Despite reports that linked Novartis to cutting back on its cell therapy work, the Swiss major said it is going full steam ahead for its CAR-T research as a potential approval for its candidate appears on the horizon.
In August of last year, Endpoints broke the news that the Big Pharma was integrating its once standalone gene and cell therapy unit into the company. Most employees would be redeployed, but around 120 potentially face job losses.
This unit was doing work on the next new cancer class CAR-T, but some speculated that the disbanding of this unit meant that Novartis was looking to take a step back from research in this area.
Talk of its death was, however, greatly exaggerated according the the company. It said its leading CAR-T candidate, CTL019 (tisagenlecleucel), now has two FDA breakthrough tags in two blood cancers, and was given a priority review for the med by the agency at the end of March.
The company is now in a race with biotech Kite Pharma to be the first to market this new type of cancer therapy that has shown some stellar results in clinical trials (although it also has revealed some serious side effects from other companies, including Juno Therapeutics).
Speaking to FierceBiotech, Vas Narasimhan, M.D., global head of drug development and CMO at Novartis, said that there was “a lot of interpretation last year regarding our reintegrating our cell and gene therapy unit into our R&D infrastructure,” but was adamant that this “did not create any difference in regards to our commitment in this space.”
He said the integration of the unit into Novartis proper was primarily due to its success.
“We had incubated the technology which came out of [its 2012 CAR-T deal] with Penn as a dedicated unit, and that was something that made sense: If you had immediately put that into the larger infrastructure of Novartis, it would have got lost, especially in the early stages when it was risky and it was unclear if this would be tractable," he said.
But Narasimhan said that as the unit became scaled, the parallel infrastructure scheme no longer made optimal sense.
“To give this technology the best chance of succeeding, and in the most cost-effective way, we decided we should integrate [the unit] into our normal operations, and so CAR-T agents were then no different to an I-O agent, or anything else that we developed at Novartis, other than the fact that the process here is very important for the product," he said. “We have the scale to work on these sorts of things quickly. So, the integration has allowed us to work on multiple programs in parallel, where I think the unit was focusing on just one or two programs at a time.”
Now integrated, Narasimhan said it’s full steam ahead for CAR-T, and the immediate focus is to see through the two indications: r/r B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients and r/r diffuse large B-cell lymphoma (DLBCL) for tisagenlecleucel this year, as well as a combined ALL and DLCBL submission in Europe in 2017.
On the R&D side, he sees a three-pillar approach for CAR-T. The first pillar is to continue to be innovative on the manufacturing side of things, which is a tricky and cutting-edge science in itself for CAR-T. “We need to continue to invest to optimize our manufacturing platforms, bringing it to more patients as we expand indications,” he says.
The second is to continue to work in blood cancers, where results for Novartis and others have been the strongest. He said that they have programs in CAR-T in combination with other meds, as well as research in multiple myeloma, with additional blood cancer programs also slated to run on its CAR-T platform.
And the third pillar, which could turn out to be the toughest for all involved, is the move into solid tumors.
“We have a few different constructs now and we’re moving into the clinic,” Narasimhan explains. “Our most advanced CAR-T is targeting ovarian cancer as well as a few other solid tumors.”
Solid tumor research in the industry using CAR-Ts has not to date, however, seen a translation from the strong data coming out of blood cancers, and a lot of uncertainty remains as to whether, and how, CAR-T can treat these types of cancer.
I asked Narasimhan how confident he and Novartis were in holding up its third pillar.
“For solid tumors, we really need to wait for the clinical data to make a judgement and see how tractable it is. We know in the solid tumor microenvironment there is a lot more going on, and the question of course will be combination therapies and what kind of I-O combinations might be required to see deep and durable responses in solid tumors," he said."It’s too soon to say what our confidence level is in solid tumors, other than to say that we have targets that we are interested in and we’ve built those constructs and are taking them into the clinic.”
One of the big questions surrounding Novartis’ CAR-T program is the outcome of its JULIET trial for tisagenlecleucel, a study looking at the med’s ability in DLCBL (where rival Kite is also working on). The data are in, but Novartis isn’t sharing yet.
“Our plan with JULIET is to announce it at an upcoming medical event, and once we get acceptance at a congress, we’ll disclose it. We just want to ensure that we don’t undermine our ability to present the data to a scientific congress.”
But Narasimhan did say that the breakthrough designation it got this week from the FDA “hopefully gives some indication,” of how the data have panned out.
Lastly, we spoke about the FDA, which is under pressure from all directions as the new administration looks to cut back on regulations and direct funding (with a proposed increase in user fees), and internally, with some questioning whether it has at times lowered its standards to allow drugs through, such as those from Sarepta and more recently Marathon, and if this signals a sea change for the agency.
Narasimhan defended the FDA, saying it should be strong, but that it is “under-resourced for what they have to do. If you look at 21st Century Cures Act and all the new things they have to do, the funding isn’t necessarily all there yet for those new requirements.”
He also said that the science and the technology being put up for review “is getting more and more complex, and there is public pressure with right to try and patient group pressures as well on the FDA and these are only increasing, so they have to find the right balance."
“I would say, in general, that the FDA does an extraordinary job having worked with them for many years, including on the H1N1 pandemic, and through various cycles of innovation. But, I think they need more time and money to invest in their people, so that they are up to speed on the latest science so that they can make measured decisions.”
He said that despite the agency's outlier cases, “generally they continue to be very rigorous,” in their reviews.
He also said it was incumbent on both the agency and the industry to do more to speed up R&D and approvals, and be open to new, but scientifically-led, approaches that can help get new drugs to patients more quickly.