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Trust favourite Biogen preps for detailed Alzheimer’s trial results

Trust favourite Biogen preps for detailed Alzheimer’s trial results

Trust favourite  Biogen preps for detailed Alzheimer’s trial results

Trust favourite Biogen (Nasdaq: BIIB), the largest single holding for Biotech Growth Trust (BIOG, 11.7% of NAV) and widely held stock among other sector specialist collective vehicles – will with its joint venture partner Eisai shortly disclose detailed results from a Phase II study of the Alzheimer’s drug BAN-2401 . This disclosure, which will take place at the Alzheimer’s Association Intentional Conference (AAIC) on July 25th, is highly anticipated. A report earlier this month that the top dose tested in the study reached statistical significance caused Biogen’s share price to surge 20% in a day and added $12bn to its market cap.

The context for this is that Alzheimer’s disease is the most notoriously difficult area for pharmaceutical development. It has the highest failure rate (at almost 100%) of any disease area, added to which it is also the most expensive area in which to conduct Phase III trials. Nevertheless, Alzheimer’s remains the pharmaceutical industry’s “Holy Grail” – it represents the largest untapped commercial opportunity, given there is, as yet, no approved drug intervention that has been shown to have a disease modifying effect – one that changes the trajectory of cognitive decline.  A handful of drugs are available, mostly now generic, for symptomatic treatment of Alzheimer’s but these have only been shown to confer a short-term benefits in terms of activities of daily living (dressing etc).

Biogen and Eisai – which effectively have a 50:50 risk sharing venture for BAN-2401 and elenbecestat, another Alzheimer’s drug – have so far reported only the outcome of the 856-patient “Study 201”, namely that the highest dose of BAN2401 achieved statistical significance after 6, 12 and 18 months duration. The study’s primary endpoint was progression, as measured by the Alzheimer’s Disease Composite Score (ADCOMS) and reduction of amyloid accumulated in the brain,  as measured using amyloid-PET (positron emission tomography). The outcome was a surprise since the study had in December 2017 been reported to have failed to meet criteria for success at 12 months, albeit using Bayesian analysis (a novel statistical approach). At 18 months, however, efficacy was evaluated by using conventional statistical methods on ADCOMS, which combines items from the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale and the Mini-Mental State Examination (MMSE) to enable sensitive detection of changes in early AD symptoms. The highest treatment dose of BAN2401 began to show statistically significant clinical benefit as measured by ADCOMS as early as six months including at 12 months using these methods.

The study enrolled patients with mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s dementia with confirmed amyloid pathology in the brain and treated patients were randomised to five dose regimens, 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly and 10 mg/kg biweekly, or placebo. The Bayesian approach allows an adaptive design so that more patients are recruited to the dose(s) that show the greatest effect.

The key unknowns that are likely to emerge at AAIC include the placebo-adjusted difference in ADCOMS and the statistical confidence, essentially the “p” value, which must by definition be a below 0.05 for it to have been declared significant.  The statistical confidence will be a function of the effect size as well as the number of patients tested (at the top dose) – this is unknown but has been estimated by one analyst at between 169-217.

Biogen and Eisai have commented that the results would be discussed with regulators, which would be normal practice anyway, but it seems to have fanned excitement in the investment community that there may be some possibility of an accelerated regulatory strategy. Although the FDA has recently issued new guidance designed to allow earlier approval of promising Alzheimer’s drugs, it seems highly unlikely that data from a small Phase II study using an unvalidated endpoint would support any kind of approval.

More likely is that Biogen and Eisai will commit to conduct Phase III trial(s) of the BAN2401. This would be, however, be a major burden given it already running an  expensive phase III programme in Alzheimer’s. Biogen is conducting two large  Phase III trials with a beta-amyloid antiobody, aducanumab, and paying half the costs of two Phase III trials with Eisai for elenbecestat. The two aducanumab trials, which are due to render results in late 2019 and early 2020, are already expected to be the largest binary catalyst in biotech in many years.

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