Prelude Therapeutics (NASDAQ:PRLD) outlined progress across three priority programs at a Chardan Capital investor session, emphasizing its recently initiated JAK2 program, an IND-cleared KAT6A degrader for breast cancer and a mutant calreticulin, or mCALR, program for myeloproliferative neoplasms.
Bryant Lim, the company’s chief financial officer, said the company pivoted about a year ago to focus on the three programs because each addresses a clinically validated target. He said Prelude advanced its JAK2 JH2 program into the clinic during the second quarter of 2026 and recently received IND clearance for its KAT6 program, with patient enrollment anticipated soon.
KAT6A Degrader Strategy in Breast Cancer
Peggy Scherle, Prelude’s chief scientific officer, said KAT6A is amplified and overexpressed in estrogen receptor-positive breast cancer, where it contributes to estrogen signaling, MYC regulation and cell-cycle gene activity. She cited data from Pfizer’s KAT6-targeting program, describing monotherapy response rates of about 10% and response rates in the mid-30% range when combined with fulvestrant, alongside progression-free survival of roughly 10 to 11 months.
Prelude’s approach differs from other KAT6 programs because its candidate is designed to selectively degrade KAT6A while sparing KAT6B, rather than inhibit both proteins. Scherle said the distinction could be important because KAT6B has a role in bone marrow development, while KAT6A is believed to drive tumor biology.
She said neutropenia has been the main dose-limiting toxicity observed with Pfizer’s compound. Prelude believes sparing KAT6B could improve the therapeutic index and potentially reduce neutropenia, although Scherle noted that the hypothesis must be tested clinically. In preclinical models, the company’s KAT6A-selective degrader showed fewer effects on neutrophils, she said.
Prelude also believes degradation could offer advantages beyond selectivity. Scherle said KAT6 functions as part of a complex, and degrading the protein may disrupt the broader complex and produce deeper biological effects. The company has observed tumor regressions in preclinical models, compared with tumor stasis reported with inhibitors, she said.
The planned clinical study will evaluate monotherapy activity, safety and early combination treatment with fulvestrant. Scherle said the company ultimately aims to combine its candidate with CDK4/6 inhibitors or CDK4-selective inhibitors and potentially move into frontline treatment. She said dual KAT6A/KAT6B inhibitors may face challenges in such combinations because CDK4/6 inhibitors can also cause neutropenia.
JAK2 V617F Program
Prelude’s JAK2 program targets the JH2 domain and the V617F mutation, which is associated with myeloproliferative neoplasms. Scherle said the company used structure-based design and medicinal chemistry efforts to reach a “deep pocket” containing the V617F mutation.
According to Scherle, the mutation, together with two other residues, helps maintain JAK2 in an active conformation. Prelude’s compounds are designed to reach into that pocket and shift the protein toward an inactive conformation. The company believes its preclinical data demonstrate potency, selectivity and pharmacokinetic properties that could enable targeting of mutant JAK2 while sparing wild-type JAK2.
Scherle contrasted Prelude’s approach with Incyte’s prior efforts, saying Incyte had reported difficulties achieving the pharmacokinetic profile needed for its program despite testing different formulations. She said Prelude believes it has achieved the required potency and selectivity in preclinical testing.
Addressing comparisons with other JAK2 programs, Scherle said cross-study selectivity figures can be difficult to interpret because companies use different assays and cell lines. Prelude assesses selectivity across panels of mutant and wild-type cells, she said, rather than relying on a single pair of cell lines. She added that a flatter pharmacokinetic profile could reduce the degree of selectivity needed relative to a treatment with higher exposure peaks.
About Prelude Therapeutics (NASDAQ:PRLD)
Prelude Therapeutics Inc is a clinical-stage biopharmaceutical company focused on developing precision medicines for cancer. The company uses cancer biology, medicinal chemistry and targeted drug-discovery approaches to identify small-molecule therapies designed to address genetic and molecular vulnerabilities in tumors.
Prelude’s investigational pipeline has included PRT3789, a selective SMARCA2 protein degrader being developed for cancers with SMARCA4 loss, and PRT2527, a selective cyclin-dependent kinase 9 (CDK9) inhibitor under evaluation for oncology applications.
