On December 12, 2022 Magenta Therapeutics (Nasdaq: MGTA), a clinical-stage biotechnology company developing novel medicines designed to bring the curative power of stem cell transplant to more patients, highlights updated clinical data from the ongoing MGTA-117 Phase 1/2 dose-escalation clinical trial made in an oral presentation today at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2022 Annual (ASH) (Free ASH Whitepaper) Meeting in New Orleans and provides program updates across the portfolio.

"We have shown that a single dose of MGTA-117 binds target cells, depletes target cells, clears the body quickly as designed, and does so with a favorable tolerability profile in our ongoing Phase 1/2 clinical trial. We believe that these positive clinical data establishes proof-of-mechanism, and that we have reached an active dose. Target cell depletion is a critical measurement of success for MGTA-117, and we are encouraged by the levels of depletion we have observed in both the blood and the bone marrow of relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. We are excited about our planned next steps to take MGTA-117 into transplant-eligible AML and MDS patients as well as into patients who are receiving gene therapy. We are thankful to all of the patients and families who have participated in our trial to date as well as our investigators and the clinical site staff, all of whom have contributed greatly to the advancement of MGTA-117 for patients," said Jason Gardner, President and Chief Executive Officer of Magenta Therapeutics. "Together with the progress we are making on CD45-ADC and MGTA-145, we are pleased with the momentum across our portfolio and the multiple anticipated inflection points for Magenta in the coming year."

MGTA-117 Clinical Data and Continued Development
MGTA-117 is Magenta’s most advanced targeted conditioning product candidate designed to deplete CD117-expressing target cells in the blood and/or bone marrow prior to a patient undergoing stem cell transplant or receiving an ex vivo gene therapy product. MGTA-117 is an anti-CD117 antibody conjugated to an amanitin payload. CD117, also known as c-Kit receptor, is highly expressed on hematopoietic stem cells, progenitor cells and cancer blast cells.

Current Phase 1/2 Patient Population and Potential Significance for Clinical Development
The ongoing Phase 1/2 clinical trial is in relapsed/refractory (R/R) AML and MDS. These patients are deemed ineligible for transplant due to active disease characterized by high numbers of cancer blast cells present in the bone marrow and in the bloodstream. Over 80% of patients with AML and MDS express the CD117 receptor on the surface of their cancer cells. In these patients, CD117+ target cells are a combination of cancer blast cells in the blood and bone marrow and non-malignant stem and progenitor cells in the bone marrow. MGTA-117 is designed to target all of these cells, and clinical evidence of depletion in this patient population provides valuable support that MGTA-117 will robustly deplete target cells in the proposed next phase of development in (i) transplant-eligible AML and MDS patients who have significantly lower numbers of cancer blast cells and (ii) gene therapy patients who have no cancer blast cells. Therefore, Magenta expects MGTA-117 to bind and deplete target cells in the bone marrow in these patient populations, and potentially achieve greater levels of depletion, at the same dose levels studied in R/R AML and MDS patients.

MGTA-117 Proof-of-Mechanism and Potential Active Dose

Participants Dosed & Available Data. As of December 1, 2022, a total of 15 participants have been dosed with MGTA-117 in Cohorts 1, 2 and 3. All dosed participants contributed data in whole or in part to the preliminary data set depending on an individual’s availability for collecting assessments. Eleven of the 15 dosed participants completed the dose-limiting toxicity safety observation period of 21 days. None of the four participant discontinuations were deemed to be related to MGTA-117.

Target Cell Binding. MGTA-117 bound to CD117-expressing target cells within 15 minutes after dosing in all participants as measured by a receptor occupancy (RO) assay. RO increased with higher dose levels of MGTA-117. The percentage of occupied CD117 receptors was greater, and the receptor occupancy was more durable at the higher dose levels of Cohorts 2 and 3 as compared to Cohort 1 as expected.

Target Cell Depletion.
Depletion in Blood and Bone Marrow. MGTA-117 showed greater depletion of target cancer blast cells in the blood of participants in Cohorts 2 and 3 compared to Cohort 1. In addition, three out of the four participants in Cohort 3 for whom paired bone marrow samples were collected at baseline and post-dosing had depletion of cancer blast cells in both blood and bone marrow. This matched depletion response in the blood and bone marrow provides evidence of an active dose and dose-dependent depletion of CD117-expressing cells.
Two Transplant-Ineligible Participants Became Transplant-Eligible. Participants entering the clinical trial were considered ineligible for stem cell transplant and had active and persistent AML/MDS after receiving one or more anti-leukemic therapies. One relapsed/refractory MDS participant in Cohort 3 had a reduction of bone marrow cancer blast cells to a level that enabled the participant to become eligible for transplant. This is the trial’s second participant who became eligible for transplant after a single dose of MGTA-117. The first participant, from Cohort 1, had relapsed/refractory AML and was previously disclosed.

