Allogene Therapeutics Inc. investors will have to wait for an update in the second half of this year – probably at December’s American Society of Hematology meeting in San Diego – to find out more about whether off-the-shelf ALLO-501 can durably stand up to autologous CAR T-cell therapies, but early data disclosed at the American Society of Clinical Oncology (ASCO) meeting is creating buzz in the meantime.

CEO David Chang pointed out during the company’s earnings call in early May that “this is a phase I study that has been carried out, so obviously, the patients who were treated early on will have a longer-term follow-up, but I should remind you that the real question around the durability should be at the cell dose [given] and the lymphodepletion [LD] that we finalize for the phase II. That will be the real comparison as we go forward.”

At ASCO, the South San Francisco-based firm disclosed positive first results from the dose-escalation phase I Alpha study of ALLO-501, an anti-CD19 allogeneic CAR T (branded AlloCAR T) therapy in relapsed/refractory non-Hodgkin lymphoma. The experiment deploys ALLO-647, Allogene's anti-CD52 monoclonal antibody, as a part of its differentiated LD depletion regimen. Allogene is developing ALLO-501 with Les Laboratoires Servier SAS under an exclusive license granted by Paris-based Cellectis SA.

As of the May 2020 data cutoff, 23 patients were enrolled and 22 patients received ALLO-501, since one was removed from the study prior to LD due to acute renal failure from urinary obstruction. The median time from enrollment to the start of therapy was five days.

For the efficacy analysis, 19 out of 22 patients reached at least one month assessment as of the May cutoff. Responses were observed across all cell doses and tumor histologies (diffuse large B-cell lymphoma and follicular lymphoma) with an overall response rate (ORR) of 63% and complete response (CR) rate of 37%. Higher dose ALLO-647 was associated with a higher CR rate of 50%, deeper LD and delayed host T-cell recovery, Allogene said. With a median follow-up of 3.8 months, nine of the 12 responding patients (75%) remain in response as of the data cutoff.

One of the ongoing responders is a patient with an initial partial response (PR) who progressed by the second month. That patient achieved a CR after retreatment with the same dose of ALLO-501 and higher-dose (90 mg) ALLO-647. Included in the overall efficacy analysis are three patients who were refractory to prior autologous CAR T therapy (the best response of progressive disease or disease progression within three months). Those patients were also refractory to the company’s AlloCAR T therapy. In CAR T-naïve patients, the ORR was 75% and the CR rate was 44%.

Cytokine release syndrome occurred in 32% of the patients, was mainly mild to moderate in severity and manageable with standard recommendations; all events resolved within a maximum of seven days. Patients treated with 90-mg ALLO-647 did not experience an increase in infection as compared to those treated with 39 mg.

Four patients (18%) turned up serious adverse events (SAEs). One patient had a grade 2 pyrexia and one had grade 2 cytomegalovirus (CMV) reactivation. Those resolved in two days and six days, respectively. One patient had grade 3 rotavirus infection and one had grade 3 hypokalemia which resolved in 15 days and two days, respectively. One patient had grade 3 febrile neutropenia and one had grade 3 hypotension, each of which resolved in two days. One patient had a grade 3 upper gastrointestinal hemorrhage that resolved in one day and one had grade 3 CMV reactivation that resolved in 25 days. Adverse events were observed across all dose levels of ALLO-501 and ALLO-647. SAEs were observed at ALLO-501 cell dose level 40 x 106 and 120 x 106 and at both dose levels of ALLO-647, Allogene said.

Cowen analyst Marc Frahm said in a report that the results are moving in the right direction and “would seem to have exceeded expectations,” since company backers mostly hoped for a CR rate of greater than 40% in the cohort of patients who received high-dose preconditioning.” Jefferies’ Biren Amin said the LD regimen proved especially important. A key opinion leader he consulted said the “stringent LD condition eliminated host immune cells more thoroughly, allowing enhanced intratumoral proliferation of CAR T cells to drive deeper responses. The data suggest that host LD is not only an obligatory component of curative T-cell therapy, but also the key factor to optimize on duration front. Optimization of LD regimen is ongoing and is a key differentiator for Allogene’s platform,” he said, noting that other CD19 allogeneic T cells have not used an anti-CD52 strategy and that factor “could be what separates Allogene’s pipeline.”

Roth’s Tony Butler sounded still more enthusiastic in his report, calling the data “better than the expectations we had when the company went public two years ago, better than when we initiated coverage roughly one year ago, and better than we would have expected even three weeks ago.” He cited surprising safety along with efficacy that “appears at least as good as an autologous CAR T,” such as Basel, Switzerland-based Novartis AG’s Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel), from Gilead Sciences Inc., of Foster City, Calif. “Though early, Allogene appears to have a therapy at least for patients with refractory B-cell lymphoma. A caveat, of course, is that this profile to date is in a small number of patients,” Butler said. Cowen’s Frahm introduced a thread of caution, too, given that the median duration of response was only 1.9 months in the high-dose preconditioning cohort. “However, if one assumes that durability is primarily driven by the depth of response, then these data (and in particular the CR rate) suggest that ALLO-501 is likely to produce a similar rate of durable remissions (cures, effectively),” he said.

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