Mark J. Alles
Celgene has announced plans to acquire Juno Therapeutics, which is the developer of the chimeric antigen receptor (CAR) T-cell therapy liso-cel (lisocabtagene maraleucel; JCAR017), for $87 per share, totaling approximately $9 billion. The decision was approved by both companies and is expected to complete within the first quarter of 2018.
Juno and Celgene both anticipate a regulatory submission and subsequent approval in 2019 for liso-cel as a treatment for patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL). Although not yet submitted, the companies believe liso-cel has the potential to be a "best-in-class" CAR T-cell therapy, allowing it to achieve $3 billion in peak sales.
In data from the TRANSCEND trial, which were presented at the 2017 ASH Annual Meeting,1
liso-cel induced an objective response rate (ORR) of 81% with a complete remission (CR) rate of 63% in patients with relapsed/refractory DLBCL. At the 3-month assessment for the dose being used in an ongoing pivotal trial for liso-cel, the ORR was 74% with a CR rate of 68% (95% CI, 43%-87%). By month 6, the ORR and CR rates were both 50% in this group (95% CI, 23%-77%).
A pivotal cohort of the TRANSCEND trial exploring a single infusion of liso-cel at 1 x 108
CAR+ cells is currently enrolling patients with DLBCL (NCT02631044). If this cohort is positive, a biologics license application will be submitted to the FDA. Based on earlier findings for the CAR T-cell therapy, liso-cel received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.
Additionally, as part of the acquisition, Celgene reaffirmed its goal of $19 to $20 billion in product sales by 2020, with the hopes that liso-cel and other T cell products from Juno could help accelerate growth. In addition to liso-cel, Juno is also developing JCARH125, a CAR T-cell therapy targeted against B-cell maturation antigen (BCMA) for multiple myeloma, a disease for which Celgene has several already-approved therapeutics.
“The acquisition of Juno builds on our shared vision to discover and develop transformative medicines for patients with incurable blood cancers,” Mark J. Alles, Celgene’s chief executive officer, said in a statement. “Juno’s advanced cellular immunotherapy portfolio and research capabilities strengthen Celgene’s global leadership in hematology and adds new drivers for growth beyond 2020.”
Although one of the first companies to develop CAR T-cell therapies, Juno was hit with several hurdles along the way, namely with their initial product JCAR015. In March 2017, after a series of toxicity-related setbacks, Juno announced that it halted the development of JCAR015 and shifted its focus toward JCAR017 (now liso-cel).
Following the experience with JCAR015, Juno conducted extensive research to uncover the potential cause for the adverse events. These factors were taken into consideration when developing liso-cel, with the intention of making the CAR T-cell therapy safer.2
Although JCAR015 and liso-cel are both directed against CD19, the agents have very different constructs. The cells used to create JCAR015 are composed of CD3+ enriched peripheral blood mononuclear cells, whereas liso-cel is built using a fixed ratio of CD4+ and CD8+ T-lymphocytes. Each agent is engineered using different viral vectors, namely gamma retroviral for JCAR015 and lentiviral for liso-cel. The binding domain for JCAR015 is SJ25C1 and the costimulatory domain is CD28, whereas liso-cel has a binding domain of FMC63 and a costimulatory domain of 4-1BB.
In the TRANSCEND study, there were comparatively low rates of severe cytokine release syndrome (CRS) and neurotoxicity, suggesting the potential for outpatient administration. Of those available at the time of the analysis, 5 were successfully treated in the outpatient setting.
In the pivotal dose group, severe CRS and neurotoxicity occurred in 0% and 7% of patients and all-grade CRS and neurotoxicity was experienced by 36% and 21% of patients, respectively. Overall, 58% of patients did not experience CRS or neurotoxicity.
“The people at Juno channel their passion for science and patients towards a common goal of finding cures by creating cell therapies that help people live longer, better lives,” said Hans Bishop, Juno’s President and Chief Executive Officer. “Continuing this work will take scientific prowess, manufacturing excellence and global reach. This union will provide all three.”
Initially following the transaction, the Celgene noted there would be a $0.50 dilution in earnings per share. In the long-term, however, Celgene anticipates earnings per share of $12.50 in 2020.
- Abramson JS, Palomba ML, Gordon LI, et al. High Durable CR Rates in Relapsed/Refractory (R/R) Aggressive B-NHL Treated with the CD19-Directed CAR T Cell Product JCAR017 (TRANSCEND NHL 001): Defined Composition Allows for Dose-Finding and Definition of Pivotal Cohort. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract 581.
- Gilbert MJ. Severe neurotoxicity in the phase 2 trial of JCAR015 in adult B-ALL (ROCKET Study): analysis of patient, protocol and product attributes. Presented at: 32nd Annual SITC Meeting, National Harbor, MD, November 8-12.