These days barely a week seems to go by without some big news on the CAR-T front, and given the complexities in manufacturing/production of a distinctly personalised T-cell medicine, it is not surprising that the news is more often bad than good. That's pretty much par for the course for the evolution of a truly groundbreaking new therapy, and it is still advancing at a rather incredible rate!
After recent events that have included the clinical hold placed on Juno's Phase II trial of JCAR015 by the FDA, well, things have been a little shaky. The death of three patients under 25 was subsequently ascribed to the combination of fludaribine into a regimen that previously used only cyclophosphamide for pre-conditioning, though Juno's proposal to restart the trial using only cyclophosphamide was extremely rapidly approved by the FDA.
Some believe that it was too rapid a turnaround given the deaths, but Juno executives appear to have been extremely persuasive in their arguments, and the shares that had plunged on the bad news soared back up once more when the clinical hold was lifted. The FDA is not known for being particularly expeditious or pharma-friendly especially when people are dying in clinical trials, so the mere days required to get the clinical hold lifted are indicative of a collective enthusiasm at the agency to get this novel treatment tested and approved - apparently, at least.
Not long before the Juno problems, top competitor Kite announced that the NIH were going to review their cell therapy manufacturing facilities at the National Cancer Institute, even if such intervention was not anticipated to impact their pivotal multi-centre Phase II trial of Kite-C19 CAR-T product. However, they were not permitted to enrol more patients until such review will be completed, and the ecosystem bristled at the prospect of more bad news.
On top of all of this came the somewhat stunning news last week that pharmaceutical giant Novartis was "pulling back" from the forefront of the CAR-T race, and would be disbanding the cell and gene therapies unit (CGTU) that was behind their CTL019 treatment, currently in Phase II clinical trials. While this might have seemed a natural step to take if they were announcing it as an aspect of their success in having jumped all of the manufacturing hurdles and having flown throw the various regulatory hoops, in actuality this was hardly the case.
Au contraire, in fact. First came the news that 120 workers at CGTU were being axed, with the pharma stating that the rest of the outfit was simply being reintegrated back into the mothership as part and parcel of their immuno-oncology division. That sounds truly bizarre to me; take something that is as unique and uniquely challenging as manufacture of CAR-T therapeutics, back out of a specialised unit charged with so doing, and stick it right back into the pharmacological parent giant from which it was extruded in the first place? Right in the middle of critical clinical trials? Things that make you go "hmmm"!
Next came the news that it wasn't just laboratory hands that were being let go, but the bulk of the senior executives running the cell therapy unit were also being axed, and that doesn't sound optimistic at all. The job is not done, as far as we are aware at any rate, and why would you not let the team stick around to at least get credit for successfully applying for an NDA and having CTL019 approved for marketing?! Apparently that's not to be, as outlined in a leaked memo from Oz Asam himself:
"Unfortunately a number of colleagues will be impacted by this change as many positions are being eliminated. Impacted US-based associates are being notified in meetings today. Associates based in Basel will learn more about their individual circumstances on Thursday. The majority of the CGTU Leadership Team members, who are among the best I have worked with, are also impacted."
"Among the best that I have worked with" yet you are eliminating them? Are you kidding me? Especially given that Novartis restated their commitment to CAR-T technology and that they intend to file with the FDA in early 2017 and with the EMA later the same year? They are either confident that the job is done and no more tweaking will be needed or they know something that we don't. Rumours that some of the 120 axed job are based at their 173,000-square-foot manufacturing facility in Morris Plains, NJ, are hardly comforting in that regard.
So what is it that Novartis might know that we don't? At worst, one could imagine that there is extremely bad news coming out of their current clinical trials, and Novartis is preparing their exit bit-by-bit, in advance, to soften the blow when the hammer falls. They have invested heavily already, including $43M for the ex-Dendreon facilities in Morris Plains, but why put more good money after bad, if the news is indeed bad? A scary prospect!
Honeslty though, I don't think that's it. My take on it is that Novartis have been somewhat rocked by the recent turbulence in the field in general, and probably have come up against technical issues or clinical challenges that have convinced them that CAR-T might be too great a developmental and commercial challenge today. Given the equally turbulent political arena in the USA (hell, everywhere!) right now, and the heavy-duty governmental surveillance of the drug pricing wars, well, this could be another factor that might force a serious reconsideration of the commercial prospects for such a personalised medicine.
CAR-T manufacturing is a much more 24/7 complexity-filled process than producing tablets or even a routine (today) biologic such as a monoclonal antibody. It is clearly a high-risk venture, and in many ways, that may define it as something that only large biotech should take on and hurdle, given their increased capacity (hunger?) for such risk. Pharma tend to be more conservative, and there's not much about CAR-T therapy that aligns with with the word "conservative".
One pharma's loss is another pharma's gain, and even though he has nothing but respect for Novartis, Kite's Arie Belldegrun clearly sees added opportunity in the reported Novartis withdrawal from the CAR-T race. Ditto Hans Bishop at Juno, although Beldegrun stated that Kite has gotten both the number of cells infused and the doses of both chemotherapeutic agents (fludaribine and cyclophoshamide) worked out so as to avoid the problems experienced at Juno. So maybe Kite has the edge, in September, 2016.
I quote the month, above, because things are moving, shaking and changing on a monthly basis in this horse race to the finish line, and who knows what will happen next? Speaking personally, it is now time for this horse to put the car-t behind him, get out into the fresh air of a blustery, autumnal Sunday morning and put in some solid laps on the racetrack of Molson Stadium!
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