bmartin: May 2012 Archives

There's tremendous speculation on the pending outcome of phase 3 results with bapineuzumab, 1 of 2 anti-amyloid compounds in late-stage development for Alzheimer disease. The general buzz is that the monoclonal antibody won't perform tremendously well, given phase 2 results—specifically those indicating tepid efficacy and limited safety (particularly regarding vasogenic brain edema). But Elan chief executive Kelly Martin, whose company has a 25% stake in the drug (along with Pfizer and Janssen [ie, JNJ]), is doing what drug execs do: talking up the company's prospects vis-a-vis its pipeline. In this case, the prospects hinge mightily on bapineuzumab, the phase 3 results for which won't be publicly available until the "middle of the year," Martin confirms.

But there is other telegraphed information in Elan's latest public cheerleading for bapineuzumab. That is: the phase 3 results for the MAb won't be a clear home run, but that the compound may show some clinical benefit, however marginal. Elan's chairman, Robert Ingram, appears to predict FDA approval for bapineuzumab on the basis of 2 complementary forces: 1) increasing pressure on the agency to approve something for AD; and 2) the probability that company statisticians will be able to demonstrate some clinical benefit of the drug at least in some subset of AD patients (like those who aren't APOE e4 carriers).

The telling quote from the Elan chairman: "The FDA won't approve the drug if it doesn't have a single benefit but they are signalling that they will be very reasonable about getting something to patients that has a modicum of benefit [emphasis added]"

And this statement predicts a really unsatisfactory outcome for bapineuzumab's clinical development and, more importantly, the therapeutic prospects for patients with AD and their caregivers. That is: there won't be a clear-cut thumbs up or thumbs down for the MAb, because the efficacy and safety data won't allow a clear-cut thumbs up, and the backing companies and prevailing zeitgeist won't allow a clear-cut thumbs down. In other words, the drug, at best, may provide some benefit (however minimal or marginal) in AD (or more likely, a subset of AD patients) that may or may not outweigh safety concerns. And Elan, more or less, predicts that the FDA will be pressured to approved the iffy* drug, because there's no other disease-modifying** option on the market.

That's a disappointment all-around.

* And likely, very expensive.
** That is, putative disease-modifying option.

The Hospital (1971): Paddy Chayefsky's biting satire of the bureaucracy and incompetence of inpatient care, some of which rings true 40 years later...sadly. George C. Scott plays a suicidal Chief of Medicine, who simultaneously confronts serial murders in his big-city medical center. A zone of confusion, the hospital is also beset by some serious 60s-type social anarchy from community activists. Chayefsky's story goes off the rails during a prolonged encounter between Scott's character and the daughter of a comatose inpatient (played by Diana Rigg and Barnard Hughes, respectively). But the film still amuses owing to the fact that several actors—including Nancy Marchand, Frances Sternhagen, and an uncredited Stockard Channing—were cast in bit roles.

A buried joke:
Patient: At 9:15 this morning I rang for my nurse.
Doctor: You rang for your nurse?
Patient: To ensure one full hour of uninterrupted privacy.

A remarkable, unprecedented development. Roche's anti-amyloid MAb, crenezumab (for which there are no entries at PubMed—!), will be given in an attempt to stave off familial Alzheimer disease. According to Reuters and the NYT, the experimental drug will be studied in members of an extended Colombian family who harbor mutations in a deterministic gene (presenilin 1*) for AD. The US DHHS and Banner Health are providing $16 million and $15 million, respectively, to fund the study. The US government's support is part of the new National Alzheimer's Project (announced yesterday), which has an advertised goal of finding an effective treatment for AD by 2025.

Also according to news coverage, crenezumab was chosen as a potential preemptive treatment for AD among "25 rivals," primarily because it does not cause vasogenic edema—for instance, like Pfizer/Janssen's bapineuzumab. This information is sourced in news write-ups to a Colombian neurologist. Although I have to say Roche's MAb has really come out of left field. As someone who has followed the investigational development of anti-amyloid drugs fairly closely, this molecule has flown way under my radar—partly because it has been registered heretofore under the unfriendly research name of MABT5102A. (Nevertheless, the oversight says something about my limitations.)

