Paper Alert-cum-SfN: Bapineuzumab Published, More AN1792 Presented

Phase 2 clinical trial data for bapineuzumab, Elan/Wyeth’s humanized monoclonal antibody against amyloid-β, were published ahead of print in yesterday’s Neurology online. Writing for the trial investigators, Stephen Salloway, Butler Hospital, Providence, Rhode Island, and colleagues report that there were no differences in primary outcomes between patients treated with placebo and those given various doses of intravenous bapineuzumab. The primary outcomes were the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and the Disability Assessment for Dementia (DAD). Alzforum covered the data extensively when it was presented at the 11th International Conference on Alzheimer’s Disease (ICAD) in 2008 (see ARF related news story).

This was a safety and efficacy trial of 234 patients randomized to placebo (110 patients) or bapineuzumab (124 patients), given as six infusions 13 weeks apart. Among a subgroup of patients who completed the study (78 in the placebo group and 80 in the treatment group) there was significantly less decline in both the ADAS-Cog and DAD in the treatment arms. In an accompanying Neurology editorial, Dan Kaufer, University of North Carolina, Chapel Hill, and Sam Gandy, Mount Sinai School of Medicine, New York, call this subgroup result “encouraging.” They add, “The most remarkable aspect of this study is the unanticipated effect of ApoE4 carrier status on both efficacy and safety.” The drug sponsors emphasized this in their ICAD presentation, as well. The analysis suggests that the treatment worked better in people who do not carry an ApoE4 allele, which is a strong genetic risk factor for late-onset AD. In addition, vasogenic edema (VE), a treatment-related adverse event recorded in the trial, was detected more often in ApoE4 carriers.

Whether this effect holds up in larger trials remains to be seen. Some clinical trial experts question the wisdom of attempting such analyses in what are primarily small safety studies underpowered for subgroup analysis. It seems that companies simply can’t resist taking a peek and then reporting what they see.

If the analysis does hold up (several Phase 3 trials are currently recruiting), then it could have wider repercussions. “The relative absence of therapeutic efficacy and the increased risk of VE in ApoE4 carriers make bapineuzumab a less promising candidate therapy for this group, which comprises the majority of individuals with AD,” note Kaufer and Gandy. A related question is whether the presence of an ApoE4 allele makes the disease more intractable to treatment in general. “As the most common identified AD genetic risk factor, and, as we see here, a potential impediment to drug development, ApoE4 demands greater research attention to unravel the molecular basis of its deleterious effects,” they write.

In a separate development on AD immunotherapy, Alberto Serrano-Pozo and colleagues in Brad Hyman’s group at Massachusetts General Hospital, Boston, and elsewhere reported at the Society for Neuroscience Conference held 17-21 October 2009 in Chicago that they noticed some new pathology benefits from active immunization when they compared five brains from patients who had participated in Elan/Wyeth’s AN1792 Phase 2a study with the brains of 13 AD patients who had not. AN1792 is the first-generation vaccine that removed plaques from brain and reduced CSF tau, but is now defunct because it caused meningoencephalitis in 6 percent of participants of a Phase 2a trial. In their study, Serrano-Pozo and colleagues followed up in human brain on some previous mouse 2-photon microscopy observations that had suggested immunotherapy can straighten out abnormally curved dystrophic neurites.

On a poster, the scientists reported that, besides having lower amyloid load and fewer dense-core and diffuse plaques, the immunized group also had lower scores on other pathological markers than did fellow AD patients of similar age and Braak stage. Hyperphosphorylated neurofibrillary tangles as measured by PHF-1 positivity were decreased in hippocampus, though presumably more compacted thioflavin S positive tangles were not. Curiously, the curvature of neurites was noticeably straighter. Neuritic curvature is a measure derived from the ratio of a neurite’s total length divided by the distance between its endpoints. Previous data from the Hyman lab have shown that in both transgenic mice and postmortem human AD brain, the neurites get curvier the closer they are to plaques. The SfN poster reported a straightening out of neurite trajectories among treated patients regardless of whether the neurites were far away from or near a plaque. Even within the halo of remaining dense-core plaques, the neurites looked healthier, Serrano-Pozo et al. reported. Overall, these findings indicate that immunotherapy against Aβ may eventually be able to ameliorate a measure of neuronal damage beyond removing amyloid plaques.

Elan’s AD immunotherapy program was purchased earlier this year by JANSSEN Alzheimer Immunotherapy, a newly formed subsidiary of Johnson & Johnson; Wyeth was gobbled up by pharma giant Pfizer.—Gabrielle Strobel and Tom Fagan.

Comments

  1. This may be a naive question, but if amyloid deposition in the brain is a critical factor in AD-related behavioral sequelae, why is it so difficult to induce a behavioral modification of statistical relevance following Aβ vaccination, since reports show a strong amyloid plaque clearance effect?

    View all comments by Elliott Mufson

  2. Although the outcome maybe wasn’t as good as had been hoped for, the Phase 2 study on Bapineuzumab, a humanized anti-Aβ monoclonal antibody, provided novel perspectives to the field of immunotherapy against Alzheimer disease. The study enrolled 234 patients with mild to moderate disease, and these were randomly assigned to intravenous antibody infusion or placebo in four dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). After completing the protocol with six infusions, the patients were assessed after 1.5 years. Although no significant differences were found in the primary efficacy analyses, slight differences in cognition could be seen among ApoE ε4 non-carriers. Unfortunately, vasogenic edema occurred in 10 percent of the treated patients and was more frequent in ApoE ε4 carriers who received the higher doses. Ongoing large separate Phase 3 studies on ε4 carriers and ε4 non-carriers, respectively, will be crucial for treatment evaluation—and teach us more about which patients can gain from passive anti-Aβ immunotherapy.

    View all comments by Martin Ingelsson

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References

News Citations

  1. Chicago: Bapineuzumab’s Phase 2—Was the Data Better Than the Spin?

External Citations

  1. Phase 3 trials

Further Reading

Primary Papers

  1. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M, . A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009 Dec 15;73(24):2061-70. PubMed.
  2. Kaufer D, Gandy S. APOE {epsilon}4 and bapineuzumab: Infusing pharmacogenomics into Alzheimer disease therapeutics. Neurology. 2009 Dec 15;73(24):2052-3. PubMed.

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