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Biomea Fusion Announces Preliminary Data from Ongoing COVALENT-103 Study of Investigational Covalent FLT3 Inhibitor BMF-500 in Relapsed or Refractory Acute Leukemia

On December 9, 2024 Biomea Fusion, Inc. ("Biomea" or "the company") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported preliminary data from the ongoing Phase I COVALENT-103 study evaluating BMF-500, the company’s investigational covalent FLT3 inhibitor developed using the proprietary FUSION System (Press release, Biomea Fusion, DEC 9, 2024, View Source [SID1234648892]).

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"These early findings from the COVALENT-103 study announced today highlight the potential of BMF-500 to deliver meaningful clinical benefits for patients with acute leukemia harboring a FLT3 mutation. BMF-500 is an exceptionally potent molecule and the second covalent inhibitor we have developed in-house and advanced to the clinic and has shown high target selectivity and inhibition," said Thomas Butler, CEO of Biomea Fusion. "Our early results are particularly exciting as FLT3 gene mutations are common in AML patients and are associated with a very poor prognosis. Patients with such mutations who have failed gilteritinib have a median overall survival of less than 2 months. We hope to provide a significant improvement in the outcome for these patients with BMF-500. Given the safety profile demonstrated to date, and the lack of myelosuppression, we think BMF-500 could be an excellent combination partner used in standard of care."

As of the data cut off, November 20, 2024, 20 patients with R/R acute leukemia had been enrolled in the dose-escalation portion of the study, all of whom received at least one dose of BMF-500. Among these, the study enrolled 13 patients with confirmed FLT3-mutations, of which 10 harbored FLT3-ITD mutations and 3 had FLT3-TKD mutations. All patients with FLT3-mutations had progressed following treatment with gilteritinib, and 5 had received at least 2 prior FLT3 inhibitors. The study enrolled 5 patients with wild-type FLT3 and 2 patients with an unknown FLT3 mutation status. The median number of prior lines of therapies among the enrolled patients was 4. No QT prolongations or related cytopenias were observed and no dose-limiting toxicities (DLTs) were reported as of the data cut off. BMF-500 was generally well tolerated, and dose escalation is continuing per protocol.

Pharmacokinetic/pharmacodynamic data confirmed on-target FLT3 inhibition, as BMF-500 and its metabolites showed bone marrow penetration and near complete FLT3 inhibition as early as Day 1 of dosing, as well as dose-proportional FLT3 inhibition.

Preliminary data supports BMF-500’s potential as a transformative therapy for patients with FLT3 mutated R/R acute leukemia. During dose escalation, BMF-500 achieved a first CRi at the end of Cycle 2, in 1 of 2 (50%) FLT3 mutated patients dosed at 100 mg twice daily (BID), while the other patient experienced a clearance of peripheral blasts, greater than 50% reduction in bone marrow blasts and reduced transfusion frequency. The majority (5 of 6) of efficacy evaluable FLT3-mutated patients experienced a reduction of their bone marrow blasts. Other evidence of clinical activity such as: clearance or reduction of peripheral blasts, reduction of transfusion frequency, reduction in use of hydroxyurea were observed.

Case Study Highlights of Patient with Complete Response (CRi)

61-year-old patient with R/R AML, post allogenic transplant, with six co-occurring mutations (FLT3-ITD, ASXL1, IDH2, PHF6, RUNX1, SRSF2)
4 prior treatment regimens including venetoclax and gilteritinib
Confirmed CRi at 100 mg BID dosing
Progressive improvement in normal white blood cells, neutrophils, and monocytes despite ongoing transfusion needs
Webcast and Conference Call Details

Biomea Fusion will host a webcast and conference call today, Monday, December 9 at 4:30 pm EST. Interested parties will be able to join the webcast and view the related presentation under the Investors and Media section of the company’s website at View Source A replay of the webcast and conference call will be archived on Biomea’s website following the event.

About COVALENT-103

COVALENT-103 is a multicenter, open-label, non-randomized trial seeking to evaluate the safety and efficacy of BMF-500, a twice daily oral treatment, in adult patients with relapsed or refractory acute leukemia with FMS-like tyrosine kinase 3 (FLT3) wild-type and FLT3 mutations. The Phase I COVALENT-103 study aims to evaluate the safety and tolerability of BMF-500, determine the optimal biologic dose and recommended Phase II dose. Additional information about the Phase I clinical trial of BMF-500 can be found at ClinicalTrials.gov using the identifier, NCT05918692.

