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  • Stocks To Watch: Sanofi SA Rights [View article]
    Lemtrada was resubmitted to the FDA in late May (press release 5/30) so a decision should be out by late November. I expect they will approve. Unfortunately, this will be too late for the first milestone. Ramping up in EU is very slow (see below --- only €6 million in sales). Even with US (assuming launch January 2015 and 2015Q2 as first quarter to count), the second (first sales) milestones will be very difficult to reach.

    from: http://bit.ly/1nXj5QE

    Following its approval by the European Commission in September, Lemtrada™ is currently commercially available in a number of countries such as Germany, Nordic countries and Canada with additional launches expected in the second half of 2014. Second quarter and first-half sales of Lemtrada™ were €6 million and
    €11 million, respectively. In May, the U.S. Food and Drug Administration (FDA) accepted for review the resubmission of the supplemental Biologics License Application (sBLA) seeking approval of Lemtrada™. A six-month review period has been assigned for the Lemtrada™ sBLA.
    Aug 2 12:34 PM | 1 Like Like |Link to Comment
  • Orexigen Will Run: Here's Why [View article]
    I write a ton of meds off-label and have often prescribed drugs through compounding pharmacists so will add my two cents. Here's why OREX investors do not have to fear the generic issue

    First, off-label prescription is legal, moral and common. Probably 20% of scripts I write are off-label--- almost always it is a drug approved for another indication. A good example is gabapentin, FDA approved only for for seizures and post-herpetic neuralgia. Of my 300 patients on gabapentin, 2-3 have seizures and 4-5 have PHN. The other scripts are off-label for fibromyalgia, radiculopathy, diabetic and other polyneuropathy, insomnia, restless legs,etc. If poorly tolerated, I will consider Lyrica and maybe Horizant or Gralise (branded better tolerated preparations of gabapentin). This is low risk and can save patients a ton of money.

    I also use compounding pharmacists for unusual dose strength, non-FDA approved combinations (mostly for intrathecal pumps) and rarely because a patient can not get an extremely expensive drug covered by their insurance plan. An example of the latter I did once is 4-aminopyridine (active ingredient of Ampyra) BUT only in a patient who did not get the drug because they did not meet insurers guidelines -- i.e. a patient who cannot walk > 25 feet. I can get this drug for the patient at about 50-60/month --- so why not get it for everyone? Most patients have insurance and end up paying much less for branded Ampyra than for compounded 4-AP. (I've never had a compounding pharmacy turn down a script because it is FDA approved -- this is a theoretical concern easy to overcome by alternative dosing, i.e. 4-AP 5 mg tid vs. Ampyra 10 mg po bid)

    There will be very little compounding or duel generic prescribing of Contrave once approved. Nothing prevents me from writing Buproprion XL 300 (or Buproprion SR 200 mg bid) plus 25 or 50 mg naltrexone but I doubt I will write this. If I do, the patient has 2 generic copays instead of 1 branded and coupons will bring the vast majority of insured patients to $20 or less/month. No one will use a compounding pharmacist. Yes, one could likely get #30 400/32 Contrave for $50 or so (or have them make 400/30 to avoid the FDA issue). But insurance will not cover this so patient will pay the entire amount.

    So, a patient with insurance will never want compounded or dual generic drugs --- they will personally pay less out of their pocket for Contrave. That does not mean there will be no off-label use (of dual generic scripts). I would certainly consider doing this for a patient with absolutely no insurance but still capable of paying $50/month or so for Bup XL plus naltrexone. Of course that uninsured patient was not going to be going on Contrave anyhow, so the company will not really be losing the sale.
    May 27 08:30 PM | 2 Likes Like |Link to Comment
  • GCVRZ Forum Archive  [View instapost]
    I agree that a bottom's up analysis of market share has more value than top down ---- it is just too easy to say something like "if 65% of the patients have relapsing MS and 20% of them are failing, we need only to get 20% of that pool to have 2.5 % of the 1,000,000 first world patients on drug".

    I had a few patients who were interested in switching to Lemtrada this spring after approval (which did not come). Therefore, all of these patients are now on other meds and may not be wanting to go on Lemtrada late in year or next year if approved.

