs on p.69 show the big concern. 323 failed to show significance for SAD. IMO, SAD should have been a secondary endpoint for 323 and a primary endpoint for 324. 323 used only never before treated patients (naïve), thus they had early MS. Disability does not rapidly accumulate over 2 years in this population, even with placebo. Some of the arguments about bias are always going to be present when there is an active comparator (i.e. Tecfidera CONFIRM; Gilenya AFFIRM) and a drug still gets approved. And of course, the EMEA (EU) was ok with the data. A negative vote by the panel on this point will be very bad for approval chances.

     

    2. Have they proved a beneficial effect on disability? IMO, they have, as 324 clearly shows a good result. However, 323 with a naïve population did not and this vote could go either way. Note, that there is no argument as to whether or not the ARR endpoint was met, that is a given. A negative vote will not preclude approval by the FDA but would knock GCVRZ down hard.

     

    3. Do safety concerns preclude approval? After the two sides present the safety issue data, this point becomes pure opinion. If the comparator was placebo, and all primary endpoints not met, the modest benefit would not offset safety risk. However, with an active comparator, I believe the need for additional effective treatments make the risks acceptable.

     

    4. If approved, should alem be indicated for firstline use? I expect, if approved, the vast majority of use will be second line. So this is not an important point. The first line study (323) only met the ARR endpoint because proving superiority against an active comparator over two years with a naïve population is very difficult. ARR data was excellent. I would consider it first line in a highly active patient. A negative vote will not mean much (assuming 1 and 2 are positive). If approved, I expect language similar to Tysabri for indication

     

    5. Discussion of REMs. Sanofi has set up a comprehensive REMS to ensure patients will be tested monthly. If many changes are recommended, the launch could be delayed but probably not the decision.

     

    Milestones: Assuming approval in late December and launch in February, I expect a slow launch and slow acceptance. The REMS is going to scare a lot of patients and be too much hassle and concern for neurologists who treat less than 50 patients. Only about half the MS patients are followed by MS neurologists --- some aggressive, some conservative. Happy patients do not switch to a drug with safety issues. The main source of patients will be high titer Anti-JCV Ab positive patients who would have too much risk on Tysabri but need to switch for efficacy reasons. A second pool of patients will be highly active new patients. In 2015/2016 ocrelizumab comes on line. At that point, there will be 3 highly effective therapies: Tysabri, ocrelizumab and Lemtrada (I could include Novantrone but no one uses it much anymore)all competing for the same pool of patients. Thus, I expect a slow 2014 and 2015 launch followed by low steady use after 2016. I assume a price of 120,000 for year one and 72,000 for year 2 (adjusted up 5%/year). I expect a steady state of 2000 new patients/yr (and 1800 pts/yr for second 3 day course) so the drug will likely peak around 400-500MM annual sales.
    10 Nov 2013, 10:55 AM Reply Like
  • Thanks for your analysis. Is that 400-500mm annual sales figure you are estimating for the US or global?
    10 Nov 2013, 11:12 AM Reply Like
  • S19104 - Fantastic stuff thanks. A couple points:

     

    Valuation: Just making sure you realize the $1 payment only kicks in for FDA approval before 3/31/14 and if met will be paid 20 days thereafter (4/20/14), so the time value of money calculation is basically irrelevant. If you’re saying there’s a 60% chance of approval before 3/31/14 and that the sales milestones won’t be met in any event, then you’d have a fair value of $0.60. Am I correct with your thinking there?

     

    ARR Endpoint: You say there’s no argument that the ARR endpoint was met, but table 25 on page 322 of the briefing document makes exactly that argument. Under-reporting of relapses in the interferon arm and over-reporting in the Lemtrada arm could have easily led to a lack of significance in the ARR. Those reporting biases would make sense if the interferon arm patients wanted to switch out and the Lemtrada arm patients wanted to stay in.
    10 Nov 2013, 03:21 PM Reply Like
  • S19104, thanks for your important argument!