Clearance. MGTA-117 was shown to be rapidly cleared from the body as expected. No MGTA-117 was detectable in the blood 48 hours after dosing in Cohorts 1 and 2, and over 95% of MGTA-117 was cleared in the blood 48 hours after dosing at the higher dose level of Cohort 3. Rapid clearance of MGTA-117 was engineered into the molecule to ensure avoidance of depleting newly transplanted donor cells in allogeneic transplant or, in the case of gene therapy, of autologous gene-modified cells. In addition, the MGTA-117 ADC was shown to be stable in blood over time in all participants, and no free payload was detectable in the blood of any participants at any time point.

Tolerability. MGTA-117 was well-tolerated in all participants. No serious adverse events were deemed to be related to MGTA-117, and no dose-limiting toxicities were observed. Treatment-related adverse events deemed to be related to MGTA-117 were low-grade liver enzyme elevations, low-grade fever, and grade 3 and grade 4 leukopenia in two participants who had baseline grade 2 and grade 3 leukopenia, respectively. All instances of observed liver enzyme elevations were low-grade, transient and resolved without intervention, as expected.

Continued Trial Progress and Data Expectations. The Phase 1/2 clinical trial is currently enrolling in Cohort 4 (0.13 mg/kg) and Magenta anticipates presenting aggregate clinical data from the clinical trial, including Cohort 4, at a scientific conference in Q1 2023.
MGTA-117 Regulatory Engagement and Clinical Development Next Steps in Transplant-Eligible AML/MDS and Autologous Gene Therapy
As previously disclosed, Magenta has initiated formal engagements with regulatory agencies to transition MGTA-117 into a transplant-eligible AML and MDS patient population. Magenta also plans to engage regulators in H1 2023 for the purposes of initiating a MGTA-117 clinical trial in autologous ex vivo gene therapy.

Transplant-Eligible AML and MDS. Magenta anticipates that MGTA-117’s pharmacokinetics (PK), pharmacodynamics (PD) and tolerability in Cohorts 1-3 will support alignment with regulatory authorities to study MGTA-117 in AML and MDS transplant-eligible patients. Importantly, the proposed study design in the transplant setting will allow for the measurement of depletion of CD117-expressing cells in the bone marrow after a single dose of MGTA-117 prior to reduced-intensity conditioning (RIC) and the ensuing allogeneic transplant. By depleting residual cancer blast cells prior to a standard RIC regimen, MGTA-117 has the potential to boost disease control prior to transplant and improve disease outcomes post-transplant. These potential positive outcomes could address the current significant unmet need associated with RIC-conditioning where AML and MDS patients relapse at a rate of 40%-50% within six months post-transplant1. Pending regulatory alignment, Magenta plans to share additional details of the proposed transplant-eligible MGTA-117 study design in Q1 2023.

Gene Therapy. Magenta expects to use the clinical data package from the ongoing Phase 1/2 trial, together with supporting insights from PK/PD modeling, to engage with regulators on a potential MGTA-117 clinical trial in autologous ex vivo gene therapy. In a gene therapy clinical trial, Magenta anticipates dosing patients with MGTA-117 to deplete stem and progenitor cells before the patient receives an infusion of gene-modified stem cells, with a goal of replacing the current standard-of-care conditioning that relies on high doses of chemotherapeutic agents such as busulfan, which is known to be carcinogenic. Magenta anticipates sharing more details in 2023 as development plans progress in collaboration with gene therapy partners. Magenta has existing clinical collaborations with gene therapy companies and anticipates entering into additional collaborations as MGTA-117 development advances.
CD45-ADC IND-Enabling Plans
Magenta’s CD45-ADC is a second targeted conditioning ADC, designed to selectively target and deplete both stem cells and immune cells, and is intended to replace the use of chemotherapy-based conditioning prior to stem cell transplant in patients with blood cancers and autoimmune diseases.

As previously disclosed, Good Manufacturing Practice (GMP) manufacturing and other investigative new drug application (IND)-enabling activities are ongoing for the CD45-ADC program. A Good Laboratory Practice (GLP) toxicology study is expected to be completed in H2 2023.

Magenta anticipates regulatory interactions prior to filing an IND and anticipates providing further details on the CD45-ADC program in 2023, including molecule design, key preclinical data, and timelines to IND.
MGTA-145 Phase 2 Progress
Magenta is developing MGTA-145, in combination with plerixafor, to improve the process by which stem cells are released out of the bone marrow and into the bloodstream, known as stem cell mobilization. The mobilized cells are then collected and available for transplant. This is the first step for patients and is required for the majority of transplants and stem cell gene therapies.

Magenta, in partnership with bluebird bio, is enrolling patients in a Phase 2 clinical trial evaluating the ability of MGTA-145 in combination with plerixafor to mobilize stem cells for collection in patients with sickle cell disease.

