Novartis is on track to win FDA approval later this year to market the first chimeric antigen receptor (CAR) T-cell therapy, following an advisory committee’s unanimous recommendation yesterday in favor of the company’s leukemia-fighting treatment CTL019 (tisagenlecleucel).

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 10 to 0 to recommend approval of CTL019, which is indicated for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). The FDA usually, but not always, follows the recommendations of its advisory committees.

“The panel’s support was overwhelming. One voter said this is the most exciting thing he has seen in his career.  You don’t normally hear things like that at an FDA meeting and I think it is a sign of how truly promising this therapy can be,” Brad Loncar, CEO of Loncar Investments, told GEN.

The FDA has accepted Novartis’ Biologics License Application (BLA) for CTL019, filed in March, for Priority Review—under which FDA has set a goal of taking action on Novartis’ CAR T-cell candidate within 6 months, compared to 10 months under standard review.

The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target decision date in early October.

The ODAC based its recommendation on a review of the CTL019 r/r B-cell ALL development program, which included the first pediatric global CAR T-cell therapy registration trial, the Novartis-led Phase II ELIANA study (NCT02435849).

Also supporting the recommendation, as well as the BLA, are data from a U.S. multicenter trial and a single site trial examining the safety and efficacy of CTL019 among pediatric and young adult patients with r/r B-cell ALL.

Manufacturing Considerations

CTL019 is an autologous CAR T-cell therapy. In a briefing document to the ODAC, FDA staffers cautioned that a major consideration for manufacturing CTL019 was the need for “a well-controlled manufacturing process that can consistently produce high-quality CAR T cells that are safe, pure, and potent.”

In addition to understanding that process, the staffers wrote, Novartis will need to understand critical product quality attributes unique to autologous CAR T-cell products—as well as to understand and address sources of variability seen in the products.

“This can be a challenging issue given the complex and labor-intensive manufacturing processes involved with making a CAR T-cell product,” the FDA staffers added. “These challenges can include variability in the starting materials (e.g., patient’s own leukapheresis cells) and human- or animal-derived reagents (e.g., serum, antibodies), and control of critical components that may be manufactured under contract (e.g., transfer vectors that encode CAR, final container).”

In May, Novartis signaled its interest in also developing allogeneic CAR T-cell therapies, when it entered a nonexclusive license agreement with Celyad to use its U.S. patents to produce allogeneic CAR T cells, in a deal that could generate up to $96 million in up-front and milestone payments for the Belgian biotech. The deal covers Celyad’s rights to U.S. Patent No. 9,181,527 related to allogeneic human primary T cells that are engineered to be T-cell receptor deficient and express a CAR.

First developed by the University of Pennsylvania, CTL019 uses the 4-1BB co-stimulatory domain in its CAR to enhance cellular responses as well as persistence of CTL019 after it is infused into the patient, which may be associated with long-lasting remissions in patients.

In 2012, Novartis and Penn launched their global collaboration to further research, develop, and commercialize CAR T-cell therapies, including CTL019, for the investigational treatment of cancers. Children’s Hospital of Philadelphia (CHOP) was the first institution to investigate CTL019 in the treatment of pediatric patients and led the single site trial.

“It is encouraging to see the FDA panel’s recommendation and continued momentum behind this innovative therapy, which has potential to help young patients with relapsed/refractory B-cell ALL,” the leader of the Penn team, Carl June, M.D., said in a statement. Dr. June is the Richard W. Vague Professor of Immunotherapy, director of the Center for Cellular Immunotherapies in Penn’s Perelman School of Medicine and director of the Parker Institute for Cancer Immunotherapy at Penn.

Before the Novartis collaboration, Dr. June added, CAR T-cell research was funded by a nonprofit, the Alliance for Cancer Gene Therapy (ACGT). “When other organizations, including the NIH, considered gene therapy too risky, ACGT believed in the science and funded us when no one else would. ACGT really kept us going and kept the research alive. Without them, we wouldn’t have had a clinical trial and I don’t think we’d be where we are today,” he said in a statement released by ACGT.

Several CAR-T Therapies in Development

A Novartis spokesperson told GEN that the company has several other CAR T-cell therapies in development:

  • CTL119, a humanized CD19 CAR. Recent results from a pilot study (NCT02640209) of CTL119 in combination with ibrutinib in patients with r/r chronic lymphocytic leukemia (CLL) who had been taking ibrutinib for at least six months and who were not in complete remission were presented last month at the 53rd Annual Meeting of the American Society of Clinical Oncology.
  • CAR-T-BCMA is being investigated in multiple myeloma. Early clinical data was presented in December 2016 at the 58th Annual Meeting and Exposition of the American Society of Hematology.
  • CAR-T-EGFRvIII is being investigated in glioblastoma, with data presented in April 2016 at the American Association for Cancer Research (AACR) Annual Meeting.
  • CAR-T-Meso, a fully human mesothelin CAR, is under study in ovarian cancer and mesothelioma. The first patient visit into a Phase I trial took place earlier this year.

CTL019 has also won FDA’s Breakthrough Therapy designation for r/r pediatric and young adults with B-cell ALL, as well as for a second indication, adults with r/r diffuse large B-cell lymphoma (DLBCL) who have failed two or more prior therapies. Breakthrough therapies are designed to treat a serious or life-threatening disease or condition and demonstrate a substantial improvement over existing therapies on one or more clinically significant endpoints based on preliminary clinical evidence.

Novartis said it will file applications with the FDA and European Medicines Agency seeking approval for CTL019 in adults with r/r DLBCL.

“I don’t think it is an embellishment to say that this is a historic day,” Loncar added. “This is an entirely new way of treating cancer, and I think these cellular therapies are only in their first chapter.”

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