MyVax misses the mark: Genitope seems not to notice
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.
Immediately I wondered, as apparently did at least two analysts on the conference call, whether what the secondary endpoint was measuring was a nonspecific effect of MyVax to boost immunity rather than a specific effect directed at the cancer itself. In other words, if the comparison is made between immune responders in the MyVax arm and immune non-responders in the MyVax arm, it is impossible to know whether the therapy is specific for the patients’ own cancer, or whether it simply boosts the body’s immune response against cancer generally. This is a damn important distinction, because MyVax will be damn expensive. If KLH+GM-CSF is just as good at boosting anti-cancer immune responses, no one would bother making patient-specific MyVax.
To get at this question, one analyst asked if the immune responders to MyVax were compared with the KLH+GM-CSF control group as a whole. Denney said that they were and that the comparison was favorable to MyVax. Okay, good news for MyVax supporters, but it doesn’t answer the pertinent question, because the immune system boost is likely not seen equally in all patients receiving KLH+GM-CSF, just as it was not seen equally in all patients receiving MyVax+GM-CSF (only about 40% of MyVax recipients experienced the “positive immune response” according to Denney).
Then a second analyst asked what should have been the truly revealing question. I’m paraphrasing, but the question was: Did you compare PFS in MyVax immune responsers with KLH immune responders? Dr. Denney seemed caught off guard by the question and later asked for it to be repeated. He fumbled it at first, describing the random patient assignment (presumably addressing a different question about the a priori ability to mount an immune response to either therapy), and then he explained that nearly all patients had some response to KLH+GM-CSF, but he also implied that Genitope hadn’t analyzed the data in a way that would allow the question to be addressed properly. Basically, he couldn’t (or wouldn’t) answer the question.
In my mind, Genitope has prematurely concluded that MyVax works as it was intended to work. Perhaps there is a specific anti-cancer benefit of MyVax beyond its immune-boosting properties, but we won’t know for certain until Genitope presents the analyses needed to answer this question. When they do show such analyses (not expected publicly before the summer of 2008), look for an apples to apples comparison of treatment effects. PFS in the MyVax immune responders should be compared with PFS in the KLH immune responders, where immune response is defined at a comparable level of immune response against the respective antigen. Experts should be in agreement as to how this level of immune response is measured. If such a comparison shows that MyVax-treated patients survived without disease progression significantly longer than KLH-treated patients, then Genitope will have evidence with which to make efficacy claims.
Would such forthcoming evidence suffice for U.S. marketing approval? Well, that depends on its strength. It would have to be awfully strong to overcome the missed primary endpoint. I’m not at all optimistic, and at $.75 per share, investors in Genitope tell me they’re not either.
