Had Innate Pharma been able to say in 2015 that the Effikir study dose discontinued for futility was the higher of two, investors would have written off the trial as a failure there and then. As it was, the moment of truth was put off until today, meaning that confirmation of Effikir’s flop sent Innate down 24% this morning.
The share price fall aside, there are several reasons why Effikir was highly unlikely to work. Indeed, smart investors interested in Innate’s far more important ongoing combination studies might have been waiting for precisely this scenario as a way into the stock.
After all, lirilumab, the Innate lead asset tested as monotherapy in Effikir, is mechanistically more likely to work as part of a combo, a strategy backed strongly by Bristol-Myers Squibb. And Effikir’s target indication, the highly intractable blood cancer acute myelogenous leukaemia, was clearly too tough a disease.
Seeds of doubt were sown in March 2015 when Effikir’s data and safety monitoring board declared one of two lirilumab doses futile, and recommended the study’s continuation with just two arms – one active dose and placebo – and delaying its readout.
Market jitters soon subsided with the assumption that the discontinued dose was the lower one, 0.1mg/kg, rather than 1.0mg/kg, though because Effikir had to remain blinded the dose in question could not be disclosed. Today Innate revealed that it was actually 1.0mg/kg that was futile at interim.
Hopes that Effikir still had a chance had additionally been stoked by Oddo analysts, who last September claimed that “the fact that this study is still ongoing two years down the line is an indication that lirilumab has far greater efficacy than placebo”. This lack of understanding of data analysis should be a warning to any investors attempting to guess the outcome of a blinded, event-driven study.
Beyond saying Effikir failed, Innate is releasing no data from it for now. A numerical comparison of the active versus placebo arms might be interesting, though the lack of a dose response that the higher dose’s discontinuation points to suggests that any positive hints might be down to luck.
On a call today Innate executives said Effikir would also yield pharmacokinetic and pharmacodynamic data points, but that progression-free and overall survival would not be revealed until a scientific meeting. As for a readthrough to combination trials, the company said there was “little to none”.
There are reasons to be optimistic about those combo studies of lirilumab, as well as another Innate asset, monalizumab, for investors who think that this is a good entry point (Event – Innate's value will be clearer by year end, October 27, 2016).
Lirilumab and monalizumab target immune checkpoints on natural killer (NK) cells – KIR and NKG2A respectively – and combining them with an anti-PD-1/PD-L1 antibody could achieve synergy analogous to Bristol’s Opdivo and Yervoy combo. Moreover, unlocking the activity of NK as well as T cells is an enticing prospect.
It could be hypothesised that, in Effikir, blocking KIR alone was insufficient without T-cell activation and/or a specific receptor also being targeted. Lirilumab is in an extensive programme of trials combining it with Opdivo, while monalizumab is licensed to Astrazeneca, which is combining it with durvalumab.
There is little visibility on the timing of these partner-sponsored trials. However, there is already evidence that shareholders are willing to bet on them from the lowered share price: by early afternoon trading Innate was off only 13%.
|Study||Design||Primary endpoint||Trial ID|
|Effikir||Double-blind, maintenance treatment of 150 AML pts in 1st CR given lirilumab 0.1mg/kg (arm discontinued), 1.0mg/kg or placebo||Leukaemia-free survival||NCT01687387|