On December 11, 2023 MEI Pharma, Inc. (Nasdaq: MEIP), a clinical-stage pharmaceutical company evaluating novel drug candidates to address known resistance mechanisms to standard-of-care cancer therapies, reported clinical data from the monotherapy dose escalation stage of the ongoing Phase 1 study evaluating voruciclib, a selective oral cyclin-dependent kinase 9 ("CDK9") inhibitor, alone and in combination with venetoclax (Venclexta), a B-cell lymphoma 2 ("BCL2") inhibitor, in patients with acute myeloid leukemia ("AML") or B-cell malignancies, is highlighted in a poster session at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, MEI Pharma, DEC 11, 2023, View Source [SID1234638429]).

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The poster can be viewed on the MEI Pharma website here: View Source

"The potential to use an oral CDK9 inhibitor such as voruciclib to reduce Mcl-1 protein, an established resistance factor for the BCL-2 inhibitor venetoclax, is a promising approach to improve therapeutic options for patients with hematologic malignancies," said Matthew S. Davids, MD, MMSc., Director, Clinical Research, Division of Lymphoma, Dana-Farber Cancer Institute, and study chair of the monotherapy stage of the Phase 1 study. "The data reported today, along with the experience with voruciclib in combination with venetoclax to date, provides encouraging support for the approach of this combination to address a common resistance mechanism to venetoclax therapy and improve clinical response without overlapping toxicity."

"I’d like to recognize the support and high level of engagement by our investigators, and the participation of the patients enrolling in this study, as we advance the evaluation of voruciclib in combination with venetoclax in patients with AML," said David M. Urso, president and chief executive officer of MEI Pharma. "We look forward to disclosing additional data in early 2024 from the dose escalation portion of the ongoing Phase 1 clinical trial evaluating voruciclib in combination with venetoclax in patients with AML."

Clinical Data from the Monotherapy Dose Escalation Stage of the Ongoing Phase 1 Study Evaluating Voruciclib in Combination with Venetoclax

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Presentation Title: A Phase 1 Study of the Oral CDK9 Inhibitor Voruciclib in Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL) or Acute Myeloid Leukemia (AML)
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Session Title: Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III (616)
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Presenter: Matthew S. Davids, MD, MMSc., Associate Professor, Harvard Medical School, Director, Clinical Research, Division of Lymphoma, Dana-Farber Cancer Institute
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Date: Monday, December 11, 2023, 6:00-8:00 PM (Pacific Time)
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Publication Number: 4286

Phase 1 Study Details

The Phase 1 study is a two stage, open-label, 3+3 dose escalation and expansion study evaluating voruciclib, a CDK9 inhibitor, as a monotherapy and in combination with venetoclax (marketed as Venclexta), a BCL2 inhibitor. The first stage of the study, evaluating the dose and schedule of voruciclib as a single-agent in patients with relapsed and refractory ("R/R") acute myeloid leukemia ("AML") or B-cell malignances after failure of standard therapies, is complete. The second stage of the study is ongoing and is evaluating voruciclib in combination with venetoclax in patients with R/R AML.

A total of 40 patients, median age 75 years (range 63-80), were enrolled in the first stage of the study evaluating voruciclib as a monotherapy. The majority of patients (n=21) had AML and the remaining patients (n=19) had B-cell malignancies. Enrolled patients were generally heavily pretreated; the median number of prior therapies was 3 (range 1-9) and 5 patients had prior hematopoietic stem cell transplant.

Patients enrolled in Cohort 1 (n= 16) of the monotherapy stage of the study were administered voruciclib once daily continuously at doses of 50 mg and 100 mg. Patients enrolled in Cohort 2 (n=24) were administered voruciclib on an intermittent schedule (IS) on days 1-14 in a 28-day cycle implemented after 2 dose limiting toxicities (DLT) were observed at 100 mg daily continuously. Dose escalation in Cohort 2 was stopped at 200 mg before reaching the maximum tolerated dose (MTD) at this schedule to focus on evaluation of venetoclax in combination with voruciclib.

The primary objectives of the study are to determine the safety and biologic effective dose of voruciclib monotherapy or voruciclib in combination with venetoclax. Secondary objectives of the study include assessing the preliminary efficacy, pharmacokinetics, pharmacodynamics, and biomarkers of voruciclib monotherapy or voruciclib in combination with venetoclax.

