Outside Alzheimer’s disease, it is hard to think of a field where setback after late-stage setback has failed to deter further investment along approximately the same lines. So make no mistake, while the collapse of lanabecestat’s pivotal programme is another blow to Bace inhibitors and the amyloid hypothesis more broadly, the work will go on.
Presumably not with lanabecestat itself, however. Partners Eli Lilly and Astrazeneca said lack of efficacy rather than safety prompted the end of two phase III trials – encouraging news of sorts after Johnson & Johnson abandoned its Bace inhibitor atabecestat last month due to liver toxicity. Pre-symptomatic patients are surely the only remaining hope for those still willing the amyloid hypothesis to bear fruit – but evidence remains some way away (see tables below).
Deposits of amyloid plaques in the brains of Alzheimer’s patients have long been fingered as the bad guys and beta-amyloid antibodies and Bace inhibitors – the most widely studied mechanisms in this area – are both designed to reduce amyloid levels in the brain. The former work by clearing the deposits and the latter by preventing amyloid production in the first place, though neither mechanism has managed to demonstrate any useful impact on disease symptoms.
Lanabecestat is the latest Bace inhibitor disappointment, its developers having halted two studies in early stage and mild patients. This outcome is perhaps not a huge surprise after Merck’s setback with this mechanism last year (Verubecestat halt fails to stop the Bace chase, 15 February 2017).
These and other failures have prompted the field to move towards pre-symptomatic patients, who, it has been theorised, might be better helped by these agents. A Washington University-sponsored study could yield results the soonest – the trial started back in 2012 and is testing two anti-amyloid antibodies and a Bace inhibitor against placebo treatments, with the cognitive primary endpoint being measured after four years.
The J&J Bace inhibitor only entered the study in 2016 so presumably the first results will emerge from the abeta antibodies. The trial is only recruiting those with a rare genetic predisposition to Alzheimer’s, but the hope is that the findings will translate to the much more common sporadic form of the disease (Vantage point – Preventive Alzheimer’s trials keep amyloid hope alive, 26 April 2018).
|Alzheimer's disease preventive trials|
|DIAN-TU (Phase III)||Solanezumab (anti-beta amyloid MAb)||PSEN1, PSEN2 and APP mutations||2019/20||NCT01760005 (Academic study)|
|Gantenerumab (anti-beta amyloid MAb)||2019/20|
|JNJ-54861911 (Bace inhibitor)||2023|
|A4 (Phase III)||Solanezumab (anti-beta amyloid MAb)||Patients with evidence of amyloid pathology on PET scan||2022||NCT02008357 (Eli Lilly study)|
|EARLY (Phase II)||JNJ-54861911 (Bace inhibitor)||Apo E4 mutation with evidence of amyloid pathology||2024||NCT02569398 (J&J study)|
|Generation S1 (Phase II/III)||CAD106 (beta-amyloid vaccine)||Apo E4 mutation||2024||NCT02565511 (Novartis study)|
|CNP520 (Bace inhibitor)||2024|
|Generation S2 (Phase II/III)||CNP520 (Bace inhibitor)||Apo E4 mutation with evidence of amyloid pathology||2024||NCT03131453 (Novartis study)|
|API-ADAD (Phase II)||Crenezumab (Anti-beta amyloid MAb)||Patients with with PSEN1 E280A mutation||2022||NCT01998841 (Roche study)|
As for lanabecestat, it seems that the end of the road has been reached, at least in symptomatic patients. Lilly and Astrazeneca have yet to spell out any further work, though presumably if supportive evidence emerges of pre-symptomatic treatment regimens – and biomarkers to identity those at risk – any agent from the industry’s pipeline could be resurrected.
Aside from two large studies of solanezumab in early-stage settings, Lilly’s relatively extensive work in Alzheimer’s is now geared towards phase I or II studies. It has another Bace inhibitor under investigation, LY3202626, which the company has said penetrates the brain more readily than rival compounds and could inhibit amyloid-beta production much more dramatically.
Elsewhere, its N3pG-Aβ antibody has been designed to maximise plaque clearance, although the company has come up against problems with antibody immunogenicity. Another project, the 42 amyloid-beta peptide, targets a form of a-beta that is thought to be more toxic than the more soluble a-beta 40 form, against which previous projects have acted.
Data from this earlier-stage pipeline is amassing and should read out in the coming months, indicating whether Lilly has somewhere to go in this space. Still, all depend on the amyloid hypothesis being correct and that failures have been down to investigators approaching the right problem from the wrong direction.
Of course one of the main reasons that researchers keep coming back to the amyloid approach is that alternative, plausible hypotheses do not exist. But if the early-stage trials above yield nothing and pipelines like Lilly’s fail to progress, the search for new directions will become imperative.
|Lilly's clinical-stage Alzheimer's pipeline|
|Product||Pharmacological Class||Status||NCT ID|
|Solanezumab||A-beta MAb||2 PIIIs in pre-symtompatic patients ongoing; PIII in symptomatic patients failed||NCT02008357; NCT01760005|
|Lanabecestat||Bace inhibitor||PIII in symptomatic patients failed, no development ongoing||NCT02783573; NCT02245737|
|LY3002813||N3pG-Aβ MAb||2 PII studies ongoing||NCT02624778; NCT03367403|
|LY3202626||Bace inhibitor||PII mono and combo study ongoing, with LY3002813||NCT03367403; NCT02791191|
|LY3303560||Anti-tau MAb||PI study ongoing||NCT03019536|
|MEDI1814||Abeta 42 MAb||PI study completed||NCT02036645|