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.

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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).

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.

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"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 %)

CR

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.

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.

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"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.

On December 10, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported updated interim clinical data from ongoing Phase 1/2 Study CIRM-0001 in an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2022 Annual Meeting (Press release, Oncternal Therapeutics, DEC 10, 2022, View Source [SID1234625027]). In the study, zilovertamab, an investigational anti-ROR1 monoclonal antibody, is being evaluated in combination with ibrutinib in patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and in a recently opened cohort for patients with marginal zone lymphoma (MZL). The clinical trial is being conducted in collaboration with the University of California San Diego (UC San Diego) and has been partially funded by the California Institute for Regenerative Medicine (CIRM).

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"The data presented in today’s oral session further strengthens our confidence in the significant clinical benefit the combination of zilovertamab and ibrutinib can provide to patients with MCL and CLL. The rapid onset of deep responses in patients with MCL supports our recently initiated randomized global registrational Phase 3 Study ZILO-301 of the combination of zilovertamab plus ibrutinib," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "The robust response rates and prolonged PFS seen for MCL and CLL patients expressing the p53 mutation/del(17p), who are underserved by current standard of care treatments, is especially exciting. We continue to believe that the inhibition of ROR1 with zilovertamab can play a key role in addressing important unmet medical needs in difficult-to-treat patients across various hematological malignancies."

The updated interim data presented during an oral presentation at the ASH (Free ASH Whitepaper) 2022 meeting include 33 patients with relapsed/refractory (R/R) MCL enrolled in the dose-finding and dose-expansion cohorts of Study CIRM-0001 (Part 1 + Part 2), of whom 28 were evaluable for efficacy as of the October 11, 2022 data cut-off date.

Patients had high-risk factors and were heavily pre-treated at study entry, with 52% having a high Ki-67 proliferative index (≥30%), 47% with p53 mutations or deletions in chromosome 17p (del(17p)), and 46% having an intermediate or high sMIPI prognostic score.
The objective response rate (ORR) was 89% (25 of 28 evaluable patients) and includes recently enrolled patients.
The complete response (CR) rate was 43% (12 of 28 evaluable patients) at 26 months and was already 18% (5 of 28 evaluable patients) at 3 months.
Historical data published for single agent ibrutinib for 370 patients with R/R MCL from three clinical trials showed an ORR of 66%, CR rate of 20% and median PFS of 12.8 months (Rule 2017, British Journal of Haematology).
The partial response (PR) rate was 46% (13 of 28 evaluable patients), and the stable disease (SD) rate was 4% (1 of 28 evaluable patients), for a total clinical benefit rate (CR, PR and SD) of 93%.
The median PFS has not been reached after a median follow-up of 19.5 months (95% CI: 19.4, 28.5), regardless of the number of prior systemic therapies.
Median PFS was also favorable in patients with high-risk features associated with disease difficult-to-treat with BTK inhibitors:
P53 mutation/del(17p): median PFS not reached (95% CI: 2.85, NE). Historical data for single agent ibrutinib in 20 patients with p53 mutation showed a median PFS of 4.0 months (Rule 2019, Haematologica).
Ki-67 ≥30%: median PFS 33.2 months (95% CI: 2.85, NE).
>1 prior systemic therapy: median PFS not reached (95% CI: 4.33, NE).
Thirty-four patients with CLL in the dose-finding and dose-confirming cohorts of this clinical trial (Part 1 & Part 2) as of the October 11, 2022 data cut-off date were all evaluable for efficacy. Patients had high-risk factors, and most were heavily pre-treated at study entry, with a median of two systemic prior therapies (range 1-9).

