Introduction

Indolent systemic mastocytosis (ISM) is a rare clonal mast cell disease driven by the KIT D816V mutation in nearly all patients. Patients with ISM can present with debilitating acute and chronic cutaneous, gastrointestinal, neurocognitive, and systemic symptoms caused by the release of inflammatory mediators from abnormal mast cells. In some patients, symptoms are not adequately controlled with best supportive care (BSC) medications. Elenestinib (BLU-263) is a novel, investigational, oral, next-generation tyrosine kinase inhibitor that potently and selectively inhibits KIT D816V with limited central nervous system penetration and pharmacokinetics (PK) that support once daily dosing. HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of elenestinib in patients with ISM.

Methods

Eligible adult patients with ISM, confirmed following central review of bone marrow (BM) pathology, clinical, and laboratory findings per World Health Organization criteria and a moderate-to-severe symptom score based on minimum mean total symptom score (TSS) of the ISM-Symptom Assessment Form (ISM-SAF©2018), were stratified by baseline serum tryptase (<20 ng/mL vs ≥20 ng/mL) and randomly assigned 3:1 to elenestinib 25 mg, 50 mg, or 100 mg once daily + BSC (“elenestinib”) or placebo + BSC (“placebo”). The primary objective of Part 1 was to determine the recommended dose based on safety, PK, and pharmacodynamics. Secondary endpoints included changes in biomarkers of disease burden (serum tryptase, KIT D816V variant allele fraction [VAF], and BM mast cells) and ISM-SAF TSS. Three additional open-label PK groups enrolled patients at 50 mg, 75 mg, and 100 mg to further characterize PK and safety.

Results

As of data cutoff on July 3, 2023, a total of 122 patients with ISM have received their assigned treatment in Part 1 of the study; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open-label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). Baseline demographics were similar to those reported for the general ISM population.

After 12 weeks of therapy, symptom improvement was observed for all dose cohorts, and symptom reduction by TSS was greater for patients on elenestinib versus placebo in the blinded portion of Part 1. Patients receiving elenestinib at 25 mg, 50 mg, and 100 mg doses showed reduction (mean percent) from baseline for tryptase (-15.4%, -50.9%, and -68.4% vs 3.3%, respectively) and KIT D816VVAF (-37.5%, -70.3%, and -77.0% vs -2.5%, respectively) as compared to placebo. Similar reductions in TSS and disease-related biomarkers were observed in the open-label PK cohorts.

After a median treatment duration of 35.3 weeks, elenestinib was well-tolerated at all dose levels. There were no treatment-related serious adverse events and no treatment-related adverse events that led to drug discontinuation.

Conclusion

Elenestinib at all tested doses demonstrated beneficial effects on disease-related symptoms and biomarkers of mast cell burden in this large and maturing cohort of patients with ISM with a moderate-to-severe symptom burden. Elenestinib was well tolerated across all dose levels with a promising early benefit-risk profile in ISM. These preliminary findings will inform dosing for the planned Part 2 of HARBOR, which will examine elenestinib versus placebo in a randomized, blinded, placebo-controlled setting.

