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Juno and partner Celgene closed the ROCKET study for JCAR015, which has been on clinical hold since November, and ended development in ALL in favor of its new and improved CD19-targeting CAR-T therapies.

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Juno Therapeutics Inc. has ended development of its CD19-targeting chimeric antigen receptor T-cell (CAR-T) therapy JCAR015 for the treatment of acute lymphoblastic leukemia (ALL) due to safety concerns, answering with certainty the question of whether the company could catch up to its competitors, which will be seek approvals for their CAR-T therapies any day now.

Juno said on March 1 in its fourth quarter and year-end 2016 earnings report that the company and its partner Celgene Corp. ended the pivotal ROCKET clinical trial that had been placed on clinical hold multiple times due to severe neurological side effects and patient deaths. The company will focus its efforts in ALL on its defined cell technology instead, including the CD19-targeting JCAR017, which it has been promoting as better and safer than JCAR015 since the first ROCKET clinical hold. (Also see "Juno Stresses Differences Between Its CAR-Ts As JCAR015 Trial Put On Hold Again" - Scrip, 23 Nov, 2016.)

Juno's stock price fell 7.9% after the stock market closed to $23.30 per share based on the JCAR015 update, keeping the stock toward the low end of its 52-week range of $17.52 to $49.72.

JCAR017 will move into a pivotal Phase II clinical trial in non-Hodgkin lymphoma (NHL) at some point in 2017, keeping Juno a year or more behind Kite Pharma Inc. and Novartis AG, which are expected to submit their CD19-targeting CAR-T therapies for US FDA approval during the first quarter of this year.

Kite is pursuing its first approval for axicabtagene ciloleucel (KTE-C19) in the treatment of aggressive relapsed or refractory NHL, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL), and reported durable response rates through six months of treatment from its ZUMA-1 study on Feb. 28. (Also see "Kite On Course For FDA Filing On Positive CAR-T Durability Data" - Scrip, 1 Mar, 2017.) The first potential indication for Novartis's CTL019 will be relapsed or refractory pediatric ALL.

Juno insisted in its 2017 financial update that JCAR017 will keep the company in a competitive position in the CAR-T field, positioning its next-generation CD19-targeting product candidate as a potential best-in-class product. The overall response rate (ORR) for NHL patients treated with JCAR017 in the Phase I TRANSCEND clinical trial was 80% in data reported in December during the American Society of Hematology (ASH) annual meeting with a 60% complete response (CR) rate. (Also see "ASH Ends With Consistent Kite CAR-T Data, Some Hope For Juno" - Scrip, 7 Dec, 2016.)

At six months in Kite's Phase II ZUMA-1 study the ORR was 82% and the CR was 41%.

"We continue to experience encouraging signs of clinical benefit in our trial addressing NHL," Juno President and CEO Hans Bishop said in the company's March 1 statement, "but we also recognize the unfortunate and unexpected toxicity we saw in our trial addressing ALL with JCAR015. We have decided not to move forward with the ROCKET trial or JCAR015 at this time, even though it generated important learnings for us and the immunotherapy field. We remain committed to developing better treatments for patients battling ALL and believe an approach using our defined cell technology is the best platform to pursue. We intend to begin a trial with a defined cell product candidate in adult ALL next year."

ROCKET was put on hold in July that was lifted within a matter of days, but the FDA stopped the trial again in November based on an unexpectedly high incidence of severe neurotoxicity, including five deaths from cerebral edema among the patients treated with JCAR015. (Also see "Three Deaths In Trial Mean Clinical Hold For Juno’s Lead CAR-T Therapy" - Scrip, 7 Jul, 2016.) The study has remained on hold while Juno conducted an investigation.

"Through the investigation Juno identified multiple factors that may have contributed to this increased risk, including patient-specific factors, the conditioning chemotherapy patients received, and factors related to the product. Although Juno believes there are protocol modifications and process improvements that could enable Juno to proceed with JCAR015 in clinical testing in adult [relapsed or refractory (r/r)] ALL, Juno would first need to establish preliminary safety and dose in a Phase I trial," the company said in its earnings report.

"As a result of the timing delay that would entail and Juno’s belief that it has other product candidates in its pipeline that are likely to provide improved efficacy and tolerability, Juno, in collaboration with partner Celgene, has made a strategic decision to cease development of JCAR015 at this time and to redirect associated resources to the development of a defined cell product candidate in the adult r/r ALL setting," Juno reported.

It's noteworthy that Juno cited time as a factor in its JCAR015 decision-making as opposed to cost. The company has been well-financed throughout its short lifespan, including large venture capital funding rounds and a successful initial public offering in December 2014. (Also see "IPO Update: Juno has biggest 2014 offering as investors chase CAR-T stocks" - Scrip, 21 Dec, 2014.) Juno also executed a rich collaboration agreement with Celgene in June 2015 that gave the CAR-T developer $1bn up front. (Also see "Celgene shows CAR-T confidence with $1bn Juno investment" - Scrip, 30 Jun, 2015.)

Juno had $922.3m in cash and securities on its balance sheet as of Dec. 31 versus $1.22bn a year earlier after burning through $232.2m in 2016; the company had said that it would spend between $220m and $250m last year. The guidance for 2017 cash burn is $270m to $300m, leaving the company with three to four years of capital without raising additional funds through a secondary offering or additional deal-making.

Patent Disputes Offer Upside

Juno did remind investors about some upside in its earnings report, however, related to Kite's CAR-T development programs. The companies are engaged in two separate patent disputes, including an inter partes review that Kite sought with the US Patent and Trademark Office (USPTO) Patent Trial and Appeal Board (PTAB) in August 2015 related to a patent for CAR-T technology used in the treatment of B cell and other malignancies, which Juno licensed from the Sloan-Kettering Institute for Cancer Research, an affiliate Memorial Sloan Kettering Cancer Center. The PTAB upheld all of the patent's claims, but Kite has appealed the decision to the US Court of Appeals for the Federal Circuit.

Meanwhile, Juno has filed a lawsuit against Kite claiming axicabtagene ciloleucel infringes the patent upheld by the PTAB, which covers a CD19-targeting CAR-T construct that uses a certain CD28 co-stimulatory domain. If the court issues a declaratory judgment in Juno's favor or if the two companies reach a settlement, Kite could be on the hook for licensing fees, royalties or other payments.

A lawsuit settled in 2015 related to a separate patent resulted in Novartis agreeing to pay Juno $12.25m plus future milestone fees and royalties. The settlement ended a dispute between Novartis's partner the University of Pennsylvania and Juno's partner St. Jude Children's Research Hospital. (Also see "Juno-Novartis CAR-T Settlement Puts Focus Back In Clinic" - Pink Sheet, 6 Apr, 2015.)


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