Monotherapy Safety and Tolerability

Voruciclib at doses up to 200 mg administered on 14 consecutive days in a 28-day cycle (Cohort 2) was well tolerated with no DLT reported. The most common adverse events (≥20% of patients) were diarrhea, nausea, anemia and fatigue. The large majority of adverse events were Grade 1-2; of note, the only Grade 3-4 adverse events in Cohort 2 were diarrhea (n=1) and anemia (n=5).Pharmacokinetics were dose proportional and mean half-life of approximately 24 hours supports once daily dosing.

Monotherapy Efficacy

In the 21 patients enrolled with AML, 1 patient at 100 mg achieved a morphologic leukemia-free state and 9 patients had disease stabilization, which lasted at least 3 months in 2 patients. In the 19 patients enrolled with B-cell malignancies, 4 patients had stable disease with a decrease in tumor size.

Initial results from correlative studies assessing myeloid leukemia cell differentiation protein ("Mcl-1") and RNA Pol II phosphorylation on Ser2 ("RNA Pol II p-S2") demonstrated reduction in expression consistent with the anticipated on-target pharmacodynamic effect of voruciclib on Mcl-1 and RNA Pol II p-S2 (Figures A and B, respectively, below).

Voruciclib Plus Venetoclax Combination: Initial Data

Voruciclib at doses up to 200 mg on the intermittent schedule have been administered in combination with venetoclax in patients with relapsed or refractory AML. Dose escalation is continuing.

No DLTs have been reported and no evidence of overlapping toxicity has been observed to date. Anti-tumor activity has been demonstrated by objective responses and reductions in transfusions, with multiple patients continuing on therapy for ≥ 4 months.

About Voruciclib

Voruciclib is an orally administered cyclin-dependent kinase 9 ("CDK9") inhibitor with potential to treat both hematological malignancies and solid tumors. It is in clinical development for acute myeloid leukemia and B-cell malignancies. Applications in solid tumors are also being considered.

The CDK family of proteins are important cell cycle regulators responsible for the control of cell proliferation, differentiation, apoptosis, and DNA repair. CDK9, one of several members of the CDK family of proteins, functions as a gene transcription controller and is also involved in regulating protein degradation. Specifically, CDK9 is a promising target to treat a range of cancers because of its role in controlling two other proteins often dysregulated in cancerous cells: Mcl-1 and the MYC proto-oncogene protein ("MYC")

Mcl-1 is a member of the family of anti-apoptotic proteins which, when elevated, may prevent the cell from undergoing cell death. Inhibition of CDK9 blocks the production of Mcl-1, which is an established resistance mechanism to the B-cell lymphoma 2 ("BCL2") inhibitor venetoclax (marketed as Venclexta).

MYC regulates cell proliferation and growth. Upregulation of MYC is implicated in many human cancers and is frequently associated with poor prognosis and unfavorable patient survival. CDK9, in addition to being a transcription factor for MYC, also decreases phosphorylation of MYC protein that is implicated in stabilizing MYC in KRAS mutant cancers. Targeting MYC directly has historically been difficult, but CDK9 is a promising approach to target this oncogene.

On December 11, 2023 Marker Therapeutics, Inc. (Nasdaq: MRKR), a clinical-stage immuno-oncology company focusing on developing next-generation T cell-based immunotherapies for the treatment of hematological malignancies and solid tumor indications, reported a clinical update on the APOLLO study (Press release, Marker Therapeutics, DEC 11, 2023, View Source [SID1234638428]). The Phase 1 APOLLO study is investigating MT-601, a multi-tumor associated antigen (multiTAA)-specific T cell product, for the treatment of patients with lymphoma who have failed or are ineligible to receive anti-CD19 CAR T cell therapy.

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The Company previously reported first enrollment in the dose escalation stage of the Phase 1 trial (Press Release, June 12, 2023). The patient had diffuse large B cell lymphoma (DLBCL) and failed four prior lines of therapy, including anti-CD19 CAR T cell therapy. Marker reported in September that the study participant tolerated the treatment well without treatment-related adverse events and achieved a complete metabolic response eight weeks after the second infusion of MT-601 (Press Release, September 11, 2023). Marker reports today that six months following the initial treatment with MT-601 the study participant has maintained complete response to treatment.

These clinical results are reinforced by non-clinical proof-of-concept data demonstrating that MT-601 has the potential to eradicate lymphoma cells resistant to anti-CD19 CAR T cells, highlighting the therapeutic potential of MT-601 in vitro (Press Release, May 31, 2023).