     

    In the document filed by Genzyme (http://1.usa.gov/1awgIZh) they say that there was a statistically significant SAD improvement in the second year of treatment in the 323 study. Also they claim a statistically significant better T2 lesion volume in the second year of the trial.

     

    By how much does this improve the result of the 323 trial? How relevant is this for assessing the efficacy of alemtuzumab?
    10 Nov 2013, 03:48 PM Reply Like
  • Doghouse and Ruerd:
    Valuation: Thank you for the information. The time value of money does not come into play as I think milestones will be missed.

     

    ARR endpoint: I see their point but still think the under/over reporting of relapses is a BS argument. Some other studies also have difficulty with blinding and have been accepted. People participate in studies for many reasons, not just because they are failing their current med. Patients may participate out of desire to advance knowledge, getting free drugs and free MRI’s, money ( study like this probably paid stipends of 1000 or so on top of free drug). There is no such thing as a perfect study. Also, 12.6% of people in the Rebif arm dropped out between randomization and starting on medicine…presumably many of the patients who theoretically would have been at risk of over-reporting a relapse to get out of the study would have been in this group. In a placebo controlled study, many patients know whether they are on drug or placebo because patient blinding is not always easy.

     

    SAD second year: Standard statistical analysis for SAD is Kaplan Meir Survival analysis. I do not think the FDA will allow them to ‘prove’ reduced SAD with second year data.

     

    T2 lesion volume: High Dose Interferons (Rebif and Betaseron) are actually fairly robust at reducing MRI lesions and proving superiority is not easy. Therefore, besting Rebif in new T2 and new T1 is favorable. The fact T2 2-year change in volume did not reach p<0.05 is probably ok as MRI data was a secondary endpoint. Of course, a hit would have been better (separating out 2nd year data won’t cut it). Copaxone has less effect on MRI than Rebif – though similar effect on ARR….thus all MRI data in 323 would have likely been positive if it was the control.
    10 Nov 2013, 08:31 PM Reply Like
  • That's US, so we can double this to 900 MM for the best year (more patients ROW than US but aggressive cost discounting elsewhere), which will probably be 2016. Its a big number but not enough to reach the milestones. Without ocrelizumab (if they are delayed), the best year may be later.
    11 Nov 2013, 12:19 AM Reply Like
  • http://bit.ly/1ah5qvk

     

    Interesting study on how often the FSA follows the panal rec.

     

    Only 74% of the time.
    10 Nov 2013, 12:19 PM Reply Like
  • Special Situations and Arbs,

     

    However, in the third paragraph:
    "Peripheral & CNS 25% are on time 100% are consistent "

     

    So the odds are that the FDA will agree with the panel but won't announce it any time soon.
    10 Nov 2013, 12:36 PM Reply Like
  • Am I the only one who sees that the FDA's briefing strongly suggests fraud in the studies? From page 367 of the briefing under "Final Discussion and Conclusions"

     

    "The big question is the source of bias. Patients were unblinded. It is not a surprise that patients carried their bias into the study. But there is no reason to allow patients to acquire knowledge of their treatment assignment before the initial treatment and baseline assessment. When the validity of the baseline is in question, the validity of the study is in question.

     

    It appears that the bias may not be limited to the patient’s side. The discrepancy in EDSS scores between screening visit and randomization visit that led to opposite directions in change of SAD event numbers cannot be explained by bias from patients."
    10 Nov 2013, 03:58 PM Reply Like
  • It seems so. See for example point 1 and 2 of one of comments above and my reply on it: http://seekingalpha.co....

     

    See also some of the comments on my SA article.

     

    I am worried about the complaints regarding the Eastern-European data from the statistics reviewer though. I find it difficult to interpret these complaints, since the reviewer does not flesh out any impact on the results.

