Bose, Prithviraj

Polycythemia vera is characterized by erythrocytosis and increased risk of thrombosis. Sapablursen is an antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6), increases hepcidin production, and reduces iron availability for erythropoiesis. IMPRSSION; an ongoing phase 2a, randomized, open-label study includes patients meeting 2016 WHO criteria for polycythemia vera, requiring ≥3 phlebotomies within 6 months of screening and ≥1 phlebotomy within the last 12 weeks. Cohort A (120 or 80 mg) and Cohort B (40 mg) received sapablursen subcutaneously once every 4 weeks (Q4W). The primary efficacy endpoint was the reduction in phlebotomy frequency from baseline to weeks 17-37 in patients who received ≥1 dose. Forty-nine patients received ≥1 sapablursen dose (median age 61 years; 82% male). The baseline mean±SD weekly phlebotomy rate was 0.15±0.07 in Cohort A; 0.17±0.07 in Cohort B and was reduced by -0.10 (95%CI, -0.13, -0.07; n=32;p<0.0001) in Cohort A; -0.10 (95%CI, -0.14, -0.06; n=17;p=0.0001) in Cohort B. Sapablursen reduced the median (IQR) number of phlebotomies from 5.0 (3.0-6.0,Cohort A; 3.5-6.5,Cohort B) at baseline (26-weeks) to 0 (0-1.0) in the efficacy evaluation window (20-weeks) in Cohort A and 1.5 (0-2.5) in Cohort B. Most adverse events were mild or moderate; anemia and fatigue were most common. The mean change in MPN-SAF-TSS at week 37 was -6.21 points (95%CI: -10.56, -1.85, p=0.0052) in Cohort A; -2.71 points in Cohort B (95% CI: -8.33, 2.91, p=0.34). Sapablursen reduced phlebotomy need, improved symptoms, and was safe and well-tolerated in patients with polycythemia vera. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov: NCT05143957)

6501 Background: Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell (RBC) production and contributes to anemia onset and severity. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Methods: RALLY-MF (NCT05320198) is an ongoing Phase 2, open-label study conducted in the US. The primary aim is to evaluate DISC-0974 efficacy in participants with MF and anemia. Secondary aims include evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD). Eligible participants are ≥18 years of age with primary or secondary MF and hemoglobin (Hgb) <10 g/dL or RBC transfusion requirement. Participants enroll into 3 cohorts based on RBC units transfused in the 84 days prior to screening: non-transfusion dependent (nTD, 0 units and Hgb <10 g/dL), low transfusion burden (TD low, 1-2 units), high transfusion burden (TD high, 3-12 units). Stable dose of concomitant Janus kinase inhibitor (JAKi) is allowed. DISC-0974 is administered subcutaneously at 50 mg monthly for up to 6 doses, with escalation to 75 mg for inadequate or lost response. Primary endpoints include major hematologic response defined as transfusion independence (TI) during any consecutive 16 weeks (TD low) or 12 weeks (TD high), or a mean Hgb increase of ≥1.5 g/dL from baseline for ≥12 weeks (nTD). Secondary endpoints include PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results: At data cut (16 Oct 2025), 47 participants enrolled in the nTD (n=30), TD low (n=10), and TD high (n=7) cohorts, with 53% on concomitant JAKi therapy. DISC-0974 led to sustained hepcidin reduction and iron mobilization across cohorts. DISC-0974 resulted in meaningful hematologic responses among evaluable participants: 50% of nTD participants achieved a mean Hgb increase of ≥1.5 g/dL for ≥12 weeks, 71% of TD low participants achieved TI for ≥16 weeks, and 67% of TD high participants experienced a ≥50% reduction in transfusion burden, with follow-up ongoing. Major hematologic response rates were 50% for participants on and off concomitant JAKi therapy (n=18 and n=16, respectively). DISC-0974 was associated with meaningful improvement in FACIT-Fatigue scores for nTD and TD low participants. Serious adverse events (AEs, n=9) and ≥Grade 3 AEs (n=16) were considered unrelated to DISC-0974. There were no early withdrawals due to AEs. Conclusions: DISC-0974 was well tolerated and shows a favorable safety profile. Anemia response and fatigue scores improved across patients with MF and anemia, including those receiving JAKi therapy. These data validate hepcidin reduction as a promising approach to treating anemia in MF. Clinical trial information: NCT05320198 .