About BMF-500

BMF-500, an investigational, novel, orally bioavailable, highly potent and selective covalent small molecule inhibitor of FLT3, was discovered and developed in-house at Biomea using the company’s proprietary FUSION System and has demonstrated encouraging potential based on extensive preclinical studies. The kinase inhibitory profile of BMF-500 showed high target selectivity, suggesting the potential for reduced off-target liabilities. BMF-500 was designed to have a therapeutic profile to allow for combinations with standard of care and/or novel targeted agents like icovamenib, Biomea’s investigational covalent menin inhibitor currently in clinical development for solid and liquid tumors as well as diabetes.

Previous data presented at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting showed BMF-500’s picomolar affinity for inhibition of activating FLT3 mutations, including FLT3-ITD and various tyrosine kinase domain (TKD) mutations. BMF-500 demonstrated multi-fold higher potency and increased cytotoxicity as compared to the commercially available non-covalent FLT3 inhibitor gilteritinib. These data also showed complete tumor regression in mouse models of FLT3-ITD acute myeloid leukemia (AML), with no tumor regrowth even after treatment cessation.

Data presented at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting demonstrated the potential utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of BMF-500 and icovamenib. Additionally, Biomea has shown the potential of combinatorial approaches of BMF-500 and icovamenib with MEK and BCL2 blockade in other preclinical studies. These data provide preclinical evidence for combining pathway-specific inhibitors as a potential therapeutic strategy for further investigation in acute leukemia.

About FLT3 in AML

FLT3 is a receptor tyrosine kinase (RTK) that plays a central role in the survival, proliferation, and differentiation of immature blood cells. FLT3 gene mutations are common in patients with AML and are associated with a poor prognosis. Nearly 40% of AML patients have a FLT3 mutation, representing more than 7,000 incident patients in the U.S. each year. Once failing the only approved agent in the R/R setting, gilteritinib, patients typically have a poor prognosis and very short survival (median overall survival ~1.8 months). Academic literature suggests that up to 50% of AML patients with an NPM1 mutation also harbor a FLT3 mutation. While FLT3-specific and pan-tyrosine kinase inhibitors are approved by the FDA across various lines of therapy in AML, these agents have produced relatively low rates of durable responses and overall survival remains an unmet need.

Arcellx Announces New Positive Data for its iMMagine-1 Study in Patients with Relapsed or Refractory Multiple Myeloma to be Presented During an Oral Presentation at the 66th ASH Annual Meeting and Exposition

On December 9, 2024 Arcellx, Inc. (NASDAQ: ACLX), a biotechnology company reimagining cell therapy through the development of innovative immunotherapies for patients with cancer and other incurable diseases, reported new positive data from its Phase 2 pivotal iMMagine-1 study of anitocabtagene autoleucel (anito-cel), in patients with relapsed or refractory multiple myeloma (RRMM) (Press release, Arcellx, DEC 9, 2024, View Source [SID1234648890]). These data will be presented during an oral presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Monday, December 9, 2024 at 5:30 p.m. PT. Anito-cel is partnered with Kite, a Gilead Company. Additional presentations during ASH (Free ASH Whitepaper) are also noted below.

The Phase 2 iMMagine-1 data are from an October 31, 2024 data cutoff date, with a median follow-up of 9.5 months for the efficacy evaluable population. At the time of the data cut, 86 patients were evaluable for efficacy based on a follow-up of at least two months after treatment with anito-cel, and 98 patients were evaluable for safety based on a follow-up of at least one month after treatment with anito-cel. All patients received a single infusion of anito-cel (target dose of 115×106 CAR+ viable T cells). In the safety evaluable population, 85 of 98 patients (87%) were triple refractory, and 41 of 98 patients (42%) were penta refractory. Patients received a median of four prior lines of therapy, with 45 of 98 patients (46%) having received three prior lines.

Overall response rate (ORR) was 97% (83/86) with a complete response/stringent complete response (CR/sCR) rate of 62% (53/86) and a very good partial response or higher (>VGPR) rate of 81% (70/86), per International Myeloma Working Group (IMWG) criteria as investigator-assessed. Of those evaluable for minimal residual disease (MRD) testing, 93.1% (54/58) achieved MRD negativity at a minimum of 10-5 sensitivity. Median progression-free survival (mPFS) and overall survival (OS) were not reached; 6-month PFS and OS rates were 93.3% and 96.5%, respectively, and 12-month PFS and OS rates were 78.5% and 96.5%, respectively.

