hpski

Dendreon's Provenge: Government Agencies Play Hide and Seek With Facts

Let's pretend for awhile that there's no emotional component to the Provenge issue. FDA's approval of what I believe is a 'breakthrough" advance in the treatment of mCRC, Erbitux, was based upon the drug given as monotherapy + BSC (best supportive care) to EGFR-expressing patients who had failed prior Irinotecan & Oxaliplatin based therapy, vs BSC alone. Overall survival was increased by 34%. Median overall survival in months was 6.14 in the Erbitux group vs. 4.57 months in the BSC group. Erbitux combined with Irinotecan resulted in a median time to disease progression of 4.1 months vs. 1.5 months using Erbitux alone. The objective lesson here is that a lot of hard work and science goes into developing new technologies that provide an incremental benefit. Approval gets the drug on the street, giving doctors and their patients an additional tool, and some very important "intangibles", e.g. greater "control" over their battle against the disease, and hope. Now Erbitux is being evaluated in head & neck, as well as NSCL cancer. Certainly it was easier to recruit study sites as well as patients to participate, since the drug was already approved. There are myriad other examples/precedents of oncology associated meds being approved on bare threads of data. I submit that a Federal Court would not allow the case cited above to proceed had, in addition to the COI issues, FDA's ruling on Provenge been even semi-consistent with previous (incremental) data driven decisions. There is definitely something hiding under a rock at FDA - the same FDA that allows drugs indicated for a specific condition, e.g. ERD due to neuropathy, peripheral vascular disease, to be marketed on TV as a recreational drug. The same FDA that allows Prilosec to go "OTC" when self treatment for occasional GERD with h2 antgonists like Zantac or generic Pepsid working as well, while NOT inhibiting protein absorption or causing increased gastrin dumping, which long term, increases colon cancer risk, which brings me right back Erbitux.....

Cancer Stocks Hammered Once Again

Great post! It would be quite useful if your excel file could be downloaded, then someone could sort on other attributes, or even add some, e.g. #drugs in phase 3, total #drugs in pipeline, #big pharma collaborations, PADUFA dates, if any, etc. I'm offering a few comments vis-à-vis individual companies: I think EXEL, which probably has the deepest pipeline on your list, is gaining because investors believe Glaxo will take XL647. I believe it's, "show's over", for TELK (Telcyta is finito). Onyx is declining because it faces stiff competition from Pfizer's Sutent & now Wyeth's Torisol in renal cell carcinoma. Any sales increases for Onyx's Nexavar will come from off-label use in liver cancer, but that is not, in my opinion, a reason to invest. CEGE's recent decline is a gift - when European Revlimid sales appear on their balance sheet, along with clinical milestone press releases, it'll get back into the 60's. GNTA has been on a slippery slope for some time now - their CEO, Ray Warrell, is very smart, very committed, and held in high regard by his oncology peers at his alma mater, MSKCC. He is making use of FDA's dispute process for Genasense in CLL, so some investors are betting FDA will offer up a conditional approval in subsets of patients. The key here is that CLL is a very heterogeneous disease - therapy needs to be more individualized. Finally, in my opinion, ISRG is absolutely the future of surgery. Any decline into the low 130's is a bargain. Thanks again for your article!

Dendreon CEO Refrains From FDA Bashing

This is a reprise of a my comment, re Kelly Holloway's open letter to FDA, which provides more (outrageous) detail on Gemzar's approval. Clearly this recent FDA Provenge fiasco was about the money - hopefully a few MOC will hold hearings. "...Your merging of humanity with scientific principle is appreciated, and obviously in short supply amongst a significant majority of White House political appointees – why should FDA be any different? The link below is another slice of oncology product history, as it pertains to FDA's approval of Gemcitabine (Gemzar) for pancreatic, ovarian & lung cancer. The pivotal pancreatic study was very light on patients, but strong on p values. TTDP was increased by 1.2 months, median survival by 1.5 months, but the survival range in the control group, treated with standard 5-FU extended out to 12 months, vs. 9.4 months in Gemzar patients. No objective tumor responses were observed. In ovarian cancer, when combined with Carboplatin vs. Carbo alone, there was no survival advantage, yet progression free median survival was increased by 2.8 months. The overall and complete response rates had a p value of .11. In lung cancer, although median TTDP was increased by a month, there was no survival advantage. Are you sitting down? Survival was the endpoint. The secondary endpoint was quality of life – that wasn’t met either. Bottom line, Gemzar was initially and subsequently approved on threads of data because it offered some hope, and subsequently the $$ flowing to the sponsoring company, E. Lilly, helped fund additional studies, which expanded its use. Additionally, it helped & enabled a very, very smart oncologist, who pays serious attention to pharmacokinetics and drug sequencing, to develop a novel protocol for treating pancreatic cancer, called “GTX” (G is for Gemzar).

www.fda.gov/cder/foi/l...

