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Servier Presents Patient Follow Up Data from the Phase 3 AGILE Study at ASH 2022

On December 10, 2022 Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, reported new data at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) characterizing clonal evolution and relapse mechanisms in patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) who are 75 years of age or older or have comorbidities that preclude use of intensive induction chemotherapy treated with TIBSOVO in combination with azacitidine (Press release, Servier, DEC 10, 2022, View Source [SID1234625039]).

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Results from the study reinforce that TIBSOVO in combination with azacitidine leads to deep, durable remissions associated with clearance of IDH1-mutated AML, with no second-site IDH1 mutations observed to date amongst the patients enrolled in the TIBSOVO plus azacitidine study arm with both baseline and longitudinal DNA sequencing available (46/72 patients). Amongst patients who relapsed (n=22), mutations in other genes, including IDH2, can emerge and provide an opportunity for relapse. Further study is needed to better characterize mechanisms of relapse for patients treated with TIBSOVO plus azacitidine combination therapy.

"Combination therapy consisting of TIBSOVO in combination with azacitidine for newly-diagnosed patients with acute myeloid leukemia and an IDH1 mutation has shown significant clinical effectiveness, but it’s important that we analyze patient response throughout their treatment to better understand mechanisms of resistance," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "We are committed to our exploratory translational efforts and will continue to update the data, as available, to contribute to a better understanding of how to improve outcomes for patients living with this aggressive hematologic malignancy."

These data presented today at ASH (Free ASH Whitepaper) 2022 represent continued clinical evidence on the effectiveness of TIBSOVO amongst newly-diagnosed AML patients with an IDH1 mutation who are 75 years of age or older or have comorbidities that preclude use of intensive induction chemotherapy, and follows the expanded approval of TIBSOVO in AML supported by data from the AGILE study. Data from the global Phase 3 AGILE study showed TIBSOVO as the first IDH1 mutation-specific targeted therapy to demonstrate improved event-free survival (EFS) and overall survival (OS) in combination with azacitidine compared to azacitidine plus placebo.

"These new data reinforce the original results from the AGILE trial, showing TIBSOVO in combination with azacitidine as an effective, first-of-its kind combination treatment option for patients with newly-diagnosed, IDH1-mutated acute myeloid leukemia," said Eytan Stein, M.D., Chief of the Leukemia Service in the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center (MSKCC). "Given the rapid progression of acute myeloid leukemia, it’s important to have a targeted therapeutic option that provides significant event-free survival and overall survival alongside a favorable safety profile, and that’s what we’ve seen clinically with TIBSOVO plus azacitadine."

About the NCT03173248 AGILE Phase 3 AML Triali

The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of TIBSOVO in combination with azacitidine compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study’s primary endpoint is event-free survival (EFS), defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.

Key secondary endpoints include CR rate, defined as the proportion of participants who achieve a CR; overall survival (OS), defined as the time from date of randomization to the date of death due to any cause; CR and complete remission with partial hematologic recovery (CRh) rate, defined as the proportion of participants who achieve a CR or CRh; and objective response rate (ORR), defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults, with approximately 20,000 new cases in the U.S., and 43,000 cases in Europe each year.ii,iii AML incidence significantly increases with age, and the median age of diagnosis is 68.ii The five-year survival rate is approximately 30.5%.iv For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia.v

About TIBSOVO (ivosidenib tablets)

TIBSOVO (ivosidenib tablets) is approved in the U.S. in combination with azacitidine for the treatment of patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) in adults 75 years of age or older, or who have comorbidities that preclude use of intensive induction chemotherapy. TIBSOVO is the first therapy targeting cancer metabolism approved in combination with azacitidine for patients with newly-diagnosed IDH1-mutated AML.

TIBSOVO is also approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly-diagnosed IDH1-mutated AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Last year, TIBSOVO garnered its first approval in a non-hematologic malignancy for patients with previously treated IDH1-mutated cholangiocarcinoma.

Please see the TIBSOVO indications and Important Safety Information with a link to the full Prescribing Information below.