No delayed or non-ICANS neurotoxicities, including no Parkinsonism, no cranial nerve palsies, and no Guillain-Barré syndrome, have been observed to date in more than 150 patients dosed with anito-cel. Of the safety evaluable population, 86% (84/98) had Grade ≤1 cytokine release syndrome (CRS), including 17% of patients with no CRS. Among patients experiencing CRS, the median onset was four days (range: 1-17 days). Eight percent of patients (8/98) were treated as outpatient. Ninety-one percent (89/98) of patients had no ICANS. Any Grade ICANS was observed in 9 patients (9%; Gr3 1%), with all cases resolved without sequelae. Three deaths occurred due to treatment-emergent adverse events (TEAEs) (related or unrelated to anito-cel: retroperitoneal hemorrhage, CRS, and fungal infection). No additional treatment or therapy-related deaths or Grade ≥3 CRS or ICANs events have occurred to date. Cytopenias were the most common Grade ≥3 TEAEs; 53 patients (54%) had Grade ≥3 neutropenia, 20 (20%) had Grade ≥3 thrombocytopenia, and 22 (22%) had Grade ≥3 anemia.

Conclusions

Preliminary results from the Phase 2 iMMagine-1 study demonstrate deep and durable responses with a predictable and manageable safety profile in a high-risk fourth-line or higher (4L+) RRMM population, including triple- and penta-class refractory disease. Notably, no delayed or non-ICANS neurotoxicities, including no Parkinsonism, no cranial nerve palsies, and no Guillain-Barré syndrome, have been observed with anito-cel to date.

Ciara Freeman, M.D., Ph.D., Assistant Member, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center said, "The data from the iMMagine-1 study demonstrate that this is a highly active product with impressive depth of responses achieved in patients with relapsed or refractory multiple myeloma. As a physician who treats many patients both inpatient and in the outpatient setting, the emerging safety profile of anito-cel is encouraging, in particular the absence of any delayed neurotoxicities reported to date. We are excited to begin enrolling patients in the iMMagine-3 study and in the near future having anito-cel as an approved treatment option."

Arcellx’s Chairman and Chief Executive Officer, Rami Elghandour, said, "It’s exciting to reach this momentous milestone in our pivotal study and present these compelling data. These data, along with the data from our Phase 1 study, which demonstrated a 30.2-month median PFS and zero cases of delayed neurotoxicity or other non-ICANS neurotoxicity with all patients having more than two years of follow-up, continue to support our conviction that anito-cel has the potential to be a best-in-class treatment option for patients with RRMM. Additionally, with iMMagine-3 underway in earlier lines in a patient population representing an unmet clinical need, we expect to further position anito-cel as a differentiated CAR-T treatment option for RRMM. Separately, this year is Arcellx’s 10th anniversary! I’m grateful for the incredible people who make up the fabric of Arcellx and have poured themselves into developing this life-saving therapy for the patients most in need. And I’m proud of how we’ve done it, leaning into our diversity as a cornerstone of our culture, which underpins our success. I especially appreciate the partnership, collaboration, and trust of the Phase 1 and iMMagine-1 clinicians who helped enroll patients in these studies and allowed us to demonstrate the potential benefit of anito-cel. I’m also grateful to those who believed in us, our founding investors and scientists, our investors who helped us go public nearly three years ago in a challenging market, and those who have joined us along the way. To our colleagues at Kite, we thank you for your partnership. To everyone who’s been part of this incredible journey, thank you! We’re just getting started!"

