Read many of the headlines in the general press today and you might well believe that the biopharma sector was on the verge of a major breakthrough in the search for a cure for Alzheimer’s disease.
The reality, however, is somewhat more prosaic; the best that can be said of the data released at yesterday’s Alzheimer's Association international conference by Biogen and Lilly is that they offer snippets of support – nothing more – for having started phase III. Thanks to the wild expectations that had built up in the run-up to the meeting, however, the markets painted a different story.
The biggest casualty was Biogen, which lost 4%, or $4.2bn, on an aducanumab update that left unresolved most of the earlier doubts about toxicity and lack of efficacy. Lilly was initially off 4%, but then recovered to close up 1% as its data were presented and the sellside worked hard to fight the fire (Sola fails to wow, but does sustain hope, July 22, 2015).
One outlier also featured yesterday: Axovant, the controversial recent Nasdaq entrant banking on RVT-101, an Alzheimer’s project ditched by GlaxoSmithKline after failing phase II (Still don’t believe in a biotech bubble? Check out Axovant, June 12, 2015).
Yesterday Axovant presented a rehash of one failed study, with the same post-hoc analysis it had detailed in its IPO filing, which it said showed efficacy in Adas-Cog and ADCS-ADL measures – but only if just the study completers were considered. The stock fell 6%, and is now 39% below its float price last month.
One concern is Axovant’s reliance on a single phase III study of as little as 24 weeks; the established competition has carried out pivotal programmes of between one and two years’ duration. RVT-101 is to be tested as an add-on to Eisai’s Aricept in 1,000 patients, and the trial is to begin in the fourth quarter.
Meanwhile, Roche confirmed its widely expected decision to plough on with two beta amyloid MAbs, crenezumab and gantenerumab, though the former has failed two phase II trials and the latter flunked an interim futility analysis in a phase III study in prodromal patients.
Roche puts its faith in higher dosing and the view that, while solanezumab targets soluble beta amyloid and aducanumab the fibrillar and oligomeric forms, its own two projects hit all three. None of this addresses a key problem underpinning the amyloid hypothesis, namely that antibodies’ inability to cross the blood-brain barrier means that they cannot exert their activity in the CNS.
Still, with the renewed hype around Alzheimer’s and the beta amyloid hypothesis, Roche can hardly be blamed for pressing on, and neither can Lilly or Biogen.
For its part Biogen filled in some important gaps in aducanumab’s multi-dose phase I trial. That had earlier shown efficacy on the MMSE measure at 3mg/kg and 10mg/kg, but with worrying imaging abnormalities thought to represent vasogenic oedema (termed ARIA-E) at the highest dose (Biogen clears one Alzheimer’s hurdle; now comes the tricky bit, March 20, 2015).
The hope was that another dose, 6mg/kg, would open up the therapeutic window, but yesterday this failed to show an MMSE benefit. Instead Biogen highlighted a neat dose-response seen in aducanumab’s effect on CDR-SB – the primary endpoint the group is using in both the phase III studies that it begun recently.
However, safety remains a big concern: ARIA-E was associated with patients' ApoE4 status, and among ApoE4 carriers – who have an elevated risk of Alzheimer's – it occurred in 5% at 1mg/kg and 3mg/kg, but 43% and 55% at 6mg/kg and 10mg/kg respectively. This might be a tiny study, but on the available data any therapeutic window looks to be tiny.
If Lilly and Biogen’s presentations do provide enough support for ongoing pivotal studies investors will have to switch their attention to solanezumab and aducanumab readouts due in several years’ time. Alzheimer’s is again providing biopharma with massive binary outcomes.
|Pivotal binary outcomes in Alzheimer's disease|
|Project||Company||Study||Design, primary endpoint||Primary completion||Trial ID|
|Gantenerumab||Roche||Marguerite Road||1,000 pts, 104 weeks, PET imaging, Adas-Cog & ADCS-ADL||Jul 2019||NCT02051608|
|Aducanumab||Biogen||Emerge||1,350 pts, 78 weeks, CDR-SB||Feb 2020||NCT02484547|
|Aducanumab||Biogen||Engage||1,350 pts, 78 weeks, CDR-SB||Feb 2020||NCT02477800|
|Solanezumab||Lilly||A4||1,150 pts, 168 weeks, ADCS-PACC||Apr 2020||NCT02008357|