Due to enrollment delays at the clinical sites that are unrelated to MGTA-145, Magenta anticipates disclosing clinical data in H1 2023.
Conference Call Information:
Magenta will host a conference call and webcast at 8:30 a.m. Eastern Time / 7:30 a.m. Central Time tomorrow, Tuesday, December 13, 2022 to review the MGTA-117 data presented at the 2022 ASH (Free ASH Whitepaper) Annual Meeting.

To access the conference call, please register online at https://register.vevent.com/register/BI872661cff05d4191a7bb100830aae147. Upon registering, each participant will be provided with call details and a conference ID. The live webcast of the call and slide deck may be accessed at View Source, or by visiting the Investors & Media section of the company’s website at View Source A replay of the webcast will be available shortly after the conclusion of the call and will be archived on the Events & Presentations page.

1 Scott, Journal of Clinical Oncology 2017. View Source

On December 12, 2022 Electra Therapeutics, Inc., a clinical stage biotechnology company developing novel antibody therapies that target signal regulatory proteins (SIRP), reported presentations and clinical progress for ELA026, the company’s first-in-class antibody in development for the treatment of secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening inflammatory disease. Three poster presentations supporting the company’s clinical development of ELA026 in sHLH are highlighted at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in New Orleans from December 10-13, 2022 (Press release, Electra Therapeutics, DEC 12, 2022, View Source [SID1234625105]).

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Electra also announced today that a Phase 1b global study of ELA026 in sHLH patients has been initiated and is ongoing (ClinicalTrials.gov identifier: NCT05416307). The Phase 1b study is highlighted as a clinical trial in progress poster at ASH (Free ASH Whitepaper), titled "A Phase 1b study of ELA026 in patients with secondary hemophagocytic lymphohistiocytosis." The Phase 1b study is an open-label, single-arm, multicenter study which will evaluate the safety and efficacy of ELA026, assess biomarkers and identify a dose for Phase 2/3 testing.

"We are excited to advance ELA026 in the clinic as a novel approach targeting SIRP to address the aberrant myeloid and T cell activity that drives the sHLH disease process," said Gary Patou, MD, Chief Medical Officer of Electra. "We have created a robust design for this Phase 1b study with the aim of progressing rapidly toward a Phase 2/3 study so we can accelerate ELA026 as a potential treatment option for sHLH patients in need."

Study Results Presented at ASH (Free ASH Whitepaper) Annual Meeting
Preclinical studies demonstrated ELA026’s proof-of-mechanism of SIRP targeting and depletion of pathological immune cells that drive sHLH. The poster presentation at ASH (Free ASH Whitepaper), titled "Characterization of ELA026, a clinical-stage monoclonal antibody that rapidly and potently depletes myeloid cells and T lymphocytes," describes the pharmacology of ELA026 which binds to and depletes SIRP-expressing cells, and its pharmacokinetic (PK) profile and pharmacodynamic (PD) effects in non-human primates. The preclinical data includes the following highlights:

In in vitro studies, ELA026 was shown to bind to SIRP proteins on the surface of primary human and cynomolgus monkey monocytes and T cells, inducing potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).
In vivo administration of ELA026 in cynomolgus monkeys showed a rapid and potent depletion of SIRP-expressing monocytes and lymphocytes, with a well-defined PK/PD relationship. Reversibility of the PD effect was achieved following washout suggesting that ELA026 treatment is not associated with long-term immunosuppression.

Electra also presented results of a sHLH natural history study at the ASH (Free ASH Whitepaper) Annual Meeting in a poster, titled "Identification and characterization of a retrospective cohort of secondary hemophagocytic lymphohistiocytosis (sHLH) patients in the US," showing that sHLH is a complex disease to diagnose and treat. The study has thus far reviewed approximately 1,500 unique patient medical records from a large medical system in the US and supports the need to improve our ability to identify sHLH patients and better understand the potential underestimation of the incidence of sHLH.

"We appreciate the dedication of the Electra team in supporting patients and families impacted by histiocytosis. sHLH is a life-threatening inflammatory disease with no approved treatments and, as a result, many patients suffer the debilitating effects of this condition," said Deanna Fournier, Executive Director, Histiocytosis Association. "We welcome the promising new approach that ELA026 offers, and we join the patient community in supporting the advancement of new treatments for sHLH. Opportunities like these are what continue to give us hope!"

The three posters are available on Electra’s website.

About Secondary Hemophagocytic Lymphohistiocytosis (sHLH)
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition for which there is no approved treatment. sHLH can be triggered by cancer, immunotherapy, infection, or an autoimmune disease. Once triggered, sHLH requires immediate intervention. Without treatment, it can rapidly progress from symptoms such as persistent fever, hepatomegaly and/or splenomegaly, and cytopenias, to multi-organ failure and death.

