Then again...Seeking Alpha:"Dendreon's Provenge: Some On The...

Then again...

Seeking Alpha:

"Dendreon's Provenge: Some On The Street Doth Protest Too Much


Forgive me if I begin with a (mis)quote:

“The [Street] doth protest too much methinks”

(Queen, in Hamlet (Quarto 2) 3.2; with apologies to William Shakespeare)

I am, of course, alluding to the constant barrage of negative articles, in print and on the internet, attacking both Dendreon (DNDN) and its lead immunotherapeutic treatment Provenge. Former White House speech writer William Safire would have labeled the authors of these articles the ‘nattering nabobs of negativism.’

Hardly a day goes by without someone attacking Dendreon’s management for pulling its revenue guidance early in August, or Provenge for any variety of reasons, most of them specious or overcome by events.

The most recent example was an article published on the internet that cited various sources who took issue with Provenge because:

the “time and inconvenience of extracting white blood cell” (I posit that six sittings in a one-month period is not onerous when you compare that to the daily regime of taking other medications, which I will get to below)
“reimbursement issues” (mostly resolved, as far as I am aware, now that CMS has issued the Q-code (.pdf) in July, 2011, providing all Medicare payers with uniform guidance, and Dendreon has provide community and academic providers with a comprehensive Reimbursement and Billing Guide (.pdf). Note: That there still may be lingering problems involving certain community providers is not disputed. Based on my own experience with doctors in private practice (don’t ask!), problems can be expected, given the unique billing services each employs as well as the varied experiences and capabilities of these services. Providers who use internal staff members to augment their back office staff may encounter a greater number of problems with reimbursement at all levels, owing to the complexities of the private and Medicare/Medicaid (federal and state) reimbursement systems.)
“The vaccine has to be made for each individual patient.” (Well, yes…Provenge is uniquely personal.)
The article published on the Internet also failed to note there is evidence that Provenge has an effect on time to disease-related pain. In an abstract presented at the ASCO annual meeting this year, the pooled results of the randomized asymptomatic sub-group from the three Phase III trials in mCRPC showed a trend to delay in disease-related pain (HR .80, adjusted for baseline predictive factors). Furthermore at 12 months, 39% percent of Provenge arm versus 19% of control arm were pain free. Although not ‘stat sig,’ possibly because of the small sample size, it is an indication that Provenge could have an impact on other important clinical outcomes besides survival.

Notwithstanding the fact that, in my opinion, the Internet article cited above was a paean to Johnson & Johnson’s (JNJ) Zytiga, it strikes me odd that week after week, month after month, “the Street doth protest too much mee thinks.”

What’s going on here?

Before I answer that question, let’s examine some facts. Zytiga (abiraterone acetate), according to JNJ, the manufacturer, in combination with prednisone, is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. More specifically, although Zytiga has shown about a four-month median survival advantage in mCRPC, it is in a patient population that has FAILED docetaxel (Taxotere®; this is from the ‘COU-AA-301’ trial). Its survival benefit has not yet been proven (the ‘COU-AA-302’ trial is currently underway) in the asymptomatic/minimally symptomatic mCRPC setting for which Provenge is indicated. Indeed, in this specific space, the National Comprehensive Cancer Network, or NCCN, has given Provenge a category 1 rating, the highest evidence level recommendation based upon its three Phase III clinical trials.

By contrast, and in Provenge’s ‘space’— asymptomatic/minimally symptomatic mCRPC setting— Zytiga has a category 2B rating, the second lowest rating, based upon small single arm Phase II trials. ("Abiraterone acetate can also be considered for men with metastatic CRPC who are not candidates for chemotherapy. Use of abiraterone acetate in patients who have not received prior docetaxel is based on single arm Phase II clinical trial data. A Phase III placebo-controlled trial in the pre-docetaxel setting has been completed; results are not yet available. Until those results are available, docetaxel remains the standard of care for CRPC for patients refractory to secondary hormone therapy who are candidates for chemotherapy."(NCCN; log-in required)

This isn’t to imply that the results of Zytiga’s pivotal Phase III, randomized, placebo-controlled, multicenter study in the post-docetaxel setting were not a major advance in the care of PCa sufferers. Indeed, at the pre-specified interim analysis, treatment with Zytiga in combination with prednisone resulted in a 35 percent reduction in the risk of death (14.8 months vs. 10.9 months [hazard ratio (HR) = 0.646; 95 percent CI: 0.543, 0.768; p<0.0001]) and a 3.9 month difference in median survival compared to placebo plus prednisone. In an updated analysis, results were consistent with those from the interim analysis with a 4.6 month difference between the two arms in median survival (15.8 months vs. 11.2 months [HR = 0.74]).

Admirable. And indeed, JNJ, has much to crow about.

So, let’s talk cost. Zytiga costs $5,000 a month, and is usually given for eight cycles. Some argue that these two factors alone make it a preferred treatment.

But wait a minute. What about prior authorization? Here’s what Medicare (.pdf) has to say (among other things):

Prior Authorization Group: ZYTIGA

Drug(s): ZYTIGA (abiraterone acetate tablets)

Covered Uses:

All FDA-approved indications not otherwise excluded from Part D.

Required Medical Information:

Symptoms and biopsy confirming diagnosis of metastatic castration-resistant prostate cancer
Documented progression on docetaxel treatment.
Prescriber Restrictions: Oncologist.

Other Criteria:

Use in combination with prednisone.

