The Betting On Wyeth & Elan’s Alzheimer’s Drug
5 CommentsBy Ed Silverman // July 29th, 2008 // 8:32 am
Last month, a closely watched Phase II study of an experimental Alzheimier’s drug being developed by Elan and Wyeth found the med appears to be effective in some patients. Known as bapineuzumab, the drug failed to achieve statistically significant results in primary outcomes, but managed to do so in subgroups lacking a higher genetic risk to develop the disease.
More details will be released and scrutinized this afternoon at the International Conference on Alzheimer’s Disease by doctors and investors. Here are what some Wall Street analysts wrote in their investor notes over the past few days…
Barbara Ryan, Deutsche Bank: “In post-hoc analyses of non-carriers of Apo E4 allele (a gene thought to be a predictor of dementia and constituting up to 60 percent of the Alzheimer’s population), the trial showed clear indications of clinical benefits and improvements in surrogate measures of brain and ventricular volume with the therapy.
“Given the size and design of this study, we think these outcomes are very encouraging and as good as could be expected at this time. For Apo E4 carriers, on the other hand, by these same measures there was no indication of efficacy or favorable trends for most endpoints, and perhaps an undesirable effect on ventricular volume (which has been associated with progression of Alzheimer’s). Additionally, serious AEs were more frequent in carriers receiving the drug.”
Ian Sanderson, Cowen & Co: “Our clinical consultants predict that the bapineuzumab Phase II data will demonstrate clear evidence of activity and good safety in patients (not carrying ApoE4), but an inconclusive efficacy/safety profile in ApoE4 patients. We believe the bapineuzumab Phase II data will signal success in Phase III for patients (without the gene) and may provide some evidence of Phase III success for patients (with the gene).
“The most important measure of bapineuzumab’s efficacy signal will be the graphs of the relative change from baseline for the cognitive measures and the global measure over 18 months (when Phase III data is available). A sustained separation of the curves defines the strength of the efficacy signal, and a clear widening of the gap between bapineuzumab and placebo over time is consistent with, but does not prove, disease modification.
“Biomarkers are supporting data for disease modification. Reduction in p-tau levels would be most impressive. Reduction in brain volume loss and correlation with cognitive measures supports DM claim. And vasogenic edema events may be a minor concern. The frequency, predictability, and reversibility of VE events will drive the risk/ benefit analysis, which in patients with the ApoE4 gene is likely a tough call.”
Catherine Arnold, Credit Suisse: “The top-line results of the phase II bapineuzumab study suggest that in patients with mild-moderate AD who are not carriers of the Apo E4 allele, bapineuzumab could be a safe and effective disease-modifying therapy. The consistently positive results released to date across clinical and MRI endpoints in this group of patients are especially encouraging.
“We will be focused on a few key points that could foretell the outcome of the ongoing phase III program: The number of Apo E4 carriers and non-carriers across the different dosage arms and other intergroup imbalances; separation of the curves in regards to timing and dose and absolute effect rates; rates and severity of vasogenic edema and other serious safety issues in both carriers and non-carriers, and reasons for the lack of efficacy seen with Apo E4 carriers (high dropout rates and safety concerns limiting the doses).
Chris
Farrer et al. 1997 JAMA 278:1349 found that about 58% of AD patients are ApoE4 carriers. So if it works in non-carriers but not in carriers, the majority of patients would not benefit.
Nathan
42% of ~30 million people is still a HUGE number. Considering the lack of effective treatments, even if it was only effective in 10% of patients, it could still be a major blockbuster.
Jeffrey Clark, CEO of Beaker.com - The Online Community for Life Sciences Professionals
I need a scientist on this blog to help me understand. Less than a month ago, Myriad Genetics stopped developing Flurizan.
From the NY Times:
“The failure is significant because Flurizan was one of the first drugs to reach late-stage testing that was seen as working by trying to prevent the buildup of toxic amyloid plaques in the brain. Such plaques are the focus of the leading theory for the cause of Alzheimer’s disease. The drug’s failure might cast some new doubt on that theory as well as on other experimental drugs to block amyloid plaques. That treatment focused on amyloid plaques in the brain, the current popular target as to the cause of ALZ.”
So why has this not caused great pessimism around the potential of the treatments from Elan/Wyeth & Lilly that focus on the same root cause of the disease? While they may have a unique mechanism of action, from what I can tell, both focus on amyloid plaque as the culprit when Myriad’s results hint that may not be the case.
Jack2
Flurizan is a small molecule that hopefully reduces the generation of the protein (A-Beta) that forms the plaques. It blocks the enzmes that makes A-beta. The hope here is to stop/reduce plaque formation.
Secondarily, the drug could promote plaque clearance. It’s possible the plaques always exist in a dynamic equilibrium, with some plaques breaking down and others forming. In a patient with AD, the equilirium gets shifted towards the plaques. If you stop a patient from making new plaques, then the existing ones might breakdown.
Bapineuzumab is an antibody that targets A-Beta. It hopes to promote clearance (probably immune-system mediated clearance) of plaques. It’s easier to see how this drug could potentially more directly target existing plaques, and help someone with existing disease, rather than just preventing progression.
I think Merck has a drug like bapin., and it failed, not because of lack of efficacy - but because of safety. Patients suffered an immune reaction in their CNS.
Of course, it is possible these treatments are misguided, and A-beta plaques are just a symptom of AD (or even a protective mechanism), and modulating plaque formation will not help AD symptoms (and maybe even worsen it).
However, *most* evidence points to A-beta plaques (along with, possibly, tangles of another protein - tau), as the major culprit in the disease. The three hallmarks of AD are A-beta plaques, tau tangles, and neuronal loss. It’s certainly the best available lead.
bapineuzumab
Nathan
Jeffrey - That’s a great question - I was wondering the same thing myself. I guess that the report did not promote pessimism around bapineuzumab because bapineuzumab had already shown a hint of efficacy. (as in the press release last month) Ultimately, the validity of the amyloid plaque hypothesis is irrelevant. What matters is efficacy — regardless of mechanism. There are many drugs that have been designed with a particular hypothesis in mind. The products work, but then the underlying hypothesis is disproven by some other scientific work. Later, it’s found that the drugs seem to work by a completely different mechanism than what was originally intended. Many CNS drugs and cancer drugs that are on the market fall into this category. There is WAY more serendipity in drug discovery than we like to admit.