Solanezumab

Despite a pair of drug approvals within the last three years and millions of patients in need, Alzheimer’s disease treatments have struggled with a gamut of safety, efficacy, and accessibility problems. As a third anti-beta amyloid antibody – Eli Lilly’s donanemab – nears FDA clearance, Alzheon is taking a different tack with its lead programme that it thinks will address all three pain points that have plagued drug development in the field.On Wednesday, the biotech raised a $100-million series E to wrap up the APOLLOE4 Phase III study of valiltramiprosate (ALZ-801) in patients with early Alzheimer’s, and ready it for commercialisation. The round, led by Alerce Medical Technology Partners, brings Alzheon’s total equity financing to $185 million.The pivotal trial is expected to read out in the third quarter, and the company plans to begin a regulatory submission to the FDA by year-end. If all goes well, CEO Martin Tolar expects the oral small molecule to be available to US patients in 2025. “We truly are at the dawn of a new era,” he said. “We understand the biology [of Alzhiemer’s] and we have an opportunity to transform the standard of care with our treatment.”Genetically defined diseaseAlzheon was founded over a decade ago to develop a treatment for Alzheimer’s by methodically determining which toxic agent is driving the disease, and which biomarkers are effective at tracking progression and gauging the efficacy of a given treatment.Notably, Alzheon’s clinical programme is initially enrolling patients who are homozygous for APOE4, a strong genetic risk factor of the disease.Around two-thirds of patients with Alzheimer’s have one copy of the gene, but in people with two copies, “virtually everybody” will develop the disease, Tolar said. About 15% of Alzheimer’s patients are homozygous for APOE4. While the high-risk group might seem the most likely to benefit from treatment, both of Biogen and Eisai’s anti-beta amyloid antibodies, Leqembi (lecanemab) and the now-abandoned Aduhelm (aducanumab), as well as Lilly’s donenamab, have not been as effective in APOE4-homozygous patients and in fact had increased side effects in this population.  Plaque precursorsWhile Alzheon has also landed on beta amyloid as the main cause of Alzheimer’s, the team importantly singled out small, soluble amyloid aggregates – the precursors of the plaques targeted by most antibody therapeutics – as the molecules responsible for disease pathology. Beta amyloid is a key neurological protein that responds to damage, but as we age, levels of the monomer increase and the brain becomes less efficient at clearing it. As the molecule accumulates, it can misfold and begin aggregating into toxic, soluble oligomers that cause damage to the brain, Tolar explained.The brain will then sequester these aggregates into insoluble amyloid plaques, which have been the target for much of the drugs in development for Alzheimer’s.But, Tolar said, plaques are “the wrong target” to achieve cognitive and functional improvement, which the company says it has demonstrated in multiple published studies. Rather, the key is to prevent these plaques from forming in the first place – valiltramiprosate accomplishes by blocking beta amyloid from clumping into oligomers.Positive safety, efficacy signsSo far, clinical data seem to support Alzheon’s tactic. While Leqembi and donanemab led to patient improvements of 27% and 29%, versus placebo, respectively, on the Clinical Dementia Rating scale, Phase II results for valiltramiprosate demonstrated an 81% functional benefit on the same measurement. “These patients usually are at the edge of a cliff. They are a little forgetful. But in a year and a half they don't recognise their children, their spouses. And we can keep them stable for two years,” Tolar commented. “These are the data that really gave us confidence [in valiltramiprosate], and in fact helped us raise $100 million at a time where nobody can raise money.”Additionally, because plaques can occur in blood vessel walls, they could also be the reason why amyloid-related imaging abnormalities (ARIA), which can cause both brain oedema and haemorrhage, are a serious side effect associated with both Leqembi and donanemab.  However, since valiltramiprosate doesn’t act on plaques, it could be a safer option. “We have shown in over 3000 patients, in a three-year follow-up, that we don't have an increase in brain haemorrhages,” Tolar said. Another potential benefit of valiltramiprosate is simply by virtue of its oral administration, which would make it cheaper and easier for patients to take for years to stave off disease progression, rather than an antibody IV infusion.