Abstract Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to the onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. In studies involving healthy volunteers (Novikov, et al, J Clin Pharmacol 2024:64(8):953-962) and participants with MF (Gangat et al, Blood 2024;144(Suppl1):657), DISC-0974 dosing resulted in reduced serum hepcidin levels and increased serum iron, with a favorable safety profile. Clinically meaningful improvements in anemia were also observed: 50% of non–transfusion-dependent (nTD) participants achieved a mean hemoglobin increase of ≥1.5 g/dL for at least 12 weeks, while 80% of participants with low transfusion burden (TD low) and 40% of participants with high transfusion burden (TD high) achieved transfusion independence (TI) for ≥16 and ≥12 consecutive weeks, respectively. Aims This Phase 2, open-label, multiple-ascending dose study (NCT05320198) assesses efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) in participants with MF. Methods Participants were enrolled into 3 primary cohorts (n=30 per cohort), categorized by the units of red blood cells transfused in the 84 days prior to screening: nTD (hemoglobin &lt;10 g/dL with 0 units), TD low (1-2 units), and TD high (3-12 units transfused). Additionally, an exploratory cohort of participants receiving concomitant treatment with momelotinib or pacritinib (n=10) was included. Eligible participants were ≥18 years of age with hemoglobin &lt;10 g/dL or a transfusion requirement meeting World Health Organization diagnostic criteria for primary or secondary MF. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor (ruxolitinib and fedratinib for primary cohorts; momelotinib and pacritinib for exploratory cohort) was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight (TD high only) and nutritional, genetic, infectious, or autoimmune anemia. DISC-0974 was administered subcutaneously at a dose of 50 mg once monthly for a total of 6 doses. Dose escalation to 75 mg was required for inadequate or loss of response. Primary endpoints included evaluating hematologic response defined for TD low and TD high as TI during any 16- and 12-week consecutive period, respectively, and for nTD as a mean hemoglobin increase of ≥1.5 g/dL from baseline for at least 12 weeks. Secondary endpoints included PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results As of 01 July 2025, enrollment of the exploratory cohort of momelotinib was complete (n=10). Baseline hepcidin values in the exploratory cohort were similar (mean (SD) of 83.6 (62.8) ng/mL) to baseline hepcidin values from the DISC-0974 Phase 1b study (mean (SD) of 85.8 (71.0) ng/mL, n=35), and sustained hepcidin reduction was observed after DISC-0974 dosing. Early hematologic responses observed after 1 to 3 doses in the exploratory cohort were comparable to those reported in the Phase 1b study (Gangat et al, Blood 2024;144(Suppl1):657). Based on these initial data, the protocol was amended to allow concomitant momelotinib or pacritinib in all cohorts. Preliminary results, including baseline characteristics, PD, and hematologic responses across all cohorts, will be presented.

