Pharma’s Cutting Edge

Results from ENHANCE are now available.  I don’t think anyone is terribly surprised, given the delay in reporting the results, that addition of ezitimibe to simvasatin (i.e. Vytorin) did not have a sigificant impact on carotid intimal media thickness compared with simvastatin (Zocor) alone in subjects with heterozygous familial hypercholesterolemia (a disorder of LDL receptors that affects about 1 in 500 people globally). 

See my prior post on the implications of ENHANCE for most current Zetia users.  As I indicated previously, these results will likely have very little impact on prescribing of Vytorin or Zetia, despite pronouncements to the contrary yesterday, primarily from Steve Nissen of the Cleveland Clinic.  Dr. Nissen apparently gave lots of interviews yesterday, saying things like:

This wraps it up…That’s all there is. There just isn’t any evidence that adding ezetimibe to simvastatin produces any advantage.

to the Washington Post.

Of course that isn’t all there is.  One trial with an iffy surrogate endpoint in a highly selected population does not a definitive treatment recommendation make (said Master Yoda).

Since my last post, I was happy to learn about another trial of Vytorin underway, one with a hard outcome.  The IMPROVE-IT trial, sponsored by Merck and Schering-Plough, is a randomized, active-control, double-blind study of subjects with stabilized high-risk acute coronary syndrome. The primary objective in IMPROVE-IT is to evaluate the clinical benefit of Vytorin 10/40mg compared with Simvastatin 40 mg alone, where clinical benefit is the reduction in the risk of the occurrence of a composite endpoint of CV death, major coronary events, and stroke.  Nice.  Now enroll this sucker.

I’m not stopping my Zetia because of ENHANCE, and I’m confident that most other users of Zetia and Vytorin will not either.  Once the ENHANCE dust settles, it’ll be clear that ezitimibe remains our first best hope for atherosclerosis therapy beyond statins, at least until a definitive study demonstrates otherwise.

Disclosures:  I have no financial ties to Merck or Schering-Plough.

Genitope’s Webcast

A week ago Genitope reported the results of a pivotal Phase 3 trial for its only clinical candidate, the idiotype-specific, personalized active immunotherapy for Non-Hodgkin’s Lymphoma, known as MyVax.  I’ve been interested in this budding therapy since around the time the company went public in early 2004, which roughly coincided with the start of the Phase 3 study.  That was back when I was testing my proclivity for biotech equity analysis, so I began following the company.  

I remember being impressed with the long clinical experience with this form of personalized therapy, which dates back some two decades and which was nurtured by no less than Dr. Ronald Levy of Stanford (who you might know as one of the founders of IDEC Pharmaceuticals and a pioneer of immunotherapy for cancer, lymphoma in particular; see this profile).  Based largely on the Phase 2 experience of Dr. Levy and others, which included a convincing number of long-term remissions with MyVax and MyVax-similar idiotype immunotherapy, I recommended investors buy Genitope stock.  I think the stock was just under $10/share then.

My feelings about the stock and the likelihood of a successful Phase 3 study changed dramatically after a second planned interim analysis of efficacy of the MyVax Phase 3 study failed to demonstrate superiority of the therapeutic vaccine over control measured as progression-free survival, but I’m getting ahead of myself.

Backing up to the beginning of the Phase 3 study, its purpose was to test the ability of MyVax to prolong PFS in patients with newly diagnosed NHL who had received one course of chemotherapy  After a 6-month rest, patients with at least a partial response to the course of chemo were randomly assigned to therapy with either MyVax immunizations (recombinant, cancer-specific idiotype protein conjugated to KLH) + GM-CSF or KLH + GM-CSF.  Multiple immunizations were given and PFS, along with a number of biomarkers, was determined.

As mentioned, a second planned interim analysis for efficacy was perfomed in July 2006.  Based on my own accrual and hazard rate assumptions, I had expected that sufficient evidence of efficacy would be seen to allow stopping the trial at that point.  However, the trial was continued.  I suspected then that the study would miss its primary endpoint.  Full planned follow-up was completed earlier this month and, as you’ll see from the market reaction, the study missed its primary endpoint.