Sumitomo Pharma Oncology Presents Preliminary Data from Phase 1/2 Clinical Study Evaluating Investigational Agent TP-3654 in Patients with Myelofibrosis at American Society of Hematology 2022 Annual Meeting & Exposition

On December 10, 2022 Sumitomo Pharma Oncology, Inc., a clinical-stage company focused on novel cancer therapeutics, reported new data from the ongoing Phase 1/2 study evaluating TP-3654, an investigational selective oral PIM1 kinase inhibitor, in patients with myelofibrosis (MF) previously treated with or ineligible for JAK inhibitor therapy (Press release, Sumitomo Pharmaceuticals, DEC 10, 2022, View Source;exposition-301699788.html [SID1234625038]). These results were presented during an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, being held Dec 10-13, 2022, in New Orleans, LA.

Preliminary findings from the Phase 1 dose escalation study indicated TP-3654 is well tolerated with limited myelosuppressive adverse events. TP-3654, as a single agent, showed preliminary signs of clinical activity in the study, including spleen volume reduction, symptom improvement, and broad cytokine reduction, in patients previously treated with JAK inhibitors.1

"We are pleased by these preliminary clinical data and are encouraged by the safety and tolerability data seen in the ongoing TP-3654 dose escalation study. We remain committed to progressing this program, including expanding our clinical sites, and contributing to the advancement of possible treatment options which may improve outcomes for patients with myelofibrosis," said Patricia S. Andrews, Chief Executive Officer and Global Head of Oncology, Sumitomo Pharma Oncology, Inc.

The dose escalation portion of the study has enrolled 9 patients at the time of the analysis. To date, five dose levels of TP-3654 were evaluated, including once-daily and twice-daily regiments. No dose-limitation or related serious adverse event was observed up to the time of the analysis.

The data showed an early signal of clinical activity with spleen volume reduction (SVR). Six of 8 evaluable patients on treatment for at least 12 weeks experienced SVR, including 2 of 8 patients having at least 35% SVR. Additionally, a reduction in the symptom burden, measured by change in treatment score symptom (TSS), was experienced by 7 of the 8 evaluable patients, with 5 out of 8 patients having greater than 50% reduction. TP-3654 treatment was associated with reduced levels of cytokines associated with MF as early as 4 weeks, with cytokine reductions correlating with improved TSS.

Overall, TP-3654 appears to be well tolerated with no dose limiting toxicity (DLT) to date. The most common adverse events are Grade 1 gastrointestinal toxicities, which resolved in 1-2 weeks. Additionally, patients showed stable blood counts and no cytopenia with extended time on treatment. Currently, there are no discontinuations due to adverse events.

"These preliminary data presented at ASH (Free ASH Whitepaper) 2022 Annual Meeting & Exhibition are encouraging as we learn more about how TP-3654’s inhibition of PIM1 kinase may lead to reductions in bone marrow fibrosis and splenomegaly, and improved overall survival in patients with myelofibrosis," said Jatin J. Shah, M.D., Chief Medical Officer and Global Head of Development, Sumitomo Pharma Oncology (SMP Oncology). "We look forward to continuing to advance this study to evaluate the potential role of TP-3654 as a monotherapy, in addition to exploring combination opportunities with JAK inhibitors, for patients with myelofibrosis." Below are the details for the SMP Oncology presentation:

Abstract Title

Details

Presenter

Preliminary Data From the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients With Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Presentation #240 Saturday, December 10 at 3:15 p.m. CST
Oral Podium Presentation

Firas El Chaer, MD, Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, VA

To view the full presentation, please visit to our website here.

About TP-3654
TP-3654 is an oral investigational inhibitor of PIM kinases, which has shown potential antitumor and anti-fibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.2,3 TP-3654 was observed to inhibit proliferation and increased apoptosis in murine and human hematopoietic cells expressing clinically relevant JAK2V617F mutation.3 TP-3654 alone and in combination with ruxolitinib also showed normalized WBC and neutrophil counts, and reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.3 TP-3654 is currently being evaluated in a Phase 1/2 study of oral TP-3654 in patients with intermediate and high-risk myelofibrosis (NCT04176198).