Tashi:Blueprint Medicines Corporation, PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Other: PI on several clinical trials including PIONEER. Hermine:AB Science, BMS/Celgene, Alexion, Novartis, and Inatherys: Research Funding; AB Science: Consultancy, Other: Shareholder. Castells:Current Allergy and Asthma Reports: Membership on an entity's Board of Directors or advisory committees; ABAI: Membership on an entity's Board of Directors or advisory committees; UptoDate: Honoraria, Other: Receives authors fees; Blueprint: Consultancy, Other: PI on several Blueprint clinical trials. Guilarte:Blueprint Medicines Corporation: Consultancy. Sabato:Institutional: Other: Institution has received research funding from Blueprint Medicines Corporation for clinical trials.; Blueprint Medicines Corporation, Novartis, and Cogent: Honoraria, Other: Honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Maurer:Allakos, Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, Celldex, Dr. Pfleger, FAES, Genentech, GI Innovation, GSK, Innate Pharma, Kyowa Kirin, Lilly, Merkle Recordati, Moxie, Novartis, Regeneron, Roche, Sanofi, Third Harmonic Bio, UCB, and Ur: Honoraria, Research Funding. Panse:MSD: Consultancy; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd,: Membership on an entity's Board of Directors or advisory committees, Other: Third party writing assistance by Akshaya Srinivasan, PhD, of MediTech Media Ltd and funded by F. Hoffmann-La Roche Ltd, , Speakers Bureau; BMS: Consultancy; Alexion, AstraZeneca Rare Disease: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Ltd: Consultancy; Samsung Bioepis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Consultancy; Amgen: Consultancy. Alvarez-Twose:Blueprint Medicines Corporation: Other: Advisory Board or Speaker Fees, Research Funding; Novartis: Other: Advisory Board or Speaker Fees. Bird:Principia (Sanofi): Research Funding; Rigel: Research Funding; Amgen: Speakers Bureau. Barete:Blueprint Medicines Corporation: Consultancy, Other: Fees for symposium and scientific boards; financial support for clinical trials; AbbVie: Other: Fees; Leo Pharma Laboratories: Other: Fees. Bouillet:Takeda, Biocryst, Behring, Blueprint Medicines Corporation, Novartis: Consultancy, Other: Advisory Role; Takeda, Behring, Biocryst, Blueprint Medicines Corporation, Novartis: Other: Travel and Accommodation Expenses. Van Daele:Novartis: Other: Speaking Fees. Griffiths:Taiho Oncology: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Apellis Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; S. Karger Publishing: Honoraria; Artis Ventures: Membership on an entity's Board of Directors or advisory committees; Picnic Health: Membership on an entity's Board of Directors or advisory committees; MediCom Worldwide, Inc.: Honoraria; NextCure, Inc: Research Funding; American Society of Hematology: Honoraria; Celldex Therapeutics: Research Funding; CTI Biopharma: Consultancy; Vera and Joseph Dresner Foundation: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Partner Therapeutics: Consultancy; Blueprint Medicines, Inc: Research Funding; AstraZeneca Rare Disease: Consultancy, Research Funding; MDS International Foundation: Honoraria; Medscape: Honoraria; AAMDSIF: Honoraria; Novartis: Consultancy, Research Funding; Physicians Educational Resource: Honoraria; Takeda Oncology: Consultancy. Jurcic:Gilead/Forty Seven: Research Funding; Rigel Pharmaceuticals: Consultancy; AbbVie: Research Funding; Ionis Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Blueprint Medicines: Research Funding; Syros Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sumitomo Pharma: Research Funding. Dybedal:Novartis: Other: Advisory Board Fees. Damaj:Takeda, Blueprint Medicines Corporation, and Thermo Fisher: Consultancy, Other: Advisory Role; Takeda, AbbVie and Pfizer: Other: Travel and Accommodation Expenses. Schafhausen:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; AOP Orphan: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; BMS/Celgene: Consultancy, Honoraria, Other: Travel and accomodation support; Merck Serono: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation support. Elena:Blueprint Medicines Corporation, Cogent and Gilead: Other: Advisory Board Fees. Vachhani:Incyte, CTI BioPharma Corp, Blueprint Medicines: Speakers Bureau; Abbvie, Amgen, Blueprint Medicines, Cogent Biosciences, Incyte, CTI BioPharma Corp, Daiichi Sankyo, GlaxoSmith Kline, Karyopharm, Novartis, Pfizer, Genentech, Inc., Servier, Stemline, MorphoSys, LAVA therapeutics: Honoraria. Labe:Blueprint Medicines Corporation: Current Employment. Venugopal:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. He:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Muñoz-González:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Lampson:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Scherber:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Bose:GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria; Kartos, Telios, Ionis, Disc, Janssen, Geron: Research Funding; Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo: Honoraria, Research Funding. Grattan:Blueprint Medicines Corporation, AB Science: Other: Study Steering Commitee; Celltrion, Sanofi: Consultancy. Pongdee:AstraZeneca: Research Funding; Blueprint Medicines Corporation: Research Funding; Sanofi: Research Funding; GlaxoSmithKline: Research Funding. George:Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARUP Laboratories: Current Employment. Livideanu:Novartis: Research Funding; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees; Lilly, Novartis, UCB: Consultancy; ABScience: Membership on an entity's Board of Directors or advisory committees.

2023
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