On December 12, 2022 Keros Therapeutics, Inc. ("Keros") (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments for patients suffering from hematological, pulmonary and cardiovascular disorders with high unmet medical need, reported that it presented additional data from its ongoing Phase 2 clinical trial of KER-050 in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes ("MDS"), as well as initial data from its ongoing Phase 2 clinical trial of KER-050 in patients with myelofibrosis ("MF") and from its ongoing Phase 2 clinical trial of KER-047 in patients with iron-refractory iron deficiency anemia ("IRIDA"), at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting and Exposition, held in person and virtually December 10 through 13, 2022 (Press release, Keros Therapeutics, DEC 12, 2022, View Source [SID1234625132]). In addition, Keros presented preclinical data showing the potential of a research form of KER-050 ("RKER-050") to treat anemia and bone loss in an animal model of MDS, as well as preclinical data evaluating the treatment effect of activin receptor-like kinase 2 ("ALK2") inhibition combined with RKER-050 in a mouse model of anemia of inflammation.

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"We are pleased to present clinical and preclinical data from our lead hematological programs at ASH (Free ASH Whitepaper) this year. In our ongoing Phase 2 clinical trial in MDS, we observed a sustained response with longer-term treatment with KER-050 across all transfusion burdens. Data from our ongoing Phase 2 trial in MF support the potential for KER-050 to treat multiple cytopenias as either a monotherapy or in combination with ruxolitinib," said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of Keros. "In addition, clinical data from one IRIDA patient in our Phase 2 clinical trial of KER-047 was suggestive of iron redistribution consistent with KER-047’s mechanism of action."

Clinical Presentations

•Effects of KER-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

This ongoing, open-label, two-part, Phase 2 clinical trial is evaluating KER-050 in participants with very low-, low-, or intermediate-risk MDS. In Part 1, the dose escalation portion of the trial, enrollment was balanced approximately one-to-one between patients that did not have ring sideroblasts ("non-RS") and patients that have ring sideroblasts ("RS positive"). Patients in Part 1 received KER-050 subcutaneously every 28 days for up to four cycles at the following dose levels: Cohort 1, 0.75 mg/kg; Cohort 2, 1.5 mg/kg; Cohort 3, 2.5 mg/kg; Cohort 4, 3.75 mg/kg; and Cohort 5, 5.0 mg/kg. In Part 2, the dose confirmation portion of the trial, an identical dosing schedule was followed, and patients initiated treatment at a starting dose of 3.75 mg/kg, the recommended Part 2 dose ("RP2D"), with the opportunity to dose escalate to 5.0 mg/kg or to down-titrate based on individual titration rules. Following completion of Part 1, eligible patients were given the opportunity to escalate up to the RP2D and receive long-term treatment with KER-050 for up to an additional 20 cycles ("Part 1 Extension").

As of October 1, 2022 (the "data cut-off date"), 25 patients from Part 1, including the Part 1 Extension, and 11 patients from Part 2, had received at least one dose of KER-050 at RP2D (collectively, the "safety population"). 29 of these patients had completed eight weeks of treatment and the applicable assessments as of the data cut-off date (the "evaluable RP2D patients").

Of the 36 patients in the safety population, 63.9% (n=23/36) were RS positive while 36.1% (n=13/36) were non-RS. The safety population was comprised of 10 non-transfused ("NT"), six low transfusion burden ("LTB") and 20 high transfusion burden ("HTB") patients.

As of the data cut-off date, 51.7% (n=15/29) of the evaluable RP2D patients achieved an overall erythroid response, which is defined as meeting one of the following two endpoints:

•IWG 2006 Hematological improvement-erythroid ("HI-E"), which is defined as either:
◦a ≥ 1.5 g/dL increase in hemoglobin for eight weeks in LTB and NT patients; or
◦a reduction of ≥ 4 red blood cell ("RBC") units transfused during any eight-week period during the trial, compared with the eight-week period prior to Cycle 1, Day 1 in HTB patients.
•Transfusion independence ("TI") for at least eight weeks in transfusion-dependent patients who required ≥ 2 RBC units transfused at baseline.

Additional data from the evaluable RP2D patients, as of the data cut-off date, include:

•51.7% (n=15/29) of the evaluable RP2D population achieved HI-E over an eight-week period.
•50.0% (n=9/18) of the transfused RP2D patients receiving ≥ 2 RBC units at baseline achieved TI for at least eight weeks. Of these 18 patients, 12 were RS positive and six were non-RS.
◦50.0% (n=6/12) of these RS positive patients achieved TI for at least eight weeks.
◦50.0% (n=3/6) of these non-RS patients achieved TI for at least eight weeks.
•Of the transfused RP2D patients, 50.0% (n=8/16) of those who are HTB achieved TI for at least 8 weeks. Of these 16 patients, 11 were RS positive and five were non-RS.
◦45.5% (n=5/11) of these RS positive HTB patients achieved TI for at least eight weeks.
◦60.0% (n=3/5) of these non-RS HTB patients achieved TI for at least eight weeks.
•53.3% (n=8/15) of the transfused RP2D patients receiving ≥ 2 RBC units at baseline, with the opportunity to extend treatment beyond four cycles, achieved TI for at least 12 weeks, demonstrating a sustained TI benefit with continued treatment.
◦Of these transfused RP2D patients, 50.0% (n=7/14) of those who are HTB achieved TI for at least 12 weeks.

