- D1.529 - Evaluating the Disease-Modifying Potential of Elenestinib, a Highly Potent and Selective Tyrosine Kinase Inhibitor, in Patients With Indolent Systemic Mastocytosis: An Update on the Pivotal HARBOR Study

Indolent systemic mastocytosis (ISM) is a clonal mast cell (MC) disease driven by D816V-mutant KIT in ~95% of cases. ISM is characterized by aberrant MC accumulation and activation with potentially chronic and debilitating features, such as anaphylaxis, skin lesions, gastrointestinal and neurocognitive symptoms as well as osteoporosis, which can significantly impact patients’ quality of life (QoL).

Elenestinib is a potent and highly selective KIT D816V inhibitor with nanomolar inhibitory potency (half-maximal inhibitory concentration, 3.1 nM; selectivity score, 0.035). It has also shown limited central nervous system penetration. The phase 2/3 study, HARBOR (NCT04910685), is an ongoing study evaluating the efficacy and safety of elenestinib in patients with ISM. Data from HARBOR Part 1 and pharmacokinetic groups supported the tolerability and clinical activity of 75 mg and 100 mg doses.

In HARBOR Part 2, ~350 patients will be randomized 2:1 to elenestinib 75 mg once daily (QD) + symptom-directed therapy (SDT) or placebo + SDT. After completing the double-blind Part 2 (assessed at 48 weeks), patients will cross over to Part 3 (long-term extension) to receive elenestinib 75 mg QD + SDT. In Part 3, patients may escalate to elenestinib 100 mg QD + SDT. Key inclusion criteria include centrally confirmed ISM  and 14-day average total symptom score (TSS) ≥28 evaluated by the ISM Symptom Assessment Form (ISM-SAF; © 2018 Blueprint Medicines Corporation). Primary endpoint is mean change in ISM-SAF TSS from baseline to 48 weeks. Key secondary endpoints include proportions of patients achieving normalization of tryptase, undetectable or ≥50% reduction in KIT D816V variant allele fraction, and symptom control; change in bone mineral density; change in anaphylaxis frequency; and change in QoL. Other secondary endpoints include disease control per the patient-reported Mastocytosis Control Test, change in bone marrow MCs, change in SDT use, and change in skin lesions. Safety data will also be collected.

Trial in progress.

The innovative HARBOR Part 2 design represents the largest double-blind, placebo-controlled study in ISM to date. The endpoints have been optimized to evaluate both symptom control and disease modification, including anaphylaxis control and bone health. The 48-week endpoint timing reflects the chronic nature of the disease. HARBOR Part 2 is ongoing and is actively enrolling patients across a large global network of sites.