RIP BAPI

The other bapi shoe has now dropped, with the first non-ApoE4 Phase III top line results showing nothing, nothing at all. The IV bapineuzumab program has been discontinued, with two Phase III trials yet to report, but certain to do nothing more than shovel more earth on the coffin. A small trial using amyloid imaging and subQ bapi continues, but that will do little other than provide a post-mortem on target engagement. Given the enormous cost of this ill-starred leap into the void ($700 million? $800 million?), those who championed bapi within JNJ and Pfizer should  be checking their parachutes, just in case. The most important question at this point is: What does this say, if anything, about the validity of the amyloid hypothesis that has consumed the vast bulk of industry expenditures on Alzheimer’s over the past fifteen years? The reasonable suggestion that has become endemic amidst the backpedaling is that bapi was given too late in the Alzheimer’s process to make a difference. That may be so; it could be that, by the time MMSE scores show cognitive decline, that the sheer volume of beta-amyloid in the brain, both soluble and insoluble, exceeds the grasp of the six IV infusions of antibody eventually received by these  patients. But we would assume that Pfizer and JNJ retrospectively parsed out the most mild patients among the 2400 in these two trials, to see if there was any glimmer of disease-slowing in those patients who still had the ‘most to lose.’ The inclusion criteria required MMSE scores between 16 and 26–how many of them were enrolled with scores of say, 23-26? The trial sponsors have not disclosed what the distribution of scores was in these trial populations, and this detail will undoubtedly wait for presentations and publications.  But had there been any hint of effect in that subgroup, the IV program would have been revised, but not terminated. Apparently there was not, which should be the most troubling finding of all for those who continue to define amyloid as the most important target in the Alzheimer’s process. For now, we expect that the emphasis will shift to ‘earlier’, both in terms of the clinical status of the patients and the amount of damage done, and earlier in the pathophysiology of the disease, aiming to reduce the production of beta-amyloid via secretase inhibition, for example, rather than seeking to neutralize beta-amyloid that is already on-site. But industry’s ‘bets’ must be more evenly distributed among mechanistic contenders going forward, because the CNS industry has yet to establish  a therapeutic beachhead, let alone high ground.

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One Response to RIP BAPI

  1. Michael Gold, MD says:

    The failure of the two Bapineuzumab studies is not surprising and serves as yet one more stark reminder of the dangers of sub-group, post-hoc analyses serving as the rationale for large phase III studies. The phase II study for Bapi failed to detect any sort of dose-response relationship. The segmentation of the phase II data into APOEe4+ vs. APOEe4- was not based on an apriori hypothesis, but on safety observations during the conduct of the study. There was no signal of efficacy in the ITT population at any dose level and it was only when every dose level was pooled and only the per-protocol data used that a signal emerged on the NTB. One has to really wonder how low a threshold there was in order to justify proceeding into phase III studies.

    The real damage is not just to those who supported the Bapi program and the patients who desperately need new and effective treatments. We will now see a headlong rush into studies of patients at earlier and earlier stages of the disease based on the hypothesis that by the time patients present with symptoms, the damage is beyond repair. This approach has all the flavor of a “non-falsifiable” hypothesis. As soon as data emerge that there is a serious problem with the amyloid hypothesis, core elements of the hypothesis are revised to prevent a conclusion that the hypothesis is wrong. In this regards, it is entirely appropriate that anti-amyloid mAbs are going to be tested in EOAD where amyloid overproduction is known to be pathogenic

    Lastly, there will also be serious collateral damage to those of us committed to developing new treatments for neurological conditions. The loss of credibility that follows from the nearly religious acceptance of the amyloid hypothesis and the clear failure of two large, and well powered studies of an amyloid-specific therapy will make it that much harder to convince either investors or senior managers to fund new programs in neurodegenerative diseases regardless of how good the data are. Programs aimed at symptomatic therapy or non-amyloid targets have either withered on the vine or have been delayed in anticipation of the emergence of Bapi and it is unclear if momentum can be regained in these areas

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