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 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported four presentations at the 65th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper) detailing results from the Phase 3 SIERRA trial of Iomab-B and Phase 1 trial of Actimab-A in combination with Venetoclax in patients with relapsed or refractory acute myeloid leukemia (r/r AML) (Press release, Actinium Pharmaceuticals, DEC 11, 2023, View Source [SID1234638442]). Iomab-B and Actimab-A are the only two clinical stage targeted radiotherapies in development for patients with AML, which is known to be highly sensitive to radiation.

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Sandesh Seth, Actinium’s Chairman and CEO, said, "Earlier in 2023 we presented data from both Iomab-B and Actimab-A highlighting positive outcomes in patients with relapsed or refractory AML. We are particularly excited by these results as our trials enrolled patients with difficult to treat disease as they were heavily pre-treated, elderly in age, or had adverse cytogenetic or molecular mutations. As evidenced by the data presented at ASH (Free ASH Whitepaper) in the oral presentation of the Phase 3 SIERRA trial results, Iomab-B produced improved outcomes in patients with a TP53 mutation, which is associated with dismal outcomes. We are proud to have showcased Iomab-B and Actimab-A at ASH (Free ASH Whitepaper) and excited by the enthusiasm for which the data were received. We look forward to progressing both programs with key BLA and MAA filings for Iomab-B next year and advanced development for Actimab-A."

ASH Presentations and Highlights:

131I-Apamistamab-Led Allogeneic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients with TP53 Mutated R/R AML

Patients receiving Iomab-B had significantly greater median overall survival of 5.49 months compared to 1.66 months in patients on the control arm that received conventional care
24% of patients (37/153) enrolled on the SIERRA trial had a TP53 mutation, which is associated with the worst outcomes
Iomab-B produced response rates and overall survival in these very high-risk patients similar to those observed in patients without a TP53 mutation
131I-Apamistamab Effectively Achieved Durable Responses in Patients with R/R AML Irrespective of the Presence of Multiple High-Risk Factors

Patients receiving Iomab-B were able to receive a BMT and achieve durable Complete Remission (dCR), the primary endpoint in the SIERRA trial, irrespective of having multiple high-risk factors
Iomab-B met the dCR rate primary endpoint with high statistical significance (p<0.0001) with 22% dCR rate in the Iomab-B arm vs. 0% dCR rate in the control arm
53% of patients had 2-3 high-risk factors and 29% had 4-5 high-risk factors that included adverse-risk cytogenetics, age >65, prior treatment failure with Venetoclax, BMT comorbidity index > 3, and Karnofsky Performance Status < 90
There was no statistical difference in the rate of dCR in patients receiving Iomab-B across the high risk-factor categories (0-1, 2-3 & 4-5)
High-Dose Targeted Radiation with 131I-Apamistamab Prior to HCT Demonstrated a Dose-Response for Durable Complete Remission in Patients with R/R AML

Patients with higher bone marrow/liver absorbed dose ratios experienced considerably higher rates of dCR demonstrating a dose dependent response
27% of patients achieving dCR when receiving > 22 Gy to the liver vs 13.5% dCR rate in patients receiving < 22 Gy to the liver; maximum tolerable dose in SIERRA was 24 Gy administered to the liver
Rates of Grade 3 > treatment emergent events were similar between patients receiving < 22 Gy to the liver and those receiving > 22 Gy to the liver
Iomab-B led BMT produced to significantly higher rates of dCR with patients achieving dCR having a 92% 1-year overall survival and 60% 2-year overall survival
These results demonstrate the importance of maximizing the dose to target tissues within the established dose tolerances
Updated Results from Phase 1 Study of Targeted Radiotherapy with Lintuzumab-Ac225 in Combination with Venetoclax in Relapsed/Refractory AML

Actimab-A dosed up to 2.0 μCi/kg with Venetoclax in patients with relapsed/refractory AML was well-tolerated, with a manageable adverse event profile
Maximum tolerated dose was not reached with no dose-limiting toxicities observed at the 3 highest dose levels (1.0, 1.5 & 2.0 μCi/kg)
Complete responses were achieved including a complete response in a patients with prior Venetoclax treatment and a TP53 mutation
These results support the continued evaluation of Actimab-A in combination with Venetoclax-based treatment