Although CD19-targeting CAR T cell therapies have gained acceptance as treatment for patients with lymphoma, up to 60% of patients treated with CAR T therapies relapse within one year (Chong EA et al, N Engl J Med, 2021). This APOLLO study participant relapsed within 90 days after CAR T cell therapy, yet maintained a complete response for at least six months after treatment with MT-601, suggesting that MT-601 is more durable compared to CAR T cells in this study participant.

CAR T cell therapies, which have known severe side effects such as neurotoxicity, are also currently being investigated by the FDA for the risk of potential induction of secondary cancers (U.S. Food and Drug Administration, November 28, 2023), adding another layer of concern for patients and clinicians. Notably, multiTAA-specific T cell therapies have been well-tolerated in clinical trials, and Marker believes that multiTAA-specific T cells are a safe alternative to CAR T cells due to their non-genetically engineered approach that selectively expands tumor-specific T cells from a patient’s/donor’s blood without the risk of mutagenesis.

"Witnessing the sustained complete response in our first patient treated with MT-601 over six months has been an encouraging and rewarding experience," commented Dr. Geoffrey Shouse, the Principal Investigator at City of Hope National Medical Center in Duarte California. "This is a remarkable achievement, demonstrating the potential impact of MT-601 in patients with lymphoma who have relapsed after anti-CD19 CAR T cell therapy. We are encouraged by the benefit this therapy has provided for one our patient’s life, the newfound hope it brings, and the potential impact MT-601 could have as a novel treatment option for patients with lymphoma."

"Relapse rates following CAR T cell therapy are high," said Juan F. Vera, M.D., President and Chief Executive Officer of Marker Therapeutics. "The ongoing complete response observed after MT-601 infusion in a CAR relapsed patient with lymphoma suggests superior durability of our therapy over CAR T cells in this patient. To further validate these observations, we have already enrolled additional patients in this study to replicate and reinforce these promising results."

Dr. Vera continued: "The sustained complete response is a significant milestone in our Phase 1 study and highlights the potential benefit of MT-601 in patients who relapse after anti-CD19 CAR T cell therapy. We will continue to monitor long-term treatment effects and durability of response and look forward to treating additional participants in this Phase 1 study."

About MT-601

MT-601 utilizes a novel non-genetically modified approach that specifically targets six different tumor antigens upregulated in lymphoma cells (Survivin, PRAME, WT-1, NY-ESO-1, SSX-2, MAGEA-4). Marker is currently investigating MT-601 in the Company-sponsored Phase 1 APOLLO trial (clinicaltrials.gov identifier: NCT05798897) for the treatment of lymphoma patients who are relapsed/refractory after or ineligible to anti-CD19 CAR T cell therapies.

About APOLLO

The APOLLO trial (clinicaltrials.gov Identifier: NCT05798897) is a Phase 1, multicenter, open-label study designed to evaluate the safety and efficacy of MT-601 in participants with relapsed or refractory lymphoma who either failed anti-CD19 chimeric antigen receptor (CAR) T cell therapy or are ineligible for anti-CD19 CAR T cell therapy. The primary objective of this exploratory Phase 1 clinical trial is to evaluate the optimum dose, safety, and preliminary efficacy of MT-601 in participants with various lymphoma subtypes. Under the APOLLO trial, nine clinical sites across the United States will cumulatively enroll up to approximately 30 participants during the dose escalation phase.

About multiTAA-specific T cells

The multi-tumor associated antigen (multiTAA)-specific T cell platform is a novel, non-genetically modified cell therapy approach that selectively expands tumor-specific T cells from a patient’s/donor’s blood capable of recognizing a broad range of tumor antigens. Clinical trials that enrolled more than 200 patients with various hematological malignancies and solid tumors showed that autologous and allogeneic multiTAA-specific T cell products were well tolerated and demonstrated durable clinical responses, and consistent epitope spreading. The latter is typically not observed with other T cell therapies and enables the potential contribution to a lasting anti-tumor effect.

On December 11, 2023 MaaT Pharma (EURONEXT: MAAT – the "Company"), a clinical-stage biotechnology company and a leader in the development of Microbiome Ecosystem TherapiesTM (MET) dedicated to improving survival outcomes for patients with cancer, reported positive results from the Early Access Program (EAP) in Europe involving 111 patients with steroid-refractory (SR) or steroid-dependent (SD) gastrointestinal acute graft-versus-host Disease (GI-aGvHD) treated with MaaT013, at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, MaaT Pharma, DEC 11, 2023, View Source [SID1234638427]).

