Much research has been done in the field of Alzheimer’s disease. Yet, to date, no drug candidate has convincingly translated the battle against beta-amyloid into cognitive benefits across all study phases. What about the new active ingredient BAN2401?
From vaccinations, i.e. immunizations actively and passively with antibodies, to the development of various secretase inhibitors, the constant failure of numerous therapeutic approaches based on the amyloid hypothesis implies a high frustration tolerance not only of physicians and patients, but also of pharmaceutical companies active in the field of Alzheimer’s disease. It is therefore not surprising that some major players are already turning their backs on the troublesome “stepchild” of diseases of civilization and discontinuing their research activities in this area. Experts are also increasingly wondering whether the traditional, more than 20-year-old theory of Alzheimer’s pathogenesis, which nevertheless enjoys enormous support in the scientific world, is really as accurate as has long been assumed. In recent years, Alzheimer’s research has increasingly addressed critical questions [1,2]: Are amyloid deposition and neurodegeneration perhaps two independent, unrelated phenomena after all, so must the focus be increasingly on tau pathology in the future? Is the former predominantly an age phenomenon? Is this why the disease can be slowed down so poorly despite intervention in the postulated amyloid cascade? Or do soluble oligomers, i.e. less aggregated forms of beta-amyloid proteins, play the decisive role instead of the larger deposits (plaques)? If the treatment in therapy studies was possibly started too late or not at all. the target population wrongly chosen? Or could it simply not work because it was too little (or wrongly) selective, be it in the secretases or even in the different amyloid aggregation forms such as oligomers or larger fibrils?
Questions about questions. One thing is certain: there are symptom-free persons with amyloid deposits (observed, for example, in autopsies) and, conversely, Alzheimer’s patients with only a few such deposits. In old age, they show up in non-demented as well as in demented persons, in some cases even to the same extent. Among other things, advances in imaging made this clear. A clear linear correlation between deposits and cognitive deterioration cannot be established. Moreover, not all amyloid is the same – it occurs as a monomer, but can also assemble into oligomers and eventually into fibrils or plaques. The processes could be involved in the disease process to varying degrees, and some could even be protective. On the basis of new findings, research is currently focusing primarily on oligomers or with intermediates of the larger amyloid fibrils and plaques. They are considered to be particularly toxic (oligomer hypothesis), whereas the plaques themselves are seen by some authors as protective “buffers” against toxic oligomers in the sense of largely harmless reservoirs.
Another candidate threatens to fail
Nevertheless, BAN2401, a new antibody candidate that selectively binds to and eliminates toxic intermediates of amyloid fibrils, namely soluble beta-amyloid protofibrils, could not expect advance praise. Too much has simply gone wrong in the field of Alzheimer’s drug research in recent years for that. And indeed, in December 2017, the manufacturer also announces a failure in the primary endpoint of its randomized-controlled phase II trial after twelve months for BAN2401. Nevertheless, the trial remained blinded until the final analysis at 18 months, and there was still one or two positive signals to report from the secondary endpoints at the congress (although the trial was not powered for definitive proof of efficacy of cognitive outcomes). The sample consisted of 856 patients with MCI due to Alzheimer’s disease or mild Alzheimer’s dementia and amyloid pathology (161 patients had received the maximum dose):
- The reductions in amyloid plaques were dose-dependent and significant.
- Within 18 months, the antibody at the highest dose reduced amyloid accumulation in the brain from an initial 74.5 to 5.5 (in standardized PET on the centiloid scale with 100 points for “typical AD patients” and 0 for “most likely amyloid-negative patients”). 81% of all previously amyloid-positive patients were considered amyloid-negative after 18 months (p<0.0001).
- Clinical cognitive decline in the internally developed new endpoint ADCOMS (Alzheimer’s Disease Composite Score) slowed in a dose-dependent manner.
- Although the required success criterion at twelve months, i.e., at least an 80% probability of slowing in cognitive decline (ADCOMS) of at least 25% compared to placebo, was not achieved (primary endpoint): At six and twelve months, the highest dose already showed significantly slowed cognitive decline compared to placebo (p<0.05), which persisted until the end of the study period after 18 months (slowed by 30% at the highest dose, p=0.034). The latter is also true for the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog; dose-dependent, slowed by 47% at the highest dose, p=0.017) and for the CDR-SB (Clinical Dementia Rating Sum of Boxes; dose-dependent, slowed by 26% at the highest dose).
- The safety profile was acceptable as far as it went, the most common being abnormalities in imaging (ARIA) associated with amyloid (edema at the highest dose: 9.9%, which led to study discontinuation for these patients) and side effects of the infusion itself. Serious adverse events were not found more frequently than with placebo, even at the highest dose.
Whether these positive signals are enough for the manufacturer to push the development further remains to be seen. The study was also viewed critically in other respects at the congress. After many setbacks, however, this is at least the second clinical trial and the first major Alzheimer’s trial that can combine the fight against beta-amyloid (clearance) with positive cognitive effects. So is it worth pursuing the amyloid approach? Will it be one of several therapeutic pathways within combination treatments in the future? One will see. Another candidate in this field, aducanumab – co-developed by the UZH spin-off “Neurimmune” – also showed promising early results [3], results from two large follow-up studies are expected in 2020.
Source: Alzheimer’s Association International Conference (AAIC), July 22-26, 2018, Chicago.
Literature:
- Verma M, Vats A, Taneja V: Toxic species in amyloid disorders: oligomers or mature fibrils. Ann Indian Acad Neurol 2015 Apr-Jun; 18(2): 138-145.
- Kametani F, Hasegawa M: Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer’s Disease. Front Neurosci 2018; 12: 25.
- Sevigny J, et al: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016 Sep 1; 537(7618): 50-56.
- Jang H, et al: Differential effects of completed and incomplete pregnancies on the risk of Alzheimer disease. Neurology 2018 Jul 18. DOI: 10.1212/WNL.00000000006000 [Epub ahead of print].
- Shumaker SA, et al: Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003 May 28; 289(20): 2651-2662.
InFo NEUROLOGY & PSYCHIATRY 2018; 16(5): published Aug 15, 2018 (ahead of print).
