elenestinib (BLU-263) / Sanofi - LARVOL DELTA

Development of an Optimized superRCA KIT D816V Test for Mast Cell–Driven Diseases (USCAP 2026) - P1/2, P2 | "Clinical validity of the optimized superRCA assay was assessed in PB from healthy donors and patients with ISM previously tested for KIT D816V by ddPCR in PIONEER (NCT03731260; limit of detection [LOD]: 0.022%) and HARBOR (NCT04773782; LOD: 0.03%) studies of avapritinib and elenestinib. The optimized superRCA assay improved KIT D816V detection, with ≥30-fold higher sensitivity than ddPCR without loss of specificity, expanding the diagnostic toolkit for clonal mast cell disease, including ISM."

Tumor mutational burden • TMB

Ultra-Sensitive SuperRCA Assay Enhances the Ability to Detect KIT D816V Mutations in Peripheral Blood With a Sensitivity Comparable to That of Bone Marrow Testing (AAAAI 2026) - P1/2, P2 | "We compared KIT D816V detection with each method and baseline characteristics for ddPCR detectable (ddPCR+) versus ddPCR undetectable (ddPCR–)/superRCA detectable (superRCA+) patients from PIONEER (NCT03731260) and HARBOR (NCT04773782) studies of KIT inhibitors avapritinib (approved for ISM) and investigational elenestinib. Baseline median serum tryptase and BM mast cells were significantly higher in ddPCR+ versus ddPCR–/superRCA+ patients (P<0.0001). Conclusions The superRCA assay increased PB KIT D816V detection comparable with local BM testing, highlighting the potential for ultra-sensitive testing to improve ISM diagnosis, especially with low baseline serum tryptase."

Tumor mutational burden • TMB

A Study of Elenestinib in Healthy Adult Female Participants (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Blueprint Medicines Corporation

New P1 trial

Relationship between KIT inhibition by bezuclastinib and effects on disease burden in mouse models of systemic mastocytosis (ASH 2025) - P2 | "The approval of the first KIT-targeted therapy, avapritinib (AVA),demonstrates proof-of-concept clinical efficacy in these patients, but effects on mast cell burden in bloodand bone marrow are limited...For a functional target engagement readout, Ba/F3-KIT-D816V cells were injectedintravenously into nude mice, and spleen weights and drug exposure (AUC) analyzed after 9 days drugadministration of BEZU (0.1-200 mg/kg), AVA (0.3-100 mg/kg), or the AVA analog, elenestinib (ELE, 1-200mg/kg)... Overall, these analyses suggest that while partial inhibition of KIT achieved clinically mayyield a measurable clinical effect, substantially higher target coverage is likely needed to observesignificant impact on clonal mast cell expansion."

Preclinical • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • 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 • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

MODULE 5: Current and Future Management of Systemic Mastocytosis (SM) (ASH 2025) - "This program is supported by educational grants from Blueprint Medicines, Bristol Myers Squibb, GSK, and Incyte Corporation. Rationale for targeting the KIT D816V mutation in patients with SM; mechanism of action of avapritinib Published efficacy and safety findings from the pivotal Phase II PIONEER trial of avapritinib versus placebo for patients with indolent SM whose symptoms were not adequately controlled with standard therapy Outcomes achieved in key studies, such as EXPLORER and PATHFINDER, evaluating avapritinib for advanced SM Selection of patients with various SM subtypes for whom treatment with avapritinib would be appropriate Mechanistic similarities and differences between avapritinib and next-generation KIT D816V inhibitors, such as elenestinib and bezuclastinib; implications for efficacy and tolerability Preliminary safety and efficacy data with elenestinib for patients with indolent SM whose symptoms are not adequately controlled by best supportive care;..."

Myelofibrosis

Tyrosine Kinase Inhibitors for the Treatment of Mast Cell Diseases: Review and Update. (PubMed, J Investig Allergol Clin Immunol) - "TKIs represent a major advance in the management of MCDs, with more patients being able to benefit from a treatment that addresses pathophysiology. We review the main TKIs currently available for SM, their indications, and their safety and effectiveness."

Journal • Review • Bone Marrow Transplantation • Transplantation • KIT

Press Release: Sanofi completes acquisition of Blueprint Medicines (Sanofi Press Release) - "Sanofi today announces the completion of its acquisition of Blueprint Medicines Corporation (Blueprint), adding to its portfolio a commercialized medicine, a promising pipeline, and the expertise of a company specializing in systemic mastocytosis (SM), a rare immunological disease, and other KIT-driven diseases....The acquisition includes a rare immunology disease medicine, Ayvakit/Ayvakyt (avapritinib), approved in the US and EU....The acquisition also includes elenestinib, a next-generation medicine for SM that is a potent and highly selective KIT D816V inhibitor with limited central nervous system penetration....Sanofi also acquired BLU-808, an investigational oral, highly potent and selective wild-type KIT inhibitor."

M&A • Aggressive Systemic Mastocytosis • Immunology

PHASE 2/3 HARBOR STUDY OF ELENESTINIB IN ISM: A TRIAL-IN-PROGRESS UPDATE OF NOVEL ENDPOINTS AND BIOMARKERS AIMED AT EVALUATING DISEASE MODIFICATION (EHA 2025) - P2/3 | "HARBOR Part 2 is optimized to assess symptom control, and disease modification endpoints including anaphylaxis frequency and bone health, on timelines that reflect the chronic nature of the disease. The exploration of multiple doses throughout the trial will provide dosing flexibility. HARBOR Part 2 has initiated and will be expanded internationally."

Biomarker • P2/3 data • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

HIGH ACCURACY OF PERIPHERAL BLOOD TESTING AND MACHINE LEARNING-DERIVED PREDICITIVE MODELS TO DISTINGUISH ADVANCED FROM INDOLENT SYSTEMIC MASTOCYTOSIS: ANALYSIS OF AVAPRITINIB AND ELENESTINIB TRIAL DATA (EHA 2025) - P1, P2, P2/3 | "We have successfully created and validated two predictive models that can distinguish AdvSM from ISM with a high degree of accuracy. Their accuracy, when tested across multiple independent patient cohorts, highlights the expected broad applicability of these models in a variety of clinical practice settings."

Machine learning • Metastases • Anemia • Hematological Disorders • Oncology • Thrombocytopenia

New treatments for systemic mastocytosis in 2025. (PubMed, Curr Opin Allergy Clin Immunol) - "Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results."

Journal • Aggressive Systemic Mastocytosis • CD33 • IL6

(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

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