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"GvHD remains a significant challenge and source of mortality following allogeneic HSCT," said Professor Mohty, Professor of Hematology at Sorbonne University, and head of the Clinical Hematology and Cellular Therapy Department at Saint-Antoine Hospital, Paris, France. "The clear connection between treatment response and overall survival demonstrates Microbiome Therapies as a potentially life-saving approach, particularly in patients who have failed earlier treatment lines, corticosteroids and ruxolitinib. MaaT013 introduces a novel therapeutic approach by restoring the gut microbiome ecosystem, offering a distinct immuno-restorative option that could complement standard immunosuppressive drugs, and could become a potential breakthrough for patients with limited options."

"These promising findings pave the way for advancing the treatment landscape for aGvHD, with microbiome-based innovations, especially when they achieve complete responses," said Hervé Affagard, CEO and co-founder of MaaT Pharma. "It reinforces our approach based on restoring patients’ immune systems through gut microbiome ecosystem therapies. The efficacy and safety results underscore the strong favourable benefit-risk profile for MaaT013, and we look forward to continuing to investigate MaaT013 with the aim of having it accessible globally for patients in need as soon as possible".

MaaT013 shown to have a safe profile and translates into increased overall survival:

GI-ORR of 53% at day 28, with Complete Response observed in more than two thirds of responders (35%); Overall Response Rate (ORR) considering all organs was 50% with 31% Complete Response (CR).
OS was 56% at 6 months and 47% at 12 months with a median follow up of 355 days.
OS was significantly higher in patients who responded to MaaT013 compared to non-responders (67% versus 24% at 12 months).
The Company defined a subgroup of 38 patients with similar treatment sequence to the ongoing Phase 3 ARES clinical trial, which included patients previously treated with steroids and ruxolitinib. GI-ORR was 61% at day 28, mainly driven by GI Complete Response (CR) with 58%. ORR was 54% including 51% with CR. Overall Survival (OS) in this group was 55% at 6 months and 52% at 12 months, confirming the CR as a proxy of survival at one year. OS was significantly higher in responders to MaaT013 treatment compared to non-responders (81% versus 8% at 12 months, respectively).

MaaT013, a pooled-donor microbiome ecosystem therapy, displayed a good overall tolerability and safety profile in the EAP population. As of today, MaaT013 has been administered to more than 200 patients. Full details on safety are available here. A Phase 3 trial is currently ongoing in Europe to confirm these results in ruxolitinib-refractory patients (NCT04769895) with ORR expected in mid-2024. The Company has an open-IND granted by the U.S. FDA with active discussions ongoing with potential clinical investigation sites.

MaaT Pharma also presented its ongoing Phase 2b trial design for MaaT033, its second candidate, at the 2023 ASH (Free ASH Whitepaper) Annual Meeting. Developed as an adjunctive therapy to enhance OS in HSCT (hematopoietic stem cell transplantation) and cellular therapy recipients, MaaT033 targets optimal microbiota function for a broader patient population in a chronic setting. This international, multi-centre trial (NCT05762211) is the largest randomized controlled study to date of a microbiome-based therapy in oncology, spanning up to 56 sites and enrolling 387 patients.

Company to host key opinion leaders’ discussion on Monday, December 18 at 6:00 pm CET. To register, please click here.

On December 11, 2023 Keros Therapeutics, Inc. ("Keros") (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on developing and commercializing novel therapeutics to treat a wide range of patients with disorders that are linked to dysfunctional signaling of the transforming growth factor-beta ("TGF-ß") family of proteins, reported that it presented additional data from its two ongoing Phase 2 clinical trials of KER-050, one in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes ("MDS") and one in patients with myelofibrosis ("MF"), at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting and Exposition, held in person in San Diego and virtually from December 9 through 12, 2023 (Press release, Keros Therapeutics, DEC 11, 2023, View Source [SID1234638425]). In addition, Keros presented preclinical data showing that a research form of KER-050 promoted erythropoiesis in an animal model of MF, as well as preclinical data evaluating the treatment effect of activin receptor-like kinase 2 inhibition in a mouse model of iron-refractory iron deficiency anemia.