Failure of docetaxel treatment or significant adverse effect.

Exclusion Criteria: Zytiga will not be covered in the following situations:

Frequency/dose greater than FDA approved labeling
Development of severe hepatotoxicity.
Uncontrolled hypertension.
Uncorrected hypokalemia.
ALT greater than 5 X ULN during treatment of Zytiga
AST greater than 5 X ULN during treatment of Zytiga
Total bilirubin greater than 3 X ULN
Prior ketoconazole treatment for prostate cancer AND history of adrenal gland or pituitary disorders.

And what about side effects? Comparing side effects on the ‘ability to go out and do what patients normally would do’, the Zytiga prescribing information (.pdf) lists as the most common adverse reaction as ‘ joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection.’ This doesn’t even mention, of course, potential liver toxicity, which requires continual liver function testing. By contrast, the most common side effects of Provenge (.pdf) are ‘chills, fatigue, fever, back pain, nausea, joint ache, and headache.’ basically flu-like symptoms that typically resolve themselves within a few days.

Finally, many overstate the convenience of Zytiga relative to Provenge. Zytiga dosing is not just ‘taking a pill.’ It is taking three pills every day (Zytiga once, and prednisone, a powerful steroid, twice) for eight months based on MEDIAN duration of treatment in the ‘301’ trial. As far as ‘ability to eat and drink,’ Zytiga must be taken on an empty stomach, with no food for at least two hours prior to and for at least one hour after taking Zytiga—every day for eight months. By contrast, Provenge requires a 3-4 hour leukapheresis to harvest white blood cells and upon being processed into Provenge, about an hour to re-infuse. This occurs three times over the course of a month and then, the entire course of treatment is completed.

Zytiga and Provenge each have their place in the PCa treatment spectrum. Instead of trying to promote one drug while minimizing another using canards, fabrications, and rumors, the message should be that men with late stage prostate cancer have a number of treatment options available that did not exist as little as two years ago, with more drugs on the horizon.

Another important message should be that the use of different drugs is not an either-or proposition. In many cases, and specifically in the case of Zytiga and Provenge, the use of one does NOT preclude the use of the other. This is related to the fact that the mechanisms of action, or MOAs, are different. Thus, in the case with Zytiga and Provenge, optimal sequencing may extend survival even further.

Here’s what the Journal of Clinical Oncology recently said about that subject:

[T]he practical dilemma of the appropriate sequence of use of the two new noncytotoxic agents (sipuleucel-T [Provenge] and abiraterone) is being addressed by trials that are under development. For now, given the broader window of applicability of abiraterone and the longer time required to develop an immune response with sipuleucel-T, if both agents are to be used, it seems reasonable to administer sipuleucel-T first with Abiraterone after additional disease progression. Biomarkers to help define the optimal use of immunotherapy are needed.

So, what’s my ‘take’ regarding all the ‘noise’ in the press and on the Internet that appears intended to smear Dendreon and Provenge? Simply this. The incessant, almost shrill attacks against the company and its lead treatment speak, I think, not only to competitive pressures within the pharmaceutical industry, but also, to efforts that are intended to thwart the introduction of twenty first century treatments based on harnessing the body’s own immune system. To this end, Dendreon’s competitors and ‘antagonists’ alike have enlisted a cadre of analysts, ‘journalists,’ and so-called ‘experts’ willing and, unfortunately, able to spread fear, uncertainty, and doubt among both patients and investors regarding the company’s immunotherapeutic treatment for end stage prostate cancer. Fortunately, it is doctors who will be looking out for the best interests of their patients, and not journalists or analysts that will recommend and prescribe Provenge.

The availability of Provenge heralds the delivery of a new age of immunological weapons in our armamentarium of treatments against cancer. It is the fulfillment of an age old promise. After all, wasn’t a Nobel Prize for Medicine just awarded to Ralph Steinman, who discovered so-called dendritic cells in 1973. These cells regulate the activity of other cells. Steinman called them the conductor of the immune system. As many authors noted (here and here, for example), one example of this type of technology is the drug for incurable prostate cancer called sipuleucel-T (brand name is Provenge).

Investors, of course, risk only their money when they invest in the companies that populate the biotech universe. Sufferers of prostate cancer and other serious illnesses who have run out of options, and who fail to see through the smoke screen of disinformation as they search for data on potential treatments, risk paying with the quality of their lives, if not their lives themselves, should they are unable to gather, often from the popular literature, unbiased information that can inform their medical decisions.

As for the Dendreon’s goal of signing 700 infusion sites* by the end of calendar year 2011, the current site count, determined using Dendreon's Provenge site stood at 680 as of September 30, 2011. States with the highest number of infusion sites at that time were California (60 sites), Illinois (57), Florida (41), Texas (40), and North Carolina (34).

From a technical standpoint (insert the ‘Symbol’ DNDN where indicated on the Web page), DNDN currently is hovering just below $9. Bearish sentiment reigns across the markets worldwide following credit rating cuts of Spain and Italy. The stock is still coming off its oversold conditions, and the Daily MACD line is climbing. On a Weekly basis, the stock is oversold, and the Weekly MACD line is showing signs of bottoming.

*As this article was just about to go the publisher, I learned that the number of infusion sites has climbed to 700, a 16% increase from the number authorized to deliver the treatment at the beginning of August, 2011.

Disclosure: I am long DNDN and will not change my position with 72 hours of the time this article is published."