elenestinib (BLU-263) / Blueprint Medicines - LARVOL DELTA

(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis (clinicaltrials.gov) - P2/3 | N=534 | Recruiting | Sponsor: Blueprint Medicines Corporation | Trial completion date: Jun 2028 ➔ Sep 2032 | Trial primary completion date: Jun 2028 ➔ Sep 2032

Trial completion date • Trial primary completion date • IL2RA

AZURE: Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov) - P1 | N=9 | Terminated | Sponsor: Blueprint Medicines Corporation | N=67 ➔ 9 | Trial completion date: Dec 2025 ➔ Mar 2025 | Active, not recruiting ➔ Terminated; Terminated - alignment of strategic priorities

Enrollment change • Monotherapy • Trial completion date • Trial termination • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Lymphoma • Mast Cell Leukemia • Oncology • PDGFRA

HARBOR: An Ongoing Phase 2/3 Study of Elenestinib in Patients With Indolent Systemic Mastocytosis (AAAAI-WAO 2025) - P2/3 | "Results N/A. Conclusions N/A."

Clinical • P2/3 data • Inflammation

AZURE: Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov) - P1 | N=67 | Active, not recruiting | Sponsor: Blueprint Medicines Corporation | Recruiting ➔ Active, not recruiting | Phase classification: P1/2 ➔ P1 | Trial completion date: Nov 2029 ➔ Dec 2025 | Trial primary completion date: Nov 2029 ➔ Jan 2025

Enrollment closed • Monotherapy • Phase classification • Trial completion date • Trial primary completion date • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Lymphoma • Mast Cell Leukemia • Oncology • PDGFRA

FMC60: Mastocytosis and mast cell activation syndromes: diagnostic and therapeutic progress in 2024. (JDP 2024) - "Therapeutically, there is cladribine (off-label) which retains a place and avapritinib which is a tyrosine kinase inhibitor (TKI) which has obtained European marketing authorization for indolent systemic forms and also advanced forms. Other TKIs, such as elenestinib and bezuclastinib, are in phase 2 trials...Educational objectives The educational objectives are to better understand mast cell pathologies and what to do when faced with a patient with a suspicion or diagnosis of mast cell pathology with a therapeutic proposal. Content of this training Clinical cases, new developments, literature review and sharing of experience."

Dermatology

Blueprint Medicines Reports Third Quarter 2024 Results… (PRNewswire) - "Key Upcoming Milestones - Mast cell disorders: Initiate registration-enabling Part 2 of the HARBOR trial of elenestinib in ISM by the end of this year. Cell cycle inhibition: Continue strategic business development discussions. Complete Phase 1 combination dose escalation for BLU-222 by end of year to inform registration plans."

Trial status • Aggressive Systemic Mastocytosis • Oncology • Solid Tumor

Management of Advanced Systemic Mastocytosis: Clinical Challenges. (PubMed, J Blood Med) - "Identification of the gain-of-function KITD816V in the majority of cases has accelerated pharmaceutical development culminating with the development of selective KIT inhibitors such as avapritinib...In this review, we summarize the present and future therapeutics landscape of AdvSM, highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib. We also explore the continued role of additional treatment modalities including allogeneic stem cell transplantation before discussing unresolved clinical challenges in the management of AdvSM."

Journal • Metastases • Review • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Oncology • Transplantation

Managing Systemic Mastocytosis (SOHO 2024) - P2, P2/3 | "Midostaurin was approved by the Food and Drug Administration (FDA) in 2017 for frontline treatment of AdvSM patients. Avapritinib is an oral, highly selective inhibitor of KIT D816V.8 The multi-center phase 1 EXPLORER trial accrued 69 patients in dose escalation and expansion cohorts.9 The ORR was 75%, with a 36% complete remission rate with full or partial hematologic recovery...Imatinib lacks activity against KIT D816V but was approved by the FDA almost two decades ago for adult patients with ASM without the KIT D816V mutation or with unknown KIT mutational status...Elenestinib (HARBOR [NCT04910685] and bezuclastinib (SUMMIT) [NCT05186753]) have also entered clinical trial testing in ISM/ SSM patients with TSS as the primary endpoint...Interrogating the dynamic clonal landscape responsible for clinical progression under the pressure of KIT inhibition is a major translational focus. In addition, the role and timing of hematopoietic stem cell transplantation..."

