The past few years have seen many experimental Alzheimer’s drugs completely fail, and specifically in the period of 2017-2018, no less than half a dozen succumbed to the pits of history.
In addition to these failures, pharmaceutical companies have expressed concerns as to which aspects of the disease need the greatest attention: is success simply gaged by amyloid plaque, or are there other biomarkers which have equal importance in measuring the success of a specific treatment, or is it a combination of both.
What we can discern is that the vast majority of experimental drugs were and are based on the ‘amyloid hypothesis’ which postulates that clumps of protein or beta-amyloid, which are found in the brains of all Alzheimer’s patients are the primary cause of the disease.
The hypothesis was so strong and based on such solid science that over the past few decades big pharma companies have thrown billions in the hope of an eventual massive payout, remaining somewhat oblivious to the fact that there have been the discovery of other biomarkers, such as the presence of neurofibrally tangles called ‘tau’.
This biomarker has actually shown itself in some studies to be more of a valid indicator of disease progression in patients where symptoms are more severe.
Here at PharmaSciMed we outline some of the most recent failures as well as potentially positive studies currently in play.
Indianapolis-giant Eli Lilly has probably suffered the worst financially in its pipeline Alzheimer’s drug with the failure of solanezumab which was unable to slow cognitive deterioration even in patients with a very mild form the condition.
However, December last year saw the company announce it was partnering with Switzerland’s AC Immune with payments due to the company estimated to be $1.6bn if the treatment goes to market. The specific treatment in question is the tau-targeting ACI-3024.
Aside from that, Lilly stopped the development of a few BACE inhibitors, and in relation to its Alzheimer’s failure this contributed to the company losing 3,500 workers or 8% of its global staff.
Given some of big pharma’s failure with amyloid-plaques, Biogen have actually deepened their interest alongside Japan-based Eisai in three drugs: BAN2401, aducanumab, and elenbecestat.
Last summer, results for BAN2401 on the Alzheimer’s Disease Composite Score (AD-COMS) – the highest dose of BAN2401 (10mg/kg biweekly injections) slowed progression by 30% compared to placebo, while on the more widely-used ADAS-Cog rating it did even better, with a 47% reduction. The results came on the backdrop of a 93% clearance rating of amyloid plaques showing that the treatment works.
Biogen is currently placing its hopes on at least one of the three Alzheimer’s showing significant therapeutic benefit, allowing it to be brought to market.
One of the more prominent of the so-called ‘BACE’ inhibitors completely failed for pharma-giant Merck was called verubecestat. BACE inhibitors are designed to block the formation of amyloid plaques, which differ from other drugs such as Lilly’s solanezumab which tried to break down already-established plaques.
Verubecestat showed little effect in patients with the earliest signs of disease and the studies’ negative results were so profound that it put into question the entire ‘amyloid hypothesis’.
Other Setbacks and Prospects
Verubecestat’s demise follows a series of recent casualties in the Alzheimer’s pipeline. Since the start of the year, Boehringer Ingelheim has stopped development of its PDE9a inhibitor BI 4093906, Takeda and Zinfandel abandoned efforts to repurpose diabetes drug pioglitazone for the disease, and Axovant Sciences dropped its 5-HT6 receptor antagonist intepirdine. Recently as well, Roche has halted its amyloid-targetting drug crenezumab after phase III data showed it had little chance of any positive outcome.
Just last week however United Neuroscience announced positive results for its Alzheimer’s vaccine UB-311 with a 96% response rate.
The consistent failures and missed goals in the Alzheimer’s race have now led some of the big pharma giants to consider that prevention may be the first option even before disease-associated symptoms occur.