Autolus Therapeutics plc (AUTL)

As of the data cut-off date of May 17, twenty patients in Cohort A with R/R aALL had received obe-cel. The therapy was well tolerated, with no patients experiencing Grade 3 or higher CRS. Three patients (15%), all of whom had high leukaemia burden (over 50% blasts), experienced Grade 3 ICANS that resolved swiftly with steroids.

Of the twenty patients evaluable for efficacy, seventeen achieved minimum residual disease negative complete response at one month. Most notably, the durability of remissions is highly encouraging. Across all treated patients, event free survival at twelve months and twenty-four months is 50.2% with the median not being reached.

The company has received innovative licensing and access pathway designation from the UK MHRA for obe-cel, the company's CAR-T cell therapy being investigated in the ongoing trial in R/R aALL).

''The ILAP designation, alongside the recent PRIME designation from the EMA, is another step forward in accelerating the review process of this promising therapy,'' said Dr. Christian Itin. ''Obe-cel continues to show the potential to be differentiated on efficacy, durability and safety from other CAR-T cell products and could change standard of care by offering a potentially curative therapy for R/R aALL.''

Obe-cel in Adult Acute Lymphoblastic Leukemia patients (FELIX study)

Initial experience in the phase 1b portion of the FELIX 1b/2 study resulted comparable results as seen in the Phase 1 ALLCAR19 study. As of the cut-off date of 13 September, 16 patients in the Phase 1b part of the FELIX study had received obe-cel. Patient characteristics in the FELIX 1b portion were broadly comparable to those observed in the ALLCAR19 study in r/r adult B-ALL.

As of the data cut off date of 15 October 2021, ALLCAR19 data shows morphological EFS for obe-cel is 46% at 24 months with a median follow-up of 29.3 months and patients approaching up to 42 months of durability. Baseline characteristics between FELIX Phase 1b and ALLCAR19 studies are similar. 75% patients in the FELIX Phase 1b had >20% blasts at pre-conditioning, compared with 60% patients in ALLCAR19. 56.3% patients received prior blinatumomab in the FELIX Phase 1b study compared with 25% in ALLCAR191. High level of CR/CRi response rate at 1 month observed across both studies, with 12/16 patients in the FELIX Phase 1b study, consistent with 17/201 patients in the ALLCAR19 study. Safety consistent between the ALLCAR19 study and FELIX Phase 1b study, with no patient having high grade (≥Grade 3) cytokine release syndrome (CRS). 1 of 16 patients experienced a Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) in the FELIX Phase 1b study, as compared with 3 of 20 patients in ALLCAR-19 study1.

Obe-cel
Pivotal trial data expected mid year.
Evaluation in R/R B-NHL and CLL ongoing, with next data update expected in H1.
Evaluation in primary CNS lymphoma ongoing with initial data update expected in Q1.

AUTO1/22
Paediatric ALL: PhI initial data expected in H1 and longer follow-up data in H2.

AUTO4: Peripheral T-cell lymphoma PhI interim data expected in H1.
AUTO6NG: PhI starting in H1.
AUTO8: PhI starting in H1.

Also, AUTO7 and ALLO trials could start in H1 as well.

The company announced today new data highlighting progress on AUTO3, the first-in-human bicistronic CD19 and CD22 CAR, in patients with R/R DLBCL and pediatric ALL. The data were presented the ASH Annual Meeting.

“DLBCL is an aggressive and rapidly progressing cancer, and early response is critical to ensuring positive outcomes for these patients. The data from the AMELIA trial of AUTO3 in pediatric ALL has informed us on the encouraging role of dual antigen targeting in reducing target-negative relapses and delivering high levels of complete molecular remission with well-tolerated safety,” said Dr. Christian Itin, chairman and chief executive officer. “We look forward to advancing AUTO3 to a decision point in R/R DLBCL by the mid-point of next year.”

Title: Phase 1/2 study of AUTO3, the first bicistronic chimeric antigen receptor (CAR) targeting CD19 and CD22 followed by an anti-PD1 in patients with relapsed/refractory (r/r) Diffuse Large B Cell Lymphoma (DLBCL): Results of cohort 1 and 2 of the ALEXANDER study (Abstract # 246)

Dr. Kirit Ardeshna, consultant hematologist, Department of Hematology, University College London Hospital NHS Foundation Trust, gave an oral presentation with updated data from the ALEXANDER Phase I/2 study of AUTO3, the first bicistronic CAR T targeting CD19 and CD22 followed by an anti-PD1, in R/R DLBCL. The trial is divided into a phase 1 safety cohort and a phase 2 efficacy cohort, and is designed to assess safety (incidence of ≥ Grade 3 toxicity occurring within 75 days of AUTO3 infusion) and other primary and secondary endpoints including overall response and other safety, efficacy and product generation measures.