According to the NIH database, crenezumab/MABT5102A is currently being investigated in two phase 2 studies in the United States, Canada, and/or the United Kingdom (see here and here). Respective study completion dates are currently designated as June and August of 2014. Presumably the data regarding vasogenic edema (or lack thereof) were determined during phase 1 study and/or confirmed during the ongoing phase 2 trials.

Roche also has the investigational anti-amyloid MAb gantenerumab, which is also in phase 2 development.

As previously written, phase 3 data for the anti-amyloid MAbs bapineuzumab and solanezumab (in existing AD) are expected sometime this summer—which is drawing nigh.

DHHS = Department of Health and Human Services; MAb = monoclonal antibody.
* Presenilin 1 is a component of a metabolic enzyme that cleaves amyloid precursor protein to ultimately create beta amyloid--the stuff the aggregates and forms plaques in the brains of patients with AD.

Update: AC Immune, from which crenezumab was licensed by Roche/Genentech, reported last year that the "drug showed no signs of cerebral vasogenic edema in any of the [phase 1 trial] patients at any dose."

Another update: You have to wonder, though. If crenezumab doesn't cause (or isn't associated with) vascular edema, how effective is it at removing amyloid? If the cause of vasogenic edema with these anti-amyloid compounds is due to the immune-mediated vascular removal of amyloid and/or a direct attack on vascular amyloid (see, for instance, Figure 5 in Sperling et al. Lancet Neurol. 2012:11:241-249), then you would expect some kind of class effect given the putative mechanism of action. Consequently I wonder at the efficacy of an anti-amyloid MAb that doesn't cause some vasogenic edema in a percentage of patients. Certainly amyloid PET imaging in this Colombian study will allow researchers to visualize the removal or prevention of amyloid buildup with crenezumab. So...wait to see. Of course, the bigger question is whether the targeting of amyloid is associated with clinical improvement or, as in this study, the prevention of AD dementia.

The FDA has revised its recommendations for cardiovascular monitoring after the initiation of Gilenya (fingolimod), Novartis's oral drug for relapsing-remitting MS. The new recommendations, which extend the post-dosage monitoring for bradycardia from 6 to 24 hours, are based on the report of a woman who died within a day after starting the drug.

Although the cause of the woman's death was not determined, the agency reported that she was taking two antihypertensive medications, including the beta-blocker metoprolol. In addition, she had "extensive" MS lesions in her brainstem, which have been associated with sudden death.

On the basis of a post-hoc analysis of clinical-trial data, the FDA also concluded that the possible depressant effect of Gilenya on the heart rate is biphasic: There is an initial risk during the first 6 hours after the first dose and a second risk during hours 12-20. Therefore the agency believes that cardiac monitoring beyond 6 hours is warranted in patients whose heart rate falls below 45 bpm during the first 6 hours after the first dose.

Other reports of cardiovascular death in Gilenya-treated patients are being examined. However, the FDA cautions, "For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya."

Regardless it seems prudent to consider the drug very carefully in MS patients with concomitant cardiovascular disease (especially arrhythmia) and particularly those patients taking beta-blockers or antiarrhythmics.

This morning, the FDA has finally stepped in and is warning healthcare professionals and MS patients alike about death and other injuries associated with the so-called "liberation procedure" (ugh), which amounts to either angioplasty or stenting of (typically) jugular veins. The procedure, which is ostensibly designed to promote the egress of blood flow from the brain, has no basis for use, because there is no confirmed link between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis. For background on this ever-vexing issue, start here.

The FDA has received reports of associated adverse events, which include "death, stroke, detachment and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage and abdominal bleeding." In February, the agency sent a letter to a NY vascular surgeon, warning of "objectionable conditions" and the lack of regulatory protocol and oversight for what amounts to an investigational (ie, non-FDA-approved) procedure.

For the Internet's edification, the phase 3 trials of MAbs in AD are tabulated by drug (bapineuzumab, solanezumab) and expected completion date.