ASH Presentation Details

Phase 2 Registrational Study of Anitocabtagene Autoleucel for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma: Preliminary Results From the iMMagine-1 Trial (abstract #1031)

Speaker: Ciara Freeman, M.D., Ph.D., H. Lee Moffitt Cancer Center

Session Name: 655. Multiple Myeloma: Cellular Therapies: Unleashing Cell Therapies Against Myeloma

Session Date: Monday, December 9, 2024

Session Time: 4:30 p.m. – 6:00 p.m. PT

Presentation Time: 5:30 p.m. PT

Location: Marriott Marquis San Diego Marina, Pacific Ballroom Salons 24-26

Publication Number: 1031

Submission ID: 198499

Phase 1 Study of Anitocabtagene Autoleucel for the Treatment of Patients With Relapsed and/or Refractory Multiple Myeloma (RRMM) (abstract #4825)

Speaker: Michael R. Bishop, M.D., The University of Chicago

Session Name: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities

Session Date: Monday, December 9, 2024

Presentation Time: 6:00 p.m. – 8:00 p.m. PT

Location: San Diego Convention Center, Halls G-H

Publication Number: 4825

Submission ID: 201080

Health Related Quality of Life (HRQoL) in Relapsed/Refractory Multiple Myeloma (RRMM): A Systematic Literature Review (SLR) and Meta-Analysis (abstract #4721)

Speaker: Rahul Banerjee, M.D., Fred Hutchinson Cancer Center

Session Name: 653. Multiple Myeloma: Clinical and Epidemiological: Poster III

Session Date: Monday, December 9, 2024

Presentation Time: 6:00 p.m. – 8:00 p.m. PT

Location: San Diego Convention Center, Halls G-H

Treatment Patterns and Outcomes in Triple-Class Exposed Patients with Relapsed and Refractory Multiple Myeloma: Findings from the Flatiron Database (abstract #6962)

This abstract will be published in a supplemental issue of Blood in November 2024.

Webcast Event (New Start Time):

Arcellx will host a live webcast event with an expert panel of clinicians to discuss the clinical results on Monday, December 9, 2024 at 8 p.m. PT. The event will be accessible from the Investors section of the Company’s website at ir.arcellx.com. A webcast replay will be archived and available for 30 days following the event.

About Multiple Myeloma

Multiple Myeloma (MM) is a type of hematological cancer in which diseased plasma cells proliferate and accumulate in the bone marrow, crowding out healthy blood cells and causing bone lesions, loss of bone density, and bone fractures. These abnormal plasma cells also produce excessive quantities of an abnormal immunoglobulin fragment, called a myeloma protein (M protein), causing kidney damage and impairing the patient’s immune function. Multiple myeloma is the third most common hematological malignancy in the United States and Europe, representing approximately 10% of all hematological cancer cases and 20% of deaths due to hematological malignancies. The median age of patients at diagnosis is 69 years with one-third of patients diagnosed at an age of at least 75 years. Because MM tends to afflict patients at an advanced stage of life, patients often have multiple co-morbidities and toxicities that can quickly escalate and become life-endangering.

About Anitocabtagene Autoleucel (anito-cel)

Anitocabtagene autoleucel (anito-cel, previously ddBCMA) is the first BCMA-directed CAR T-cell therapy to be investigated in multiple myeloma that utilizes Arcellx’s novel and compact binder known as the D-Domain. The small, stable D-Domain binder enables high CAR expression without tonic signaling and is designed to quickly release from the BCMA target. This combination may allow for the effective elimination of multiple myeloma cells without severe immunotoxicity. Anito-cel has been granted Fast Track, Orphan Drug, and Regenerative Medicine Advanced Therapy Designations by the U.S. Food and Drug Administration.

About iMMagine-3, A Global Phase 3 Randomized Controlled Clinical Study

iMMagine-3 is a global Phase 3 randomized controlled study designed to compare the efficacy and safety of anitocabtagene autoleucel (anito-cel) with standard of care in patients with relapsed and/or refractory multiple myeloma (RRMM) who have received one to three prior lines of therapy, including an immunomodulatory drug (lMiD) and an anti-CD38 monoclonal antibody.

iMMagine-3 will enroll approximately 450 adult patients. Prior to randomization, investigator’s choice of standard of care (SOC) regimens include: pomalidomide, bortezomib, and dexamethasone (PVd); daratumumab, pomalidomide, and dexamethasone (DPd); carfilzomib, daratumumab, and dexamethasone (KDd); or carfilzomib and dexamethasone (Kd). Patients in the anito-cel arm will undergo leukapheresis and optional bridging therapy (with the SOC regimen selected by the investigator prior to randomization) followed by lymphodepleting chemotherapy (fludarabine 30 mg/m2/d and cyclophosphamide 300 mg/m2/d for 3 days) and one infusion of anito-cel (115×106 CAR+ T cells) on Day 1.

