Welcome to your weekly roundup of approaching clinical readouts. While Atara investors fret over problems like the repeated delays to the group’s cancer cell therapy Tab-cel, and its C-suite overhaul, they have an important clinical readout to look forward to: by the end of the year ATA188, an allogeneic T-cell immunotherapy, will generate efficacy data in progressive multiple sclerosis.
The therapy comprises donor T cells that have been sensitised against Epstein Barr virus (EBV) antigens, and HLA typed so they can be matched to recipients. Atara argues that they can recognise and eliminate EBV-infected B cells and plasma cells that are present in the CNS and might be involved in MS pathophysiology.
A key driving force behind the hypothesis that EBV plays a role in MS has been Dr Michael Pender, at the University of Queensland, Australia. Atara already had access to a bank of EBV-specific T cells from Memorial Sloan-Kettering for oncology use, and was spurred to pursue MS a couple of years ago.
At the European Academy of Neurology meeting last month the group presented early data from its clinical trial, backing the HLA matching approach and showing no dose-limiting toxicities with three ATA188 doses. However, what investors most want to see is efficacy, to back up Dr Pender’s EBV hypothesis.
Efficacy measures in the 60-subject safety study include EDSS scores, brain imaging and biomarker data. On the basis of this a 36-subject phase II study of ATA188 could begin at the recommended dose. Separately, Atara wants to start a randomised study of ATA190, an autologous MS product, in the second half.
How any success in MS might fit into Atara’s plan to become a Car-T player – the specialist area of its new chief executive, Pascal Touchon – is a separate question.
|Study||Key aims||Trial ID||Data|
|60 progressive MS subjects, four ATA188 dose levels||Show safety and determine recommended phase II dose||NCT03283826||Safety at EAN (Jun 2019); efficacy H2 2019|
Meanwhile, Aslan’s lead project, the pan-Her inhibitor varlitinib, bombed in gastric cancer in January. The company is running low on cash, and desperately needs a win in varlitinib’s next targeted setting, biliary cancer; potentially registrational data from Treetopp, a phase II/III study, are due in the coming months.
The second-line, chemo-combo trial has 127 patients recruited into an initial phase II portion. Clinicaltrials.gov lists four primary measures: safety, objective response rate, progression-free survival and overall survival; the last is unlikely to read out at this stage, so ORR and PFS are crucial.
According to analysts the statistical analysis plan allows for primary success if either endpoint is significant at the one-sided p=0.05 level, or if both endpoints are significant at a one-sided p=0.1. If either is positive Aslan plans to file for accelerated US approval.
After the gastric failure in January Aslan slashed its cost base in half, and with only $22m in the bank any signal of efficacy will likely be used to raise money. The prospect of such a move has probably contributed to the 53% slide in Aslan’s ADRs over the past 12 months.
Lack of confidence in varlitinib will also not have helped. Biliary tract cancer is known to be a very difficult tumour type; no targeted agent has worked, and surgery and chemo-radiation remain standard of care. The disease is much more prevalent in Asia than in the US.
The company's rationale is based on evidence suggesting that a large proportion of biliary tumours overexpress Her receptors. Varlitinib, which Aslan licensed from Array, hits Her1, Her2 and Her4.
Earlier this year the company reported encouraging responses in a small first-line biliary tract study: a 44% response rate improved to 60% in patients given a higher dose, which is being tested in Treetopp; chemo typically generates responses of around 26%.
However, as Leerink points out, much stronger clinical validation is still needed, particularly as the mechanistic advantage of varlitinib being a pan-Her inhibitor remains unclear. Such a cautious statement from the typically optimistic sellside should probably not be overlooked when assessing varlitinib’s chance of success.
|Consensus sales forecasts for varlitinib|