So, there is precedent for granting highly toxic chemo drugs with questionable efficacy marketing clearance, and as physicians become familiar with them, there’s a good chance someone will find a way to harness the drug to a particular protocol to help the victims of these dreaded diseases even more. This is a dynamic business, subject to the winds of personnel change and philosophy. But looking back might be instructive – after all, isn’t that why we have historians?

Why Did the FDA Decide to Flunk Dendreon's Provenge?

I recently posted a comment re: Echo to All's post, focusing on the regulatory history of thalidomide. Your merging of humanity with scientific principle is appreciated, and obviously in short supply amongst a significant majority of White House political appointees – why should FDA be any different? The link below is another slice of oncology product history, as it pertains to FDA's approval of Gemcitabine (Gemzar) for pancreatic, ovarian & lung cancer. The pivotal pancreatic study was very light on patients, but strong on p values. TTDP was increased by 1.2 months, median survival by 1.5 months, but the survival range in the control group, treated with standard 5-FU extended out to 12 months, vs. 9.4 months in Gemzar patients. No objective tumor responses were observed. In ovarian cancer, when combined with Carboplatin vs. Carbo alone, there was no survival advantage, yet progression free median survival was increased by 2.8 months. The overall and complete response rates had a p value of .11. In lung cancer, although median TTDP was increased by a month, there was no survival advantage. Are you sitting down? Survival was the endpoint. The secondary endpoint was quality of life – that wasn’t met either. Bottom line, Gemzar was initially and subsequently approved on threads of data because it offered some hope, and subsequently the $$ flowing to the sponsoring company, E. Lilly, helped fund additional studies, which expanded its use. Additionally, it helped & enabled a very, very smart oncologist, who pays serious attention to pharmacokinetics and drug sequencing, to develop a novel protocol for treating pancreatic cancer, called “GTX” (G is for Gemzar).

www.fda.gov/cder/foi/l...

So, there is precedent for granting highly toxic chemo drugs with questionable efficacy marketing clearance, and as physicians become familiar with them, there’s a good chance someone will find a way to harness the drug to a particular protocol to help the victims of these dreaded diseases even more. This is a dynamic business, subject to the winds of personnel change and philosophy. But looking back might be instructive – after all, isn’t that why we have historians?

Dendreon's Provenge: Is it Over?

When CELG brought Thalidomide (Thalomid) to market in July 1998, it's indication was limited to a certain type of Leprosy symptom, but was soon used off-label by the oncology community to treat certain types of multiple myeloma (MM). This, merged with proven fetal teratogenicity, resulted in, the "STEPS" program - the short version - a required patient registry. Meanwhile CELG was sponsoring registrational studies of Thalomid in MM and other neoplasms, resulting in FDA marketing clearance for MM on May 26, 2006. So here is a case of a medication which was used off-label for years by the oncology community, then in a, "fait d'accompli" move, FDA granted approval for it in combination with dexamethasone for the treatment of newly diagnosed MM patients. This mandatory STEPS registry is still in effect, includes authorized patients, prescribers pharmacies, and patient education regarding thalidomide’s safety. Now of course CELG markets Revlamid, approved for MM and 5q minus subsets of MDS. An analogue of Thalomid about 1000 times more potent but with fewer CNS side effects, CELG is required to build out a registry for this medication (RevAssist) as well. So, although Provenge & Thalomid / Revlamid are apples & oranges, they can share a fruit basket. Conditional approval of Provenge, taking a page out of the above playbook, would not have been unprecedented, and it would have made lots of sense, not only for patients, but also for investment in ongoing immunotherapy approaches to cancer. Will there be a grass roots backlash to FDA’s bewildering decision? Will the political hacks in Washington rattle FDA’s cage? I have no idea. One thing for sure – the hypothetical politically connected short sellers have made their money – maybe now after “careful reanalysis”, FDA will work out a compromise, perhaps some kind of, “compassionate use” registry, with drug cost sharing. Who knows? Am I delusional? If I knew I wasn’t, would I be deluding myself?