The primary endpoint is progression-free survival (PFS) per blinded independent review according to the 2016 IMWG uniform response criteria for multiple myeloma (MM) with the hypothesis that anito-cel will prolong PFS compared to SOC. Key secondary endpoints include complete response rate (CR/sCR), minimal residual disease negativity, overall survival, and safety.

The iMMagine-3 study was initiated in the second half of 2024 at approximately 130 study sites across North America, Europe, and the rest of the world.

Aptose Clinical Data Featured in Poster Presentation at the 2024 ASH Annual Meeting Support Tuspetinib Triple Drug Therapy for Newly Diagnosed AML

On December 9, 2024 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated targeted agents to treat hematologic malignancies, reported a wealth of clinical data for Aptose’s lead compound tuspetinib (TUS) in a poster presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (Press release, Aptose Biosciences, DEC 9, 2024, View Source [SID1234648889]).

Poster title: "Phase 1 Safety and Efficacy of Tuspetinib Plus Venetoclax Combination Therapy in Study Participants with Relapsed or Refractory Acute Myeloid Leukemia (AML) Support Exploration of Triplet Combination Therapy of Tuspetinib Plus Venetoclax and Azacitidine for Newly Diagnosed AML"

Key Findings and Messages:

TUS+VEN+AZA triplet trial is proceeding in newly diagnosed AML patients
TUS+VEN retains activity in the difficult-to-treat prior-VEN AML population
TUS+VEN is active in FLT3 wildtype, representing ~70% of AML patients
TUS+VEN is well tolerated and can be safely co-administered
TUS+VEN is active across broad populations of R/R AML
Combination of TUS with VEN may avoid VEN resistance
TUS+VEN+AZA triplet may establish a more effective, mutation agnostic standard of care for chemotherapy ineligible AML patients
Tuspetinib (TUS), being developed by Aptose and originally created by Hanmi Pharmaceutical Co., is being advanced as the TUS+VEN+AZA triplet (tuspetinib+venetoclax+azacitidine) for frontline therapy of newly diagnosed AML patients ineligible for intensive chemotherapy. TUS is a once daily, oral, multi-kinase inhibitor selectively targeting kinases that drive AML cell proliferation. In the Phase 1/2 APTIVATE trial of relapsed/refractory (R/R) AML patients (NCT03850574), TUS single agent and the TUS+VEN doublet demonstrated excellent safety and broad efficacy across AML genetic subgroups – including those with adverse mutations in TP53 and RAS genes, and those with mutated or unmutated (wildtype) FLT3 genes.

"Our extensive dataset with TUS and TUS+VEN support advancement of the TUS+VEN+AZA triplet frontline therapy and we are pleased to now have the TUSCANY triplet clinical trial up and running," said Rafael Bejar, MD, PhD, Chief Medical Officer at Aptose. "TUS targets known VEN resistance mechanisms, and in combination with VEN, could prevent emergence of resistance to both agents. Moreover, with its breadth of activity and unique safety profile, TUS, as part of a triplet therapy regimen, may target AML’s greatest unmet needs and largest markets."

Highlights of the ASH (Free ASH Whitepaper) poster presentation:

TUS as Single Agent (n= 93 Patients)

60% and 42% CR/CRh with 80 mg TUS in FLT3 mutated and all-comer VEN-naïve AML
33% CRc & 42% ORR (CR, CRp, CRh, CRi or PR) in FLT3 mutated and VEN-naïve patients
Includes 40, 80, 120, and 160 mg TUS dose as a single agent
Includes those who failed prior therapy with venetoclax
Includes those with mutated or unmutated FLT3, those who failed prior-HSCT, priorFLT3i, prior-chemotherapy, prior-HMA
TUS once daily orally as a single agent achieved CR/CRh responses at four different dose levels (40, 80, 120, and 160 mg) with no dose limiting toxicities (no DLTs)
TUS showed a favorable safety profile with no DLTs through 160 mg per day, and no drug related discontinuations, no QTc, no differentiation syndrome, and no deaths
TUS/VEN Combination Therapy (n= 79 Patients)