    With my practice I would estimate 5% are candidates. This includes:
    1. Those with somewhat aggressive MS who are JCV Ab positive and prefer not to take the PML risk of Tysabri. (largest pool for me and likely largest pool in year one)
    2. Very aggressive initial presentation of MS (options would be Tysabri or Lemtrada and decision may comer down to whether or not they are JCV Ab pos). small pool but one of my off label patients was in this group and did well
    3. Significant breakthrough while on another agent (options would be Lemtrada, Tysabri, Gilenya > Tcfidera). (second largest pool)

    So about 5% of my patients may be candidates in any calendar year --- how many will go on? Many will choose another option. This will depend on patient and doctor's perceptions of risk. Some of my patients would be afraid to take anything with significant risk. > 1/3 of patients are followed by neurologists who would not be comfortable with a drug like this (they follow < 50 MS patients each but overall see many patients, likes to take 2-3 years wait to see if something bad happens so that they can say "see I told you the medication was too dangerous"). So I really can't say what I would end up doing --- prob somewhere between 1-2% (as a more aggressive than average neurologist). So in US, I would estimate 1000 patients year one, 1500 patients (plus 85% second dose) year two. Less year 3 because ocrelizumab competes for the same patients (likely with better safety). Therefore only milestone 1 will be in play. I can't estimate EU and ROW but I actually expect Germany will have a much better second quarter than first quarter. Novantrone (another strong IV MS agent with so many safety concerns nobody uses anymore) did fantastic in France but not so great here.
    Apr 28 02:12 PM | 1 Like Like |Link to Comment
  • GCVRZ Forum Archive  [View instapost]
    Lemtrada will likely be covered very similarly to Tysabri as both are IV drugs with very strong efficacy and defined REMS plan due to potential for serious side effects.

    Here is a clip from the Canadian MS Society about Tysabri:
    COST REIMBURSEMENT
    Private and group health plans may provide some coverage for people who meet the prescribing criteria. Financial assistance through the Canadian Tysabri Care Program may be available to people who cannot afford the drug. For more information, call 1-888-827-2827.

    REIMBURSEMENT CRITERIA
    Assistance with treatment costs varies among provinces and private insurance companies. In most cases, to be reimbursed an individual must have active relapsing-remitting MS (at least 1 or 2 MS attacks in the 1 or 2 years prior to starting treatment) and be ambulatory. The exact definition of “ambulatory” varies among the provincial drug programs and private/group insurance plans. For more information on reimbursement, please contact your nearest division office at 1-800-268-7582, or your provincial government program office (telephone numbers are listed under Provincial Drug Programs - Contact Information).

    And here is what they say about Lemtrada (interesting about Quebec --- they really want to be a separate country):
    COST REIMBURSEMENT
    Genzyme is currently working closely with private and public payers to ensure Lemtrada will be accessible to all individuals who need it. The Common Drug Review advises whether or not a drug is cost effective and should be covered by public drug programs. Provincial drug programs then use this information in making their decisions. It should be noted that Quebec conducts its own review, independent of the CDR. Please call 1-800-268-7582 for additional information on reimbursement in your province. For additional information about Lemtrada, please contact MS One to One™, at 1-855-MS1-2ONE (1-855-671-2663). Please discuss any other questions about treatment options with your physician.


    Note: I am a practicing Neurologist specializing in MSwith many patients on Tysabri who has used Campath off label a few times in the past (when available). I was long GCVRZ in December, expecting a rise from 0.50 to 1.50-2.00 on what I estimated was a 60%$ chance of approval. I am less enthusiastic about the milestones (and hence am unlikely to invest in the CVR again) as ramping up will be slow due to complicated REMS, fear (patients and some neuros). By the time they start hitting their stride in early 2016, ocrelizumab will come along for the same niche.
    Apr 28 11:28 AM | 1 Like Like |Link to Comment
  • GCVRZ Forum Archive  [View instapost]
    Lemtrada should be considered cost effective and get approved publicly, but I have no idea how fast/slow their bureaucracy moves. Lets say a course is 100k the first year and 60k the second year (will be less outside US where I expect price to be 120k and 72k year 2). Year 3 and 4 are 'free'. Then at some point during or after year 4 another medication is added or patients wait until a breakthrough and then go on another medication or take another 3 day course of Lemtrada which hold then another 2 years or so. So over the 4 years we can calculate, average cost is 40k/year. This is about what Canada is now paying for the MS drugs (they average 50K in US). Tysabri, which is +/- equivalent in efficacy, also has infusion costs of 3-4K/year.

