On June 8, 2022 Precision BioSciences, Inc. (Nasdaq: DTIL) a clinical stage gene editing company developing ARCUS-based ex vivo allogeneic CAR T and in vivo gene editing therapies, reported its latest program updates across its allogeneic CAR T pipeline (Press release, Precision Biosciences, JUN 8, 2022, View Source [SID1234615759]). The Company provided new clinical data and outlined the opportunity for its lead candidate, PBCAR0191, as a potential first-in-class allogeneic CD19 CAR T for the growing autologous CAR T relapsed patient population with aggressive lymphomas. Precision also shared updates on its PBCAR19B and PBCAR269A candidates in development as potential best-in-class allogeneic CAR T therapies for relapsed/refractory (R/R) patients with non-Hodgkin lymphoma and multiple myeloma, respectively.
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"The new interim clinical data we are sharing today from the Phase 1/2a study demonstrated that PBCAR0191 produced high clinical response rates in CAR T relapsed patients who received a median of five prior lines of therapy. Evaluable subjects in the study had 100% ORR, 73% CR rate and 50% durable response rate greater than six months. We believe the data validate the signal we reported at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) meeting among CAR T relapsed subjects and further supports our potential path forward in this patient population with what we believe is the highest unmet medical need," said Michael Amoroso, Chief Executive Officer at Precision BioSciences.
"We are encouraged that our in-house manufacturing and clinical teams continue to optimize the PBCAR0191 treatment regimen resulting in a product candidate that could potentially be the first allogeneic CAR T therapy to reach the market. Most importantly, we are optimistic that, if approved, this could potentially help patients with aggressive lymphomas that relapse after CAR T treatment. We believe this data is timely and highly relevant. By 2025 the number of autologous CAR T relapsed patients is expected to grow four- to five-fold based on data from late 2021 that advanced autologous CAR T into the second line diffuse large B-cell lymphoma (DLBCL) setting. Today, patients who relapse after CAR T treatment remain highly underserved with no approved standard of care and a progression free survival of only one to two months," added Mr. Amoroso.
As of the May 31, 2022 data cutoff, continued positive efficacy results, including high overall and CR rates and duration of response, and an improved adverse event profile have been observed among evaluable CAR T relapsed subjects. This included six subjects who received PBCAR0191 Dose Level (DL) 31 with enhanced lymphodepletion – the "ASH Cohort" – and six subjects who received PBCAR0191 DL4b2 with decreasing lymphodepletion since January 2022 – the "New Cohort."
Results are as follows:
Efficacy across both the ASH (Free ASH Whitepaper) and New Cohorts: Achieved 100% (11/11) ORR and 73% (8/11) CR rate among 11 evaluable subjects. Six subjects remain in ongoing response (up to 18+ months).
Duration of response in the ASH (Free ASH Whitepaper) Cohort: 50% (3/6) of evaluable subjects had a response duration greater than six months.
Efficacy in the New Cohort: Among subjects treated with DL4b and reduced intensity lymphodepletion, 100% CR was achieved among evaluable subjects (5/53).
Adverse events of special interest comparison between the ASH (Free ASH Whitepaper) and New Cohorts: No Grade 3 or greater cytokine release syndrome (CRS) was observed in either dosing cohort. One Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) was recorded in each cohort that rapidly resolved to Grade 1 within 24 to 48 hours. Two Grade 5 events associated with late occurring encephalopathy suspected to be related to fludarabine-associated neurotoxicity occurred in the New Cohort. There was no evidence of graft versus host disease in either cohort.
Hematologic recovery comparison between the ASH (Free ASH Whitepaper) and New Cohorts: Grade 3 or greater infections occurred less frequently in the New Cohort with one out of six (17%) subjects compared to four out of six (67%) subjects in the ASH (Free ASH Whitepaper) Cohort.
"We are encouraged by the 100% overall and 73% complete response rates as well as durability of response that exceeds the current standard-of-care for this CAR T relapsed patient population who continue to experience poor clinical outcomes. We are also pleased that our manufacturing process is yielding improved product attributes, which enable us to deploy a lower dose of lymphodepletion in this fragile and heavily pre-treated CAR T relapsed patient population. We believe these improvements contributed to a faster and improved hematologic recovery without compromising efficacy," said Alan List, M.D., Chief Medical Officer at Precision BioSciences. "Importantly, we have achieved a key milestone for allogeneic CAR T therapy. The cell expansion observed with PBCAR0191 cells at DL4b with lower dose lymphodepletion – the New Cohort – matched the median autologous CAR T peak expansion in subjects who achieved a long durable response in the ZUMA-1 trial. We believe this to be a first for allogeneic CAR T therapy studied in any population (earlier lines or more heavily pre-treated)."
"In the second half of this year, we plan to continue dosing subjects with optimized PBCAR0191 in this CAR T relapsed patient population while further reducing the lymphodepletion dose to standard levels with the goal of improving upon overall therapeutic index for these patients in need. We also expect to request a meeting with the FDA to review our data for guidance on a path forward and to provide our next update on PBCAR0191 toward year end," added Dr. List.
PBCAR19B and PBCAR269A with Goal of Potential Best-in Class Allogeneic CAR T Products
PBCAR19B and PBCAR269A allogeneic CAR T clinical programs also continue to progress.
For PBCAR19B, the Company’s second generation, anti-CD19 targeting allogeneic CAR T candidate, a flat dose of 270 million cells following standard lymphodepletion (sLD)4 has been administered to three subjects with R/R DLBCL. Prior to commencing DL2, and as a result of the promising data with PBCAR0191 leading to the expanded cohort (New Cohort), Precision opted to expedite the next round of manufacturing process optimization for PBCAR19B. This manufacturing optimization was implemented in the first quarter of 2022. New clinical trial material is expected to be released and dosing at the next cohort, DL2 (flat dose of 540 million cells), in the third quarter of 2022.
"As we previously announced, we strategically paused dosing in our PBCAR19B program to implement a manufacturing process enhancement suitable for pursuing a best-in-class therapy with the goal of displacing autologous CAR T," continued Dr. List. "We look forward to resuming dosing with our optimized cells in the third quarter of 2022 and expect to provide an update on this program around year end."
For PBCAR269A, Precision has continued to enroll subjects in its PBCAR269A Phase 1/2a study in combination with nirogacestat, a gamma secretase inhibitor (GSI) developed by SpringWorks Therapeutics, in pursuit of an allogeneic alternative to autologous CAR T therapies targeting B-cell maturation antigen (BCMA) for R/R multiple myeloma.
Precision has completed DL2 (2.0 × 106 cells/kg) of PBCAR269A plus GSI and is initiating the next cohort at DL3 to further evaluate efficacy. To date, peak expansion rates observed at DL2 plus the GSI have been equivalent to DL4 (960 × 106 cells flat dose) monotherapy with no dose limiting toxicities observed. The company expects to also provide an update on this program around year end.
The Company’s balance of cash and cash equivalents was approximately $121 million as of May 31, 2022. The Company continues to expect that existing cash and cash equivalents, expected operational receipts, and available credit will be sufficient to fund its operating expenses and capital expenditure requirements into mid-2023.
Company-Hosted Webcast and Conference Call Information
Precision will host a conference call and webcast today at 8:00 AM ET to review its ongoing allogeneic CAR T programs. The dial-in conference call numbers for domestic and international callers are (866) 996-7202 and (270) 215-9609, respectively. The conference ID number for the call is 5754683. Participants may access the live webcast, and accompanying presentation materials, as well as the archived webcast on Precision’s website in the Investors section under Events & Presentations: View Source