I am long DNDN, CEGE, CELG, ISRG, OMRI

Dendreon's Provenge: Looking Past The Noise

H.S. makes an excellent point vis-a-vis "non-medical", AKA, "it's about the money", theoretical short seller pressure on FDA. FDA's decision is what it is, and I am not a conspiracy theorist by any means. However, when viewed within the context of the current WH residents; their criminal arrogance and contempt for anything interfering with wealth accumulation for themselves and a few cronies, the blatant, intelligence insulting lies and verbal shell games, makes me takes H.S.'s suggestion seriously. Had I connected these, "gray area', albeit theoretical dots, I would have sold my entire position into the post AC meeting run-up. Never underestimate this crew's sociopathy - whenever we do, "boom!", there's another malignancy rearing its ugly head, and, as will all neoplasms, it's only the tip of the iceberg. If a nouveau rich short seller needs to reply by calling me a, "whiner", go for it - I figure in the 80's you were long IBM and short Wang......

ODAC Member Raises Concerns About Dendreon's Provenge

I have previously posted a comment to PharmaTracker's presentation of Dr. Scher's letter, which, I believe dovetails with Dorotie97's collaborative discussion. I would like to build upon Dorotie97's fourth paragraph, "To begin with, one must ask why an expert invited by the FDA as a “special Federal employee” with expert knowledge in the given field....chooses to question the outcome of the Committee’s recommendation, including his own vote on Safety, after the fact. Absent new material information, Committee members, if no one else, should respect the fairness of the process and the final vote of the Committee", with an historical perspective, the words of a forward looking 14th century surgeon, John of Arderne:

Born circa 1308, John of Arderne practiced as a surgeon in Nottinghamshire and London. He is said to have developed his skills as a military surgeon during the 100 Years War. The evidence suggests that he traveled abroad, and his writings indicate that he was man of wide experiences. He wrote in Latin, and had read many of the scholastic authors closely, quoting extensively Galen, Guy of Chauliac, Avicenna, and Dioscorides. Having lived & practiced medicine through the great plague epidemic of 1347-51, his fame rests on a number of medical works that he produced towards the end of his life in the 1370s. His great advance at the time was to avoid the corrosive after-care treatment used by other practitioners; a great believer in cleanliness, Arderne counseled against overly meddling with wounds and dressings, thereby aiding the healing process. His thorough knowledge of the medical uses of herbs and plants is well documented, and he was fully aware of the effects of the mind on the body in sickness and health. Excerpted below from one of his many surviving manuscripts is his discussion of standards of deportment that all physicians should follow, as it CURRENTLY applies to the public display of antipathy by a high profile COI physician towards Provenge marketing approval:

“...And he be courteous at the Lord’s table, and he be not displeasing in words or deeds to the guests sitting nearby, hear he many things but let him speak but few…And when he shall speak let the words be short, and as far as possible, fair and reasonable…Beware that there never be found double words in his mouth, for if he be found true in his words few or none shall doubt his deeds”.

Arderne was way ahead of his time, maybe even ours, as evidenced by a tiny minority of contemporary physician(s) who make the mistake of thinking their titles and standings make them beyond reproach and outside Government agency S.O.P. More to the point, even during the middle ages, Arderne and a few other exquisitely learned, multilingual physicians, writing in Latin, were attempting to describe standards of professional behavior amongst their peers. Perhaps if Dr. Scher had reviewed and/or revered Arderne’s treatise for his professional progeny, he might have thought twice about having his dissent published in a non-peer reviewed throwaway publication.

Why Dendreon's Provenge Must Be Approved

Target price with approvable letter = $10. Marketing clearance = $40. Expect price swings reflecting market conditions and short seller noise in between clearance this month and product availability, most likely after Labor Day. Chris makes some compelling, insightful arguments. D WB likes to scrape his finger nails on a blackboard.