Abstract Background and Significance: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with pathologic erythrocytosis, most often driven by somatic mutations in the JAK2 gene. A key treatment goal is maintaining hematocrit (HCT) below 45% to reduce thromboembolic complications. Current standard of care for patients diagnosed with PV, including phlebotomy (PHL) and cytoreductive therapies (CRT), can be burdensome, may lead to intolerable adverse effects, and often are associated with symptoms of iron deficiency. DISC-3405 is an investigational, novel, humanized immunoglobulin (Ig)G1 monoclonal antibody that targets transmembrane serine protease 6 (TMPRSS6, also known as matriptase 2) to stimulate endogenous production of hepcidin, a peptide hormone secreted by hepatocytes and the key regulator of iron homeostasis. In a randomized, placebo-controlled study in healthy volunteers (DISC-3405-101), DISC-3405 administered subcutaneously at doses between 37.5-300 mg was well-tolerated, resulted in dose-dependent pharmacokinetic (PK) profiles, significantly increased hepcidin production with corresponding reductions in serum iron levels, and reduced HCT (Liu et al, EHA 2025, PS2207). DISC-3405 is being developed as a potential treatment for patients with PV requiring HCT reduction, regardless of baseline risk or concurrent CRT. Study Design and Methods: This is a multi-center, open-label, 52-week Phase 2 study enrolling up to 20 patients with PV in the United States to assess the safety, tolerability, PK, pharmacodynamics (PD), and therapeutic effect of DISC-3405 on PV disease control as evidenced by HCT reduction and PHL requirements. After an observation period of 4-12 weeks, participants will be treated and followed for 52 weeks and dosed up to 300 mg every 2 weeks. After 52 weeks, participants can continue in an optional 2-year continuation phase where long-term safety and efficacy will continue to be assessed. The main efficacy endpoints of the study include the proportion of participants achieving therapeutic response, defined as absence of PHL eligibility; number of PHLs during the treatment period; and proportion of participants with HCT values &lt;45% throughout the study. PHL eligibility is defined as (1) HCT ≥45% and ≥3% (absolute change) of pre-treatment values or (2) HCT &gt;48%. Eligible participants include adults 18 or older who meet the 2022 World Health Organization diagnostic criteria for PV. Clinically acceptable laboratory values include HCT &lt;45% prior to Day 1 (dosing) or HCT &lt;48% if followed by a PHL within 2 weeks prior to first dose of study drug, white blood cells 4000/μL to 20,000/μL (inclusive), and platelets 100,000/μL to 1,000,000/μL (inclusive). Participants should have at least 3 PHL in 26 weeks or 5 PHL in the 52 weeks prior to screening, and at least 1 PHL within 12 weeks prior to screening. Participants receiving CRT must have been on the therapy for at least 6 months and on a stable PV treatment regimen, including hydroxyurea, interferon, or ruxolitinib, for at least 2 months. Participants treated with only PHL must have stopped CRT 6 months before screening. Key exclusion criteria include participants that require PHL at HCT levels &lt;45%, clinically significant thrombosis within 2 months prior to study treatment, active or chronic bleeding, estimated glomerular filtration rate of &lt;30 mL/min/1.73 m2, and history of invasive malignancies within the last 5 years, except localized cured prostate cancer and cervical cancer, or other malignancies deemed acceptable in discussion with the Sponsor. The study will enroll participants from approximately 15-20 sites in the United States. Additional details can be found at https://clinicaltrials.gov/study/NCT06985147.

