Pharma: February 2011 Archives

The WSJ Health Blog is reporting this afternoon that Lilly's head of neuroscience research, David S. Bredt, MD, PhD, is unexpectedly leaving the company after tomorrow. The doc's immediate exit, which is described as voluntary by a Lilly spokesperson, comes in the midst of Lilly's seriously troubled clinical-development program for anti-amyloid compounds to treat Alzheimer disease and the curious (at least to me) purchase of Avid Pharmaceuticals (for $800 million ultimately), which owned a PET amyloid tracer.

Up to the very present, Lilly seemed to be heavily, if not overly, invested in the idea that detecting and attacking amyloid is the major avenue toward the diagnosis and effective treatment of AD. In multiple posts, I begged to differ (see here, here, and here, for instance). Notably last year, Lilly scrapped its clinical development of the anti-amyloid compound semagacestat, because treated patients actually faired worse than placebo-treated patients. Then in January, at the JP Morgan conference, Lilly's CEO suggested that its other investigative anti-amyloid compound, the monoclonal antibody solanezumab, might also be associated with vasogenic edema (which makes sense, actually). Most recently an FDA panel conditionally endorsed the approval of the PET amyloid tracer, florbetapir; although the clinical utility of detecting amyloid in the brains of an aged population is, at the very least, debatable.

Bredt, 46, was evidently some kind of wunderkind in the neuroscience world, obtaining an MD and PhD from Johns Hopkins in the early 90s and thereafter serving on the faculty at UCSF until 2007, when he made the transition to Lilly. Seems like a sashay back to academia is possible, if not probable, after such an abrupt and unceremonious departure from the private sector.

Very delayed update: JNJ "poached" Bredt, said the WSJ Health Blog in March. So he remains in industry.

As of February 2nd, the total number of PML cases associated with Tysabri (natalizumab) use equals 95 (since the relaunch of the drug in 2007). Risk data on the monoclonal antibody, which is a highly effective disease-modifying agent for relapsing-remitting MS, comes by way of comarketer Biogen Idec, which recently disclosed to news sources that 10 patients developed the life-threating brain infection last month. Four of these patients may have died, according to Reuters, bringing the total number of Tysabri-related cases of fatal PML to 20.

The overall rate of PML with Tysabri use is now calculated at 1.6 per 1000 patients. Unfortunately there is no reported information on the duration of treatment in the newly affected patients with PML. It is a vital piece of missing data, given that the risk of PML with Tysabri use increases substantially after 18 months of treatment: from 0.1 per 1000 after 12 monthly infusions to 1.64 per 1000 after 25 monthly infusions.

According to Biogen Idec's annual report for 2010, approximately 56,600 patients were receiving Tysabri worldwide as of December 31st. Last year's product revenues for Biogen Idec, which shares Tysabri income with developer Elan, were $900 million—a 16% increase over 2009 revenues.

PML = progressive multifocal leukoencephalopathy.

In November, BMS and Pfizer halted a large phase 3 study of their factor Xa inhibitor apixaban in patients with acute coronary syndrome (ACS), because of excess bleeding with the drug. It was a serious blow to the development program of a potentially viable alternative to existing, old-as-dirt anticoagulants, like heparin or warfarin. But the halted study, APPRAISE-2, was just 1 of 9 industry-sponsored trials assessing the potential benefits of apixaban in patients at risk of ischemic events. The companies were investigating the drug in other at-risk populations, like patients with a-fib or venous thromboembolism.

Now the highly favorable results of one of those studies, AVERROES, has been published in the NEJM.* In the double-blind study of 5599 patients with a-fib who were deemed unsuitable for warfarin therapy, apixaban (5 mg BID) reduced the risk of stroke by 55%, when compared with aspirin therapy (81-324 mg QD) at about 1 year (stroke rate, 1.6% vs 3.7%). There was also a statistical trend toward the reduction of death with apixaban (3.5% vs 4.4%; P = .07). Rates of major bleeding were nonsignificantly higher with the new agent (1.4% vs 1.2%). The number of intracranial bleeds were 11 with apixaban and 13 with aspirin. Apixaban may also provide some cardiovascular protection, as evidenced by the relative reduction of hospitalization for CV causes (12.6% vs 15.9%; P < .001).

The study, by design, may have been an easy score for BMS and Pfizer, because the comparator drug was aspirin in a population known to be at increased risk of stroke. But another study (ARISTOTLE) is comparing the investigational agent with standard-of-care warfarin. Study completion, according to clinicaltrials.gov, is expected in April.

ARISTOTLE = Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES = Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment.

* The results were published ahead of schedule because the study was terminated early, in February of 2010, owing to the protective benefit of apixaban in patients with a-fib.

Horizontal CT image of massive, acute right hemispheric brain infarct with midline shift from Wikipedia.

Because I am a subscriber to Neurology (as an active member of the American Academy of Neurology), this e-mail popped up in my inbox yesterday.

Dear Readers of Neurology,

A story aired last night on World News Tonight with Diane Sawyer disclosing that Dr. Kenneth Shay was on the payroll of, or a consultant to, Proctor and Gamble at the time he peer-reviewed an article authored by Dr. Sharon Nations that was published in 2008 in Neurology, the medical journal of the American Academy of Neurology.

Neurology has a well-established and well-known policy at http://www.neurology.org/site/misc/info_review.xhtml that authors and reviewers must disclose conflicts of interest. Dr. Shay did not disclose any conflict of interest to the Editor-in-Chief of Neurology. Furthermore, it appears that Dr. Shay improperly shared the manuscript authored by Dr. Sharon Nations to Proctor and Gamble, in violation of the journal's confidentiality policy. The American Academy of Neurology considers any violation of these ethics policies to be egregious misconduct, and the Academy's General Counsel is reviewing its options with the editors.

Physician reviewers must disclose all conflicts of interest in order to maintain the integrity of Neurology, which is the world's most widely read and highly cited peer-reviewed neurology journal.

Regarding reports that the publication of Dr. Nations' article was delayed by two years, much of the delay was a result of the time it took the authors to resubmit a revision; the editorial office's review procedure was in line with standard time frames.

We hope you continue to enjoy reading Neurology. We welcome feedback at journal@neurology.org on this and any other issues.

Robert A. Gross, MD, PhD, FAAN

Editor-in-Chief

Neurology

The e-mail refers to this formulaic write-up (ABC News's "Cuomo on the Case"*) of a class-action personal-injury suit, in which plaintiffs are alleging that zinc in Fixodent denture cream (made by P&G) caused their neurologic damage.

The peer-reviewed article in question, published in Neurology in 2008, was featured at this blog (here), at the time of its publication. The study, a small case report, described 4 patients who developed myeloneuropathy (much like what would be expected with severe vitamin B12 deficiency) due to zinc overload (which chelates copper). The subjects, as it turns out, were massive consumers of zinc-containing denture cream (like 2 tubes per day).

Dr. Kennethy Shay, a dentist, was evidently one of the peer reviewers of the Neurology article, who (according to Dr. Gross's e-mail) failed to disclose his financial tie(s) to P&G. In the ABC News piece, the authors of the case report claim that Dr. Shay somehow delayed publication of their study; however, Dr. Gross implies in his e-mail that this was not so.

* !