    The spread of time between public and private insurance will be harmful to the FSM since the time starts the quarter after any sale. I don't know the number of patients on private vs public in Canada.

    My first patient who went on off-label Campath just reached the 4 year milestone and we started another drug per their preference. I heard Coles, the 'clinical father of Lemtrada', in England gives a 3 day course of alemtuzumab to anyone who breaksthroughs, often in year 4-6. Some patients have never broken through.
    Apr 21 07:03 AM | Likes Like |Link to Comment
  • A Nice Buying Opportunity In Tonix Pharma [View article]
    lets make it a survey of two. I agree with 10slinger. This medication will not sell well. The problem with FMS studies is that the enrollment criteria almost always exclude the most difficult to treat patients (the ones that end up seeing us 5 times a year). To be in a FMS study, patient must be willing to wash out many other drugs and not have other sources of pain. Mild FMS responds to many different therapies.

    However, the stock might do very well over the next two years as the chance of good outcomes (we know cyclobenzaprine should beat placebo). Therefore , we are likely to hear good outcomes from this study and another phase III and eventually approval. Thus, this is a good stock to buy on a major dip and sell right after good news.

    Disclosure: Neither long nor short but will placed on watchlist.
    Apr 2 07:47 AM | 3 Likes Like |Link to Comment
  • The One Question I'd Ask Questcor [View article]
    If A=B and B=C, then A=C
    The bioassay used is the Sayer's assay. Basically, you 'prepare' mice by sucking out their pituitaries (also known as their hypophysis). The next day, you inject either a reference standard preparation of corticotrophin or the sample you want to test. Three hours later, you sacrifice the mice, remove their adrenal glands and assay the abscorbic acid in the glands by spectrophotometry. You then can compare the activity of the samples to the activity of the standards and calulate the potency.

    So, you can get the samples to test from ACTH vials...where do you get the reference standard? You can get them USP or WHO (NIBSC)
    http://bit.ly/OhwaFR

    from that document:
    "The bulk material. This consisted of 4.5g of a batch of corticotrophin
    made by the Armour Laboratories, Chicago, and generously donated by
    the Armour Company of Great Britain, and a further 4.5g of material from
    the same manufacturing batch that were supplied through the courtesy of
    the United States Pharmacopeia. The material was made from pig
    pituitaries and purified by glacial acetic acid extraction, ethyl ether
    precipitation, oxycellulose adsorption and elution, removal of electrolytes
    by ion exchange, and freeze-drying. Its stated potency was 99.9 IU/mg by
    subcutaneous Sayers' assay and 31.8 - 34.5 IU/mg by intravenous
    Sayers' assay. "

    So, NIBSC got their samples from Armour (the original makers of Acthar) and from the USP and the USP got their batch from Armour. They then find that the potency of this material is 99.9 IU/mg. So, Acthar, by definition of the reference standard should have +/- 99.9 IU/mg as measured by the Sayer assay. The reference standard is Acthar, deamidated ACTH, secret sauce and all.

    But if the lab is correct (and that is not a given), then Acthar is almost entirely dACTH and there is only 0.21 mg/ml of that. That corresponds to only 21 IU/ml not 80 IU/ml. Unless the lab made an error or the sample was diluted, then $7500 of material is being sold for $30000.
    Mar 20 07:38 PM | Likes Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    There is a biosimilar in the works. The FDA will get hundreds of letter/petitions from doctors and patients to approve a biosimilar (when the exclusionary period expires) due to the ridiculous price of Acthar.