Tessa Therapeutics Announces New Clinical Data from Phase 1 Allogeneic Study Presented at 2022 Annual Meeting of American Society of Hematology (ASH)

On December 10, 2022 Tessa Therapeutics Ltd. (Tessa), a clinical-stage cell therapy company developing next-generation cancer treatments for hematological malignancies and solid tumors, reported that enhanced clinical data from an ongoing Phase 1 study (NCT04288726) of TT11X, an allogeneic "off the shelf" CD30 (Press release, Tessa Therapeutics, DEC 10, 2022, View Source [SID1234625033]).CAR-modified Epstein-Barr virus-specific T-cell (EBVST) therapy being co-developed by Baylor College of Medicine and Tessa. The results, detailed in an oral podium presentation at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) on December 10, demonstrated TT11X to be well-tolerated at all dosing levels, eliciting a 79% overall response rate and complete disappearance of tumor in six patients.

The podium presentation, entitled, "Evaluating Safety and Clinical Efficacy of Off-the-Shelf CD30.CAR-Modified Epstein-Barr Virus-Specific T cells in Patients with CD30+ Lymphoma," reported data from 14 heavily pre-treated patients with advanced CD30-positve Hodgkin lymphoma who were administered TT11X across three dosing levels (4 × 107 CD30.CAR EBVSTs, 1 × 108 CD30.CAR EBVSTs, and 4 × 108 CD30.CAR EBVSTs). An overall response rate of 79% (11/14 patients) was observed across all three dose levels, including six complete responses and six partial responses. The strongest responses were achieved in patients treated at the higher dose levels with additional infusions resulting in increasing effectiveness.

TT11X was demonstrated to be well tolerated with no dose limiting toxicities observed, including no evidence of graft-versus-host disease (GVHD) and only two patients having reversible grade 4 cytopenia.

"The data reported at ASH (Free ASH Whitepaper) suggest that allogeneic CD30.CAR EBVSTs provide a potentially safe and efficacious treatment for CD30-positive lymphomas and affirm previously reported data indicating the technology may avert GVHD and immediate rejection even after multiple infusions," stated David H. Quach, Ph.D., Instructor at Center for Cell and Gene Therapy, Baylor College of Medicine, USA. "Importantly, CD30.CAR EBVSTs elicited a clinical response in 11 of 14 patients with advanced CD30-positve Hodgkin lymphoma including six complete responses. Based on these results, CD30.CAR EBVSTs appear to be a promising platform for off-the-shelf cancer immunotherapy."

Tessa is currently advancing a pipeline of products that utilize CD30.CAR-modified EBVSTs, including its lead allogeneic cell therapy, TT11X, which is being co-developed with the Baylor College of Medicine for the treatment of relapsed or refractory CD30-positive lymphomas. Tessa’s proprietary "off-the-shelf" CD30.CAR EBVST allogeneic cell therapy platform is based on decades-long research and development by researchers at Baylor College of Medicine into the unique properties of virus specific T-cells (VSTs). These highly specialized T cells have the ability to recognize and kill infected cells while activating other parts of the immune system for a coordinated response. CD30 Allogeneic VSTs without genetic modification have demonstrated a strong safety profile and efficacy in early trials with minimal risk of GVHD.

"The safety and efficacy data presented at ASH (Free ASH Whitepaper) were very compelling and indicate that our "off-the-shelf" CD30.CAR EBVST allogeneic cell therapy platform could provide a potential leap forward in the treatment of CD30 positive lymphomas," stated Ivan Horak, M.D., Chief Medical Officer and Chief Scientific Officer of Tessa Therapeutics. "We look forward to continuing the development of TT11X as a potential treatment for CD30-positive lymphomas, while exploring opportunities to extend the EBVST platform to other cancer indications, including solid tumors where there is significant unmet medical need."

