Pharma’s Cutting Edge

This is a f/u to the piece I wrote in January describing the preliminary (but widely publicized) results from the ENHANCE study of simvastatin and ezetimibe (Zetia) (combination tablet sold as Vytorin by Schering-Plough and Merck) in patients with familial hypercholesterolemia.  The study looked at the effects of the combination versus simvastatin alone on carotid intima-media thickness.  My previous opinions of the study’s meaning aren’t changed with publication of the final results in the NEJM to coincide with the ACC meeting.  In case you were asleep for the past couple of months, ENHANCE was negative for signs of IMT improvement with the combo. 

Expert opinion of the findings has been decidedly negative and prescriptions for ezetimibe (a $5 billion a year drug, counting both Zetia and Vytorin) have tumbled.  Schering-Plough reported that scripts were 3.2 million in January and 2.8 million in February for both drugs combined (a 12.5% drop), while others have reported that Vytorin scripts have fallen 18%.  Several sell-side analysts believe the latest pronouncements from experts at the ACC will further erode sales of Zetia and Vytorin and have cut their sales forecasts and share-price targets for Merck and Schering-Plough.  Given the overreaction to the results thus far, it’s hard to find fault with their reasoning.

I await results from ongoing studies (particularly IMPROVE-IT) with hard CV outcomes as the primary endpoint in a less highly selected population before changing my own use of Zetia.   If ezetimibe doesn’t work to reduce hard CV outcomes despite robust LDL-C reductions, the findings will be strong evidence supporting pleiotropic benefits of statins and arguing against routine use of ezetimibe.  If ezetimibe does work, the utility of CIMT progression in hypercholesterolemia will be dubious. 

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 »

PharmaGossip: More on ENHANCE - the case of the shifting endpoint

The controversy has arisen from Merck/Schering-Plough’s failure to date to publish or present in full data from a trial that started in 2002 and was completed in April 2006. While the joint venture put the delay down to technical difficulties – notably, the need to examine more than 40,000 scans of the arterial intima-media thickness (IMT) of patients’ carotid and femoral arteries collected from 18 multinational study sites – some observers inevitably concluded that the companies had something to hide.

As PharmaGossip indicates the New York Times is fueling a controversy over Zetia that now has spilled over into Congress.  Initially, the story simply concerned delay in publishing results from ENHANCE, a Phase 3 study of 700 subjects with a genetic form of hypercholesterolemia, which was completed in April 2006.  Merck and Schering-Plough chalked up the delay to complicated logisitics analyzing 40,000 IMT scans.  Now, the Times is implying that the Merck/Schering-Plough alliance might have purposely delayed publication of studies, including ENHANCE, that might contain information indicating a liver toxicity problem with Zetia. 

By way of full disclosure, I have no personal financial relationships with either Merck or Schering-Plough, but my employer might.  I’ll also state that I have been medicated with statins for many years and began using Zetia shortly after its U.S. launch.  I’ve personally had no problems with the drug and continue using it at its maximal recommended dose daily in combination with a statin at its maximal recommended dose.  It has effectively reduced my LDL-cholesterol by around 20% over statins alone.

Published data on Zetia is plentiful, although more is always welcome.  The reports of a complete lack of public results from the ENHANCE study, however, are correct.  There are no data, published or simply posted in the PhRMA’s clinical study results registry, from ENHANCE (search ZETIA with and without the registered trademark symbol if you look for it on the PhRMA results website).  Should Merck/S-P eventually be proven to have purposely delayed publication of this study or to have attempted to rig publication in favor of Zetia by changing the pre-specified primary endpoint, then shame on them.  Those responsible will deserve punishment and public embarassment.  If, though, the logisitical nightmare of coordinating the reading and interpretations of the tens of thousands of IMT scans are to blame for a conclusive efficacy read-out, then it’s reasonable to expect Merck/S-P to delay both a peer-reviewed publication and any public release of safety and secondary endpoint results as well, so as not to provide a false impression of the benefit to risk ratio in this study population.