Landmark PFS was 100% at 42 months in patients with R/R CLL expressing p53 mutation/del(17p) treated with the combination of zilovertamab plus ibrutinib. The most recent data update from the ALPINE study in patients with R/R CLL expressing p53 mutation/del(17p) showed a landmark PFS of 77.6% at 24 months for zanubrutinib monotherapy and 55.7% at 24 months for ibrutinib monotherapy (Brown 2022, ASH (Free ASH Whitepaper)).
Landmark PFS was 95% at 24 months in all patients with R/R CLL treated with the combination of zilovertamab plus ibrutinib. The most recent data update from the ALPINE study in R/R CLL patients showed a landmark PFS at 24 months of 79.5% for zanubrutinib and 67.3% for ibrutinib monotherapy (Brown 2022, ASH (Free ASH Whitepaper)).
The median overall survival (OS) was not reached at 40 months for patients with CLL with p53 mutation/del(17p).
Thirty-one patients with CLL have also been enrolled in the randomized efficacy cohort of this clinical trial (Part 3), of which 23 were evaluable for efficacy. Data from this cohort are maturing. The median PFS had not been reached for either group as of the October 11, 2022 cut-off date after a median follow up of 29 months.

The combination of zilovertamab plus ibrutinib has been well tolerated as of the October 11, 2022 cut-off date, with treatment emergent adverse events consistent with or slightly improved compared to those reported for ibrutinib alone. There have been no dose-limiting toxicities and no serious adverse events attributed to zilovertamab alone. Atrial fibrillation was observed in only 9.4% of the patients and febrile neutropenia in 1.2% of patients.

About the CIRM-0001 Study
The CIRM-0001 Study is a Phase 1/2 trial evaluating zilovertamab in combination with ibrutinib in separate groups of patients with CLL, MCL or MZL. Enrollment of the dose-finding cohorts in CLL and MCL, dose-expansion cohort in CLL and MCL and randomized Phase 2 cohort in CLL has been completed. An additional dose-expansion cohort of up to 10 patients with MZL has started enrolling patients. Additional information about the CIRM-0001 clinical trial and other clinical trials of zilovertamab may be accessed at ClinicalTrials.gov.

About Zilovertamab
Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). A Phase 3 registrational trial evaluating zilovertamab plus ibrutinib versus ibrutinib plus placebo in relapsed or refractory Mantle Cell Lymphoma (MCL) has been initiated (NCT05431179). Zilovertamab is also being studied in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL, chronic lymphocytic leukemia (CLL) or marginal zone lymphoma (MZL), in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1-expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.

On December 10, 2022 MaaT Pharma (EURONEXT: MAAT – the "Company"), a French clinical-stage biotech and a pioneer in the development of Microbiome Ecosystem TherapiesTM (MET) dedicated to improving survival outcomes for patients with cancer, reported data from the continuing compassionate use program (EAP) in France for MaaT013 at the Annual Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans, U.S. To see the abstract, click here (Press release, MaaT Pharma, DEC 10, 2022, View Source [SID1234625025]).

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The EAP consolidated results, presented in an oral format on December 10 at 5:15 pm CET/ 10.15am CST by Prof. Mohamad Mohty, Head of the Clinical Hematology and Cellular Department at the Saint-Antoine Hospital and Sorbonne University, include data from 81 patients treated with MaaT013, the company’s high-richness, high-diversity lead Microbiome Ecosystem TherapyTM (MET) for hospital use in an acute setting. Patients developing refractory acute Graft-versus-Host Disease with gastrointestinal involvement (GI-aGvHD) following hematopoietic cell transplantation demonstrated an overall response rate (GI-ORR) of 56% at day 28 following MaaT013 treatment. In patients responding to MaaT013 therapy, the overall survival (OS) rate at 12 months was 59% (compared to 14% for non-responders) indicating a significant clinical benefit with MaaT013.

In aGvHD patients refractory to 1st-line (steroids) and 2nd-line (ruxolitinib) treatments (n=31) and receiving MaaT013 as a 3rd-line therapy, 65% demonstrated a GI-ORR at day 28. The 12-month OS rate in the MaaT013-responding group was 74%. This patient population resembles the ongoing Phase 3 ARES clinical trial (NCT04769895) being conducted in Europe.

"The clinical benefits we continue to observe with MaaT013 are promising and reinforce the potential for our MET to improve survival outcomes for aGvHD patients when early treatment lines are unsuccessful" said Hervé Affagard, CEO and co-founder of MaaT Pharma. "The year 2022 will be remembered as a turning point for the microbiome therapeutics industry as it continues to mature. We expect to see an acceleration in the field following the first FDA approval for a microbiome-based product in preventing C. difficile infection as well as promising clinical results in various infectious disease and oncology indications."