What interests me about this story is less the ostensibly failed study and more the way Genitope spun the news into a positive story about MyVax.  “Simply put,” said CEO Dan Denney Jr., “MyVax works.”  Dr. Denney went on to explain that the primary endpoint was missed because the KLH arm did better than expected, with some patients mounting an immune response that caused prolonged PFS.  However, a secondary endpoint that was “highly statistically significant” showed that MyVax prolonged PFS in a subgroup of the subjects who mounted a “positive immune response” to the therapy when compared with those who did not mount such a response to MyVax. Read the rest of this entry »

Common virus may contribute to obesity in some people

Last September, I noted that the epidemiology of modern obesity (in the last couple decades) strongly suggests transmissible or pervasive environmental factors–more persavive even than junk food and sedentary behavior–at work in its etiology.  Now, Magdalena Pasarica, M.D., Ph.D., of the Pennington Biomedical Research Center and her colleagues are reporting at the American Chemical Society meeting that adenovirus-36 (Ad-36), a common form of this common human-infecting virus, is capable of differentiating adult human stem cells into fat:

In the current study, Pasarica and her associates obtained adult stem cells from fatty tissue from a broad cross-section of patients who had undergone liposuction. Half of the stem cells were exposed to Ad-36 and the other half were not exposed to the virus.  After about a week of growth in tissue culture, most of the virus-infected adult stem cells developed into fat cells, whereas the non-infected stem cells did not, the researchers say.  Funded by the National Institutes of Health (NIH), Dr. Dhurandhar’s group recently identified a gene in the Ad-36 virus that appears to be involved in causing fat accumulation observed in infected animals. That gene, called E4Orfl, is now emerging as a promising target for future human therapies, such as vaccines and anti-viral medicines, aimed at preventing or inhibiting the obesity virus, she says.

About 30% of obese people are infected with Ad-36, compared with 11% of nonobese people.  While this evidence doesn’t prove an etiologic link between Ad-36 and obesity–that ultimately requires evidence that eradication of the virus or its effectors ameliorates obesity–it is a necessary step up the proof ladder.  Personally, I’m thinking that environmental factors that alter the gut microbiome (antibiotics? environmental pollutants?), increasing the efficiency of intestinal energy absorption, are more likely culprits than adenovirus, but then again, multiple etiologic agents are likely contributing.

On June 29th, I discussed a story originally published in ClinPage that Pfizer was signing investigators to exclusive contracts.  The story was picked up by several blogs, and had the potential to become mainstream news (but didn’t).  After that post, I received a confidential note from a Pfizer employee indicating that the story was flawed; that, in fact, Pfizer was NOT asking clinical investigators to sign exclusive contracts.  I didn’t report on this email, as its sender asked me not to for some reason.  ClinPage has now “clarified” its coverage of the presentation made by Andy Lee of Pfizer at DIA (see Pfizer Site Strategy).  As they are now reporting, Pfizer did not attempt to get investigators to sign exclusive sponsor contracts but rather asked investigators who were not recruiting for a particular study to serve the study or the project otherwise (as an advisor, for instance).

A couple thoughts, first I’m glad for the industry that Pfizer is not using a risky sponsor-exclusivity arrangement to improve recruitment.  This aggressive strategy would have made them and, by way of association, the entire industry look mean and greedy–you know, like they look now, only more so.  Still…now that the idea has been floated, publicly without making headlines I wouldn’t be surprised to see another sponsor actually try it, particularly in a niche therapeutic area crowded with several sponsors.

The other thought is that we who blog, including this part of we, need to be careful how we write our stories that rely on second-hand reporting.  I wasn’t at the DIA to hear Andy Lee’s talk.  I relied on what someone else heard, and I didn’t properly caution readers to be skeptical of the controversial story’s accuracy.  My analysis of the recruitment strategy would have been the same, but the impetus for my analysis wasn’t accurate, and it’s doubtful that I would have ever written the analysis had the story not appeared.  In the future, I’ll wait for independent confirmation before propagating any first-person information coming from ClinPage.  I’ll likewise raise doubts about the accuracy of any story, from any source, whose subject matter is controversial and not independently confirmed.  I don’t hold myself out as a source of news, but I do want my readers to trust that my analyses are based on accurate descriptions of the state of affairs about which I’m opining.