Dendreon: Provenge's Shortcomings Have the Shorts Coming

Mr. Kapur, you're right about one thing, you are NOT an expert in biotechnology, or even close to being well informed pharmacologically. I have addressed Dr. Scher's antipathy towards Dendreon in a previous post - read between the lines and draw your own conclusions - you seem like a fairly smart young guy. Your discussion of insider trading is old news, and for us older folks who've worked within this industry, the CEO exercising & flipping his options is not surprising - I'm sure he'll be getting a bunch more options when FDA approves their drug, they'll be strike priced at a premium, and there may be option by-laws that we're too busy to research that required him to limit the # of options outstanding. Bottom line in biotech, most employees sell some of their options into good news to hedge their bets. In terms of, "less than perfect" research data, there is, NO SUCH THING AS PERFECT RESEARCH DATA, which is why the statisticians make the big bucks, and P values exist, and why they are not 100% correct 100% of the time. Biology & medicinal chemistry are not exacting sciences, for example, Rituximab, an anti CD20 mab, is approved for low grade NHL - the drug reps would like the docs to believe this Mab makes a "b-line" for cancerous b-lymphocytes presenting CD20, but healthy cells exhibit CD20, and they get whacked as well. What's more, Rituximab often illicits an allergic response, e.g fever & chills, anaphylaxis has been reported. Is it a great drug? Yes. Does it work all by itself? No, major league no. How did Idec come up with the dosage? Answer, it was determined as much by their ability to produce a finite supply of drug during the pivotal study as pharmacokinetics. CBER knows all this, now you do as well. Finally, when you look at the big picture, politics enters the playing field - I think the political climate in Wash. D.C., merged with prostate cancer being the, "step child" vis-a-vis breast cancer, makes Provenge ripe for approval. Adding this all up, my conclusion is FDA approval will happen May 15. Sure, there is a chance CBER will cave to a few dissenters, they may think the AC was caught up in "irrational exuberance". If that happens, I will not retract what I wrote here. This is a high risk business, these boards, as well as the calls & puts reflect it. I am long Dendreon, Celgene, OMRI, EXEL.

ODAC Member Raises Concerns About Dendreon's Provenge

Thank you, PharmaTracker, for posting this letter. There are a few aspects of its content I would like to address. Specific sections of Dr. Scher’s correspondence are pasted below, followed by my comments. I have not taken the time to access the actual publication for verification of the doctor’s remarks, trusting the poster to have presented it in its entirety. My comments are not intended to personalize these issues and certainly not intended to challenge Dr. Scher’s exquisite record of accomplishment and valued contributions to this process.


“I have been one of the Academic Leaders of the Prostate Cancer Clinical Trial Endpoints initiative begun under the joint Sponsorship of the FDA, AACR, ASCO and PCF in 2004, which were presented at the February 2007, Prostate ASCO Meeting in Orlando”. Tell FDA something they don’t know. Why does Dr. Scher go out of his way to build himself up to an agency that is well acquainted with his academic status?


“This, and the Sponsor’s recognition that an additional prospective study was needed, mandates deferring any decision on whether an approval should be granted until the results of the ongoing 500 patient phase 3 trial that is powered on a primary endpoint of survival, is accrued and analyzed”. Mandates? Should FDA, in consideration of his minority opinion, merged with his status as chief of genitourinary at MSKCC, make Dr. Scher their defacto reviewer of all immunotherapy BLA’s for prostate cancer?


“Concerns about the validity of the findings were reinforced by the absence of other signals of an antitumor effect. Specifically there were no data provided of a favorable effect on PSA, regression or stabilization of soft-tissue or boney disease radiographically, health related quality of life, or that administration of the product delayed the development of pain”. Dr. Scher recently reported, in December 2006, on, “ Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials”. The abstract he co-authored, below, suggests that PSA is not a reliable representation of treatment success or failure;

Fleming MT, Morris MJ, Heller G, Scher HI.
Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancer, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used, as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.


Boney disease? How realistic is it to expect any treatment approach, other than palliation, usually in the form of biophosphomates, to arrest bone infiltrates? For example, oncologists are certainly aware that, “in patients with hormone-refractory prostate cancer and bone metastases, zoledronic acid is the only bisphosphonate indicated for the prevention of skeletal complications. In conclusion, patients with prostate cancer are at high risk for skeletal morbidity”. (Clin Genitourin Cancer. 2006 Mar;4(4):257-62). When metastatic prostate cells are already present in the bone microenvironment, researchers have shown that transactivation of the alpha-platelet-derived growth factor receptor may provide select prostate phenotypes with a growth advantage. I submit that being disappointed in Sipuleucel T’s impact on radiographically proven boney disease is akin to being disappointed that the Sorceror’s Apprentice couldn’t keep up with his rapidly flooding basement.

Again, I’m sure Dr. Scher will agree that, “quality of life” in this studied population is another, “Sorcerer’s Apprentice” issue, since medical castration and/or radiotherapy reeks havoc with libido, bowel function, etc. So, IMO, a patient’s already dismal quality of life is iatrogenic (graviora quaedam sunt remedia periculis ). Thus at this stage, it is not realistic to expect a specific immune system boost to provide an objective improvement in this parameter, in my opinion.


