Juno Therapeutics Inc. "invested to learn deeply" from last year's deaths in clinical trials, Sunil Agarwal, president of research and development, told BioWorld, and "having put both feet in at the beginning" is what led to the success with a chimeric antigen receptor (CAR) T-cell therapy disclosed Wednesday.

"If you make changes to an antibody, even a few amino acids, it can fundamentally be a different antibody," he said, and CAR T-cell therapies are even more complicated, with alterations possible to "the construct, the binder, the spacer and the cell itself."

Made public were Seattle-based Juno's 15 abstracts on clinical and preclinical data to be presented at the American Society of Hematology (ASH) annual meeting next month. Included among the results from its pipeline of CD19- and BMCA-directed CAR T candidates are updated data from the phase I Transcend study of JCAR-017 in patients with relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. JCAR-017 is a defined composition CD19-directed CAR T using a 4-1BB co-stimulatory domain, and Juno has said the drug's clinical profile could allow for outpatient treatment.

The primary Transcend abstract described outcomes from the core analysis group (n=49), which includes patients that represent the population that Juno is studying in ongoing pivotal work. Dose level two (100 million cells), which is being used in that cohort, yielded a three-month overall response rate (ORR) of 80 percent (12/15) and a three-month complete response (CR) rate of 73 percent (11/15) in the core group. The findings support a dose-response relationship, the company said, noting that dose level one (50 million cells) turned up a three-month ORR of 52 percent (11/21) and a three-month CR rate of 33 percent (7/21). Specifically, the core group includes patients with diffuse large B-cell lymphoma (DLBCL not otherwise specified, or NOS – i.e., conforming to no known subtypes – and transformed from follicular lymphoma) who are Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1, an especially refractory population.

"The data cut is from July, and we will have a data cut for ASH approximately three months later," Agarwal said. "The amount of patients doesn't substantially change. We don't believe the evaluation or the data itself with respect to interpretation would change."

Across both doses in the core group, the best overall response was 84 percent (41/49) and the best overall CR rate was 61 percent (30/49). There was no increase in cytokine release syndrome (CRS) and neurotoxicity (NT) rates associated with the higher dose or between the full and core groups. Across doses in the full group, 1 percent (1/69) experienced severe CRS and 14 percent (10/69) ended up with severe NT. Thirty percent (21/69) had any grade CRS and 20 percent (14/69) had any grade NT. Sixty-four percent (44/69) had no CRS or NT. The most common treatment-emergent adverse events other than CRS and NT that occurred at ≥25 percent in the full group included neutropenia (41 percent), fatigue (30 percent), thrombocytopenia (30 percent) and anemia (26 percent).

About a year ago, two cases of cerebral edema, both ending in death, led Juno to put a clinical hold on the phase II trial of CAR T-cell therapy JCAR-015 for the second time in five months. An FDA-initiated hold on the trial, testing JCAR-015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) had held up the study the previous July because of three earlier fatalities. (See BioWorld Today, Nov. 28, 2016.)

'Comparable' to Kymriah, Yescarta ... or better

Juno CEO Hans Bishop said CAR T research is "still early. What you're seeing in these [JCAR-017] data and other data as well, is the fact that these therapies are evolving and improving," he told BioWorld. "There's still a lot to learn. The point that sits behind is that we're seeing a really clear dose response between 50 [million] and 100 million cells, both of which are relatively low doses, compared to what others are using in the field," he said. "What's promising about the JCAR-017 data is that the technologies can apply to our other pipeline candidates, multiple myeloma being the one that is behind JCAR-017."

Agarwal said that "having humility is absolutely critical for everyone" doing CAR T work. Though the findings so far support the biological hypothesis, "we still have more data to go, and are enrolling our pivotal cohort at dose level two as we speak." A BLA filing expected in the second half of next year.

The first FDA-approved CAR T-cell therapy is Basel, Switzerland-based Novartis AG's Kymriah (tisagenlecleucel), a CD19-directed genetically modified autologous T-cell immunotherapy for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Results evaluating Kymriah in pediatric ALL and in relapsed/refractory DLBCL will be presented at ASH, too. The data include results from the primary analysis of the Juliet study in adult patients with relapsed or refractory DLBCL, showing sustained CR rates based on extended follow-up, and efficacy and safety findings from additional treated patients compared to a previously disclosed interim analysis. (See BioWorld, Aug. 31, 2017.)

CEO Bishop said that "certainly, the scientists that have been working in this field for two decades would agree" that the advancement of CAR T research has proved slow going. "They'll remind us all that, even five years ago, at major scientific meetings the room was often empty when these types of technologies were being presented." But he said that, given the hurdles, companies have performed well in translating academic work to drug candidates. "I'm sure the future will include periods of great progress and periods when there are setbacks," he said.

J.P. Morgan analyst Cory Kasimov liked the JCAR-017 data. "Importantly, these CR rates appear to be better (at least at this point) than the rates reported by competitors in pivotal trials, albeit from slightly different patient populations," he wrote in a report, adding that "the safety profile of JCAR-017 continues to impress."

Leerink's Michael Schmidt found the results promising as well. "The prevailing question for many investors has been whether CAR T differentiation across the different platforms (primarily Gilead Sciences Inc., Kite Pharma Inc./Novartis, and Juno) will occur based on efficacy, safety, or a combination. Although still early and difficult to compare across trials," the JCAR-017 findings in DLBCL "provide support to our thesis that the product could potentially emerge as a best-in-class CD19 CAR T therapy," he wrote in a report. Updated data "were comparable (or better) in most efficacy and tolerability endpoints" compared to Kymriah and Foster City, Calif.-based Gilead's Yescarta (axicabtagene ciloleucel, previously KTE-C19), cleared last month to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma. (See BioWorld, Oct. 20, 2017.)

Shares of Juno (NASDAQ:JUNO) closed Wednesday at $48.31, up $3.4o, after trading as high as $52.