     

    It might be that the reviewers are outsiders, scientists not specialized in MS. It could be that the FDA chooses outsider reviewers on purpose to ensure objectivity. Any opinions?
    10 Nov 2013, 04:21 PM Reply Like
  • My takeaway on the "non-EU region" (Croatia, Russia, Serbia, Israel) data from study 324 (page 365 of the briefing) is that there was very little change in EDSS scores between screening and randomization, which highlights the huge changes in EDSS scores in the other regions. Apparently the stats weren't juked in the non-EU region, and as a result SAD was actually HIGHER in the Lemtrada group vs. the interferon group in that region.

     

    The fact that "16 of the 25 subjects in Ukraine had no change in EDSS scores in all scheduled visits during the entire study from screening to month 24" and that ZERO of the 25 Ukrainian patients had SAD suggests the entire Ukraine trial was BS.
    10 Nov 2013, 04:50 PM Reply Like
  • Re Ukraine - the briefing makes the point that if the suspect Ukrainian data (no EDSS change, no SAD) were removed, the non-EU region results would show even more starkly that Lemtrada is substantially WORSE than interferon. In other words, the suspect data had a dampening effect on the results.
    10 Nov 2013, 09:29 PM Reply Like
  • I found a 116 page EU document discussing the reasons for the Eu approval. Note that almost all FDA negative points with respect to the efficacy are discussed by the EU as well.

     

    In particular pages 72-78, 101-105 and 116 are interesting.

     

    http://bit.ly/HPz3L8
    11 Nov 2013, 05:21 AM Reply Like
  • Interesting. Lots of disagreement in that document about how broadly the compound ought to be indicated, but not much about the claim that it ought to be approved as a last-line treatment for those with advanced disease.

     

    certainly highly divergent from the FDA staff report.

     

    I really don't know what to make of all this. Holding for now.
    11 Nov 2013, 12:30 PM Reply Like
  • Does anyone know the frequency of FDA not approving a drug so approved by the EU agency?
    11 Nov 2013, 06:21 AM Reply Like
  • Eu Asia tend to be more like a cc to Harvard, look up recalls, us doesn't take them lightly. If you want experimental meds look abroad,if you took approved us meds that had a recall look to retire after your lawyer buys his 2nd condo. Give and take not a chance us FDA will let anything slide w/o due process
    12 Nov 2013, 12:38 AM Reply Like
  • Minor interesting tidbit from Twitter:

     

    Adam Feuerstein ‏@adamfeuerstein 7m
    Interesting? FWIW: Couple of MS docs (U.S.) have reached out to me, angry about FDA's Lemtrada review. They want drug approved. $GCVRZ

     

    Adam is the biotech columnist for TheStreet.
    11 Nov 2013, 10:58 AM Reply Like
  • Author’s reply » Sanofi ($SNY) statement on Lemtrada briefing documents:
    Our company is confident that Lemtrada offers an important step forward in the way physicians and patients will think about treating multiple sclerosis. Given the importance of addressing unmet medical need, Genzyme decided to introduce a high bar to the demonstration of efficacy by comparing Lemtrada to the standard of care, which at the time of the study initiation was interferon beta-1a. Given the differences in how the drugs are administered – injections versus infusion regimens – and dosing schedules (thrice-weekly versus annually) a double-blinded study was not feasible. However, the interpretation of relapses and the interpretation physical disability were performed by independent experts who were blinded to the therapy of the patients. Furthermore, five-year follow-up data for patients in the phase II studies and three-year follow-up data of patients in phase III demonstrate findings that are consistent with results from the clinical studies years after dosing.
    These are, of course, issues that will be considered by the Advisory Committee and we look forward to our discussion with them.
    - http://bloom.bg/17ZHhKe
    11 Nov 2013, 11:15 AM Reply Like
  • MS doc weighing in here:

     

    http://bit.ly/17ZJS6I
    11 Nov 2013, 11:34 AM Reply Like
  • Wisful thinking:

     

    The EU approval document and the FDA review document are almost completely different. Probably one of them presents an extreme view on alemtuzumab. Given the postings of s19104, the MS doctor, and the signature of just more experts under the EU approval than under the FDA review, it may be that the FDA reviewers present an extreme view.