40% ORR with 80 mg TUS + 400 mg VEN in FLT3 mutated patients. Among these 83% (5/6) had failed prior-VEN treatment and 50% (3/6) had failed both prior-VEN and FLT3i treatment.
TUS+VEN achieved responses among diverse R/R AML with adverse mutations in VEN-naïve, prior-VEN, FLT3WT, FLT3MUT, prior-FLT3
TUS+VEN showed favorable safety and tolerability with no new or unexpected safety signals, no drug related CPK elevations, no differentiation syndrome, and no deaths

Protara Announces Proposed Public Offering

On December 9, 2024 Protara Therapeutics, Inc. (Nasdaq: TARA) ("Protara"), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported that it has commenced an underwritten public offering of shares of its common stock or, in lieu of issuing common stock to certain investors, pre-funded warrants to purchase shares of its common stock (Press release, Protara Therapeutics, DEC 9, 2024, View Source [SID1234648887]). All of the shares of common stock and pre-funded warrants to be sold in the proposed offering will be offered by Protara. In addition, Protara expects to grant the underwriters a 30-day option to purchase additional shares of common stock at the public offering price, less underwriting discounts and commissions. The proposed offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or the actual size or terms of the offering. Protara intends to use the net proceeds received from the offering to fund the clinical development of TARA-002, as well as the development of other clinical programs. Protara may also use the net proceeds from the offering for working capital and other general corporate purposes.

TD Cowen, Cantor, LifeSci Capital, Oppenheimer & Co. and Scotiabank are acting as joint book-running managers of the proposed offering.

The shares of common stock and the pre-funded warrants will be issued pursuant to a shelf registration statement on Form S-3 (File No. 333-275290) that was declared effective on November 14, 2023 by the U.S. Securities and Exchange Commission (the "SEC"). The offering is being made only by means of a preliminary prospectus supplement and the accompanying prospectus. A preliminary prospectus supplement and the accompany prospectus relating to the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Copies of the preliminary prospectus supplement and the accompany prospectus relating to the offering, when available, may be obtained from the offices of TD Securities (USA) LLC, 1 Vanderbilt Avenue, New York, New York 10017, by email at [email protected] or by telephone at (855) 495-9846; Cantor Fitzgerald & Co., 110 East 59th Street, 6th Floor, New York, New York 10022, Attention: Capital Markets, or by email at [email protected]; or LifeSci Capital LLC, 1700 Broadway, 40th Floor, New York, New York 10019, or by email at [email protected].

Before investing in the offering, interested parties should read the preliminary prospectus supplement and related prospectus for this offering, the documents incorporated by reference therein and the other documents Protara has filed with the Securities and Exchange Commission. The final terms of the offering will be disclosed in a final prospectus supplement to be filed with the Securities and Exchange Commission.

This press release shall not constitute an offer to sell or a solicitation of an offer to buy any of these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to registration or qualification under the applicable securities laws of such state or jurisdiction.

Molecular Partners Presents Clinical Data Supporting its Ongoing MP0533 Study and Preclinical Data on Next-Gen Conditioning Agent MP0621 at ASH 2024

On December 8, 2024 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics ("Molecular Partners" or the "Company"), reported the presentation of additional data pertaining to two programs, including preclinical data on MP0621, a potential next-generation conditioning regimen for patients undergoing hematopoietic stem cell transplantation, and comprehensive data from the first seven cohorts of the ongoing phase 1/2a dose-escalation study of MP0533 (Press release, Molecular Partners, DEC 8, 2024, View Source [SID1234655798]). The data are presented in two posters at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting, being held December 7-10, 2024 in San Diego, CA.

"We are at a unique crossroads with the MP0533 program. Data from our Ph1/2a study indicate antitumor and pharmacodynamic activity despite currently sub-optimal exposure levels, mostly driven by target-mediated drug disposition," said Patrick Amstutz, Ph.D., CEO of Molecular Partners. "The sum of these data, reviewed in close collaboration with our KOLs, allowed us to define a clear hypothesis that introducing a loading-dose-phase will improve MP0533 exposure, thereby testing the full therapeutic potential of MP0533 in AML patients. We are happy to report that these amendments are submitted, while patient treatment is still ongoing. We look forward to providing updates to the program in 2025."

MP0533: Acceptable safety profile, exposure being optimized via protocol amendment

MP0533 is a novel tetraspecific T cell engaging DARPin which simultaneously targets the three tumor-associated antigens (TAAs) CD33, CD123 and CD70, as well as CD3 on T cells. The mechanism of action of MP0533 is designed to preferentially kill AML cells that express any combination of these three TAAs while sparing healthy cells, which express only one or none of these targets. The immune activation against the malignant cells is achieved through CD3-mediated T cell-engagement.