It was bound to happen sooner rather than later, and Pfizer or GSK was likely to be the first to do it: create exclusive contracts with investigators I mean.  That would be your best enrolling sites.  Scared?  You should be. 

As reported by ClinPage from the annual DIA meeting last week, Pfizer’s Andy Lee let on that Pfizer has been signing exclusive deals with Pfizer’s best enrolling sites.  Either the sites will contract for studies only with Pfizer or they will not contract with Pfizer for any studies.  It takes chutzpah to make a move like that, but more than chutzpah it takes research volume, lots and lots of money devoted to clinical research.  Without the money to keep a site at capacity, or on the sidelines getting paid to be at less then full capacity, no company can hope to craft such deals.  Only the very largest research companies can afford this, and even the largest CROs will not be able to wrest a site from big pharma’s grip for the benefit of its more modestly sized clients.  Talk about a game changing situation.

As I say, it wasn’t hard to predict this move, I’m only surprised that it’s been going on for a while, and I hadn’t heard about it.  These things tend not to stay secret.  Why am I not surprised?  Because pharma development productivity, particularly in the later stages of clinical development, must improve to compensate for environmental pressures on sales and volume growth.  It must, or the industry’s entire business model is in jeopardy, and I don’t see the industry allowing its model to collapse without a good fight.

Despite some propaganda to the contrary, the workflow inefficiencies constraining overall development productivity are not widely appreciated, and no company has demonstrated that it knows how to improve productivity, however it is (reasonably) defined.  That said, it is likely that local operational inefficiencies, such as those confounding clinical study enrollment, are disrupting local process flows sufficiently to negatively affect cumulative study completion rate.  In other words, know one knows for sure, but it’s likely that decreasing the average time from protocol approval to final subject enrolled will ultimately decrease total development cycle time without diminishing the quality of development (i.e. the learning that accrues from doing studies), thus improving R&D productivity.  It’s also pretty clear that if you can find a way to contract with better performing (in terms of enrollment) sites more frequently, you are more likely to decrease this cycle time.  As Pfizer’s Lee noted in his DIA appearance, and is generally appreciated now, some investigative sites consistently enroll better than others, and it’s believed that they do so without diminishing the quality of research.  If you can lock these high-performing sites up, with exclusive contracts say, you’re more likely to increase enrollment speed than if you must compete for sites and risk losing high-performer to your competitors.

As far as I know, Pfizer is the first to try this all-or-none strategy.  I think other firms will wait to see how it shakes out before following their lead.  Although, as I say, exclusivity is the surest way of locking up the best performing sites, it’s also probably the riskiest.  A company the size of Pfizer doesn’t have to worry about not doing enough studies to keep a site busy–thereby wasting the premium it must pay to maintain exclusivity–but it does have to worry about frightening or angering the doctors that prescribe its drugs.  It’s easy to imagine that an investigator or research institution might wish not to engage in an exclusive relationship with a single sponsor:  Will it create a perception among patients, insurers, regulators, or professional associations that she is in the sponsor’s back pocket?  Maybe such thinking is reasonable, especially for academic sites.  Harmful perceptions aside, I would imagine that many high-performing sites will find such strong-arm negotiating tactics ridiculous.  After all, from the investigator’s perspective, it’s not as though research studies are hard to find.  It’s a supplier’s (investigator’s) market in developed countries by all accounts.  Why not hold out from such a deal, and let competition decide who gets the best sites?  If supply remains regionally and situationally constrained, as it is presumed to be, investigator grant payments will continue to increase.  Exclusive deals, unless very lucrative, will not benefit sites in these regions.  And perhaps no amount of money will satisfy some site’s need to work on the most promising medicines, regardless of who is developing them. 

This enrollment strategy absolutely is worth keeping an eye on.  If any investigators have signed such a deal with Pfizer or another firm, I’d love to hear from you.