    http://bit.ly/Osaqaj
    Mar 18 07:53 AM | Likes Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    Please note that I took 7-8 courses in chemistry/biochem in the past but I am a neurologist, not a biochemist.
    1. I wasn't sure what to make of the gln/glu ---- is it a typo in the PI. If so, they will just fix this going forward and no problem. However, if they approved one peptide and another is in the vial, then this could indicate a manufacturing problem. I actually think typo is more likely ---dACTH has Glu and Citron found Glu. Deamidation is a simple reaction and can occur spontaneously in some buffers (according to Bhatt paper). My organic chemistry is too rusty to know whether glu to gln can be done easily (and specifically enough to not also re-amidate asp to asn)and I couldn't find a reference to see if it would have more or less activity than what was actually found.
    2. Once an equivalence between biologic activity and mg has been made to define the IU, I believe it is appropriate to use either test. The only peptide Citron found in reasonable quantity mg/ml was the dACTH. I believe to get to 80 iU/ml that there should be 1.5 to 2 mg/ml and they found 0.21. All other peptides would be trace. Although they could have activity (recall Synacthen and cortrosyn are the first 24 amino acids of ACTH and are equipotent to ACTH), it would be unlikely that trace amounts could make up enough additional IU/ml. The special sauce is unlikely to be that special. This brings me back to my main concern --- are they putting 80 iU/ml in the vial and if not they could be liable for large rebates to insurers (best case) to legal issues (worse case). Could this have something to do with the Medeiros reassignment/demotion?
    Mar 17 08:01 AM | 2 Likes Like |Link to Comment
  • Supernus Pharmaceuticals: 2013 Revenues Exceed Analyst & Company Expectations; Maintaining Positive Outlook [View article]
    I like SUPN. I don't treat much epilepsy but see a fair amount of migraine. I generally don't prescribe reformulated generics as the vast majority of the time, the increase in price to the healthcare system is not justified by the incremental benefit to the patient. Trokendi is different. Topamax is not tolerated well by many patients but Trokendi is much better tolerated. I think they could increase market share many-fold from here.
    Mar 16 09:37 PM | 2 Likes Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    ACTH is a natural product. For review, there is a gene (DNA) coding for prepro-opiomelanocortin. This gene is expressed with mRNA transcription and the mRNA is translated into PPOMC, which is converted into POMC and then is further cleaved into many bioactive peptides, of which ACTH is a prominent one. ACTH is 39 amino acids in length and porcine ACTH has the sequence in Row B. ACTH is a real medical term not one created by Questcor or me. There is one amino acid difference (serine instead of leucine at 31) between human and pig. Just as with pig, the 25th AA is Asparagine. You put the term “real Acthar” in quotes followed by “you stated” but I never used that term! Please don’t put in “quotes” something I never said. “Real Acthar” would be deamidated porcine ACTH because that is what is in their package insert and by the Citron article what is actually in the vial.

    My concerns are twofold (1) Has the formulation changed between the time many studies were done in the 1980’s and the present. If so, are the old studies valid. As the FDA knows dACTH is in the vials, they seem to be ok with this. However, as a treating physician, if the formulation has changed, I would like to know whether the old studies are valid with dACTH and (2) If Citron’s analysis is correct, then there is possibly nowhere near 400 iU/vial because the purest preparations of ACTH have an activity of 100 U/mg and only 0.21 mg/ml of the less potent dACTH was found.

    It is possible to cheaply extract ACTH from porcine pits. According to Bhatt 1990, ACTH can be easily deamidated in certain buffers. I assume QCOR has a good reason for deamidating it (either incidentally as part of their proprietary purification method or purposely if the stability in gel is enhanced). It is also possible that they realized many years after Acthar was first formulated that it was actually dACTH and not ACTH.
    You state that I was not clear that the Sigma product is not Acthar. I reread the post and don’t see where the confusion lies. They are selling ACTH, while Acthar is dACTH. I never said nor implied they were selling Acthar for $100. My statement is accurate.

    The bioassay (World Health Organization definition of the porcine ACTH iU) defines 100 iU as being equivalent to 1 mg. IMO, 0.21 mg of dACTH can’t be equal to 1 mg of ACTH, even if the two peptides were equipotent. Citron over-reached with the revelation that Acthar was dACTH and not ACTH as the FDA approved the package insert (which is indeed dACTH). It is interesting, but not fraud, that QCOR never bother to identify this fact. Whether or not Citron also erred in their analysis of the mg/ml remains to be determined. I feel there is enough evidence to be concerned and I think you feel there is not enough evidence to be concerned. We will have to agree to disagree on this one. Best of luck with your trade.
    Mar 16 09:32 PM | 3 Likes Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    physdude:
    My understanding is that, despite the label saying corticotrophin (another name for real ACTH), that Acthar is actually deamidated ACTH (dACTH)....according to both the 8-k and the package insert (which has Asp instead of Asn at position 25 --- real ACTH has Asn). Now according to the reference in the initial Citron piece, dACTH has 1/2 the activity of real ACTH. What I do not know and could not determine with definite accuracy looking at several older papers, is whether Acthar gel in the 1980's (when studies were done) was ACTH or dACTH. As a treating neurologist, if there is twice the concentration of a 1/2 potent related substance, I am somewhat ok with that because my patient is still getting 80 U/ml. However, I have to wonder why QCoR and the FDA still use the term corticotrophin. I also have to wonder whether the formulation has changed and whether current ACTH will give me the same results seen in the 1980's if the formulation has changed. dACTH is a degraded ACTH but if it is much more stable than real ACTH (and I don't know for sure whether it is or not), then I can see why it might be preferable for the gel. If the formula has changed, I think the FDA should have demanded some sort of updated study for each indication. Anything less does not assure doctors and patients of efficacy and safety. If the formula has not changed over time, then this last point is moot, but the dosage issue remains a real concern.