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"We believe the data presented at ASH (Free ASH Whitepaper) from our ongoing KER-050 Phase 2 clinical trial in MDS supports the potential of KER-050 to ameliorate ineffective hematopoiesis and treat anemia and thrombocytopenia in difficult to treat patient populations, including those with greater transfusion burden and bone marrow dysfunction," said Simon Cooper, MBBS, Chief Medical Officer of Keros. "Additionally, we are encouraged by the preliminary data from the lowest three dose cohorts from our ongoing Phase 2 clinical trial in MF. KER-050 treatment in combination with ruxolitinib and as KER-050 monotherapy led to improvements as assessed by changes in markers of hematopoiesis, reductions in spleen size and improvement in Total Symptom Score. We look forward to confirming this profile of benefit in the now enrolling dose confirmation part of our trial."

"The encouraging broad profile of KER-050 that we have observed supports its potential to treat not just the disease-associated cytopenias, but also impact the pathogenesis of the respective diseases, as supported by the observed improvements in bone health and reduction of cardiac stress," said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer. "We are excited by the results we presented including the durability of transfusion independence observed with KER-050 and to engage with regulators in the first half of next year and look forward to sharing the design of a Phase 3 clinical trial evaluating KER-050 in lower-risk MDS following that feedback."

Clinical Presentations

•Durable Clinical Benefit with KER-050 treatment: Findings From an Ongoing Phase 2 Study in Participants with Lower-Risk MDSThis ongoing, open-label, two-part, Phase 2 clinical trial is evaluating KER-050 in patients with very low-, low-, or intermediate-risk MDS. As of September 1, 2023 (the "data cut-off date"), 79 patients had received at least one dose of KER-050 at the recommended Part 2 dose ("RP2D") (collectively, the "safety population"). Of these patients, 60 had completed at least 24 weeks of treatment or discontinued as of the data cut-off date (collectively, the modified intent to treat 24-week population, or the "mITT24 patients"). Data for hematological response and markers of hematopoiesis were presented from exploratory analyses of these mITT24 patients. All data presented from this trial is as of the data cut-off date.

Of the 79 patients in the safety population, 55.7% (n=44) were high transfusion burden ("HTB") while 25.3% (n=20) were low transfusion burden and 19.0% (n=15) were non-transfused ("NT").
KER-050 was generally well tolerated by the 79 patients in the safety population. The most commonly reported treatment-emergent adverse events ("TEAEs") (in ≥15% of patients) were diarrhea, dyspnea, fatigue, nausea and headache. No patients had progressed to acute myeloid leukemia.

50% (n=30/60) of the mITT24 patients achieved an overall erythroid response over the first 24 weeks of treatment, which is defined as meeting either modified IWG 2006 Hematological improvement-erythroid ("HI-E") or transfusion independence ("TI") for at least eight weeks in transfusion-dependent patients who required ≥ 2 red blood cell ("RBC") units transfused at baseline.

Additional data from the mITT24 patients include:

•39.1% (n=18/46) of the TI-evaluable patients achieved TI for at least eight weeks over the first 24 weeks of treatment. 13 of those 18 patients (72.2%) achieved TI for at least 24 weeks over the first 48 weeks of treatment.
•Of the patients with HTB, 33.3% (n=11/33) achieved TI for at least eight weeks during the first 24 weeks of treatment. 7 of those 11 patients (63.6%) achieved TI for at least 24 weeks over the first 48 weeks of treatment.
•Of the patients with baseline erythropoietin level less than 500 U/L, 44.7% (n=17/38) achieved TI for at least eight weeks over the first 24 weeks of treatment. Of the patients with baseline erythropoietin level less than 500 U/L and HTB, 38.5% (n=10/26) achieved TI for at least eight weeks over the first 24 weeks of treatment.

The FACIT-Fatigue scale, a measure of self-reported fatigue and its impact upon daily activities and function, was utilized to assess health-related quality of life in 45 of the mITT24 patients who were TI-evaluable and with baseline FACIT-F assessment. A difference of three in the FACIT-Fatigue scale is considered a minimally clinically important difference. In this group, patients who achieved TI had durable and clinically meaningful improvements in self-reported fatigue. At Week 24, patients achieving TI of eight weeks or longer within first 24 weeks had a mean score of 5.8 (n=10) versus patients who did not achieve TI who reported a mean score of -3.2 (n=11), for a mean difference of 9.0. At Week 24, patients achieving TI of 24 weeks or longer with first 48 weeks had a mean score of 7.8 (n=9) versus patients who did not achieve TI who reported a mean score of -3.9 (n=12), for a mean difference of 11.7.