Abstract Introduction: Indolent systemic mastocytosis (ISM) is a clonal mast cell disease driven by the KIT D816V mutation in ~95% of cases and is associated with symptoms of mast cell activation and tissue infiltration. It can cause chronic, debilitating symptoms − including life-threatening anaphylaxis and impaired bone health. While historically most patients have relied on symptom-directed best supportive care (BSC) therapies, avapritinib is used as a new standard of care targeting KIT D816V, the primary driver for SM. Avapritinib is an oral, potent, selective KIT D816V inhibitor, and the first and only approved targeted therapy for adult patients with ISM in the USA and the EU. Approval was based on results from the phase 2 PIONEER trial. Here, we present the findings from ~3.5-year long-term follow-up. Methods: Adults with centrally confirmed ISM and uncontrolled moderate-to-severe symptoms who completed the randomized dose-finding (Part 1), or randomized, double-blind, placebo-controlled (Part 2) portions of PIONEER (NCT03731260) rolled over to the open-label, long-term extension (Part 3). This cumulative analysis includes patients who initiated avapritinib at the recommended dose of 25 mg once daily (QD) in either Parts 1, 2, or 3. All patients received BSC. Per investigator discretion and based on disease burden, dose titration up to 50 mg QD of avapritinib was permitted in Part 3. Long-term efficacy was assessed by measuring changes in symptoms and QoL, using the ISM-Symptom Assessment Form (ISM-SAF; ©2018 Blueprint Medicines, a Sanofi Company) and the Mastocytosis Quality-of-Life Questionnaire (MC-QoL). Safety was also assessed. Results: Overall, 226 patients initiated avapritinib 25mg QD across Parts 1, 2, and 3. This longer-term analysis is inclusive of 65 patients who dose titrated from 25 mg to 50 mg QD in Part 3. Median (range) treatment duration was 40.0 months (0.7‒67.2) as of February 21, 2025. Longer-term efficacy data with ~3.5 years of follow-up demonstrated sustained disease-related symptom improvements. The mean change (standard deviation [SD]) in total symptom score (TSS, per ISM-SAF), was −19.80 (19.81) at Week 144 (Month 33) and −20.43 (20.57) at Week 168 (Month 39) from a baseline of 48.08 (19.47). Additionally, avapritinib-treated patients demonstrated durable improvement in their most severe symptoms (mean change [SD] from baseline of −3.35 [3.02] at Month 33 and −3.47 [3.19] at Month 39) per ISM-SAF. Sustained responses were observed across all individual symptom domains (0–30) with mean changes (SD) at Month 33 and Month 39 of −3.77 (5.52) and −3.84 (6.05) for the gastrointestinal domain, −8.21 (7.70) and −8.20 (7.85) for the skin domain, and −4.66 (6.24) and −4.87 (6.51) for the neurocognitive domain. The mean percent change (SD) in MC-QoL was −34.67 (40.16) at Month 33 and −40.72 (33.24) at Month 39 from a baseline of 54.24 (18.32). Treatment with avapritinib was well tolerated, and its safety profile was similar to the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were Grades 1–2, and 7% of patients experienced Grade ≥3 TRAEs of which diarrhea, neutrophil count decrease, and weight increase occurred in &gt;1 patient. No Grade ≥3 TRAEs of increase in transaminases were observed. Edema (peripheral and periorbital), the most frequently reported TRAE, was mostly Grade 1 and occurred most frequently during the first 3–4 months of treatment. Three patients (1%) experienced serious adverse events assessed as treatment related. However, none led to treatment discontinuation and no trends were observed. After approximately 3.5 years of follow-up, low rates of treatment discontinuations (n=7, 3%) due to TRAEs were observed. Conclusion: Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for up to 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition on anaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment for adult patients with ISM.

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C&gt;T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P&lt;0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P&lt;0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (&lt;45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have &gt;3 phlebotomies within six months prior to screening, including &gt;1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p&lt;0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (&lt;45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p&lt;0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.

Abstract Most myelofibrosis (MF) drug approvals by Health Authorities are based on 1 or 2 outcome measures such as spleen volume reduction and/or improved quality-of-life. This 1–2 dimensional approach fails to capture the clinical complexity of MF. A European LeukemiaNet (ELN) taskforce developed a composite endpoint which allows multiple outcomes to be simultaneously measured. The panel used the Desirability-Of-Outcome-Ranking (DOOR) method to assign 25 outcomes into 4 quartiles based on a multi-dimensional desirability score and build a 5-layer composite outcome named Desirability-of-Myelofibrosis-Outcomes (DEMYO). Outcome operational definitions were tested by Delphi consensus and correlations with survival validated by a literature review. The outcomes assigned to the first two quartiles were negatively correlated with leukemia-free survival and survival. DEMYO comprehensively captures relevant MF clinical features and meaningful endpoints. Despite DEMYO requires validation based on available trial data, it is expected to improve the quality of Health Authority approvals for new drugs for MF.