I think I can speak for most people who use and prescribe Zetia when I say that we would love for Merck and Schering-Plough to study hard outcomes (MI, death, stroke) with the combination of Zetia and maximal doses of statins versus statins alone in high-risk patients.  In the meantime, we rely on reductions in LDL-cholesterol as an unproven surrogate marker for the particular mechanism of action of Zetia (reduced intestinal cholesterol absorption), hoping that reduction in LDL-C with Zetia will offer benefits similar to those of statins alone.  The ENHANCE study will offer little additional evidence of efficacy, or lack thereof, to the majority of Zetia users who more closely resemble me than the subjects studied in ENHANCE.  Whether Zetia reduces or leaves unchanged carotid IMT compared with statins alone will not change my decision to use the drug in the hope that it is reducing my risk of MI.  Likewise, the drug has not adversely affected my liver, so I will not stop using it if ENHANCE shows that some patients with heterozygous familial hypercholesterolemia experience liver damage while using it.  Only if ZETIA increases IMT significantly in this population would I think consider stopping it.

I, like many people at high risk for heart disease, need help keeping my LDL-C in a safe range, and Zetia plus statins is the only reasonable choice for me at the moment.  Clearly, people in my position need more choices.  We could benefit from more information on the long-term effects of Zetia too.  But the results from ENHANCE and other “hidden” Zetia data (that have been reviewed by regulators) are unlikely to be of any consequence for all but a small percentage of Zetia users.

NEJM — Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes

Following up Oct 24th’s post reporting on the news of Phase 1 trial suspensions of prasugrel to adjust dosage, we have today’s results of the TRITON-TIMI 38 Phase 3 pivotal trial of prasugrel vs. clopidogrel, published online in the NEJM to coincide with a presentation at the AHA annual meeting.

The editorial accompanying the detailed trial results, written by Deepak Bhatt of the Cleveland Clinic, sums up the study findings and implications nicely and sheds some light on the decision to study the antiplatelet pharmacodynamic effects at lower doses in subgroups of patients with differing baseline risks for serious bleeding:

The degrees of reduction in all these important ischemic events were substantial and robust [~19% in the primary efficacy endpoint, up to 52% for reduction in stent thrombosis with drug-eluting stents]. Beyond  comparing one drug with another, the TRITON–TIMI 38 study validates the hypothesis that greater degrees of adenosine diphosphate–mediated platelet inhibition are indeed associated with a greater suppression of clinical ischemic events. This is a major scientific contribution to our understanding of antiplatelet therapy….

Of concern, however, was the excess in TIMI major bleeding not related to coronary-artery bypass grafting that was life-threatening in the prasugrel group (1.4%, vs. 0.9% in the clopidogrel group; P=0.01), even fatally so (0.4% vs. 0.1%, P=0.002)….Thus, there is a price to pay for greater platelet inhibition and the accompanying reduction in ischemic events: higher rates of serious bleeding. In TRITON–TIMI 38, for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel…..[I]n a “real-world” setting, such as in an elderly patient with multiple coexisting conditions, the risk of major bleeding and even fatal bleeding may be increased to an even greater degree than was seen in TRITON–TIMI 38. Correspondingly,the benefits may also be greater in actual practice….

Bottom line:  Prasugrel more effectively prevents acute coronary syndromes than clopidgrel at its approved dosage, probably by stronger ADP-mediated platelet inhibition at the one size-fits-all dose of prasugrel studied.  However, one-size-fits-all appears to be an undesirable approach to this form of therapy, as evidenced by the significantly higher bleeding risk with prasugrel.  A more personalized approach, perhaps to the level of an individual patient, is necessary to improve on the efficacy of clopidogrel in the real world.  Thus, further clinical study of prasugrel , perhaps in conjunction with a point-of-care theranostic, will be needed to guide its tailored prescription.  That said,  I see nothing in these results that would preclude FDA approval of prasugrel now, without further clinical study, albeit with limitations on its use to low bleeding-risk patients.  Realistically, though, Lilly and DaiichiSankyo must perform additional studies to justify prescription of prasugrel to broader populations of patients and reap the financial rewards they are seeking.