On December 11, 2023 Shanghai Yingli Pharmaceutical Co., Ltd. ("Yingli Pharma"), a biopharmaceutical company focused on developing oral therapies for cancer and metabolic diseases, reported the pivotal Phase 2 clinical trial results of the investigation of linperlisib in the treatment of patients with relapsed or refractory (r/r) peripheral T-cell lymphoma (PTCL) (Press release, Yingli Pharmaceutical, DEC 11, 2023, View Source [SID1234638458]). Linperlisib is a phosphoinositide 3-kinase delta (PI3Kδ) oral inhibitor, approved in China for treatment of patients with r/r follicular lymphoma after systemic therapy.

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"There is a vital need for new therapies to treat highly aggressive cancers such as r/r PTCL where there are very limited treatment options." said Dr. Jun Zhu, Professor, Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China, who was the leading investigator for this pivotal clinical trial. "In addition to the promising efficacy and well manageable safety of linperlisib in r/r PTCL, it is noteworthy that a high proportion of the treated patients were shown to have a complete response, and responses have been seen in all the major PTCL subtypes."

"Our approach is to develop novel oral agents that will allow patients to safely administer at home," said Michael Hui, CEO of Yingli Pharma, "We are delighted that the encouraging results of this study support the use of linperlisib in this hard-to-treat disease and are excited to continue developing linperlisib in more indications. The company has applied for linperlisib marketing approval in r/r PTCL in China based on these pivotal study findings." Mr. Hui added, "We look forward to the results of an ongoing open-label multi-center Phase 2 study in the U.S. and Italy in r/r PTCL and r/r CTCL."

Safe and effective treatment of r/r PTCL patients

The pivotal r/r PTCL Phase 2 clinical trial enrolled 98 patients (pts) from May 2021 to October 2022 at 25 clinical sites in China. The pts had a median of two lines of prior systemic therapies. Sixty-four pts (73%) had refractory disease, 59 pts (67%) had relapsed disease, and 35 pts (40%) had both relapsed and refractory diseases. All patients received linperlisib at 80 mg QD, the RP2D for the drug, with a minimum of 6 months follow-up.

The linperlisib-treated patients (Full Analysis Set N = 88) evaluated by Lugano criteria, had a 48% overall response rate, including 30% complete responses and 18% partial responses, as well as a 68% disease control rate. The median Duration of Response was not reached although the 6-month DOR rate was 75%. The median PFS was 5.5 months (95% CI, 3.5, 15.6) and the median OS was 14.2 months (95%CI, 7.9, not reached). Responses were observed across PTCL subtypes.

Linperlisib was well tolerated with a differentiated and manageable safety profile, specifically having very low levels of immune-mediated toxicities. In the linperlisib-treated patient safety dataset (N=98) for the pivotal study, the most common hematologic treatment related adverse events (TRAEs) of Grade≥3 were neutropenia (32%), leukocytopenia (10%), Anemia (6%), Thrombocytopenia (5%), and Lymphocytopenia (5%). The most common nonhematologic TRAEs of Grade≥3 were pneumonia (14%) and upper respiratory tract infection (5%). Immune-mediated Grade≥3 TRAEs including elevated ALT, AST, diarrhea, colitis, rash were not reported or were <5%. Nine patients (9.2%) discontinued from the study due to various adverse events. The safety results of this study were consistent with previously reported data in other linperlisib clinical studies.

About linperlisib

Linperlisib, a next-generation PI3K-selective oral inhibitor, received marketing approval in China in 2022 for treatment of patients with relapsed and/or refractory follicular lymphoma after two or more systemic therapies. Linperlisib also received U.S. FDA Orphan Drug Designations for follicular lymphoma, chronic lymphocytic leukemia, and T cell lymphomas.

Linperlisib is under investigation in multiple additional clinical trials as a monotherapy: frontline PTCL, r/r large granular T lymphocytic leukemia, r/r autoimmune hemolytic anemia; and in combination with other agents: in second line follicular lymphoma and marginal zone lymphoma, frontline PTCL, and r/r CTCL. In the U.S. and EU, linperlisib is being developed by 280Bio, Inc (San Francisco, CA., USA), a wholly-owned subsidiary of Yingli Pharma, in a Phase 2 clinical study in r/r T Cell Lymphomas [PTCL and CTCL].

