Pharma’s Cutting Edge

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.

As you might have noticed, I’m finding it increasingly difficult to keep up a weekly or even biweekly posting schedule lately.  It’s not for a lack of interest I assure you. 

I’m revisiting the year-end best-of list that was popular last year (everyone loves a ranking, but I refuse to author a hot or not post!).  So, without further ado, these are my totally subjective picks for the best pharmaceutical (including biopharmaceutical/biologics) innovations this past year.  Only drugs eligible for sale in the US or EU after January 1st, 2007 are eligible.

1. TIE: maraviroc (Selzentry, Pfizer) and raltegravir (Isentress, Merck).  Two NMEs that attack HIV-1 via novel mechansims tie for first place in this year’s best-of list, despite the relatively modest fanfare that greeted their arrivals.

Maraviroc is the first in a class of drugs called chemokine (C-C motif) receptor 5 (CCR5) co-receptor antagonists that are designed to interfere with white blood cell entry of HIV via CCR5. CCR5 is likely the most physiologically important co-receptor during natural infection, and at least 50% to 60% of treatment-experienced infected patients harbor CCR5-using viruses.  When added to optimized therapy in clinically advanced patients, maraviroc led to virologic responses in roughly twice as many patients relative to placebo.

Raltegravir is the first in a class of antiretroviral agents known as HIV-integrase strand transfer inhibitor (HIV-1 INSTII) that are designed to slow HIV-1 progression by blocking the integrase enzyme required for viral insertion into human DNA.  It is approved for clinically advanced patients with evidence of viral replication and multi-drug resistant HIV-1.  Like maraviroc, raltegavir was tested as add-on to optimized therapy and resulted in similar virologic response rates relative to placebo.  However, Merck has the PR advantage over Pfizer.  Here’s a representative quote for Isentress, courtesy of SFGate.com: “This drug looks more potent than virtually anything we have ever seen.” (UCSF Professor Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology)  I found no similar effusiveness over Selzentry, but rest assured that both drugs represent welcome advances in AIDS treatment and deserve to share top innovation honors this year.

2.  Lapatinib (Tykerb, GSK).  Lapatinib is a small molecule, orally-active tyrosine kinase inhibitor (TKI) that targets both erbB1 (EGF) and erbB2 (Her2/neu) receptors. Its dual mode of action distinguishes it from other marketed small-molecule TKIs, such as gefitinib (Iressa) and erlotinib (Tarceva), which target just EGFR, and the monoclonal antibody trastuzumab (Herceptin), which targets just Her2/neu. In theory, dual TK inhibition might diminish drug resistance  arising from single TK inhibition.  In practice, we just don’t know.  The pivotal trial tested lapatinib combination therapy with capecitibine versus capecitabine alone in women whose Her2/neu-overexpressing breast cancer had progressed after therapy with taxanes, anthracycline, and Herceptin.  I’ve read several different reports of the results of this study, probably because the interim results were published in the NEJM, and updated results were used by FDA to support approval.  Furthermore, FDA relied both on the investigator-reported and independent assessments of TTP.  The bottom line is that lapatinib did NOT “nearly double” TTP, as you might have read; rather, addition of lapatinib increased TTP by 33-40% over capecitabine alone and had no effect on survival.  Still, lapatinib represents the best option for women with Her2-overexpressing breast cancer whose disease has progressed despite chemotherapy and Herceptin and holds promise for earlier disease stages as well.

3.  Eculizumab (Soliris, Alexion).  Eculizumab is a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation.  It is the first complement activation inhibitor approved for human use and is also the first drug indicated for Paroxsymal Nocturnal Hemoglobinuria (PNH), a rare, complement-mediated disease characterized by red blood cell destruction.  Eculizumab was approved for its ability to stabilize hemoglobin (49% versus 0% with placebo) and reduce transfusion requirements (mean 3 U versus 11 U with placebo) in PNH.  Eculizumab represents a tremendous clinical advance for PNH and represents clinical proof-of-concept for inhibition of complement activation generally.  Its downside is its exorbitant cost of nearly $400k per year, which keeps this innovation out of my top 3.

4. Ixabepilone (Ixempra, BMS).  Ixabepilone is the first approved epothilone analog.  Epothilones are microtubule inhibitors found naturally in a myxobacterium.  BMS developed ixabepilone first as treatment for advanced breast cancer, testing it as monotherapy and in combination with capecitabine.  Both indications were approved in the US, with ixabepilone demonstrating improved progression-free survival in the combination therapy study (5.7 vs. 4.1 months) and objective tumor response (median response time of 6 months in up to 18% of subjects) as monotherapy.  Ixabepilone and other epothilones are currently being studied for other advanced cancers, includeing hormone-refractory prostate cancer.

5. Temsirolimus (Torisel, Wyeth).  A metabolic parent of Wyeth’s immunosuppresant sirolimus (Rapamune), temsirolimus is an mTOR inhibitor that arrests the cell cycle at G1 in kindey tumor cells in vitro.  In its pivotal studies in previously untreated advanced renal cancer, temsirolimus improved overall and progression-free survival versus interferon-alpha alone (10.9 vs. 7.3 months and 5.5 vs. 3.1 months, respectively).  More mTOR inhibitors will follow in the footsteps of temsirolimus in the years ahead, and, along with PI3/Akt inhibitors, should be important advances in the treatment of a wide variety of cancers.

6. Aliskerin (Tekturna/Rasilez, Novartis).  Aliskerin, the first approved renin inhibitor, is probably best known for the story of its development, which I won’t recount here.  Aliskerin inhibits the renin-angiotensin-aldosterone axis without increasing bradykinin, circumventing bradykinin-induced cough and angioedema that is a problem with inhibitors of downstream RAAS effectors.  We can’t have too many useful treatments for hypertension and heart failure.

7. Ambrisentan (Letairis, Gilead).  Ambrisentan is the second approved Endothelin A receptor antagonist following bosentan (Tracleer, Actelion, which is also an Endothelin B antagonist) for treatment of pulmonary artery hypertension (PAH).  Both are oral therapies.  So, what puts ambrisentan on this list?  It’s more convenient (once-daily versus twice) and has the potential for fewer drug interactions (Tracleer induces 3A4 and 2C9, reducing the plasma concentration of sildenafil, used to treat PAH).  It’s also shown to be safe in patients who have discontinued Tracleer due to elevated hepatic enzymes.  Neither ambrisentan nor bosentan has powerful efficacy, however, and there have been no head-to-head studies.

Honorable Mention:  Protein C Concentrate (Ceprotin, Baxter).  Baxter studied nearly every patient with severe inherited Protein C deficiency during the long development of Ceprotin.