Upcoming events – Neurotrope aims for Alzheimer’s while brigatinib comes late to the Alk party
Welcome to your weekly digest of approaching regulatory and clinical readouts. Phase II data are expected this month from Neurotrope’s Alzheimer’s project Bryostatin-1, which aims to activate protein kinase-c, though the litany of failures targeting this tricky disease is hard to ignore.
Meanwhile, Takeda’s Alk inhibitor brigatinib will go before the US regulators by April 28 in second-line NSCLC. This asset came through Takeda's acquisition of Ariad, and if approved it will be entering a crowded market: only this week Roche’s competing asset Alecensa proved itself in a first-line setting, reinforcing it as the one to beat.
Bryostatin-1's phase IIb study tests 20 or 40 micrograms administered intravenously over 45 minutes every other week after two initial loading doses, in 148 patients with moderate to severe Alzheimer’s, versus placebo.
Primary endpoints measure adverse events and change from baseline in the severe impairment battery, which assesses cognition, while secondary endpoints include activities of daily living, neuropsychiatric inventory and mini-mental state exam. Topline efficacy data are due this month.
Bryostatin-1 is a protein kinase-c-epsilon activator said to target multiple pathways, including activating synaptic growth factors and amyloid-beta degrading enzymes. A phase IIa study in nine patients with mild dementia showed good tolerability, and while there was no improvement in cognition Neurotrope said only a single dose was given, and that previous animal studies showed improvement with multiple doses.
Three patients have also been treated in a compassionate-use programme, where the company has reported improvements in cognition and daily living, and even states the possibility of disease reversal, but obviously this will need to be proven in upcoming trials.
Neurotrope was formed in 2012 out of the Blanchette Rockefeller Institute. It was originally listed on the OTC bulletin board, but last month began trading on Nasdaq after a 1-for-32 stock consolidation, since which shares are up 161% and the market cap now sits at $137m.
The company will need to raise more cash in the not too distant future; as of March it had approximately $24.1m, sufficient to fund operations for the next 18 to 24 months. Funds will be used to complete phase II study, and start an open-label extension trial and a study in Fragile X syndrome.
Bryostatin is purified from Bugula neritina, a marine invertebrate first isolated in the 1960s. It was initially tested in oncology by the NCI, but proved ineffective. The private company Aphios is also investigating it preclinically in Alzheimer’s with APH-0703 and its analogue APH-1104.
Numerous competitor failures have turned Alzheimer's into a development graveyard, but this has not stopped investment. Biogen just paid $300m up front for Bristol-Myers Squibb's phase I anti-tau MAb BMS-986168, for instance (For $300m Biogen beefs up its Alzheimer’s attack, April 13, 2017).
Takeda's brigatinib is filed for metastatic Alk-positive NSCLC patients resistant to or intolerant of Pfizer’s Xalkori, and has a PDUFA date set for April 28.
The market is getting increasingly crowded with the likes of Xalkori, Zykadia and Alecensa all competing for a small patient population – only 3-5% of NSCLC cases are Alk-driven. Roche reported topline data this week showing Alecensa beating Xalkori in the first-line setting, highlighting Alecensa’s potential to become the best seller in this class.
Brigatinib was one of the main drivers of Takeda’s move on Ariad, and it must show that it can compete with Alecensa to justify the $5.2bn price tag. Results from brigatinib’s first-line trial Alta-1L are likely to emerge towards the end of 2018, while a study in Alecensa failures started last month (Therapy focus – Roche looks ready to rule another cancer niche, March 6, 2017).
|Bryostatin-1||NCT02431468||Phase IIb, 148 patients with moderate to severe Alzheimer's|
|Bryostatin-1||NCT02221947||Phase IIa, 9 patients with mild Alzheimer's|
|Brigatinib||NCT02737501||Alta-1L, brigatinib versus Xalkori in first line use, primary completion April 2019|
|Brigatinib||NCT02706626||After treatment with 2nd generation Alk inhibitors, primary completion June 2018|