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell (MC) infiltration of extracutaneous tissues. Nonadvanced SM (NonAdvSM) is associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL). In up to 95% of patients (pts), SM is driven by the somatic KIT c.2447 A&gt;T (p.D816V) missense mutation. Bezuclastinib (bezu; CGT9486) is an oral, potent, small molecule, selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Results from Part 1 of the 3-part Summit trial demonstrated that bezu is well-tolerated and is associated with encouraging clinical activity, including both reduced MC burden and improvement in symptoms over a 12-week (wk) period vs placebo (PBO). Based on safety, PK, biomarker, and efficacy results, a dose of 100mg QD bezu (optimized formulation) was selected for Summit Part 2. Trial Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, double-blind, PBO-controlled RCT of bezu in pts with NonAdvSM who have inadequate control of symptoms despite treatment with best supportive care (BSC). A novel pt-reported outcome measure, the Mastocytosis Symptom Severity Daily Diary (MS2D2), was designed to assess disease-specific symptom severity in NonAdvSM pts. Eleven symptoms are included in the MS2D2 Total Symptom Score (TSS). Summit Part 1a randomized pts 1:1:1 to PBO, 100mg, or 200mg, original formulation while Part 1b randomized 1:1:1 to PBO, 100mg, or 150mg, optimized formulation. Pts completing Part 1 of the Summit trial were allowed to receive bezu in the open-label extension (OLE) Part 3 of the trial. Results: As Part 2 will evaluate safety and efficacy of 100 mg bezu at 24 wks, this abstract reports on pts treated with both bezu formulations at 100mg in Parts 1a or 1b, which had similar PK exposures. The presentation will focus on 24-wk outcomes in pts receiving the selected 100 mg bezu dose and participating in the OLE. In Summit Part 1, 19 pts received PBO and 18 received 100 mg bezu for 12 wks. At baseline (BL), the symptoms identified as most severe were within the skin and fatigue domains. At BL, pts were managing their symptoms of NonAdvSM with 2 (43%), 3 (24%), or ≥4 (32%) BSC medications. At the 12-wk assessment in Part 1 (datacut 18Dec2023), the safety and tolerability profile was encouraging, with the majority of TEAEs low grade and reversible without dose modification. The most common TEAEs (&gt;10% in 100 mg bezu) included hair color changes, nausea, diarrhea, peripheral edema, GERD, taste disorder, and neutropenia. There were no reported bleeding or cognitive impairment events. Of 37 pts randomized to PBO or 100 mg QD bezu, 36 (97%) received bezu in the OLE; one pt randomized to the 100 mg original formulation dose reduced and subsequently discontinued due to TEAE of ALT increase. All 19 PBO pts (100%) crossed over to receive bezu in the OLE; of these, 9 were randomized to the 100mg QD bezu dose. Reduction in MC burden was robust among those treated with 100mg bezu - 94.4%, 100%, and 92.3% of pts had at least a 50% reduction in basal serum tryptase, KIT p.D816V variant allele frequency, and bone marrow MCs, respectively. Pts treated with 100 mg bezu had reduction in MS2D2 TSS by 49.1% vs 21.1% with PBO. On a 0-10 scale, the most severe MS2D2 symptom mean change from BL was -3.03 from a BL mean of 7.6 with bezu vs -1.04 from a BL mean of 7.7 with PBO. Individual symptoms of the MS2D2 TSS, as well as others not in the TSS including diarrhea and brain fog, improved more with bezu than with PBO; mean change from BL ranged from -1.66 to -2.69 with bezu vs. a range of -0.52 to -1.58 with PBO. LS mean change from BL in quality of life (Mastocytosis (MC)-QoL, a disease-specific measure) was -22.05 in pts treated with 100mg bezu versus -10.71 in pts treated with PBO. Objective measurements of skin lesions, including centrally adjudicated longitudinal assessments of skin photography, also significantly reduced on bezu. Conclusions: In Part 1 (12 wk assessment), treatment with 100mg bezu resulted in favorable safety and tolerability, significant and deep reductions across all markers of MC burden, and clinically meaningful reduction in all individual MS2D2 TSS symptoms and across domains. The presentation will report on durability and safety/tolerability data beyond 12 wks for those pts randomized to 100 mg in Part 1 and pts who crossed over from PBO in Part 1 to 100mg in Part 3. Summit Part 2 is actively enrolling.

Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. A completed healthy volunteer study demonstrated serum hepcidin reductions, serum iron increases, and increasing trends in hematologic parameters, with no safety signal identified. Aims This Phase 1b/2, open-label, multiple-ascending dose study (NCT05320198) assessed safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of DISC0974 in patients with MF and anemia. Methods Eligible participants were ≥18 years of age with intermediate-2 or high-risk MF and anemia. Anemia was defined as baseline hemoglobin (Hgb) &lt;10 g/dL with or without intermittent transfusion requirement (non-transfusion dependent [nTD]) or transfusion dependent (TD), as defined by the IWG-MRT. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight and nutritional, genetic, infectious, or autoimmune anemia. Dose escalation was based on a Bayesian optimal interval design with accelerated titration. DISC-0974 was administered subcutaneously monthly for 6 doses. Primary endpoints included evaluating DISC-0974 safety and tolerability. Secondary endpoints included PK/PD markers of iron regulation and hematologic parameters. Hematologic response was defined for TD as transfusion independence (TI) during any 12-week consecutive period and for nTD as ≥1.5 g/dL Hgb increase from baseline at any time point. Durability was evaluated as mean Hgb ≥1.5 g/dL above baseline during any 12-week period. Data were summarized using descriptive statistics. Results At the time of data cut, 34 participants were enrolled at 5 dose levels: 14 mg (n=1), 28 mg (n=7), 50 mg (n=12), 75 mg (n=8), and 100 mg (n=6). Treatment with DISC-0974 resulted in meaningful and sustained hepcidin reductions with mean change from baseline (mean 88.2 ng/mL; range [8.7, 374.7]) reaching over 80% across treated participants. This corresponded to iron mobilization at all dose levels. Efficacy Hematologic responses were evaluated in participants dosed at 28 to 100 mg. Responses were achieved independent of baseline transferrin saturation (TSAT) values. Initial hematologic responses in nTD participants were observed around the time of administration of the second dose, with a rise in absolute reticulocyte count preceding responses. Mean erythropoietin values decreased from baseline (mean 68.2 mIU/mL; range [13.2, 1815]) in participants treated at 50 to 100 mg. Hemoglobin responses were achieved in 69% (20/29) of nTD participants; 60% of nTD participants (9/15) achieved a durable response. TSAT values above normal range (50%) were observed in all participants with a durable response. One of two evaluable TD participants achieved TI at the end of study. All evaluable participants with a baseline transfusion requirement (n=8) had ≥50% reduction in transfusions over a rolling 8-week window compared to baseline. Hematologic response was observed in 6 of 10 participants with concomitant JAK inhibitor therapy. Safety One adverse event (AE), diarrhea, was at least possibly related to DISC-0974 and reported in ≥2 participants. Grade 3 AEs included headache reported in 1 participant treated at 28 mg (not related to DISC-0974) and Grade 3 anemia reported in 2 participants treated at 28 mg and 4 participants treated at 50 mg (1 at 50 mg was deemed related to DISC-0974; all others were deemed not related). One serious AE of Grade 2 arthralgia was reported and deemed not related to DISC-0974. Summary/Conclusions DISC-0974 demonstrated acceptable safety and tolerability at all evaluated dose levels. Hematologic responses were achieved in nTD and TD participants, regardless of concomitant JAK inhibitor use. Sustained hepcidin reduction with DISC-0974 led to increased serum iron that preceded hematological response. Additional Phase 1b data, including longer follow-up, will be presented.