Details of the podium presentation are as follows:

Presentation Title: Evaluating Safety and Clinical Efficacy of Off-the-Shelf CD30.CAR-Modified Epstein-Barr Virus-Specific T cells in Patients with CD30+ Lymphoma

Presenting Author: David H. Quach, PhD, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX

Session Date: Saturday, Dec. 10, 2022, at 1:00 PM CT; Ballroom AB

A second oral podium presentation scheduled for Monday, December 12 at 5:45 PM CT p.m. and a poster presentation scheduled for Sunday, December 11 will highlight data from the Phase 2 CHARIOT trial evaluating the safety and efficacy of TT11, Tessa’s autologous CD30.CAR-T-cell therapy in patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

Syndax Announces Positive Updated Data from Phase 1 Portion of AUGMENT-101 Trial of Revumenib in Patients with Acute Leukemias During Oral Presentations at 64th ASH Annual Meeting

On December 10, 2022 Syndax Pharmaceuticals, Inc. (Nasdaq: SNDX), a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported updated positive data from the Phase 1 portion of the ongoing Phase 1/2 AUGMENT-101 trial of revumenib in patients with nucleophosmin mutant (mNPM1) and KMT2A rearranged (KMT2r) relapsed/refractory (R/R) acute myeloid or acute lymphoid leukemias (ALL or AML) (Press release, Syndax, DEC 10, 2022, View Source [SID1234625031]). Revumenib is the Company’s highly selective, oral menin inhibitor. The data were featured during two oral sessions today at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"Both AUGMENT-101 data presentations featured today at the ASH (Free ASH Whitepaper) Annual Meeting highlight revumenib’s compelling clinical profile and continue to support the potential for revumenib to be a first-in-class and best-in-class therapy for both KMT2Ar and NPM1 acute leukemias," said Michael A. Metzger, Chief Executive Officer. "We previously announced that revumenib received Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia (AML or ALL) harboring KMT2A rearrangements, further emphasizing the compelling data that we have generated in the Phase 1 portion of the trial that included 46 R/R KMT2Ar acute leukemia patients as well as the unmet need that exists in this population. We remain on track to report top-line data from at least one of the cohorts from the pivotal Phase 2 portion of the trial beginning in the third quarter of 2023, followed by a potential New Drug Application filing by the end of 2023."

"Patients with genetically-defined acute leukemias, including those harboring NPM1 mutations and KMT2A-rearrangements, have a limited number of effective treatment options and face a particularly poor prognosis," said Ghayas C. Issa, M.D., Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "The deep, durable responses and manageable safety profile observed continue to support the potential for revumenib to serve as a meaningful new addition to the treatment armamentarium for this patient population. I look forward to contributing to the continued advancement of this promising therapeutic option."

The oral presentation titled "The Menin Inhibitor Revumenib (SNDX-5613) Leads to Durable Responses in Patients with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase 1 Study" featured updated results from the Phase 1 portion of the AUGMENT-101 trial. As of the March 2022 data cutoff date, 60 patients with R/R mutant NPM1 or KMT2Ar acute leukemia were efficacy evaluable. In the efficacy evaluable population, the ORR was 53% (32/60) with a CR/CRh rate of 30% (18/60), and 78% (14/18) of patients with CR/CRh attaining minimal residual disease (MRD) negativity. Additional analyses from the trial indicate that at doses which met the protocol defined criteria for a recommended Phase 2 dose (RP2D), the CR/CRh rate was 27% in both the KMT2Ar (10/37) and the mutant NPM1 (3/11) patient populations. A total of 38% (12/32) of responders proceeded to transplant. The median time to response in the trial was 1.9 months, and the median duration of CR/CRh response was 9.1 months in the efficacy evaluable population as of data cutoff.

Additional results included:

Best Response

Efficacy Population

(N=60)

Efficacy Population

Doses Meeting Criteria for
RP2D

(n=48)

Response

Overall response rate1, n, (%)

32 (53 %)

25 (52 %)

CR/CRh

18 (30 %)

13 (27 %)

12 (20 %)

8 (17 %)

CRh

6 (10 %)

5 (10 %)

CRp

5 (8 %)

5 (10 %)

MLFS

9 (15 %)

7 (15 %)

MRDneg rate2

18/32 (56%)

14/25 (56%)

within CR/CRh MRDneg, n, (%)

14/18 (78%)

10/13 (77%)

within CR/CRh/CRp MRDneg, n, (%)

18/23 (78%)

14/18 (78%)

KMT2Ar (MLLr)

