The biotech company BioArctic Neuroscience announced positive topline results at the 18-month mark of a Phase 2b trial of BAN2401. This anti-Aβ protofibril immunotherapy was developed originally by Lars Lannfelt at Sweden’s Uppsala University following his discovery of the “Arctic” APP mutation E693G in a family in Swedish Lapland. The current trial enrolled people with early Alzheimer’s disease, and the highest antibody dose reportedly slowed cognitive decline and reversed accumulation of amyloid as seen on positron emission tomography (PET) scans. It is the largest proof-of-concept study of a disease-modifying drug in AD.
- Anti-Aβ protofibril antibody BAN2401 shows positive results in Phase 2b.
- It slowed cognitive decline in MCI and mild AD during 18 months.
- At the highest dose, the antibody appears to clear Aβ plaques.
“I’m encouraged about these preliminary findings,” said Paul Aisen, University of Southern California, La Jolla. He cautioned that while a treatment benefit is plausible, researchers need to see overall study results, and subject them to multiple analyses to avoid a false positive result, before they can be sure the effect is real. “I’m hoping that these results will hold up under scrutiny and will reinforce the attention on the amyloid hypothesis in the face of so many negative studies,” Aisen said.
BAN2401—which binds selectively to large, soluble Aβ protofibrils—was developed by Stockholm-based BioArctic, then licensed to Eisai, and subsequently Biogen acquired a stake through an AD partnership with Eisai. The Phase 2b trial tested five dose regimens in people who had mild cognitive impairment due to AD or mild AD and who had evidence of brain amyloid pathology by cerebrospinal fluid analysis or PET. Patients received a 60-minute infusion of 5 or 10 mg/kg once a month, or 2.5, 5, or 10 mg/kg twice a month.
After years of discussion about the challenges of clinical trials in AD research, researchers led by Andy Satlin, who led AD research at Eisai but has since left the company, took a stab at innovating on both design and outcome measures for early AD progression. For the first time in a large AD trial, researchers employed a Bayesian statistical model, where they tried to enrich enrollment of patients into the more effective dose regimens based on frequent interim analyses (Satlin et al., 2016). The hope was that this approach would yield a result sooner, with fewer than 800 patients needing to be enrolled.
The primary outcome was change at 12 months on the ADCOMS, which combines all six items of the CDR sum of boxes, four items of the ADAS-Cog, and two items of the MMSE. This composite was developed by Veronika Logovinsky and colleagues at Eisai as a more sensitive measure to track progression at early disease stages (Wang et al., 2016). An 80 percent chance of a 25 percent slowing of cognitive decline would have triggered a Phase 3 trial.
This did not pan out. By 12 months, the trial did not meet its primary endpoint or futility criteria, indicating the antibody neither had a large effect size nor was clearly ineffective (Dec 2017 news). Hence the trial continued to 18 months, eventually enrolling 856 participants. 18-month amyloid PET was a secondary outcome.
For this time point, the researchers applied a prespecified, conventional statistical analysis. They now report a statistically significant reduction in cognitive decline at six, 12, and 18 months for people receiving 10 mg/kg of BAN2401 twice monthly. In addition, at 18 months patients on this dose reportedly had a significant reduction in standard uptake value ratio for the amyloid PET ligand, and some converted from amyloid-positive to -negative.
“It’s encouraging that there was a significant effect in the correct direction, both for the clinical endpoint and the biomarker,” said Lawrence Honig, Columbia University, New York. While this is potentially promising, it is worth remembering that this was a Phase 2 study, he added. Nevertheless, Honig was optimistic. “To me, it follows a trend that we are getting closer to potentially having an agent that shows some efficacy,” he said.
Overall, the treatment appeared safe. Patients most commonly reported mild to moderate infusion-related reactions, while MRI scans showed ARIA-E (edema) in fewer than 15 percent.
The researchers will present trial data at AAIC this month. Kramer said Eisai/Biogen plan to start a Phase 3 trial of BAN2401 during this fiscal year. He noted that this is the first large study to find both a reduction in cognitive decline and reduction in amyloid plaque in a substantial number of patients. “That correlation is very important,” Kramer said. “There is a biomarker change along with a clinical one.” The press release did not disclose how many of the 856 participants received the 10 mg/kg dose.
Since these are topline, descriptive results devoid of methods or numbers, one cannot interpret these findings, cautioned Lon Schneider, University of Southern California, Los Angeles. “There’s no reason to doubt that the cognitive outcomes and PET data are statistically significant in the models they used, but scientists will have to wait for formal presentations—hard data on the effect sizes, sample sizes, and p-values—to make inferences,” he told Alzforum. “This is especially true because it’s a complex Bayesian study, not just a simple parallel group, dose-ranging design.”
- Satlin A, Wang J, Logovinsky V, Berry S, Swanson C, Dhadda S, Berry DA. Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease. Alzheimers Dement (N Y). 2016 Jan;2(1):1-12. Epub 2016 Feb 4 PubMed.
- Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, Rabe M, Luthman J, Cummings J, Satlin A. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep;87(9):993-9. Epub 2016 Mar 23 PubMed.