Eli Lilly’s anti-beta amyloid antibody is a step closer to FDA approval after an advisory committee for the US regulator voted unanimously in favour of both the safety and efficacy of donanemab to treat Alzhiemer’s disease. Although briefing documents released ahead of Monday’s meeting flagged safety concerns with donanemab, the advisory committee ultimately supported the treatment’s risk-benefit profile in an 11-0 vote.In particular, FDA staff had noted that patients who received the experimental monoclonal antibody (mAb) had a higher rate of amyloid-related imaging abnormalities (ARIA) – and three ARIA-related deaths – versus the placebo arm. The safety data for donanemab so far is not as strong as demonstrated by Eisai and Biogen’s Leqembi (lecanemab). For more, see Spotlight On: Donanemab briefing docs bode well for Leqembi.To manage these risks, panel participants emphasised that patient and provider education will be necessary.Committee member Kathleen Poston, neurological sciences director at the Stanford Movement Disorders Center, noted that frequently requiring patients to undergo MRI scans to check for ARIA is not an insignificant burden.“Also, the interpretation of those MRI scans, it's not a black-and-white super easy thing to always interpret. And if areas don't have access to a neuroradiologist, they might have challenges knowing what's sort of just normal for age versus what's changed and could be evidence of ARIA,” Poston added. “So again, I think education around the interpretation of monitoring risk needs to be taken into consideration because it's non-trivial.”Colette Johnston, the committee’s patient advocate, argued that any potential benefit to people with Alzheimer’s is worth a risk, and should be up to the individuals to decide.    “When you get a diagnosis of Alzheimer's, you don't have anything but risk,” said Johnston, whose father had the disease. “We live in a society now where we get to have clinicians and caregivers and family members help us make choices, and it's up to the patient to be their own advocate and have their own advocates there to really research those risk-benefit ratios…. When you think of risk-benefit, we tend to… look at it as scientists, but my role here is to get you to look at it as caregivers. And so, inasmuch as it is not perfect [for donanemab], it is acceptable as far as I'm concerned.”Tau testing The panel did not raise concerns with the efficacy data supporting donanemab’s use in patients with mild cognitive impairment and mild dementia, voting 11-0 in its favour, though several participants called for more data in underrepresented patient populations, particularly African Americans and Hispanics. That additional subgroup data, Poston said, “will be important in the future… to make sure that these encouraging findings can be extrapolated to everyone with Alzheimer's disease.”In the 18-month Phase III TRAILBLAZER-ALZ 2 study, donanemab slowed cognitive and functional decline by 29% based on Clinical Dementia Rating-Sum of Boxes (CDR-SB), similar to Leqembi's 27% result.However, in addition to being positive for amyloid, trial participants also had to test positive for tau on PET scans in order to be included in Eli Lilly's study. Two main groups based on tau imaging were analysed; those with low/medium tau levels and the overall population consisting of patients with low, medium or high tau levels.Some analysts speculated that, if approved, donanemab might carry a more restrictive label than Leqembi that requires patients to undergo tau-detecting PET scans. However, the advisory committee seemed overwhelmingly against adding an additional burden to patients seeking Alzheimer’s treatment. “Access to a tau PET scan would be virtually impossible for a lot of these communities,” said committee member Cynthia Carlsson, a professor of medicine and Alzheimer'sdisease at the Wisconsin Alzheimer's Institute at the University of Wisconsin School of Medicine and Public Health. “I think that, given the data that we have, and the scientific knowledge that we have of how amyloid and tau progress, that I would say we do not need tau PET in this population.” Summing up the panel's stance, chair Thomas Montine said “the vast majority of the committee feels as though imposing a requirement for tau imaging is not necessary and would raise serious practical concerns and access concerns to the treatment."