As of the data cut-off data, sustained increases in platelet counts were observed for patients achieving HI-E or TI over a 24-week treatment period, supporting a potentially differentiated mechanism of KER-050 to promote hematopoiesis across multiple cell lineages.

As of the data cut-off date, KER-050 was generally well tolerated by the 36 patients in the safety population. No dose-limiting toxicities were reported, and no patients progressed to acute

myeloid leukemia. There was one case of a fatal treatment-emergent adverse event ("TEAE") in the trial that was determined to be unrelated to treatment. There were three additional TEAEs that led to discontinuation of treatment, one of which was deemed treatment related (injection site reaction) and two of which were determined to be unrelated to treatment (dyspnea and chronic obstructive pulmonary disease). The most commonly reported TEAEs were diarrhea, fatigue, dyspnea and nausea.

An exploratory analysis of biomarkers of iron overload ("IO") was also presented, with data from the 31 participants who received up to four cycles of treatment in the completed Part 1. 58.1% (n=18/31) of these patients were classified as HTB. At baseline, transfusion-dependent patients exhibited biomarkers suggestive of a greater degree of ineffective hematopoiesis than NT patients, including lower levels of hemoglobin, reticulocytes and soluble transferrin receptor. In addition, lower levels of transferrin and elevated levels of serum ferritin at baseline, especially among HTB patients, suggest more severe IO in transfusion-dependent patients as compared to NT patients. Key observations from this analysis, as of the data cutoff date, are as follows:

•Soluble transferrin receptor levels generally increased with KER-050 treatment, particularly in HTB patients, while ferritin levels decreased.
•On an individual level, most patients who achieved HI-E or TI also showed decreases in serum ferritin. Such decreases were generally greater in patients with baseline ferritin of >500 ng/mL, suggesting potential for KER-050 to reduce IO in the most impacted patients.
•Reductions in transfusion burden, based on transfused RBCs over eight weeks, was generally associated with reductions in serum ferritin, especially for patients who achieved TI.

Taken together, the results from the trial and the exploratory analysis as of the data cut-off date suggest that KER-050 has the potential to improve hematopoiesis, reduce transfusion burden and reduce IO, particularly in patients receiving frequent RBC transfusions.

•Modulation of TGF-β Superfamily Signaling to Treat Myelofibrosis and Mitigate JAK Inhibitor Toxicity: A Report on the Phase 2 Study of KER-050 in Participants with Myelofibrosis

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. Part 1, the dose escalation portion of the trial, is designed to assess the safety and tolerability of KER-050 at dose levels of 0.75 mg/kg, 1.5 mg/kg, 3.0 mg/kg and 4.5 mg/kg, both in a monotherapy arm and in a combination therapy arm with ruxolitinib, to identify doses of KER-050 to be evaluated in Part 2, the dose expansion portion of the trial.

As of the data cut-off date of October 1, 2022, 12 patients were enrolled in Part 1, with six patients in each arm receiving 0.75 mg/kg dose of KER-050. For the patients in the combination therapy arm, the median ruxolitinib dose was 12.5 mg twice daily at baseline. As of the data cut-off date, in each of the arms, at least half of the enrolled patients had received three or more doses of KER-050. At baseline, 41.7% (n=5/12) were transfusion-dependent, with an average transfusion burden of 9.8 RBC units in the 12 weeks preceding Cycle 1, Day 1.

As of the data cut-off date, KER-050 was generally well tolerated, with no drug-related serious adverse events or dose-limiting toxicities reported. No participants had a treatment-related dose reduction of KER-050 or ruxolitinib as of the data cut-off date. The most commonly reported TEAEs were diarrhea, COVID-19, dyspnea and fatigue. One patient withdrew from the trial due to an unrelated adverse event.

Although variability was observed, as of the data cut-off date, treatment with KER-050 at the lowest dose in the trial (0.75 mg/kg) resulted in increased reticulocytes and platelets on aggregate across cycles 1 and 2. These increases were observed in both monotherapy and combination arms, as well as in both non-transfusion-dependent and transfusion-dependent patients. These data support the potential of KER-050 to potentially promote differentiation of erythroid and megakaryocytic precursors and treat anemia and thrombocytopenia in patients with MF.