On December 11, 2023 Novartis reported results from the extension period of the pivotal Phase III APPLY-PNH trial of oral monotherapy Fabhalta (iptacopan) in adults with paroxysmal nocturnal hemoglobinuria (PNH) who had residual anemia (hemoglobin <10 g/dL) despite previous anti-C5 therapy (Press release, Novartis, DEC 11, 2023, https://www.novartis.com/news/media-releases/novartis-presents-new-48-week-results-from-phase-iii-apply-pnh-trial-showing-sustained-efficacy-and-long-term-safety-fabhalta-iptacopan-adults-paroxysmal-nocturnal-hemoglobinuria-pnh [SID1234638372]). Continuous Fabhalta treatment (200 mg twice daily) for 48 weeks enabled sustained hemoglobin-level increases to near-normal (12 g/dL or more), blood transfusion avoidance, and reduced patient-reported fatigue in the majority of patients; comparable benefits emerged in those patients switching from anti-C5 therapy to Fabhalta in the extension1. Data will be presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper).

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"The new APPLY-PNH data are an expansion of the robust outcomes we saw in the randomized phase and demonstrate that patients with PNH who took Fabhalta experienced meaningful hemoglobin improvement over the longer term – nearly a year," said principal co-investigator Antonio Risitano, M.D., Ph.D., President of the International PNH Interest Group and Head of the Hematology and Hematopoietic Transplant Unit, Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria at the AORN San Giuseppe Moscati, Avellino, Italy. "Additionally, the new data confirm that these benefits may occur within weeks after switching from anti-C5s. The APPLY-PNH findings continue to confirm Fabhalta as a promising therapeutic option for people living with PNH."

Patients completing the 24-week randomized treatment period of APPLY-PNH could elect to enter the extension, continuing Fabhalta (61/62 patients; one patient discontinued due to pregnancy) or switching from anti-C5s to Fabhalta (34/35 patients; one patient discontinued based on investigator decision) through week 481,2.

In the continuous Fabhalta group, outcomes achieved in the randomized period were sustained at 48 weeks: mean hemoglobin level continued to be near-normal (12.2 g/dL), nearly all patients (91.9%) remained free of transfusions (Weeks 2-48), and improvements in patient-reported fatigue were observed (adjusted mean change from baseline: 9.80-point increase in Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F] score)1.

In the anti-C5-to-Fabhalta group, similar benefits emerged after switch: mean hemoglobin levels increased to near-normal (from 9.1 g/dL at 24 weeks to 12.1 g/dL at 48 weeks), transfusion avoidance was achieved for almost all patients (94.1%, Weeks 26-48), and improvements in patient-reported fatigue were observed after switching to Fabhalta (adjusted mean change from baseline between Week 48 and Week 24: 10.79-point increase in FACIT-F score)1.

"Coming on the heels of Fabhalta’s recent approval in PNH, these extended data from the APPLY-PNH phase III trial reinforce Fabhalta’s utility as an important new oral monotherapy for people living with PNH," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. "We are eager to bring this novel treatment to even more people living with rare complement-driven disorders as we pursue several additional indications for Fabhalta."

Fabhalta had a similar safety profile at 48 weeks vs. 24 weeks1,2. Three patients had major adverse vascular events (MAVEs), all considered unrelated to Fabhalta (one serious transient ischemic attack [TIA] occurred in the randomized period and was reported previously)1,2. In the extension, there was one non-serious TIA and one serious portal vein thrombosis (PVT; this patient had a history of PVT and discontinued heparin prior to the MAVE)1. Six patients of 62 receiving continuous Fabhalta for 48 weeks had clinical breakthrough hemolysis (BTH); one patient in the anti-C5-to-Fabhalta extension arm had clinical BTH after switching (compared to six of 35 patients while on anti-C5s prior to switch)1,2. All cases of clinical BTH resolved without changing Fabhalta dosing1. During the 48-week study period, the most frequently reported treatment-emergent adverse events (TEAEs) in the Fabhalta arm were COVID-19 (29.0% of patients), headache (19.4%), and diarrhea (16.1%)1. Throughout the full 48 weeks on Fabhalta, 9.7% of patients experienced any severe TEAE and 14.5% experienced any serious TEAE, none of which was suspected to be related to Fabhalta treatment; there were no serious hemolysis TEAEs on Fabhalta1,2. There were no serious infections caused by N. meningitidis, S. pneumoniae, or H. influenzae and no treatment discontinuations because of TEAEs1,2.

