If insanity is doing the same thing again and again expecting a different result then some Immupharma investors need to pay their psychiatrists a visit. Today’s unmitigated failure of the UK company’s lead, Lupuzor, should have come as no surprise to anyone with more than a passing acquaintance with this troubled asset.
Lupuzor had already failed two mid-stage lupus trials before more funds were raised for its latest ill-fated foray, this time into a woefully underpowered phase III study. As Immupharma looks set to attempt yet another resuscitation the markets must quickly take on board the lessons from today’s disaster.
The upbeat tone of the group’s statement announcing the phase III failure can scarcely be believed. Immupharma today hailed Lupuzor’s “superior response rate over placebo”, and said it would share the data with potential commercial partners, with some of which it claims to be in ongoing discussions.
Yet in the phase III trial Lupuzor showed a highly non-significant p value of 0.2631 for its primary endpoint, 52-week response versus placebo. With Immupharma stock off 75% the market is clearly not buying this, though why the shares had doubled in the six-month runup is a mystery.
Writing on the wall
After all, to seasoned UK biotech watchers the writing had been on the wall for some time – even if Immupharma managed to find excuses for every setback it encountered.
Lack of a dose response in an earlier 147-subject phase II trial was blamed on stimulation of negative feedback loops in the immune system, and when even this study’s “active” dose failed this was put down to a statistical quirk.
Immupharma did license Lupuzor to Cephalon eight years ago, and when that company’s phase II trial was deemed “inconclusive” this setback was put down to Cephalon’s use of trehalose rather than mannitol as an excipient. Dissolution of that deal was apparently due to Teva’s takeover of Cephalon. Today’s excuse was an excessive response among placebo recipients.
|The Lupuzor timeline|
|Oct 2006||24-pt study shows an effect on disease markers; analysts pencil in 2010 launch|
|Feb 2008||Despite filing IND for phase II/III trial, Immupharma starts 200-pt phase II study|
|Jan 2009||Interim analysis of first 147 pts suggests stat sig effect for lower – but not higher – of two doses|
|Feb 2009||Cephalon licensing deal gives Immupharma $15m option fee plus $30m up front|
|Dec 2009||Phase II analysis gives lower dose p value of 0.048 – missing 0.025 significance threshold (higher dose still not sig)|
|Jun 2010||Instead of going into phase III Cephalon opts to start another phase II trial, in 220 pts, hoping for 2014 filing|
|Oct 2011||Teva buys Cephalon, and Lupuzor is handed back to Immupharma|
|2012||Cephalon's phase II study deemed "inconclusive"; Immupharma blames use of trehalose instead of mannitol|
|Jan 2015||Immupharma strikes deal with Simbec-Orion (CRO) to run phase III; study to begin "immediately"|
|Nov 2015||Phase III study recruits first of 200 patients|
|Apr 2018||Phase III study fails; Immupharma blames high placebo response|
Despite the warning signs Immupharma had embarked on its current course three years ago, signing an unusual collaboration with the contract research organisation Simbec-Orion, which accepted stock in lieu of cash as Immupharma’s reserves were desperately low.
It then took 10 months to start the current trial, which Immupharma only later raised money to complete. While Benlysta, the first drug to be approved for lupus for 50 years, underwent a pivotal programme in over 2,000 subjects Immupharma opted for just 200 in what, despite being termed a phase III study, looked like nothing more than yet another phase II to overcome the earlier setbacks.
Lupus is notoriously hard to diagnose owing to its relapsing nature, which makes it difficult to ensure that patients enrolled actually have the disease. Immupharma hinted at this today when highlighting a subset of subjects with anti-dsDNA autoantibodies, though in a trial this small it is hard to see what it could demonstrate statistically.
The company insists that today’s results “provide evidence for the continued investigation into the development and commercialisation of Lupuzor”. Investors should look beyond such hype.