The following data from two patients enrolled in this trial were also presented:

•In a 60-year-old, non-transfusion-dependent female patient with primary MF in the monotherapy arm, an increase in reticulocytes was observed after a single 0.75 mg/kg dose of KER-050, which was followed by a sustained increase in hemoglobin of >1.5 g/dL over baseline with continued dosing for >12 consecutive weeks in the first 24 weeks of the trial. The observed increases in erythropoietic markers corresponded with sustained decreases in ferritin and erythropoietin, which is consistent with upregulation of erythropoiesis. An overall increase in platelet count was also observed in this patient.
•In a 75-year-old, transfusion-dependent male patient with high-risk MF and severe thrombocytopenia in the combination arm, increases in reticulocytes and soluble transferrin receptor levels were observed following the first cycle of treatment. Though platelet counts fluctuated over the treatment period, improvements were observed following the second and third cycles. The patient experienced a reduction in RBC transfusion burden from nine units per 12 weeks pre-treatment to six units per 12 weeks post-treatment.

•Preliminary Results of a Phase 2 Clinical Trial of the ALK-2 Inhibitor KER-047 for Treatment of Iron Refractory Iron Deficiency Anemia

This ongoing, open-label, two-part Phase 2 clinical trial is evaluating KER-047 in patients with IRIDA, which is an inherited form of iron deficiency anemia in which matriptase-2, a cell surface protease, does not function properly, resulting in elevated ALK2 signaling and high hepcidin levels. In Part 1, the dose escalation portion of the trial, patients will receive KER-047 once daily for 14 days, starting at the lowest dose of 25 mg in Cohort 1, followed by a 14-day washout period.

This presentation reported observations from one patient enrolled in Cohort 1 of Part 1 who completed the 14-day treatment and washout periods. Treatment with KER-047 was generally well tolerated by this patient, with no serious adverse events or dose-limiting toxicities reported during treatment. There was one TEAE reported, which was determined to be unrelated to the treatment.

In this patient, hepcidin and serum ferritin levels decreased following administration of KER-047. Serum ferritin returned to baseline levels in the washout period, indicating that the effect was potentially treatment-associated. Reticulocyte hemoglobin also increased in this patient during the treatment period. Taken together, these data are suggestive of iron redistribution consistent with the mechanism of action of KER-047.

Preclinical Presentations

•RKER-050, a Novel Activin Receptor Type II Ligand Trap, Rescued Anemia and Reduced Bone Loss in a Mouse Model of Myelodysplastic Syndromes

RKER-050 was tested in a mouse model of MDS. Male MDS mice with established anemia were administered either vehicle or 7.5 mg/kg of RKER-050 once weekly for six weeks. Healthy male mice received only vehicle.

The vehicle-treated MDS mice showed reductions in RBCs, hemoglobin, hematocrit and reticulocytes compared with healthy controls. Relative to vehicle-treated MDS mice, RKER-050-treated MDS mice showed increases in those RBC parameters, demonstrating that RKER-050 can mitigate anemia in an MDS mouse model.

Additionally, analysis of bone microarchitecture showed significantly weaker bone in MDS mice compared to healthy controls. In contrast, bone parameters in RKER-050-treated MDS mice were significantly improved relative to the vehicle-treated MDS mice.

These results suggest that RKER-050 can mitigate anemia and bone loss in an MDS mouse model, potentially by rebalancing hematopoiesis and bone turnover. In particular, the ability of RKER-050 to improve bone microarchitecture within the trabecular region could be an important step in reestablishing healthy blood cell production. Accordingly, Keros believes that KER-050 has the potential to treat patients with MDS and other hematological diseases, including MF, where a disease-impacted bone marrow microenvironment contributes to ineffective hematopoiesis and bone loss.

•ALK2 Inhibition and a Modified Activin Receptor Type IIA Ligand Trap Co-therapy Maximized Hematologic Improvements in a Mouse Model of Anemia of Inflammation

This preclinical study evaluated whether RKER-050 combined with KTI-m216, an investigational neutralizing antibody to ALK2, could ameliorate anemia in a mouse model of induced chronic kidney disease ("CKD") representative of anemia of inflammation ("AI").

To induce a model of CKD, mice were fed a diet containing 0.2% adenine and 40 ppm iron for five weeks. After AI was confirmed, CKD mice were treated with 3 mg/kg of KTI-m216 or vehicle twice a week for four weeks. In a separate study, CKD mice received biweekly KTI-m216 or vehicle with a weekly dose of vehicle or 7.5 mg/kg RKER-050 intraperitoneally for four weeks.

•KTI-m216-treated CKD mice exhibited a decrease in serum hepcidin by >95% and an increase in circulating iron levels compared to vehicle-treated CKD mice. KTI-m216-treated CKD mice also showed similar improvements in hematological parameters compared to vehicle-treated CKD mice, suggesting that KTI-m216-mediated suppression

of hepcidin levels improved erythropoiesis and subsequently increased serum iron levels.
•While KTI-m216 monotherapy improved hemoglobin levels in CKD mice relative to vehicle-treated CKD mice, combination treatment with RKER-050 resulted in a greater magnitude of increase in hemoglobin levels. RBC counts were also observed to significantly increase in CKD mice receiving combination therapy compared to monotherapy. No significant differences in serum hepcidin or iron were observed between CKD mice receiving combination therapy or monotherapy.