Acute Myelogenous Leukemia • Aggressive Systemic Mastocytosis • Leukemia • Mast Cell Leukemia • Oncology • ASXL1 • RUNX1 • SRSF2

Systemic Mastocytosis: State of the Art. (PubMed, Curr Hematol Malig Rep) - "Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions...The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology • KIT

SOHO State of the Art Update and Next Questions: Current and Emerging Therapies for Systemic Mastocytosis. (PubMed, Clin Lymphoma Myeloma Leuk) - "Midostaurin inaugurated the era of KIT inhibitors and was approved for AdvSM in 2017. Avapritinib is the first highly potent and selective inhibitor of KIT D816V that was approved to treat AdvSM and symptomatic ISM (platelets ≥ 50 × 109/L), in the US, in 2021 and 2023, respectively...Bezuclastinib reduced markers of MC burden by ≥ 50% in ≈50% of AdvSM patients and ≈90-100% of nonAdvSM patients and reduced symptoms (≥ 50%) in the APEX and SUMMIT studies, respectively. Elenestinib demonstrated dose-dependent efficacy in reducing MC burden markers and improved symptoms in ISM patients in the HARBOR study."

Journal • Review • Gastrointestinal Disorder • Hematological Malignancies • Oncology

Elenestinib, an Investigational, Next Generation KIT D816V Inhibitor, Reduces Mast Cell Burden, Improves Symptoms, and Has a Favorable Safety Profile in Patients with Indolent Systemic Mastocytosis: Analysis of the Harbor Trial (ASH 2023) - P2/3 | "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."

Clinical • Gastrointestinal Disorder

BLU-263-1201: (HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis (clinicaltrials.gov) - P2/3 | N=443 | Recruiting | Sponsor: Blueprint Medicines Corporation | Trial primary completion date: Aug 2023 ➔ Jun 2028

Trial primary completion date • IL2RA

AZURE: Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov) - P1/2 | N=67 | Recruiting | Sponsor: Blueprint Medicines Corporation | Initiation date: Apr 2023 ➔ Sep 2023

Combination therapy • Metastases • Monotherapy • Trial initiation date • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Lymphoma • Mast Cell Leukemia • Oncology • PDGFRA

Current and Emergent Therapies for Systemic Mastocytosis (SOHO 2023) - "A very rare variant of SM, seen across its subtypes, is well-differentiated SM (WDSM), characterized by rounded instead of spindled MCs, lack of CD2/25 expression, lack of KIT D816V and responsiveness to imatinib.16 KIT Inhibitors In recent years, the advent of targeted therapy in the form of smallmolecule KIT inhibitors has transformed the management of SM...Subsequent analyses revealed 2 predictors of inferior survival on midostaurin: the presence of S/A/R mutations and a <25% reduction in KIT D816V VAF.19 A more recent registry-based analysis has demonstrated superior outcomes with midostaurin therapy of AdvSM as compared to cladribine.20 Avapritinib Avapritinib is a highly potent (IC50 0.27 nM) and selective inhibitor of KIT D816V and similar mutations.21 It was approved for the treatment of AdvSM (ASM, SM-AHN and MCL) by the FDA on June 16, 2021 at a starting dose of 200 mg daily and for the treatment of ISM on May 22, 2023 at a starting dose of 25 mg..."

Aggressive Systemic Mastocytosis • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • ASXL1 • CD2 • IL2RA • RUNX1 • SRSF2 • TNFRSF8

Blueprint Medicines Reports Second Quarter 2023 Results (PRNewswire) - "Blueprint Medicines plans to achieve the following milestones by the end of 2023: Present data from Part 1 of the HARBOR trial of elenestinib in indolent SM. Continue AYVAKIT commercial launch execution in SM....Revenues: Revenues were $57.6 million for the second quarter of 2023, including $39.9 million of net product revenues from sales of AYVAKIT/AYVAKYT and $17.7 million in collaboration revenues. Blueprint Medicines recorded revenues of $36.5 million in the second quarter of 2022, including $28.5 million of net product revenues from sales of AYVAKIT/AYVAKYT and $8.0 million in collaboration revenues."

Launch • P2/3 data • Sales • Aggressive Systemic Mastocytosis • Oncology • Solid Tumor

Systemic mastocytosis: 2023 update on diagnosis and management in adults. (PubMed, Expert Opin Emerg Drugs) - "In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future."