The data presented at ASH (Free ASH Whitepaper) 2024 are from the ongoing first-in-human dose-escalation phase 1/2a study of MP0533 in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)/AML. MP0533 continues to show an acceptable safety profile in 37 patients up to dose cohort 7, with the majority of adverse events reported being infusion-related reactions and cytokine release syndrome. Initial pharmacodynamic data provide evidence of MP0533 target engagement and resulting immune activation. Despite lower than anticipated drug exposure, four responders in total were reported in cohorts 1-7 and encouraging blast reductions were observed in patients bone marrow, particularly in patients with lower disease burden.

Based on these observations Molecular Partners is amending the protocol of this study to further optimize the dosing schedule and improve the exposure profile of MP0533 in subsequent dosing cohorts. The goal is to achieve higher response rates, as well as an improved quality and duration of response in this heterogeneous patient population.

MP0621: Intended mechanism of HSC depletion confirmed preclinically

MP0621 is a Switch-DARPin candidate designed to induce killing of hematopoietic stem cells (HSCs) as a next-generation conditioning regimen for HSC transplantation (HSCT). The Switch-DARPin platform provides a logic-gated "on/off" function (the "Switch") to multispecific DARPin candidates leading to target activation only in the presence of defined antigens. In MP0621, the Switch-DARPin binds to either cellular cKit or to the anti-CD47 DARPin binder. Upon MP0621 binding to cKit on HSCs, the Switch-DARPin will unmask the anti-CD47 DARPin, which in turn will bind CD47 and block the "don’t-eat-me" signal, leveraging the power of CD47 inhibition without its associated toxicity to healthy cells

The preclinical results presented support the intended MP0621 mechanism of action and provide further evidence for its potential as a viable approach for HSC depletion in patients. The blockade of CD47 exclusively on target cells allows MP0621 to enhance efficacy of cKit-targeting, while reducing off-target effects seen with systemic anti-CD47 blockade. The currently available non-human primate data however do not allow Molecular Partners to conclude that MP0621 would serve as a treatment for AML patients, as previously hypothesized. As Molecular Partners’ portfolio strategy prioritizes therapeutic candidates for oncology, MP0621 is being evaluated for partnering.

Details of the poster presentations at ASH (Free ASH Whitepaper) 2024:

Session Name: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster II
Publication Number: 2881
Title: MP0533 (CD33 x CD123 x CD70 x CD3), a Tetra-Specific CD3-Engaging DARPin for the Treatment of Patients with Relapsed/Refractory AML or MDS/AML: Results of an Ongoing Phase 1/2a Study
Session Location: San Diego Convention Center, Halls G-H
Presentation Date & Time: Sunday, December 8, 2024, 6:00–8:00 pm PT

Session Name: 701. Experimental Transplantation: Basic and Translational: Poster III
Publication Number: 4775
Title: MP0621 (cKit x CD16a x CD47), a Multi-Specific Switch-DARPin with Conditional Blockade of CD47 Targeting Hematopoietic Stem Cells: Preclinical Evaluation of a Next-Generation Conditioning Agent for Stem Cell Transplantation
Session Location: San Diego Convention Center, Halls G-H
Presentation Date & Time: Monday, December 9, 2024, 6:00–8:00 pm PT

Both posters will be made available on Molecular Partner’s website in the Scientific Documents section.

About DARPin Therapeutics
DARPin (Designed Ankyrin Repeat Protein) therapeutics are a new class of custom-built protein drugs based on natural binding proteins that open new dimensions of multi-functionality and multi-target specificity in drug design. The flexible architecture, intrinsic potential for high affinity and specificity, small size and high stability of DARPins offer benefits to drug design over other currently available protein-based therapeutics. DARPin candidates can be radically simple, with a single DARPin unit acting as the delivery vector to a specific target; or multispecific, with the possibility of engaging more than five targets, and combining multiple and conditional functionalities in a unique DARPin drug candidate. The DARPin platform is designed to be a rapid and cost-effective drug discovery engine, producing drug candidates with optimized properties and high production yields. DARPin therapeutics have been clinically validated across several therapeutic areas and developed through to the registrational stage.