By suppressing hepcidin through ALK2 inhibition, KTI-m216 increased circulating iron for erythropoiesis and improved, but did not fully rescue, anemia in the CKD mice. However, combining RKER-050 with KTI-m216 increased RBC production and provided a greater degree of benefit in treating anemia in CKD mice compared to KTI-m216 monotherapy, which supports the potential benefits of this combination therapy.

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

Keros is conducting an open label, two-part, multiple ascending dose Phase 2 clinical trial to evaluate KER-050 in participants 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 participants 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

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 participants with MF-associated cytopenias.

The primary objective of this trial is to assess the safety and tolerability of KER-050 in participants with MF-associated cytopenias. The primary objective of Part 2 of this trial is confirmation of the safety and tolerability of the selected dose levels. The secondary objectives of this trial are to evaluate the pharmacokinetics, pharmacodynamics and efficacy of KER-050 administered with or without ruxolitinib.

About the Ongoing Phase 2 Clinical Trial of KER-047 in Patients with IRIDA

Keros has initiated an open-label, two-part Phase 2 clinical trial to evaluate KER-047 in participants with IRIDA. Part 1 is the 14-day dose-escalation portion of the trial consisting of up to four ascending dose cohorts starting at 25 mg once daily. Part 2 is the 28- to 56-day dose-expansion portion of the trial, with treatment dose and duration to be selected based on Part 1 results.

The primary objective of this trial is to assess the safety of KER-047. The secondary objectives of this trial are to evaluate the pharmacokinetics and pharmacodynamics of KER-047.

Conference Call and Webcast Information

The Company will host a conference call and webcast today, December 12, 2022, at 4:01 p.m. Eastern time, to discuss the additional results from its ongoing Phase 2 clinical trial of KER-050 in patients with MDS, as well as initial data from its ongoing Phase 2 clinical trial of KER-050 in patients with MF and from its ongoing Phase 2 clinical trial of KER-047 in patients with IRIDA, which was presented at the 2022 ASH (Free ASH Whitepaper) Annual Meeting and Exposition.

The conference call will be webcast live at View Source;tp_key=6cc8555aa4. The live teleconference may be accessed by dialing (877) 405-1224 (domestic) or (201) 389-0848 (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 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-β 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.

About KER-047

Keros’ lead small molecule product candidate, KER-047, is designed to selectively and potently inhibit ALK2, a TGF-β receptor. KER-047 is being developed for the treatment of functional iron deficiency which is a consequence of elevated ALK2 signaling, including the Company’s initial target, IRIDA.

On December 12, 2022 Regeneron Pharmaceuticals reorted positive initial data from a pivotal Phase 2 expansion cohort evaluating investigational linvoseltamab (formerly REGN5458) at the 200 mg dose recommended for further development in patients with heavily pre-treated, relapsed/refractory (R/R) multiple myeloma (Press release, Regeneron, DEC 12, 2022, View Source [SID1234625126]). The results were part of a broader presentation of new and updated data from a Phase 1/2 trial and were shared at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in New Orleans, LA. Linvoseltamab is an investigational bispecific antibody designed to bridge B-cell maturation antigen (BCMA) on multiple myeloma cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing.

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"The need for innovative medicines is critical for patients with multiple myeloma who inevitably face a downward spiral of relapses, reduced responses to subsequent therapies, and increasingly shorter remissions," said Naresh Bumma, M.D., Hematologist and Assistant Professor in the Division of Hematology at Ohio State University, and a trial investigator. "At the recommended 200 mg dose in a pivotal Phase 2 trial, linvoseltamab demonstrated early, deep and durable responses in patients living with multiple myeloma who had been on at least three prior therapies, including those with higher risk and high disease burden. These clinically meaningful outcomes at 12 weeks reinforce the positive linvoseltamab results seen in the Phase 1 dose escalation portion, and we look forward to seeing data from more patients and longer follow-up."

As presented at ASH (Free ASH Whitepaper), out of 252 patients treated in the Phase 1/2 trial, 81% of patients were triple-refractory to existing therapeutic options, including an immunomodulatory drug, a proteasome inhibitor and an anti-CD38 antibody. Additionally, 37% had bone marrow plasma cells ≥50%, and the median soluble BCMA was 0.43 mg/L, representing a patient population with a higher disease burden than those enrolled in similar trials. Of the 87 patients in the 200 mg cohort, 58 were evaluated for efficacy. With a median follow-up of 3 months (range: 0 to 30 months), efficacy results were as follows:

64% objective response rate (ORR), with 45% achieving a very good partial response or better, as determined by an independent review committee. Based on earlier results, responses may increase with longer follow-up.
Median time to response was <1 month (range: <1 to 5 months).
79% probability of maintaining a response at 6 months (95% confidence interval: 50% to 92%), per Kaplan-Meier estimates.
Among the 87 patients treated in the 200 mg cohort assessed for safety, adverse events (AEs) occurred in 95% of patients, with 66% being ≥Grade 3. The most common AEs occurring in ≥20% of patients were cytokine release syndrome (CRS; 37%), fatigue (32%), anemia (28%), diarrhea, cough, headache (23% each) and neutropenia (20%). Discontinuations due to an AE occurred in 6% of patients. When CRS occurred, in 32 out of 87 patients, 23 of those patients experienced Grade 1, 8 experienced Grade 2, there was 1 transient Grade 3 case, and none were ≥Grade 4.

