Novartis - a huge horse pulling a massive CAR-T!

The horse and car-t race between Kite, Juno and the behemoth Novartis (among a few others) took a turn in a considerably optimistic direction yesterday, following the news that Novartis had nicely hurdled none other than the FDA, at least for now. An external panel of experts, convened by the agency to assess the usefulness and risks of this groundbreaking new technology, delivered a resounding 10-0 victory to the pharma yesterday.

That technology, referred to as CTL019 (or tisagenleleucel) currently, is the first in a new wave of leukemia treatments that have the potential to revolutionise the therapy of not just leukemias and blood-borne cancers, but ultimately solid tumors as well. We are not there yet though, and for now the focus is on hematological cancers, using a patient's own T-cells to attack the problem, once they have been biomolecularly retuned to seek out signals on the patient's cancer cells. 

The FDA is well aware of the risks inherent to the approach, which has even resulted in patient deaths on several occasions in various clinical trials, but for those individuals who have been through the agony of chemotherapy and stem cell transplants without success, the one certainty in their short term future is death, itself, so anything viable is worth trying. Furthermore, cytokine storms and rare patient deaths aside, the approach has seen resounding responses in many, with Novartis themselves observing >80% of patients remaining in remission some 12 weeks after treatment in a recent trial. 

Unquestionably that kind of success outweighed the considerable safety concerns that the panel had, given the type of patients being treated. The CAR-T field has been in the news for years, in both good and bad ways, but it is the way forward (among other avant garde developments) and I think many are breathing a huge sigh of relief that the FDA is not going to be the elephant-in-the-room on this, and Novartis et al. are being given a green light. That green light won't be official until sometime in October this year, and Kite themselves will be flying high just behind Novartis in November, all being well. 

All of the high-level publicity is good for business, of course, but the practicalities of actually rolling it out and delivering the quality-controlled "product" is a very different matter than simply producing pills, when it comes to autologous cell therapy. Novartis has to ensure safe and robust manufacturing processes that involve taking blood from patients all over the country, shipping it to one of several specialised sites available, manipulating those cells, and subsequently shipping them back to the hospital for direct delivery into the bloodstream of those same patients. 

Clearly there are numerous points where this kind of drug product could vary or go awry from one sample to another, given just the number of different individuals involved in handling the samples from hospital to pharma and back to hospital again. It seems somewhat daunting but Novartis appear confident that they are ready for the task at hand, with reportedly some 30 centres readied for the manufacturing process. Nevertheless, Novartis has estimated a 22-day turnaround on such manufacturing and supply, which is pretty impressive! This scenario is quite different from how things appeared in the third quarter of 2016, when they seemed to be pulling back, if not pulling out of the CAR-T race altogether. 

In the third quarter of last year came the news that 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, then in Phase II clinical trials. 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 I/O division. Next came the blow that not just lab hands were being let go, but the bulk of the senior executives running CGTU were also being axed, which didn't look good! 

That sounded 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? The only logical conclusion if they were not in fact pulling out, was that they were demonstrating the belief they had that the major manufacturing issues worked out, and they were confidently restructuring for actual production of the drug product. 

As it turns out, that seems to have been the case, that the R&D was truly done and dusted at that point, and Novartis were indeed gearing up for NDA submission, approval, marketing and rollout. Perhaps simultaneously ruffling the feathers at a few large biotechs who may (still) prefer to have the pharma giant out of their way, if not out of their hair. But healthy competition aside, yesterday's ruling by the FDA panel is good news for everyone, particularly cancer patients desperate for some new regimens to be added to the standard-of-care. 

Those new regimens will ultimately include new technologies with on-trend monikers such as oncolytic viruses, neoantigens, natural killer cells, and of course, CAR-T. Solid tumour therapeutics is where the biggest bank for one's buck is going to come, but you've gotta start somewhere and for now the hot topic remains the fruitful passage of CAR-T out of critical clinical trials and into therapeutic reality. 

To see CAR-T therapy presumably hitting the marketplace in 2018 is a wondrous thing to ponder and hopefully witness, with an advance that truly seems like stepping into the future for anyone older than a Millennial. The entire concept of taking one's own cells out of the body and reengineering them to laser in on and kill tumour cells, is no longer the stuff of science fiction, but it does remain the stuff of pioneering genius, and my hat is off to anyone and everyone who has played a part in this particular aspect of a brave new world in medicine.