Analysts on amyloid thesis: It's not dead yet

Print 12 December 2016
Ben Adams / Fierce Biotech

Just a few weeks back, many were writing off the amyloid hypothesis in Alzheimer’s after Lilly posted top-line data showing its candidate failed a phase 3. Last night, however, Biogen released some fresh data for its drug aducanumab that, alongside some more detailed info from Lilly’s failed med, may just warrant another look.

First, to Biogen, which posted its data at the CTAD Alzheimer’s meeting in San Diego. The trial was from a phase 1 test in early forms of Alzheimer’s Disease (AD) that looked at escalating doses of its med, a med that targets beta amyloid, sticky plaques that are one theory behind why Alzheimer’s occurs in the brain.

By removing this plaque, many biotech and pharma researchers believe they can slow down the progression of the disease—although the amyloid thesis has not produced a new drug for the memory-stealing condition, and is full of failed drugs in its wake.

In the small study, Biogen’s candidate saw significant reductions in these amyloid plaques when compared with a dummy therapy in early-stage Alzheimer's patients given progressively increased dosing (a.k.a. titration) of aducanumab.

Side effects remain a concern, however, notably with a condition called “Aria” that hit 35% of patients carrying the ApoE4 allele (which can increase the risk of AD) in the titration arm. Amyloid-related imaging abnormalities (Aria) can cause serious swelling in the brain.

Meanwhile, the incidence of this condition in ApoE4 carriers in the fixed-dose arms was 5% in the 1 mg/kg and 3 mg/kg arms, 43% in the 6 mg/kg arm and 55% in the 10 mg/kg arm.

Biogen’s “exploratory results” from the early study showed dose- and time-dependent slowing of clinical decline as measured by the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), which stages the severity of the disease.

The results of the CDR-SB showed that patients in the placebo group worsened by an average of 1.89 points at 54 weeks, while this was less in the aducanumab dosing arms, and appeared to show stronger results as the dose of the drug went up. The same was also true with the MMSE scoring, which tests a number of different mental abilities, including a person's memory, attention and language.

The drug already has speedy review tags from both the EMA and the FDA, given a PRIME status in August from Europe’s regulator while in September gaining an FDA fast-track tag.

It’s currently also undergoing several late-stage tests, although read-outs from these are not expected for a few years yet. It now appears to be a front-leading med in this condition which has not had any positive R&D results for years.

As always in this field, caution is always advised: The Big Biotech has built up hopes on this drug before, but only to see weak results. Back in 2015, after posting some eyebrow raising data in March, a few months later in July the 6mg dose of failed to deliver, falling short on MMSE and CDR-SB. Safety issues also raised their heads in this study.

The company is some years away from getting the drug on the market, and in its later stage tests it will need to find the sweet spot on dosing to get the level of efficacy balanced against the risks of Aria right if it is to find a path to market. But it helped the co in the short-term, as it shares ticked up 2.7% last night afterhours on the news.

Lilly also showed its working last night on the failed solanezumab, a drug it dropped from seeking regulatory review last month after late-stage results for the med, which was also targeting amyloid plaques, showed in patients with mild Alzheimer's disease that it could produce no significant slowing in cognitive decline compared to placebo.

At the time, however, it said there were some glimmerings of a benefit. In reality, these glimmerings change nothing to its program, and the details were modest: In one update, Lilly found that changes in a biomarker for AD, known as plasma a-beta, were similar to those seen in previous studies, and the differences between treatment and placebo groups were statistically significant.

But it was a mixed message, as changes in amyloid deposition as measured by a PET scan “did not reach statistical significance between treatment and placebo groups,” the company said in a statement.

In a note from Barclays, the firm noted that: “Unlike in the top-line release, during today’s presentation, the investigators revealed that while sola seemed to have a positive, albeit small impact, on several clinical measures, the antibody failed to have a significant effect on plaque burden.

“With regards to the clinical assessments, the results directionally favored solanezumab vs. placebo—even achieving statistical significance at a number of time points—although in all cases, the magnitude of effect was minimal.”

But the note said that, when taking results from Biogen as well: “Together, these studies suggest that successfully reducing amyloid deposition may have a favorable impact on AD, i.e., that the amyloid hypothesis may be valid. 

“With additional Lilly comments that the CDR-SB measure is optimal at detecting changes in mild AD patients—the primary endpoint for Biogen’s phase 3 aducanumab studies ENGAGE and EMERGE—the outlook for Biogen looks increasingly favorable.”

Bernstein also said in a note to clients that: “Solanezumab data support amyloid hypothesis, but has small effect size and minimal impact on brain plaque load.” It noted that this was a “positive read across for Biogen.”

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