     

    That's bad for many of us, but fortunately extreme views are more likely to be ignored than negative but still balanced views.
    11 Nov 2013, 04:23 PM Reply Like
  • At best on time means 'Blackbox', hope those in need of the drug get it, $1 per cvr means all win at current prices. Pretty simple here, not a blockbuster but it will help those in need and pay $1 plus those who are wrong on future sales
    12 Nov 2013, 12:25 AM Reply Like
  • Adam Feuerstein‏@adamfeuers... 14h

     

    @Sport234a @chasingthealpha

     

    Agree. FDA review was super harsh. Just wonder if this is instance where panel overrides. $GCVRZ
    12 Nov 2013, 01:53 AM Reply Like
  • After reading the 370 page recommendation report as well as Sonofi's response, I am disappointed. The only strong response from Sonofi is in regard to the critisisim on blinding for the patient population. I do not think it is possible to truly "blind" these two drugs as both have substantial and characteristic side effects as well as wide dosing differences. The failure to successfully blind patients as to which arm of the study they would be in is evident and without response. Sonofi really does not provide details of the blinding methods used to assure rating integrity or the analysis of events. (If not fraud, then incompetence in attempting to "engineer" results.)

     

    The failure to record patients vital signs at the time of infusion is indefensible. Sonofi knew that the effects at time of infusion were substantial. One of the reviewers comments that one of the early developers of Campath always stated that the drug's administration needed to be in a fully capable medical facility. So substantial that if the vitals were known, a REMS requiring administration of the Lemtrada infusion in a hospital setting would more than likely be required. This in and of itself would cut sales by 40% and make the later payouts unlikely. Rebif is usually self injected. As s19104 commented, smaller practices would be unlikely to recommend or administer Lemtrada due to requirements.

     

    There are more questions than answers provided by Sonofi. The side effects are appalling and at times unusual, for example the higher number of Herpes incidents among those that took Acyclovir as a preventative. (?) I simply do not follow Sonofi's statistics regarding effectiveness, particularly in light of the non-EU data which infers fabrication and reads like a term report purchased on the internet.
    If I can get within a smell of a dollar, I am out. This is not the basis under which I made this investment.
    12 Nov 2013, 03:06 AM Reply Like
  • Excellent post RRR, I agree 100%. The briefing report reads that Sanofi deliberately biased the trials by:

     

    1) Releasing favorable (but extremely flawed) phase 2 trial data four months before phase 3 selection.

     

    2) Ignoring repeated and specific advice on phase 3 trial construction from the FDA (detailed in excruciating detail in the briefing, unlike any other historically).

     

    3) Choosing high-dose Rebif (with proprietary syringe) as the comparator instead of the many equally efficacious alternatives used in other trials, with the purpose of precluding proper trial blinding.

     

    4) Ignoring the massively disproportionate dropout rates in the Rebif arm vs. the Lemtrada arm.

     

    5) Using the randomization date EDSS as a baseline (after patients knew their assigned drug) instead of the screening date EDSS, despite the fact that the randomization EDSS massively favored Lemtrada AND ALSO massively handicapped Rebif (what a coincidence!)

     

    6) Ignoring Ukraine data that was patently unreliable, and non-EU data showing that Lemtrada was WORSE than Rebif

     

    7) Etc.

     

    It amazes me that people still think this is a question of known safety risks vs. known efficacy. The studies show that Lemtrada isn’t convincingly better than the interferon treatment used for the last 20 years, but it is definitely FAR less safe. Lemtrada basically wipes out the patients’ immune system (very much like HIV) with long-term degradation, and we’ve got no data on the effect of that beyond 5 years. The extension studies have 20% of patients needing another infusion in year 3 alone. How does this possibly meet the basic medical ethics criteria of “first, do no harm”? If a briefing report showing this many flaws and this strong of a recommendation against doesn’t result in a denial, then it’s hard to see any point in the FDA at all.
    12 Nov 2013, 04:54 AM Reply Like
  • Doghouse, from what specific information do you come to the conclusion that " Lemtrada basically wipes out the patients’ immune system?" I didn't see that in the report.
    12 Nov 2013, 04:40 PM Reply Like
  • "Dr. Berger: There is one other biologic agent you left out—alemtuzumab. It wipes out all of the B cells and T cells; the B cells repopulate but the T cells remain suppressed for a long period. If ever there was a drug whose action mirrors what happens in HIV, alemtuzumab is that drug."