Overall response rate1, n, (%)

27/46 (59%)

20/37 (54%)

CR/CRh

15/46 (33%)

10/37 (27%)

mNPM1

Overall response rate1, n, (%)

5/14 (36%)

5/11 (46%)

CR/CRh

3/14 (21%)

3/11 (27%)

1. Overall Response Rate = CR+CRh+CRp+MLFS; 2. MRD status assessed locally by PCR or MCF

Revumenib was well-tolerated, and no new safety signals were identified in the trial, including in patients who proceeded to stem cell transplant. There were no discontinuations due to treatment-related adverse events. The only dose limiting toxicity was asymptomatic Grade 3 QT prolongation, observed in 10% of patients treated at the RP2D and 13% of patients treated at all doses tested. No ventricular arrythmias or other clinical sequelae related to QTc prolongation were reported. Differentiation syndrome occurred in 16% of patients, and all cases of differentiation syndrome were Grade 2, and responded to standard management of steroids with or without hydroxyurea.

The oral presentation titled "Outcomes After Transplant in Relapsed/Refractory KMT2Ar (MLLr) and mNPM1 (NPM1c) Leukemia Patients Achieving Remissions After Menin Inhibition: Revumenib (SNDX-5613) Ph1 Experience" describes outcomes after transplant in patients achieving remissions in the Phase 1 portion of the AUGMENT-101 trial. Across evaluable patients with mNPM1 (n=14) or MLLr (n=46) acute leukemia who received revumenib, 12 (20%) patients proceeded to stem cell transplant, 11 (92%) of whom were MRD negative prior to transplant. Nine of the 12 patients (75%) who received a stem cell transplant remained in remission as of the data cutoff date, with a median follow-up of 12.3 months, and four patients experienced remission for longer than one year without additional maintenance therapy.

A copy of today’s presentations will be available in the Publications and Meeting Presentations section of Syndax’s website.

Conference Call and Webcast

The Company will host a conference call and webcast to discuss the ASH (Free ASH Whitepaper) data update tomorrow, Sunday, December 11, 2022 at 8:00 a.m. CT/ 9:00 a.m. ET. Joining the call will be members of the Syndax management team as well as two of the Primary Investigators on the AUGMENT-101 trial [Eytan M. Stein, M.D., Assistant Attending Physician and Director, Program for Drug Development in Leukemia, Department of Medicine at Memorial Sloan Kettering Cancer and Ghayas C. Issa, M.D., Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center].

The live audio webcast and accompanying slides may be accessed through the Events & Presentations page in the Investors section of the Company’s website. Alternatively, the conference call may be accessed through the following:

Conference ID: SYNDAX12
Domestic Dial-in Number: 800-225-9448
International Dial-in Number: 203-518-9708
Live webcast: https://www.veracast.com/webcasts/OpenEx/General/p08Np3.cfm

For those unable to participate in the conference call or webcast, a replay will be available on the Investors section of the Company’s website at www.syndax.com approximately 24 hours after the conference call and will be available for a limited time.

About Revumenib

Revumenib is a potent, selective, small molecule inhibitor of the menin-MLL binding interaction that is being developed for the treatment of KMT2A rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1 mutant AML. Revumenib is currently being evaluated in several clinical trials, including the Company’s pivotal AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Robust clinical activity with durable responses have been reported in the Phase 1 portion of AUGMENT-101. Revumenib was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was also granted Breakthrough Therapy Designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

About AUGMENT-101

AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of orally administered revumenib. The Phase 1 dose escalation portion of AUGMENT-101 was separated into two cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. Arm A enrolled patients not receiving a strong CYP3A4 inhibitor, while Arm B enrolled patients receiving a strong CYP3A4 inhibitor. The Phase 2 pivotal portion of AUGMENT-101 is currently underway. Patients will be enrolled across each of the following trial populations: patients with NPM1 mutant AML, patients with KMT2Ar (MLLr) AML, and patients with KMT2Ar (MLLr) ALL. Discussions with the FDA have confirmed that AUGMENT-101 may potentially serve as the basis for regulatory filings in each patient population. The primary endpoint for each of the trials will be efficacy as measured by complete remission rate (CR + CRh), with key secondary endpoints including duration of response (DOR) and overall survival (OS).

