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Executive Summary

Novartis and Kite both are set to submit their CD19-targeting CAR-T therapies for US FDA approval in early 2017, while neurotoxic deaths for two of Juno’s product candidates cast doubts on its programs.


Novartis, Neck and Neck article image


Both Novartis AG and Kite Pharma Inc. are stepping on the gas in the race to bring the first chimeric antigen receptor T-cell (CAR-T) therapy to the market, while Juno Therapeutics Inc. continues to lag behind, plagued by deadly cerebral edemas and a clinical hold.

Novartis and Kite revealed plans on Dec. 3 and 4, respectively, for early 2017 biologic license application submissions to the US FDA based on data presented during the American Society for Hematology (ASH) annual meeting in San Diego.

Kite said it has initiated a rolling BLA submission that the company will complete by the end of the first quarter of 2017 for KTE-C19 in relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) patients ineligible for autologous stem cell transplant. The disclosure came one day after Novartis said it will submit a BLA in early 2017 and seek EU approval later in the year for CTL019 in the treatment of relapsed and refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL) based on data from the global Phase II ELIANA clinical trial, which were presented at ASH on Dec. 3.

In ELIANA, 82% of patients – 41 out of 50 children and young adults – achieved complete remission or complete remission with incomplete blood count recovery three months after infusion of the Novartis cell therapy with no minimal residual disease detected. The relapse-free rate among the responders was 60% six months after infusion.

“The impressive data from CTL-019’s registrational ELIANA trial make a strong case for accelerated approval. This will better position it to be the first CAR-T to gain regulatory approval in a highly competitive field of contenders,” noted Dustin Phan, an analyst with Datamonitor Healthcare, an Informa Pharma Intelligence service.

“In addition to highlighting a promising complete remission rate of 82% within three months of infusion, the 6-month overall survival rate observed was slightly higher than what was seen in an earlier Phase I/II single-center pilot trial (89% vs 78%),” Phan said. “Furthermore, the 60% relapse-free survival rate at 6-months suggests durable complete remissions, an important consideration for relapsed/refractory patients who may be unable to tolerate additional lines therapy or have had prior stem cell transplantation.”

Both CTL019 and KTE-C19 consist of each treated patient’s own T-cells reengineered to express CD19 so that the T-cells will attack cancer cells expressing the antigen. Juno’s most advanced CD19-targeting CAR-T therapy, JCAR015, has been placed on a clinical hold following at least six patient deaths due to cerebral edema. (Also see "Three Deaths In Trial Mean Clinical Hold For Juno’s Lead CAR-T Therapy" - Scrip, 7 Jul, 2016.)

Juno insisted last month that JCAR015 is different from its other CAR-T product candidates, including the CD19-targeting therapies JCAR014 and JCAR017, which use a different co-stimulatory antigen. (Also see "Juno Stresses Differences Between Its CAR-Ts As JCAR015 Trial Put On Hold Again" - Scrip, 23 Nov, 2016.)The American Society for Hematology's annual meeting kicks off on Dec. 2; to get you ready for attending this year's meeting or to help you know what to lookout for online, Scrip has selected 10 of the most exciting data readouts expected at the San Diego-based event.


Another Death, New Doubts For Juno

However, the safety of the company’s platform is in question based on neurotoxicity seen in other studies, such as a death from cerebral edema that was revealed in a Dec. 3 ASH presentation of a Phase I study for JCAR014 in patients with chronic lymphocytic leukemia (CLL) who failed prior treatment with Johnson & Johnson and AbbVie Inc.’s BTK inhibitor Imbruvica (ibrutinib).

Fifteen of 17 patients (88%) evaluated for efficacy who had bone marrow disease at the start of the Phase I trial, and who received a pre-conditioning chemotherapy regimen containing fludarabine and cyclophosphamide before one of the two lowest doses of JCAR014, had a complete bone marrow response as assessed by flow cytometry. Fourteen of those responders were assessed with IgH deep sequencing and seven out of 14 (50%) had no detectable disease; all are alive and have not progressed during their three to 26 months of follow-up.

