Prelude Therapeutics (PRLD) investor relations material

Portfolio focus and milestones

• Pivoted to three clinically validated targets: JAK2 JH2, a KAT6A degrader, and mCALR.

• JAK2 entered the clinic in Q2 2026; KAT6 IND cleared, with enrollment expected soon; mCALR remains in development for the MPN community.

• In the first half of the upcoming period, clarity is expected on whether Incyte exercises its option; exercise would provide $100M in non-dilutive financing.

• Initial KAT6 degrader proof-of-concept data are anticipated in H2 2027.

KAT6 biology and differentiation

• KAT6A amplification in ER+ breast cancer drives estrogen signaling, MYC regulation, and cell-cycle genes; Pfizer reported ~10% monotherapy responses and mid-30% responses with fulvestrant, with PFS of 10–11 months.

• The approach selectively degrades KAT6A while sparing KAT6B; preclinical data show greater than 1,000-fold selectivity, intended to preserve bone marrow function and improve therapeutic index.

• Preclinical models showed less neutrophil impact with selective KAT6A degradation; the goal is to reduce neutropenia and enable combinations with CDK4/6 inhibitors, potentially supporting frontline use.

• Degradation dismantles the KAT6 complex; preclinical models showed tumor regressions, while inhibitors generally produced tumor stasis, according to the CSO.

• Planned clinical study will assess monotherapy activity and safety, followed by an early combination with fulvestrant; preclinical combinations with CDK4/6, SERD, and PI3Kα agents were encouraging.

JAK2 V617F approach

• Structure-based design targets the deep JH2 pocket containing V617F, aiming to shift JAK2 into an inactive conformation while sparing wild-type JAK2.

• Preclinical compounds showed potency, selectivity, and pharmacokinetic properties intended to target the mutant while preserving a therapeutic window.

• Reported ~10-fold selectivity was derived across panels of mutant and wild-type cell lines; a flat pharmacokinetic profile is expected to support selectivity, per the CSO.