Prof. Mohamad Mohty added, "Patients with severe acute GvHD that have undergone several lines of treatments have a high mortality risk with no currently proven salvage treatment options. The results observed with MaaT013 are very encouraging especially in the 3rd-line setting where we see that the survival outcome is significantly improved. Since the patient population being treated with MaaT013 in the company’s Phase III ARES pivotal study in Europe is similar to those treated in the EAP, we are hopeful that the clinical trial results will corroborate these positive results and will provide an important benefit to all patients who are in need."

Key clinical findings with MaaT013 in compassionate use in France (Early Access Program or ‘EAP’)

In the EAP, 81 patients with steroid-dependent or steroid-resistant, Grade II-IV, gastrointestinal aGvHD were treated with MaaT013 from July 2018 to May 2022

45 out of 81 (56%) showed objective GI response at day 28 of which 30 patients (37%) had a complete response, 11 patients (14%) had a very good partial response, and 4 patients (5%) showed a partial response.
Overall survival (OS) in MaaT013-responding patients at the 12-month follow-up was 59%, compared to 14% in non-responders (OS in all included patients was 39% at 12 months).
Considering GvHD response in all organs (GI, skin, liver), 38 out of 78 patients (49%) showed an objective response rate (ORR) at day 28, of which 24 patients (31%) had a complete response, 11 patients (14%) had a very good partial response, and 3 patients (4%) showed a partial response.
At the time of treatment, all patients had either Grade II (11%), Grade III (51%) or Grade IV (38%) aGvHD (MAGIC Classification).
Patients received MaaT013 after 1 to 6 (median: 2; 66/81 received ruxolitinib) lines of treatment
68 out of 81 patients (84%) were steroid resistant of which 33 out of 68 (49%) showed an objective GI response at day 28; among these patients, 21 patients (31%) had a complete response, 9 patients (13%) had a very good partial response, and 3 patients (4%) showed a partial response.
66 out of 81 patients (81%) were refractory to ruxolitinib (any treatment line), of which, 37 out of 66 (56%) showed an objective GI response at day 28; of these 25 patients (38%) had a complete response, 9 patients (14%) had a very good partial response, and 3 patients (5%) showed a partial response
31 out of 66 patients were ruxolitinib-refractory in 2nd-line and MaaT013 was administered as a 3rd-line treatment; 20 out of 31 patients (65%) showed an objective GI response at day 28; among these patients, 19 patients (61%) had a complete response, and 1 patient (3%) had a very good partial response.
13 out of 81 patients (16%) were steroid-dependent of which 12 out of 13 patients (92%) showed an objective GI response at day 28; among these patients, 9 patients (69%) had a complete response, 2 patients (15%) had a very good partial response, and 1 patient (8%) showed a partial response.

Evaluation of MaaT013 in the Phase III pivotal clinical trial ARES

MaaT Pharma announced the first patient enrolled in the Phase III, open label, single arm, ARES pivotal trial for MaaT013 in March 2022, with a safety and data review by an independent data safety and monitoring board (DSMB), after enrollment of half of the patients in the study, expected in the first half of 2023.

As of today, MaaT013 has been safely administered to more than 160 patients in Europe in clinical trials and in the Expanded Access Program in France. Indeed, additionally to clinical trials, MaaT Pharma has been pursuing, since 2019, the compassionate use program in France, approved by the ANSM, to faster access to MaaT013 for patients with unmet medical need, mainly for indications in acute Graft-versus-Host disease. This program also allows the Company to strengthen its supply chain and production capacities to safely provide MaaT013, on a regular basis to 24 transplantation centers in France.

About MaaT013

MaaT013 is a standardized, high-richness, high-diversity Microbiome Ecosystem TherapyTM containing ButycoreTM (group of bacterial genera known to produce immuno-regulatory metabolites). It aims to restore the symbiotic relationship between the patient’s functional gut microbiome and their immune system to correct the responsiveness and tolerance of immune functions and reduce steroid-resistant, gastrointestinal-predominant aGvHD. MaaT013 has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). MaaT013 is an off-the-shelf, healthy-multi-donors-derived product intended for acute, hospital use.