The majority of patients enrolled in this ongoing trial had HTB or multi-lineage dysplasia, indicating a difficult-to-treat trial population. Durable TI responses were observed in a broad range of patients with lower-risk MDS, including in those with HTB, which support the potential for KER-050 to ameliorate ineffective hematopoiesis across multiple lineages in patients with MDS. Patients who achieved TI showed clinically meaningful improvements in FACIT-Fatigue scores, indicating that KER-050 may improve quality of life in patients with lower-risk MDS.

•KER-050 Treatment Reduced Iron Overload and Increased Bone Specific Alkaline Phosphatase in Participants with Lower-risk MDS Supporting Potential to Restore Balance to the Osteohematopoietic Niche

Exploratory analysis of biomarkers that may indicate MDS disease modification were evaluated as of the data cut-off date in the ongoing Phase 2 clinical trial of KER-050 in patients with MDS. Observations from these biomarkers included improvements in:

•Iron metabolism: 48.3% (n=14/29) of patients with baseline ferritin ≥ 1,000 ng/ml had a decreased ferritin to < 1000 ng/ml and 69.0% (n=20/29) of patients decreased ferritin by ≥20%. Two patients, including one who was NT, discontinued iron chelator therapy due to observed decreases in ferritin. These data support potential of KER-050 to ameliorate iron overload.
•Hematopoiesis: Sustained increases in hemoglobin for 24 weeks coincided with observed increases in soluble transferrin receptor and concomitant decreases in serum ferritin, suggesting KER-050 resulted in durable restoration of erythropoiesis and improved iron metabolism.
•Bone turnover: Increases in bone-specific alkaline phosphatase, a marker of osteoblast activity, were observed with KER-050 treatment regardless of hematological response, baseline transfusion burden or RS status, suggesting KER-050 can potentially restore a bone marrow microenvironment conducive to functional hematopoiesis.
•Cardiac stress: Levels of N-terminal prohormone of brain natriuretic protein, a biomarker of myocardial stress, decreased in both HI-E and/or TI responders and non-responders, suggesting that KER-050 may ameliorate cardiac strain directly via inhibition of activin A and indirectly by improving anemia and reducing transfusion burden.

Collectively, these exploratory data suggest that KER-050 has the potential to provide benefit to patients with MDS beyond treatment of anemia, such as reestablishing hematopoiesis across multiple cell lineages, restoring homeostasis within the osteohematopoietic niche and ameliorating myocardial strain.

•Modulation of TGF-β Superfamily Signaling by KER-050 Demonstrated Potential to Treat Myelofibrosis and Mitigate Ruxolitinib-Associated Cytopenias

This ongoing, open-label, two-part Phase 2 clinical trial is evaluating KER-050 administered with or without ruxolitinib in patients with MF who have anemia and were either currently on, failed, or ineligible for ruxolitinib at baseline. Safety data are presented for all patients that received at least one dose of KER-050 in Part 1 (n=41) as of September 14, 2023. Evaluations of markers of hematopoiesis and anemia over 12 weeks, along with measurements of spleen volume and symptom scores (by the MF-symptom assessment form-Total Symptom Score, or "MF-SAF-TSS") over 24 weeks, were presented for dose levels 1 through 3, ranging from 0.75 mg/kg to 3.0 mg/kg (collectively, the "efficacy evaluable patients"). Data for dose level 4 (4.5 mg/kg), the highest dose level being evaluated in Part 1, are not included due to limited exposure as of the data cutoff date. All data presented from this trial is as of the September 14, 2023 data cut-off date.

KER-050 was generally well tolerated by the safety population. There was one dose-limiting toxicity reported from a patient in the 1.5mg/kg dose level of the monotherapy arm. The patient had an increase in hemoglobin of at least 2 g/dL, which met protocol criteria for dose reduction at the end of cycle 1. There were no adverse events associated with this event, and the maximum observed hemoglobin remained within normal limits. There were three cases of fatal TEAEs in the trial that were each deemed unrelated to treatment. The most commonly reported TEAEs (in ≥10% of patients) were diarrhea, thrombocytopenia, asthenia (weakness), fatigue and pyrexia (fever). Treatment-related TEAEs were relatively infrequent, most of which were mild to moderate, with two patients experiencing Grade 3 or higher worsening cytopenias.