     

    http://bit.ly/18pOuQ2
    12 Nov 2013, 06:29 PM Reply Like
  • I'm probably going to attend the panel in Maryland. Need to take the temperature of this thing directly. I've talked to some industry people and my sense is still 50/50.
    12 Nov 2013, 11:05 AM Reply Like
  • FYI if you've got Bloomberg, the meeting will be webcast there. Type BBTV <GO> and search for Lemtrada.
    12 Nov 2013, 06:52 PM Reply Like
  • Does Lemtrada treat nausea? I'm in need.
    12 Nov 2013, 11:34 AM Reply Like
  • Author’s reply » Appleton man wants to spread word of treatment he says removed his multiple sclerosis symptoms

     

    APPLETON — Michael Evans doesn’t use the C-word.

     

    He doesn’t want to jinx his luck. Technically, the 37-year-old still has multiple sclerosis. But after being symptom-free for almost two years, the “miracle drug” Evans received in a clinical trial is as close to a c-u-r-e as he can imagine.

     

    “This is how I felt before I was even diagnosed,” Evans tells Post-Crescent Media. “Alemtuzumab isn’t just telling my immune system to knock things off, it’s making things better.”

     

    On Wednesday, participants in the clinical trial will testify before a U.S. Food and Drug Administration advisory committee about how Alemtuzumab has changed their lives. While a work conflict is preventing Evans from testifying, he still wants people to know about the groundbreaking medicine.

     

    “MS is a thief. It stole seven years of my life that I can never get back,” he says. “It took away my career choice, and it bankrupted me, wiped me out. That’s why I want to see this stuff on the market.”

     

    At ease on a cushy recliner in his West Browning Street home in Appleton, Evans does not seem like a man who previously couldn’t walk up stairs. He does not act like someone with an illness that would trap him inside on hot, summer days.

     

    He is candid, easygoing and certainly not one to mince words.

     

    “For six and a half stinking years, every Monday, Wednesday and Friday, I gave myself a shot in the ass,” Evans says, describing his drug regiment before Alemtuzumab. “People used to ask me, ‘What’s it like to have MS?’ And I said, ‘It’s a pain in the ass, three times a week.’”

     

    Before the trial, Evans’ only source of relief was a shot of Rebif, the most effective drug currently on the market, his doctor said. Rebif would decrease flare-ups by about 33 percent, but it came at a cost — $1,300 per month, to be precise.

     

    “It bankrupted me,” Evans says. “I remember the day the nurse showed up with that thing and showed me how to do it. I remember asking her, ‘OK, how long am I going to have to do this?’ And she said, ‘For the rest of your life.’

     

    - http://post.cr/1i612nc
    12 Nov 2013, 11:52 AM Reply Like
  • Nice article. Too bad this guy can't testify, but hopefully there are others with similar results who can. Despite questions regarding the studies I think it's hard to debate the efficacy of Lemtrada and the life changing effect it has had on many MS patients.

     

    Not to mention that Alemtuzumab had been approved by the FDA previously as Campath. I know it was for a different disease and I'm sure the method of treatment is different, but shouldn't that play a factor in approval?
    12 Nov 2013, 12:08 PM Reply Like
  • This says a lot about how it was impossible to double blind this study:

     