About KMT2A (MLL) Rearranged Acute Leukemia

Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia known to have a poor prognosis, with less than 25% of adult patients surviving past five years. KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.

KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques. The median overall survival (OS) after standard of care first-line treatment, including intensive chemotherapy and transplant, is less than 1 year and the majority of patients suffer relapse within 5 years. Most R/R patients treated with second-line therapy relapse within the first year. With third line treatment or beyond, only a small percentage of patients achieve complete remission (CR), and the median OS is less than 3 months.

About NPM1 Mutant Acute Myeloid Leukemia

NPM1 mutant acute myeloid leukemia (AML), which is distinguished by mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%. Similar to mixed lineage leukemia rearranged (MLLr) leukemias, NPM1 mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-MLL interaction. NPM1 mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1 mutant AML.

Precision BioSciences Presents Analysis of Azer-Cel, Allogeneic CAR T Product Attributes Related to In Vivo Pharmacokinetics, Pharmacodynamics, and Clinical Outcomes at 2022 American Society of Hematology Annual Meeting

On December 10, 2022 Precision BioSciences (Nasdaq: DTIL), a clinical stage gene editing company developing ARCUS-based ex vivo allogeneic CAR T and in vivo gene editing therapies, reported a novel, product-attributes analysis of its lead CD19 allogeneic CAR T candidate, Azercabtagene Zapreleucel (azer-cel; PBCAR0191) that shows a relationship between CAR T cell composition and effective cell dose with pharmacokinetics, pharmacodynamics, and clinical outcomes (Press release, Precision Biosciences, DEC 10, 2022, View Source [SID1234625028]). Data from this analysis, Effective Cell Dose and Functional Attributes of Azercabtagene Zapreleucel (azer-cel; PBCAR0191) Associated with Allogeneic CAR T-Cell Safety and Efficacy in Patients with Relapsed/Refractory B-Cell Lymphoma, were presented today during a poster session at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"Autologous CAR T therapy remains one of the most promising approaches in the treatment of hematological malignancies. However, 30-60% of high-grade non-Hodgkin Lymphoma (NHL) patients relapse after treatment and, for up a proportion of patients, an effective autologous product cannot be manufacturedi," said Caron A. Jacobson, M.D., azer-cel clinical trial investigator and Medical Director for the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute. "Unlike autologous CAR T cell therapy, all allogeneic CAR T products are cryopreserved, which may alter the effective dose and composition of the post-thaw product. In this analysis, azer-cel cellular attributes were interrogated in the post-thaw product for possible relationship to in vivo pharmacokinetics, pharmacodynamics, and clinical outcomes for 44 subjects with NHL across multiple azer-cel dose levels and lymphodepletion regimens. The analysis found that CAR T expansion, a key determinant of durable response, strongly correlated with non-apoptotic CAR T cell dose."

Azer-cel is an investigational allogeneic anti-CD19 CAR T candidate currently in a Phase 1/2a clinical trial of adult subjects with relapsed or refractory NHL, who relapsed following treatment with an autologous CAR T.

"This is the first analysis of an allogeneic anti-CD19 CAR T product to examine the relationships between allogeneic CAR T cell composition, cell dose, and lymphodepletion with pharmacokinetics, pharmacodynamics, and clinical outcomes," said Alan List, M.D., Chief Medical Officer, Precision BioSciences. "These results indicate that the post-thaw CAR T product composition drives in vivo cell expansion potential and CAR T-related adverse events. We are continuing to use this information in real time, applying optimizations across our first- and second-generation allogeneic CAR T platforms with the goal of improving those attributes and characteristics that drive predictability, reliability, and performance of CAR T cell therapy."

The analysis also showed that CD4:CD8 ratio strongly correlated with in vivo CD4+ CAR T cell expansion. Similar to data reported in autologous CAR T studies, differentiated CD4+ CAR T cell dose correlated with Grade 3 or greater neurotoxicity. This was particularly observed in a subset of patients that were both CAR T relapsed and conditioned with an intensified lymphodepletion treatment regimen.