Additional data from the efficacy evaluable patients include:

•Increases in hemoglobin were observed in non-transfusion dependent patients in both arms, suggesting that KER-050 has the potential to address anemia due to MF and ruxolitinib-associated anemia.
◦Additionally, most patients had reductions in transfusion burden, including patients receiving up to 15 RBC units per 12 weeks at baseline.
•Non-transfusion dependent patients, who received a median of three RBC units per 12 weeks at baseline, experienced sustained increases in hemoglobin within the first 12 weeks of treatment in both the monotherapy and combination arms (pooled across dose cohorts).
◦Additionally, observed increases in soluble transferrin receptor, reticulocytes and hemoglobin were generally higher with increasing dose levels between 0.75 mg/kg to 3.0 mg/kg (pooled across both monotherapy and combination arms at each dose level).
•At week 24, reduction in spleen size was observed in 57.1% (n=4/7) of patients with baseline spleen size ≥ 450 cm3 and a week 24 spleen assessment, including one of three patients in the monotherapy arm and three of four patients in the combination arm.
•At week 24, decrease in disease symptoms was observed in 66.7% (n=8/12) of patients with at least two symptoms with an average score ≥ 3 or an average total score of ≥ 10 on the MF-SAF-TSS questionnaire at baseline and a week 24 MF-SAF-TSS assessment.

The data support the potential of KER-050 to ameliorate ineffective hematopoiesis and address cytopenias due to MF and associated with ruxolitinib, and provide broader clinical benefit in patients as observed by the reduction in spleen size and improvement in symptoms.

Conference Call and Webcast Information

Keros will host a conference call and webcast today, December 11, 2023, at 8:00 a.m. Eastern time, to discuss the additional data from its two ongoing Phase 2 clinical trials of KER-050, one in patients with MDS and one in patients with MF, which was presented at the 65th ASH (Free ASH Whitepaper) Annual Meeting and Exposition.

The conference call will be webcast live at: View Source;tp_key=cad9574144. The live teleconference may be accessed by dialing (877) 407-0309 (domestic) or (201) 389-0853 (international). An archived version of the call will be available in the Investors section of the Keros website at View Source for 90 days following the conclusion of the call.

About the Ongoing Phase 2 Clinical Trial of KER-050 in Patients with MDS (NCT04419649)

Keros is conducting an open label, two-part, multiple ascending dose Phase 2 clinical trial to evaluate KER-050 in patients with very low-, low-, or intermediate-risk MDS who either have or have not previously received treatment with an erythroid stimulating agent.

The primary objective of this trial is to assess the safety and tolerability of KER-050 in patients with MDS that are RS positive or non-RS. The primary objective of Part 2 of this trial is confirmation of the safety and tolerability of the RP2D (3.75 mg/kg and 5.0 mg/kg). The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of KER-050.

About the Ongoing Phase 2 Clinical Trial of KER-050 in Patients with MF-Associated Cytopenias (RESTORE trial)

Keros is conducting an open label, two-part, multiple ascending dose Phase 2 clinical trial to evaluate KER-050 as a monotherapy and in combination with ruxolitinib in patients with MF-associated cytopenias.

The primary objective of this trial is to assess the safety and tolerability of KER-050 in patients with MF-associated cytopenias. The primary objective of Part 2 of this trial is confirmation of the safety and tolerability of the RP2D (3.75 mg/kg and 5.0 mg/kg). The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of KER-050 administered with or without ruxolitinib.

About KER-050

Keros’ lead protein therapeutic product candidate, KER-050, is an engineered ligand trap comprised of a modified ligand-binding domain of the TGF-ß receptor known as activin receptor type IIA that is fused to the portion of the human antibody known as the Fc domain. KER-050 is being developed for the treatment of low blood cell counts, or cytopenias, including anemia and thrombocytopenia, in patients with MDS and in patients with MF.

On December 11, 2023 IN8bio, Inc. (Nasdaq: INAB), a leading clinical-stage biopharmaceutical company developing innovative gamma-delta T cell therapies, reported positive updated data from its Phase 1 investigator-sponsored trial of INB-100 in patients with hematologic malignancies (Press release, In8bio, DEC 11, 2023, View Source [SID1234638424]). The data, which will be presented in a poster presentation at the 65th ASH (Free ASH Whitepaper) Annual Meeting & Exposition this evening, demonstrated that 100% of evaluable leukemia patients (n=10) treated remained alive, progression-free, and in durable complete remission (CR) as of November 3, 2023. The Company believes this data indicate the curative potential of INB-100 to provide durable relapse free periods for high-risk or relapsed AML and other hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). The CRs to date, combined with INB-100’s benefit/risk profile are encouraging for the treatment of hematological malignancies and the trial is being expanded by ten patients at Dose Level (DL) 2, the recommended Phase 2 dose (RP2D). Additional expansion patient enrollment is on-going and updated data is expected to be presented at medical meetings in 2024.