In the dose escalation phase, 16 patients were treated, with 4 patients dosed at 50 x 106 cells without pembrolizumab; 11 patients were dosed at escalating doses of AUTO3 with pembrolizumab administered at day 14 as follows: 3 at 50 x 106 cells, 4 at 150 x 106 cells, and 4 at 450 x 106 of AUTO3; and 1 patient was dosed with 450 x 106 cells with pembrolizumab administered 1 day before AUTO3 infusion. Fourteen patients were evaluable at one month.

AUTO3 was well-tolerated, with no patients experiencing ≥ Grade 3 cytokine release syndrome (CRS) with primary infusion and 1 of 14 experiencing Grade 3 neurotoxicity that resolved swiftly with steroids. There were no pembrolizumab immune-related toxicities and the majority of grade 3 or higher adverse events were hematological. Low levels of serum cytokines are consistent with the observed low levels of CRS and neurotoxicity.

Across all tested doses 5 patients achieved a complete response, with 4 of 5 complete responses ongoing, the longest at 18 months. All CRs were achieved without need for steroid or tocilizumab-based management of the patients or ICU level care.

“The phase 1 preliminary data on AUTO3, the novel and first in human bicistronic CD19 and CD22 CAR in relapsed/refractory DLBCL, show that the dual targeting approach appears safe, with 0% severe CRS (≥ grade 3). The duration of complete response is impressive as well and provides hope that AUTO3 may reduce the high rates of relapse seen with CD19 CAR Ts,” said Dr. Anas Younes, Chief, Lymphoma Service at Memorial Sloan Kettering Cancer Center.

The FDA has accepted the IND application for AUTO1, for the treatment of adults with acute lymphoblastic leukemia. The active IND allows initiation of the US sites in the company's first pivotal trial (AUTO1-AL1). The AUTO1-AL1 trial application was approved by the MHRA in Jan and the first site opened in the UK in March. The COVID-19 situation has had varying degrees of impact on the ability of clinical sites to operate normally; however, based on current expectations, the company anticipates that the impact on the AUTO1-AL1 trial will be minimal. The trial has a run in phase, with a small number of patients scheduled to be enrolled into the study in Q2, limiting the impact from the COVID-19 situation at this stage. The company has continued to manufacture, without interruption, from its operations at the Cell and Gene Therapy Catapult located in Stevenage, UK, including supply to the US of clinical products for the treatment of DLBCL patients in its AUTO3 trial.

As of the October 30, data cut-off date, 49 patients have been treated and were evaluable for safety. AUTO3 was observed to be well tolerated, with low rates of cytokine release syndrome and neurotoxicity. Across all, there was only one case of Gr3 CRS with primary infusion, and only three cases of NT were reported, with two being ≥ Gr3. None of the patients achieving a complete response experienced any NT, and all cases of were seen in a setting of disease progression and with confounding factors. No prophylactic measures of any kind have been used.

The majority of patients receiving the therapy in the outpatient setting did not require hospital admission. Those patients admitted were easily managed, with no patients requiring ICU care. Combined with the overall favourable safety data across the PhI, the profile of supports administration in an outpatient setting.

Across all dose levels, 43 patients were evaluable for efficacy, with an objective response rate of 65% and a CR rate of 51%. Of the 29 evaluable patients receiving the recommended PhII dose and pre-conditioning with pembrolizumab, the ORR was 66% and the CR rate was 55%. A subsequent analysis of these data suggested a superior response rate at higher dose levels, with 15 evaluable patients achieving an ORR of 87% and a CRR of 73%.

Across all cohorts in the study, 73% (16/22) of patients achieving a CR were without disease progression at a median follow up of 4 months (1-24). Of note, none of the five patients who achieved a CR in the cohort receiving three doses of pembrolizumab had disease progression.

As of the November 12, data cut-off date, 20 patients with R/R aALL had received AUTO1. It was well tolerated, with no patients experiencing ≥ Gr3 CRS. Three patients (15%), all of whom had high leukaemia burden (>50% blasts), experienced Gr3 neurotoxicity that resolved swiftly with steroids. Of the 19 patients evaluable for efficacy, 16 (84%) achieved minimum residual disease negative complete response at one month. Most notably, the durability of responses is highly encouraging. Across all treated patients, event free survival at six and twelve months is 69% and 52%, respectively. Median survival for the latter and overall survival has not been reached at a median follow up of 16.9 months (up to 30.5 months).