The recent failure of Transition Therapeutics’ ELND005 could be seen as another nail in the coffin of the amyloid hypothesis in Alzheimer’s disease. But some researchers are still convinced that the theory is valid, and one candidate, Biogen’s aducanumab, might provide some hope.
On paper, the anti-beta amyloid antibody “looks really good”, Dr Francesca Mangialasche, a geriatrician and researcher at the Karolinska Institutet in Sweden, tells EP Vantage. Still, it will be years until there is a definitive answer to the broad question, raising another point: will pharma companies – and investors – lose patience with the approach?
Dr Mangialasche believes that aducanumab is more efficient at removing the main perpetrator, soluble amyloid, than older assets in the same class. And some of these other antibodies have not yet been written off entirely either.
Speculation over Lilly's presentation of data from an open-label extension trial of solanezumab at the upcoming AAIC meeting sent the company’s share price up 5% and led to the Alzheimer’s Association scrapping its plan to post conference abstracts in advance (Lilly’s sola still has a mountain to climb, June 11, 2015). Lilly is also evaluating the project in mild Alzheimer’s patients in the phase III Expedition 3 trial.
That brings us to the crux of the matter – are amyloid-targeting drugs being used in the right people? The thinking is that earlier treatment is better, and that by the time a patient has symptoms it is already too late.
So far, it has been difficult to prove this, but a public-private consortium called EPAD (European Prevention of Alzheimer’s and Dementia) could provide an answer, albeit in several years’ time.
As well as looking at people with mild cognitive impairment (MCI), thought to be a precursor to Alzheimer’s, EPAD will also test potentially disease-modifying drugs in asymptomatic people at risk of developing Alzheimer’s. Identifying these people, using imaging or other biomarkers, is “one of the biggest challenges”, according to Professor Craig Ritchie, EPAD co-coordinator and professor of psychiatry of ageing at the University of Edinburgh.
The €64m project, which kicked off in January, will recruit from pre-existing cohorts across Europe. For example, “there are over half a million people in the UK Biobank, many of whom are about to get imaged as part of Dementias Platform UK. And if those individuals show evidence of what we think is relevant disease, then they will be invited to come forward,” says Professor Ritchie.
EPAD is aiming for a 24,000-person register that it will use to create a 6,000-strong cohort for longitudinal follow-up. From this pool around 1,500 people will be enrolled in a proof-of-concept trial to test “any intervention that has a strong scientific rationale for disease modification, and is also ready for phase II testing”.
This could include anti-amyloid drugs, as well as nutraceuticals or products targeting Tau, among others. It could also involve combinations of different approaches.
But even if this is successful, Professor Ritchie does not expect any candidates from the EPAD study to reach the market until 2020 at the earliest, as any findings will need to be confirmed in further trials.
The new approach is too late for Transition. ELND005, a beta amyloid aggregation inhibitor, had already failed to slow the progression of Alzheimer’s in a phase II trial, but it also fell short on neuropsychiatric endpoints of agitation and aggression, wiping out over two thirds off the company’s share price on June 24. Whether this was due to the trial design, patients recruited or ELND005 itself remains unclear.
Dr Mangialasche believes that at least some of the blame for previous failures is down to older candidates not being up to scratch. “With some drugs that we thought were targeting beta amyloid, we found they didn’t reach the central nervous system in high enough doses.”
Indeed, the amount of antibody that can cross the blood-brain barrier is thought to be minuscule, which, if just targeting circulating beta amyloid is not enough, could scupper the likes of solanezumab and other MAb approaches. One company aiming to address this is Alzheon, which is developing a small molecule that it believes can penetrate this barrier (Interview – Alzheon's bid to prove the beta amyloid doubters wrong, March 23, 2015).
Other potential problems with anti-beta amyloid antibodies include an increased risk of haemorrhage if they bind to beta amyloid on blood vessel walls, or low efficacy because they target amyloid found in plaques rather than soluble amyloid, Dr Mangialasche adds. But she is optimistic that past defeats can increase the chance of success in the future, saying: “Learning from previous failures, we can refine our weapons.”
Biogen’s aducanumab could eventually become one of these weapons – but so far it has only succeeded in phase I, so it will be some time before it becomes known whether it does address the issues seen with earlier projects (Biogen clears one Alzheimer’s hurdle; now comes the tricky bit, March 20, 2015).
Muddying the waters are other Alzheimer’s hallmarks like the aforementioned Tau, a protein found in tangles in the brains of those affected alongside the amyloid plaques.
“Dementia is, for sure, caused by a combination of different mechanisms,” says Dr Mangialasche. “I think it’s reasonable to expect that we need to target more than one mechanism.” She foresees a multi-pharmacological approach in Alzheimer’s, similar to that seen in heart failure, with patients taking several different types of medications.
Both Professor Ritchie and Dr Mangialasche are confident that the amyloid hypothesis is still alive and kicking. “[It’s] really hard to kill,” concludes Dr Mangialasche. “The pathway per se is still a valid target. How you address that is another question.”
Professor Ritchie adds: “Even if solanezumab or other drugs aren’t proven effective over the next couple of years, EPAD still has a huge value because I think what we’ll find will stimulate the whole area again – [leading to] better drugs and going in even earlier.”