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"With more patients and a longer observation period, we are excited to report that 100% of evaluable dosed patients continue to remain in morphological complete remission, with six patients remaining alive and relapse free beyond one year," said Trishna Goswami, MD, Chief Medical Officer at IN8bio. "Leukemic relapse is the leading cause of death in patients undergoing HSCT and prevention of relapse remains a high unmet need. In this trial, the first three patients were high-risk or relapsed AML patients with complex cytogenetics. We are happy to report two of the patients remain alive and relapse free for over three years, and the third is now past two years. Furthermore, INB-100 has demonstrated for the first time, the in-vivo expansion and persistence of an allogeneic, or donor-derived, cellular therapy at 365 days with blood levels of gamma-delta T cells surpassing levels previously observed to be associated with greater survival."

"Our team is excited by the potential safety, efficacy and durability of this novel cellular therapy and the possibility to improve the likelihood of cure for patients with blood cancers undergoing stem cell transplantation," said Dr. Joseph McGuirk, the Schutte-Speas Professor of Hematology-Oncology, Division Director of Hematological Malignancies and Cellular Therapeutics and Medical Director, Blood and Marrow Transplant at The University of Kansas Cancer Center and the Principal Investigator on the study. "Relapse post stem cell transplant remains the primary cause of treatment failure and mortality. The results of this clinical trial are very encouraging and hold great promise that a novel cellular therapy using donor-derived gamma-delta T cells may prevent relapse, resulting in improved relapse free survival for patients with hematologic malignancies."

Summary of Data Presented at ASH (Free ASH Whitepaper)

The latest INB-100 trial data on immune reconstitution showed significant allogeneic gamma-delta T cell expansion and persistence in patients through the first 365 days post-treatment.

Patients who received INB-100 treatment at DL 2 exhibited gamma-delta T cell levels:

An average of 48.9x greater at 60 days compared with patients undergoing haploidentical HSCT without INB-100 therapy.
An average of 7.6x greater than those achieved in DL 1, which continues to demonstrate a dose-response related to the gamma-delta T cell infusion.
An average of 2.7x greater at 365 days than levels found in DL 1, which is above levels previously associated with improved survival outcomes.
Other observations:

Elevations in CD4+, CD8+ T cells, NK cells and B cells have also been observed, indicating a broad positive immune response and stable reconstitution of the immune system post-transplant.
New cytokine data following gamma-delta T cell infusion demonstrate peripheral increases in pro-inflammatory cytokines in the plasma, such as interferon-gamma, IL-6 and IL-15 early post-infusion, demonstrating broad immune activation.
Updated safety data includes three additional patients since in April 2023 (as of November 3, 2023):

Low grade (1-2) acute graft versus host disease (GvHD) observed in 60% of patients treated. Cases were all steroid responsive.
No dose limiting toxicities (DLTs) have been observed.
All evaluable patients across DL 1 and DL 2 remained on study and in CR, with two patients now remaining progression free for over 3 years.
Treated patients have remained progression free for 42.7, 40.3, 28.6, 14.3, 12.2, 12.0, 9.0, 5.6, 5.3 and 4.9 months, respectively.
Conference Call Details
IN8bio will host a conference call and webcast tomorrow, Tuesday, December 12, 2023, at 8:30 am ET to review the updated clinical data from the ASH (Free ASH Whitepaper) presentation. The webcast can be accessed by clicking this link and can also be accessed on the Events & Presentations page of the Company’s website. To participate in the live call, please register using this link. It is recommended that participants register at least 15 minutes in advance of the call. Once registered, participants will be informed of the dial-in number and will be provided a unique PIN.

About the INB-100 Phase 1 Trial
The Phase 1 clinical trial (NCT03533816) is an investigator-sponsored dose-escalation trial of allogeneic derived, gamma-delta T cells from matched related donors that have been expanded and activated ex vivo and administered systemically to patients with leukemia following HSCT. The single-institution clinical trial is currently being conducted at The University of Kansas Cancer Center (KUCC). The primary endpoints of this trial are safety and tolerability, and secondary endpoints include rates of GvHD, relapse rate and overall survival.