Among the overall patient population across different dose levels (n=252), the median time to first CRS onset was 11 hours (range: 0-47 hours) and all cases resolved, with a median time to resolution of 15 hours (range: 0-377 hours). Deaths due to AEs in the overall population were reported in 14 patients, including sepsis/bacterial infection (n=6), COVID-19 (n=4) or other causes (n=4). None of the deaths were considered related to treatment per the treating physician.

Linvoseltamab is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.

On December 12, 2022 Inventiva (Euronext Paris and Nasdaq: IVA) (the "Company"), a clinical-stage biopharmaceutical company focused on the development of oral small molecule therapies for the treatment of patients with non-alcoholic steatohepatitis ("NASH") and other diseases with significant unmet medical needs, reported the receipt of the €25 million payment under the first tranche of the unsecured loan agreement executed with the European Investment Bank ("EIB") on May 16, 2022 with a maturity date of December 2026 (the "Finance Contract") (Press release, Inventiva Pharma, DEC 12, 2022, View Source [SID1234625125]).

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Jean Volatier, Chief Financial Officer of Inventiva, stated: "We are pleased to see that our long-term partnership with the EIB is bearing fruit. This payment of the first tranche of €25 million, triggered by the progress made on our NATiV3 Phase III trial and the completion of the cash injections condition precedent for this tranche, will further support the development of lanifibranor. We remain strongly focused on the recruitment of patients in our Phase III trial and are hoping to satisfy all conditions for the disbursement of the second tranche of €25 million from the EIB."

As previously announced, the Finance Contract provides funding in two tranches of €25 million each, which are both subject to the completion of certain conditions precedent. Any drawings under the terms of the Finance Contract that have not been disbursed within 36 months from the signing of the Finance Contract, (i.e., before May 16, 2025), cannot be completed at a later date. There is no assurance that the Company will be able to satisfy the conditions precedent for the drawing of the second tranche2.

The disbursement of the first tranche (with 8% interest capitalized annually, a maturity of 4 years and a repayment in fine) was subject to, among other conditions, (i) the Company issuing warrants to EIB in accordance with the terms and conditions of the warrants agreements entered into July 1, 2022, and (ii) the Company’s receipt from the date of the Finance Contract of an aggregate amount of €18 million, paid either in exchange for new shares of the Company or through the receipt of upfront or milestone payments.

On June 15, 2022, the Company raised €9.3 million through a capital increase under its ATM program. On November 4, 2022, the Company received an upfront payment of $12 million under its collaboration agreement with Sino Biopharm.

On November 28, 2022, the Company issued 2,266,023 warrants to EIB, in accordance of the terms of the 25th resolution of the combined general meeting of shareholders of May 19, 2022 and Article L.225-138 of the French Commercial Code, as a condition to the financing of the first tranche, representing approximately 5.4% of the Company’s share capital outstanding as of the date hereof.

The exercise price of the warrants is equal to €4.0152 and corresponds to 95% of the volume-weighted average price of the Company’s shares on the regulated market of Euronext Paris during the last trading session preceding the decision to issue the warrants.

As previously announced, the warrants have a maturity of twelve years and shall be exercisable following the earliest to occur of (i) the maturity date of the first tranche (i.e. on December 8, 2026), (ii) a change of control event, (iii) an event of default under the Finance Contract, or (iv) a repayment demand by EIB under the Finance Contract. The warrants will automatically be deemed null and void if not exercised within the twelve-year period.

EIB has a put option which may require the Company to repurchase all or part of the unexercised warrants then exercisable at their intrinsic value (subject to a cap equal to the amount drawn under the Finance Contract) under certain circumstances (for example, in the event of a change of control or on the maturity date of the first tranche or in the event of default). The Company (or a substitute third party) has a call option to require EIB to sell all shares and other securities of the Company, including the warrants, to the Company, subject to certain terms and conditions. In addition, the Company has a right of first refusal to buy-back all warrants offered for sale to a third party, subject to certain terms and conditions.

On the basis of the 2,266,023 new shares of the Company issuable upon exercise of all the warrants at a price of €4.0152 per new share, the Company could potentially receive gross proceeds of up to €9,098,535. There is no assurance that EIB will exercise any or all of the warrants or that the Company will receive any proceeds from the exercise of the warrants.