Lecanemab trial 'pivotal' for other therapy developers targeting Alzheimer’s disease

Lecanemab is an anti-amyloid beta (Aβ) protofibril antibody for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD). Co-developed by Eisai and Biogen, the companies announced positive findings​​ on the drug from the Clarity AD phase 3 trial on September 27, with the results suggesting lecanemab can slow cognitive and functional decline in a group of patients in the early stages of the disease.

According to the announcement, the therapy reduced patient clinical decline by 27% when compared to a placebo after 18 months of the infused treatment. 

Michel Vounatsos, CEO of Biogen, said: “Importantly, the study shows that removal of aggregated amyloid beta in the brain is associated with a slowing of disease in patients at the early stage of the disease.”​

Weighing in on that, Gene Kinney, CEO of Prothena, said he believes the results of the phase 3 study will have a positive impact on the future of R&D linked to AD and that the insights gleaned can contribute to first-generation and subsequent second-generation amyloid beta (Aβ) targeting therapies.

“Based on Eisai’s press release results, it is really an unambiguously positive outcome, and it speaks to what we have been seeing in the field, which is that as you lower ​amyloid plaque, as measured using ​amyloid positron emission tomography (PET)​, you are seeing an increasingly consistent relationship between that effect and positive clinical outcomes. ​

“And, here, we are seeing highly statistically significant, clinically meaningful effects, and importantly, across multiple clinical domains, so not just the primary outcomes on the ​CDR-SB measurement but across the key secondary outcomes as well. ​

“The results are highly encouraging and consistent with what we and others have believed about the biology of ​Alzheimer’s disease. I think, in general, the field and patients should be excited - this really is a meaningful transition in how we think about treatment of AD, from the prior symptomatic treatments to now having potentially disease modifying treatments that can slow the disease.”​

Evolution in clinical trial design and execution  ​

While industry awaits the release of the full data from the trial at upcoming scientific meetings, Kinney said that consistency of effect across clinical domains seen in the study would appear to reflect the evolution of clinical trial design and execution in the AD field. “We are learning to better understand which patients are most likely to benefit from these kinds of treatments, how to best measure that change over team and how to optimally use increasingly sophisticated biomarkers of the biology that underlines this disease in the context of clinical trials. And we have seen that steadily improve over the years.” ​

The knowledge accured from some of the trials on first generation treatments such as anti-Aβ monoclonal antibodies like Bapineuzumab have informed subsequent studies such as those undertaken by Biogen on aducanumab as well as trials by other developers, said the Prothena lead. The Eisai study then also built on the learnings gleaned from the aducanumab studies.

“It speaks to this idea that AD is a complex enough disease that it really does take the scientific village to make meaningful progress here.”​

Changing the course of the disease

If the industry can evaluate the biological contributors to cause and progression within clinical settings and execute on those trials, then “we can demonstrate the benefit of modifying that biological underpinning and, in so doing, start to move from therapies that provide some symptomatic benefit for a limited period of time to treatments that can fundamentally change the course of the disease, to slow it down.Typically, in medicine, that always marks the beginning of where we want to get to.”​

The goal would be to raise the efficacy profile of such treatments, to slow the disease to a greater extent and expand the patient population that may benefit from these treatments.

“Ultimately, then, it is about how we bring in additional biological targeted approaches and think about combination strategies. It reminds me somewhat of how the HIV field matured, where AZT was a major shift in terms of how we thought about treatment for HIV. But the field did not rest on its hands at that point, it continued to push the ball forward​, whereby, today, we consider HIV a chronically manageable disease.”​

Prothena’s portfolio ​

Prothena’s AD portfolio​​ targets two clinical pathways: Aβ and tau.

The company was granted fast track designation from the US FDA in April to develop its investigational Aβ targeting therapy for AD, PRX012. That drug is currently being evaluated in a Phase 1 clinical study. Kinney said the therapy’s substantially higher binding strength allows for simple subcutaneous administration, a low burden approach for patients.

“We expect to start to talk about those results next year.”​

Along with PRX012, Prothena is developing PRX005, an anti-tau antibody, in conjunction with Bristol-Myers Squibb (BMS), specifically targeting an area within the microtubule binding region (MTBR). That is being clinically evaluated currently in a Phase 1 trial.

Prothena is also looking to bring about a paradigm shift to the AD field, with the company developing a single vaccine that concurrently targets amyloid beta and tau to prevent and eradicate the disease.