Two of the Juno study’s 24 CLL patients (8%) developed Grade 3-5 cytokine release syndrome (CRS) and six of the 24 (25%) developed Grade 3-5 severe neurotoxicity, including a patient who died from CRS and cerebral edema.

Juno CEO Hans Bishop told Scrip that the company is treating CRS and neurotoxicity in its CAR-T studies with Roche’s intereukin-6 (IL-6) inhibitor Actemra (tocilizumab) and steroids, but noted that “whether that is the optimal treatment is an important question for the field.” (Also see "INTERVIEW: Juno CEO Hans Bishop On The CAR-T Learning Curve" - Scrip, 2 Sep, 2016.)

Specifically, Bishop said in an interview at the ASH conference, it’s unclear whether the IL-6 inhibitor and steroids have an impact on neurotoxicity. There’s a question of whether Actemra even gets into the central nervous system, he said.

Phase I data for JCAR017, Juno’s JCAR014 follow-on product candidate, will be presented at the ASH meeting in the afternoon on Dec. 5 that may show a slightly different safety profile in 22 patients with relapsed or refractory aggressive NHL, but it’s difficult to say whether that kind of result will impact opinions about the company’s safety risk.

“Juno’s CAR-T development program suffers another blow as reports of high grade CRS and severe neurotoxicity are revealed [for JCAR014]. While Juno does not have plans to commercialize JCAR014, insights from studies using this translational drug were intended to be applied to JCAR017,” Phan said. “These worrying safety data may not only negatively impact JCAR017, but could lead to a crisis of confidence in Juno’s CAR-T program as a whole.”

Juno is still investigating why five patients died in the ROCKET trial testing JCAR015, but Bishop said the company should be able to talk “soon” about possible safety interventions to manage neurotoxicity going forward. The CAR-T field, he noted, is investigating whether neurological side effects are related to specific products, specific types and stages of cancer and patient characteristics, or safety interventions used to manage adverse events.


CTL019 Safety Sets Novartis’s CAR-T Apart

In the meantime, the safety profile of CTL019 in Novartis’s ELIANA trial appears to give the CAR-T therapy a distinct advantage over Juno’s programs. While 79% of patients in that study experienced CRS and 48% of those cases were Grade 3 or 4, there were no deaths from the side effect, which CAR-T studies developers generally are managing with Actemra, among other interventions. Grade 3 and 4 neurotoxicity was observed in 15% of the children and young adults in ELIANA, including encephalopathy and delirium, but there were no Grade 4 events or deaths.

“Safety findings from the ELIANA trial may also help set CTL-019 apart from its other contenders,” Phan said.

Kite is scheduled to present updated interim results from NHL patients enrolled in its pivotal Phase II clinical trial known as ZUMA-1 in a late-breaking ASH session on Dec. 6, where safety will be a key question as well as the durability of patients’ responses to KTE-C19 – now also known as axicabtagene ciloleucel. (Also see "ASH 2016 Preview: Don't Miss These 10 Data Presentations" - Scrip, 24 Nov, 2016.) Data from ZUMA-1 in refractory diffuse large B-cell lymphoma (DLBCL) patients that were reported in September were good enough to support a BLA submission for accelerated approval, Kite said at that time. (Also see "New Interim CAR-T Data Support Kite’s BLA Submission Plans" - Scrip, 27 Sep, 2016.)

Kite’s KTE-C19 and Novartis’s CTL019 both have received breakthrough therapy designations from the FDA, which qualifies the CAR-T therapies’ BLAs for relatively speedy reviews. That means both treatments could be approved before the end of 2017 if the applications are submitted in the first quarter of next year.

Juno hasn’t given guidance on when it may submit an application for one of its CAR-T therapies in the US, given the ongoing investigation of neurotoxicity in ROCKET, but Bishop said the company expects its first approval for JCAR017 in 2018.

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