    He was a perfect candidate, but instead of receiving Alemtuzumab, Evans was placed in the control group, which mean he was given the same Rebif he’d been taking for four years. And while it was a relief to have the company pay for the expensive drug treatment, Evans was disappointed.
    12 Nov 2013, 01:22 PM Reply Like
  • Any chance this guy could submit some written testimony??
    12 Nov 2013, 03:08 PM Reply Like
  • Those Europeans Will Approve (Almost) Anything
    http://aol.it/1aCO6gZ
    12 Nov 2013, 12:48 PM Reply Like
  • How libertarian of them.
    12 Nov 2013, 01:52 PM Reply Like
  • A story like that is why I'll hold till the end. There's some chance here.
    12 Nov 2013, 05:52 PM Reply Like
  • Tomorrow, an FDA advisory committee will address whether or not to recommend the approval of Lemtrada. The facts, not the concerns, point to recommending approval. The job of the FDA reviewers is to raise concerns so that the advisory committee can make as informed a decision as possible. Their report does this quite thoroughly. How do the facts that they present line up with the concerns?

     

    The primary concern that the reviewers raise but do not conclude on is this: As a result of the inability of the testers to run a patient blind study, there may be bias in the data that invalidates the rather impressive results of the studies. This possibility needs to be pointed out to the committee. However, they cite no facts or data from the studies that indicate that there is a reason to believe that significant bias actually existed. In fact, the data presented concerning the incidence of the blind jury's rejecting a patient relapse claim indicate no apparent difference between the test groups. The EU considered and discussed the same concerns. The CHMP members voted to make Lemtrada available to MS patients under fairly tightly controlled conditions. Not one concluded that the concern that there may be bias was reason enough to keep such a promising treatment off of the market. As these legitimately raised concerns are considered by the advisory panel, they will probably arrive at the same conclusion.
    12 Nov 2013, 06:52 PM Reply Like
  • Rtown - "However, they cite no facts or data from the studies that indicate that there is a reason to believe that significant bias actually existed." Perhaps you should re-read the report. It presents a truckload of data indicating bias, including:
    - The disproportionate dropout rates in the Rebif arm vs. the Lemtrada arm.
    - The inexplicable change in EDSS scores from randomization date to screening date that went in opposite directions - favoring Lemtrada and hurting Rebif.
    12 Nov 2013, 10:18 PM Reply Like
  • I asked the co-manager of a $500M+ investment fund based in CT who has substantial experience investing in the pharmaceutical/biotech industry what he thought about the prospects for Lemtrada, and this was his response, for what it's worth: "FDA briefing docs were as scathing as I have ever seen. The writers were unanimous in their recommendation not to approve. Approval seems remote, in my opinion."
    12 Nov 2013, 07:30 PM Reply Like
  • its seeming harder and harder to disagree with this.
    12 Nov 2013, 08:48 PM Reply Like
  • Also tend to agree that the scathing report may ultimately be too difficult to overcome. This is why I exited my position earlier this week at a substantial loss.

     

    While I think Lemtrada will and should ultimately be approved, I don't think it will take place this year.

     

    Best of luck to all the longs tomorrow.
    12 Nov 2013, 08:55 PM Reply Like
  • One small datapoint - Chairperson of FDA panel is Nathan B. Fountain. I found he was on the panel for another MS drug and thought his quote was interesting with respect to his philosophy of letting the patient decide if it's worth the risk:

     

    http://bit.ly/1hElbTs

     

    "Several panelists made the point, however, that not all MS patients respond to all MS drugs that are currently used. Nathan B. Fountain, MD, director of the Comprehensive Epilepsy Program at the University of Virginia in Charlottesville, thought the risk–benefit ratio as it can be understood to date should be presented to the patient to decide.

     

    "I think for the patients that I have with MS, anyway, if I said, 'you have a 1 in 3 chance of improving your walking speed by 30%,' or if I said, 'well, some respond and some don't, and the average improvement is a 21% increase in walking speed,' I think they'd all say yes," Dr. Fountain said. "And I think if I projected myself to that situation I'd probably say yes, all presupposed on the idea that the risk of seizure doesn't appear to be substantially increased when you take it properly."
    12 Nov 2013, 10:18 PM Reply Like
  • Thanks for your data point, Keubiko. This is consistent with the quote from Dr. Russell Katz, the head of the FDA division of neurology products.