    Highwayman: At no time did I state that the Sigma product is the same as Acthar. It is purified ACTH (not dACTH) and is a lyophilized powder and not in a gel. It is sold for lab use, and is not approved for patient care. My point on mentioning price is that you inferred ACTH “cannot be extracted without causing a disturbance in the molecular composition of the biologic” and I was pointing out Sigma not only could do that but could do it cheaply and thus your statement was incorrect. Reread my post before saying I am asserting a falsehood. Also, I said “This sounds like you are just making things up” in my next post because indeed you did make up the whole lipid in Acthar statement and I was trying to correct your misinformation before others reading this thread actually believe it. I was trying to be polite by purposefully avoiding using the inflammatory word liar because I (correctly) assumed, based on your profile, that you just don’t know much biochemistry and that you followed the negligible Citron typo error with a far bigger medium chain triglyceride error. This magnitude in error on your part, makes me question everything you assert involving the biochemistry or assay of Acthar. Also, row B is real ACTH, the same as the Sigma lab product.
    Mar 16 05:07 PM | 1 Like Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    ummm, which amino acid is mct. I never heard of it in any of my organic chemistry or biochemistry courses. The package insert has met at position 4, Sigma has met at position 4, ACTH has met at position 4.

    met stands for methionine, an amino acid, a basic building block of polypeptides/proteins. mct is a typo on citron's part carried over by QTR. If you are not certain what amino acids are, you can check the wikipedia entry.

    You said, "Mct is one of the fats that preserves the potency and efficacy of Acthar Gel."??? do you have any reference that acthar has a protective lipid in it at position 4? This sounds like you are just making things up.
    Mar 16 03:11 PM | 1 Like Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    Highwayman:
    You stated "This is essential to the argument because what Citron and Quoth are claiming is that the drug itself is a highly purified form of the adrenocorticotropic hormone...which can not be extracted without causing a disturbance in the molecular composition of the biologic."

    This is completely untrue. Sigma-Aldrich sells ACTH (with non-disturbed molecular composition) purified from porcine pituitary for the equivalent of $100/vial. And that is after their profit. So it is not only possible to purify non-disturbed ACTH from porcine pituitary but cheap and easy

    :
    http://bit.ly/1gw4bfO
    Mar 16 11:57 AM | 1 Like Like |Link to Comment
  • Questcor Questions Pile Up Again [View article]
    Questcor can't define what an international unit is (they can define a 'Questcor unit' but not the international unit). The label on the vial and the package insert both say 80 iU/ml.

    Have you ever wondered why we say "International Units"...Its for standardization and the World Health Organization (UN) defines the standard. The WHO has standardized the international unit by bioassay:
    see the link below: 5 iU = 50 microgram, hence 100 iU = 1000 microgram = 1 mg.

    A vial of Acthar should contain 400 iU of ACTH equivalence. if they are not within 20% of that value, they have a manufacturing problem that the FDA will be concerned about.

    Citron did not find enough protein concentration to get enough units/vial. Deamidated ACTH is about half as potent (which is fine if there is enough mg/ml), not more potent than ACTH. Either the Citron lab is incompetent, someone diluted the sample or Questcor has a manufacturing issue (which could be either by negligence or by intent).

    http://bit.ly/OhwaFR for link to WHO standard
    Mar 15 03:23 PM | 2 Likes Like |Link to Comment
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