Journal • Review

AZURE: Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov) - P1/2 | N=67 | Recruiting | Sponsor: Blueprint Medicines Corporation | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Monotherapy • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Lymphoma • Mast Cell Leukemia • Oncology • PDGFRA

AZURE: Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov) - P1/2 | N=67 | Not yet recruiting | Sponsor: Blueprint Medicines Corporation | N=108 ➔ 67 | Trial completion date: Nov 2027 ➔ Nov 2029 | Initiation date: Dec 2022 ➔ Apr 2023 | Trial primary completion date: Nov 2027 ➔ Nov 2029

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial completion date • Trial initiation date • Trial primary completion date • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Lymphoma • Mast Cell Leukemia • Oncology • PDGFRA

HARBOR: A PHASE 2/3 STUDY OF BLU-263 IN PATIENTS WITH INDOLENT SYSTEMIC MASTOCYTOSIS AND MONOCLONAL MAST CELL ACTIVATION SYNDROME (EHA 2022) - P2/3 | "Results Topline results of P art 1 of the study are anticipated in the second half of 2022. Conclusion Overall, the goal of HARBOR is to investigate the safety and efficacy of the selective, targeted KIT inhibitor BLU-263 as a potential treatment option to reduce symptom burden for patients with ISM."

Clinical • P2/3 data • Oncology

AZURE: A Phase 1/2 Study of Blu-263 As Monotherapy and in Combination with Azacitidine in Patients with Advanced Systemic Mastocytosis (ASH 2022) - "Primary endpoints include determination of the RD and safety profile of BLU-263 monotherapy and BLU-263 + azacitidine combination therapy, as well as efficacy according to established response criteria in AdvSM. Secondary endpoints include pharmacokinetic parameters of BLU-263 and BLU-263 + azacitidine, overall response rate, time to response, duration of response, progression-free survival, and the proportion of patients pursuing allogeneic hematopoietic stem cell transplantation."

Clinical • Combination therapy • Monotherapy • P1/2 data • Aggressive Systemic Mastocytosis • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • Transplantation

(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis (clinicaltrials.gov) - P2/3; N=403; Recruiting; Sponsor: Blueprint Medicines Corporation; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • IL2RA • Tryptase

Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms. (PubMed, Hematology Am Soc Hematol Educ Program) - "The multikinase/KIT inhibitor midostaurin and the highly selective KIT D816V inhibitor avapritinib can elicit marked improvements in measures of mast cell (MC) burden as well as reversion of MC-mediated organ damage (C-findings) and disease symptoms...BLU-263 and bezuclastinib are KIT D816V inhibitors currently being tested in trials of AdvSM...While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the "poster children" of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhibitor pemigatinib, approved in August 2022, is a promising therapy in aggressive FGFR1-driven diseases and highlights the role of such agents in bridging patients to allogeneic transplantation. This review summarizes the data for these approved and investigational agents and discusses open questions and future priorities regarding the management..."

Journal • Eosinophilia • Hematological Malignancies • Oncology • Rare Diseases • Transplantation • ABL1 • ETV6 • FGFR1 • FIP1L1 • FLT3 • JAK2 • PDGFRA • PDGFRB

Blueprint Medicines Outlines 2027 Blueprint to Achieve Precision Medicine at Scale and Reports Third Quarter 2022 Financial Results at Investor Day 2022 (PRNewswire) - "Key Upcoming Milestones: Submit a supplemental New Drug Application to the FDA for AYVAKIT for non-advanced SM in the fourth quarter of 2022; Present detailed data from the registration-enabling Part 2 of the PIONEER trial of AYVAKIT in non-advanced SM at a medical congress in late 2022 or early 2023; Report top-line 12-week data from Part 1 of the HARBOR trial of BLU-263 in non-advanced SM in the fourth quarter of 2022."

NDA • P2 data • P2/3 data • Aggressive Systemic Mastocytosis • Oncology • Solid Tumor

AZURE: Study of BLU-263 in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov) - P1/2 | N=108 | Not yet recruiting | Sponsor: Blueprint Medicines Corporation

Combination therapy • Monotherapy • New P1/2 trial • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Lymphoma • Mast Cell Leukemia • Oncology

FMC68 - Non-advanced mast cell pathologies: diagnosis and treatment around the PNDS 2022 (JDP 2022) - "On the therapeutic level, new tyrosine kinase (TKI) inhibitors are added to the midostaurin already used for the rarer advanced form of the disease, with the recent obtaining of European MA for avapritinib. A new generation of TKI, Blu263, is entering phase 2 clinical trials this year...educational goals Better control of mast cell pathologies and what to do when faced with a patient with a suspicion or diagnosis of mast cell pathology. Content of this training Clinical cases, news, literature review and experience sharing."

Dermatology • KIT • TPSAB1