PNH is a rare, chronic, and serious complement-mediated blood disorder, in which a large proportion of patients can remain anemic and some dependent on blood transfusions despite currently available standard of care, anti-C5 treatments7-10.

Full 48-week results from the Phase III APPOINT-PNH trial in treatment-naïve PNH patients will be presented at a congress in 2024.

About APPLY-PNH
APPLY-PNH (NCT04558918) was a Phase III, randomized, multinational, multicenter, active-comparator controlled, open-label trial to evaluate the efficacy and safety of twice-daily, oral Fabhalta monotherapy (200 mg) for the treatment of PNH by assessing if switching to Fabhalta was superior to continuing on anti-C5 therapies (US-approved and non-US-approved eculizumab or ravulizumab) in adult patients presenting with residual anemia (Hb <10 g/dL) despite a stable regimen of anti-C5 treatment in the last six months prior to randomization4,11. The trial enrolled 97 patients who were randomized in an 8:5 ratio to either twice-daily, oral Fabhalta monotherapy, or intravenous anti-C5 therapies (continuing with the same regimen as they were on prior to randomization)4,11.

About paroxysmal nocturnal hemoglobinuria (PNH) 
PNH is a rare, chronic and serious complement-mediated blood disorder7. People with PNH have an acquired mutation in some of their hematopoietic stem cells (which are located in the bone marrow and can grow and develop into RBCs, white blood cells and platelets) that causes them to produce RBCs that are susceptible to premature destruction by the complement system7,8. This leads to intravascular hemolysis (destruction of RBCs within blood vessels) and extravascular hemolysis (destruction of RBCs mostly in the spleen and liver), which cause anemia (low levels of circulating RBCs), thrombosis (formation of blood clots), fatigue and other debilitating symptoms7,8.
 
It is estimated that approximately 10-20 people per million worldwide live with PNH7. Although PNH can develop at any age, it is often diagnosed in people between 30-40 years old12,13,14.
 
PNH has a significant unmet need not addressed by anti-C5 therapies (eculizumab or ravulizumab): despite treatment with anti-C5s, a large proportion of people with PNH remain anemic, and some dependent on blood transfusions7-10,15.

About Fabhalta (iptacopan)
Fabhalta (iptacopan) is an oral, Factor B inhibitor of the alternative complement pathway14,16,17. Fabhalta is FDA-approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH).
 
Discovered at Novartis, Fabhalta is currently in development for a range of complement-mediated diseases including immunoglobulin A nephropathy (IgA nephropathy), C3 glomerulopathy (C3G), immune complex membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS).
 
Based on disease prevalence, unmet needs and data from Phase II studies, Fabhalta has received FDA approval in PNH, FDA Breakthrough Therapy Designation in C3G, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN.

On December 11, 2023 Biomea Fusion, Inc. (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 positive clinical data for BMF-219, an investigational covalent menin inhibitor, in relapsed / refractory AML patients with menin-dependent mutations at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Biomea Fusion, DEC 11, 2023, View Source [SID1234638410]). The poster can be viewed at Biomea’s website at View Source

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"We are very excited to present the clinical update at ASH (Free ASH Whitepaper) on our targeted, covalently binding menin inhibitor, BMF-219, achieving durable and sustained CRs in patients with menin inhibitor-sensitive acute leukemia, even at suboptimal dosing levels. The gene expression data we presented here validates the proposed mechanism of action of BMF-219 and is in-line with our preclinical models," said Steve Morris, M.D., Chief Development Officer at Biomea.