Although the phase 3 trial of bapineuzumab in APOE ε4 carriers (NCT00575055 or ELN115727-302) reached its estimated completion date last month, the online buzz indicates that Pfizer/Janssen won't publicly release these data until the phase 3 study in noncarriers is completed in August of this year. As readers may recall, the phase 2 data of bapineuzumab suggested that APOE ε4 noncarriers with AD (meaning generally those patients with a lower beta-amyloid burden) fared somewhat clinically better than APOE ε4 carriers and were specifically less likely to develop vasogenic brain edema.

The public release of phase 3 solanezumab data is also expected imminently or at least (I would think) this summer.

Bapineuzumab (Pfizer/Janssen) Phase 3 Trials*

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1121 APOE ε4 carriers	NCT00575055 (aka ELN115727-302)	1.5 years	April 2012
1300 APOE ε4 noncarriers	NCT00574132 (aka ELN115727-301)	1.5 years	August 2012
Subjects who participated in above studies	NCT00937352	2.5 years or marketing application	June 2012
1100 APOE ε4 carriers	NCT00676143 (aka 3133K1-3001)	1.5 years	June 2013
Subjects who participated in above study	NCT00998764	4 years (extension)	June 2017
1000 APOE ε4 noncarriers	NCT00667810 (aka 3133K1-3000)	1.5 years	June 2014
Subjects who participated in above study	NCT00996918	4 years (extension)	June 2018

Solanezumab (Eli Lilly) Phase 3 Trials**

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1000 AD patients	NCT00905372	~1.5 years	April 2012
1000 AD patients	NCT00904683	~1.5 years	June 2012
1250 AD patients	NCT01127633 (extension)	2 years	July 2014

In addition, there are several phase 3 studies evaluating IV Ig (eg, Baxter's Gammagard) in patients with AD. Clinical data from these trials aren't expected until 2013 and later.

MAb = monoclonal antibody.

* Owing to a dose-dependent effect on the risk of amyloid-related imaging abnormalities (aka vasogenic edema and microhemorrhages), particularly in APOE ε4 carriers, the dosage of bapineuzumab received by APOE ε4 carriers is now the lowest, tested dosage: 0.5 mg/kg. APOE ε4 noncarriers are receiving 2 dosages of bapineuzumab (0.5 or 1.0 mg/kg) in phase 3 clinical trials.

** Treated patients are receiving one, standard dosage of the MAb.

Chronic cerebrospinal venous insufficiency (CCSVI) is neither common, nor more common, in patients with multiple sclerosis, say investigators at the University of Texas Health Sciences Center in Houston. According to 2 preliminary reports presented at the recent annual meeting of the American Academy of Neurology, CCSVI—determined by blinded readers using "strict" ultrasound criteria*—was detected in only 8 of 206 (~4%) patients with MS** and 5 of 59 (~8%) patients with other neurologic disorders (eg, stroke).

In a companion MR venography study, only 9 of 63 (14%) patients with MS showed evidence of CCSVI. None of these patients met ultrasound criteria for CCSVI, but 2 patients with normal MR venography showed ultrasound evidence of CCSVI. Although MR venography appeared, therefore, to be more sensitive for detecting venous insufficiency than ultrasound, the investigators found that there was reasonable correlation between the 2 imaging techniques.

In 2009, Italian physician Paolo Zamboni proposed that the cause of MS was related to obstructed venous outflow from the brain and documented CCSVI by ultrasonography in an inordinately high number of MS subjects. His published findings led to unjustified zeal for venous stenting and other procedures that were intended to increase venous outflow from the brain. However, Zamboni's data have not been reliably replicated; more damning, in fact, is that his data have been refuted in numerous studies.

General consensus among MS specialists is that the condition is an autoimmune (not vascular) disorder, and the most effective, known treatments for delaying the progression of MS are immunomodulatory drugs.

MR = magnetic resonance.
* Consistent with those criteria outlined by Zamboni.
** Approximately two thirds of patients with MS had relapsing-remitting disease.

HT: MedPage Today.