“Consequently, the only conclusion that can be reached is that the survival difference observed may have occurred by chance alone, and that the results do not support an approval recommendation”. While Dr. Scher’s interpretation of the data, which by definition is solicited, respected and a welcomed part of the approval process, venturing it as the final word, a reverse, “fait d’accompli”, if you will, most likely is not welcomed by FDA in such a high profile format. Hopefully most of us in this industry are aware of the dangers of, “circulus in probando”. Certainly no one is “immune” to this time honored disease, which appears to be transfecting many researchers and investors these days.

Finally, it’s been my experience that the drug development process is more than about the science, more than about saving & improving lives – it’s often about alliances of interest, and by necessity, politics, internecine rivalries, about competition for research grants, unrestricted educational grants. There’s that magical time of year when all department chairmen/women are in, “grant Hell”, initiating and assessing requests, working with budgets, egos, etc. I have seen firsthand what happens when a relationship between an individual/group within medical academia falls out of bed with a biopharmaceutical company, or never gets off the ground in the first place. Everyone reacts differently, but some take a more proactive stance. I submit that there are life saving oncology products not on the market, as well as glorified placebos currently marketed; the, “no love lost”, offspring of the above intangibles.

I am long DNDN, CELG, and OMRI

Dendreon's Provenge: A New Hope For Both Patients and Shareholders

Yes yes, this therapy works, and the short sellers, aside from the arcane mechanics of hedging bets & day trading, generally do not understand this "big picture" in terms of the overdue revamping & specialization of FDA advisory committees. For example, if the ODAC roster reviewing Genasense had been comprised of physicians who have devoted their professional lives to hematological malignancies, or even chaired by one, I’m certain the outcome would have been quite different. The other possible short sell driver is a misunderstanding of the side effect issue, or no-issue, as the case may be, principally the CVA issue, which I covered in an earlier post. Finally, on the political front, I would expect, irrespective of androgen status, Tony Snow to be receiving Provenge - I have NO inside info. on this, but I do know that assorted senators & congressman can obtain meds, protocols, treatment priority, that is not yet available to the general population.

I am long Dendren.

Dendreon's Provenge: 'Substantial Evidence of Efficacy'

Again, Echo, we are on the same page. IMO, the business development people at "big pharmas" are now busy dreaming up excuses why they did not make partnership overtures, and at the same time scrambling to make a play. At this point in time, although I don't know anyone at DNDN, IMO, any cross license, co-promotion aggreement, if it is not already being squared away, is not likely till after May 15, then the cost to the assorted Pfizers, Mercks etc. will be considerably higher. Check DNDN's web site - they are already posting for sales positions, so agreements with big pharma most likely will emphasize international, with the prospect of co-promotion in the US, ala BMS & Imclone.

Update on Dendreon's Briefing Docs: Provenge Missed All Endpoints

Well, when non-clinicians comment on complex biological issues on financial sites, it's almost always about the money influencing their analysis. Echo toall is on the right track, however, since all solid organ neoplasms result in an increased state of coagulation, which oncologists, often via a hematology consult, carefully try to manage. Activation of coagulation and predisposition to thrombosis, associated with most cancers, is more common in prostatic carcinoma. As early as 1967, a large study of patients with advanced prostatic carcinoma showed that the incidence of thromboembolic disease was 2 to 3% in early-stage disease and 8 to 9% in more advanced forms. This hypercoagulability, or “disseminated intravascular coagulation” (DIC) results from several factors. Firstly, there are specific tumor properties including direct or indirect induction of thrombin generation either by cytokines or by tumor cell procoagulants (tissue factor (TF) and cancer procoagulant (CP)). Secondly, there are nonspecific factors, such as inflammatory state, tissue damage from tumor burden or necrosis leading to the activation of systemic coagulation. Chemotherapy, as well as hormone treatment is also associated with DIC, so there is a complex multifactorial hypercoagulation process that may or may not result in a CVA. No biological marker is truly sufficient for predicting thromboembolic accidents and identifying patients who may benefit from (low-molecular-weight heparin) prophylaxis. Conclusion? FDA knows that in cancer, CVA’s, “come with the territory”, it is a risk in cancer patients with or without chemo or any other anti-neoplastic therapy. Only an unqualified, albeit financially manipulative, “player”, would publish such a knee jerk over-reaction to a drug’s toxicity profile on the cusp of an FDA decision.