As of the October 31, 2023, out of 29 patients dosed in the Phase I of COVALENT-101, nearly half (45%) of the participants received prior Hematopoietic Stem Cell Transplant (HSCT) and the median prior lines of therapy was 3. A total of 7 patients were selected as evaluable for efficacy. The efficacy evaluable population includes AML patients who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A – non-CYP inhibitor Arm]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least two cycles of therapy. Within this patient population 2 Complete Responses (CRs) (CR rate 2/7 = 29%) were observed with a mean time to response of 1.8 months (1 CR patient had a NUP-98 mutation and 1 CRi patient had a NPM1 mutation).

In the CYP inhibitor arm, BMF-219 showed increasing plasma pharmacokinetic (PK) exposure with escalating dose levels, and the ability to achieve systemic exposures predicted to be efficacious based on preclinical acute leukemia models. Further dose escalation is still needed to achieve target AUC.

Pharmacodynamic data from a case study of an AML patient containing NUP98-NSD1 mutation showed suppression of key leukemogenic genes (e.g. HOXA9, MEIS1) as well as downregulation of MEN1, without noticeable increases in differentiation markers (e.g. CD14, ANPEP, ITGAM) in contrast to non-covalent menin inhibitors.

Across all patients enrolled in the trial as of the data cutoff date (n=29), BMF-219 was generally well-tolerated with no dose-limiting toxicities observed and without treatment discontinuations due to toxicity. Four participants experienced Differentiation Syndrome (DS) ≤ Grade 3, with onset 1-3 weeks after initiation of therapy and an average duration of 10 days, managed by cytoreductive therapy (hydroxyurea and steroids). Two participants recovered without dose modification or interruption, and none of the participants discontinued due to DS.

Initially, patients were enrolled agnostic to mutational status; subsequently, the study protocol was amended to enrich for patients with AML harboring menin-dependent mutations. Dose Level 4 is the first dose level which focused primarily on enrolling patients with known menin-dependent mutations. Biomea is planning to amend the dosing protocol to explore higher dosing levels in Arm B. Dose escalation is to be followed by a dose optimization/expansion to determine the recommended phase 2 dose.

About BMF-219

BMF-219 is a covalently binding inhibitor of menin, a protein known to play an essential role in oncogenic signaling in genetically defined leukemias as well as in diabetes. Preclinically, BMF-219 has demonstrated in well-established acute leukemia cell lines robust downregulation of key leukemogenic genes in addition to menin itself. Additionally, BMF-219 has shown anticancer activity in multiple in vitro, in vivo, and ex vivo models of acute leukemia, multiple myeloma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia. BMF-219 is currently being evaluated in first-in-human clinical trials enrolling patients with specific menin-dependent mutations in liquid and solid tumors as well as patients with diabetes.

About COVALENT-101

COVALENT-101 is a Phase I, open-label, multi-center, dose-escalation and dose-expansion study designed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics of oral dosing of BMF-219 in patients with relapsed/refractory (R/R) acute leukemias — including subpopulations where menin inhibition is expected to provide therapeutic benefit (e.g., patients with MLL1/KMT2A gene rearrangements or NPM1 mutations). The study is designed to enroll subsets of acute leukemia patients who are receiving a CYP3A4 inhibitor and also those not receiving a CYP3A4 inhibitor. COVALENT-101 is also investigating the dosing of BMF-219 in other patient populations where preclinical studies have shown high menin dependence, such as multiple myeloma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia. Additional information about this Phase I clinical trial of BMF-219 can be found at ClinicalTrials.gov using the identifier NCT05153330.

About Acute Myeloid Leukemia (AML)

AML is the most common form of acute leukemia in adults and represents the largest number of annual leukemia deaths in the U.S. and Europe. AML originates within the white blood cells in the bone marrow and can rapidly move to the blood and other parts of the body, including the spleen, central nervous system, and other organs. Approximately 30,000 people in the U.S. and Europe are diagnosed with AML each year, and the five-year overall survival rate in adults is roughly 29%. Among patients with relapsed/refractory disease, the need is greatest, as the overall survival is only approximately 3 to 9 months. It is estimated that upwards of 45% of AML patients have menin-dependent genetic drivers (MLL1-r, NPM1 mutant, and certain additional less common but recurrent gene mutations).