On November 6, 2024 Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, reported its financial results for the third quarter ended September 30, 2024 and provided an update on its clinical development pipeline and other corporate developments (Press release, Prelude Therapeutics, NOV 6, 2024, View Source [SID1234647825]).

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"Our third quarter was marked by dedicated execution and the achievement of essential milestones for our lead clinical programs targeting SMARCA2," stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude. "We have demonstrated the first-ever clinical proof of concept with our first-in-class, highly selective IV SMARCA2 degrader, PRT3789, in patients with aggressive SMARCA4 mutated cancers including non-small cell lung cancer (NSCLC) and esophageal cancers as monotherapy. We also demonstrated an encouraging early safety profile with no overlapping toxicities in our ongoing PRT3789 combination study with docetaxel. We are focused on completing monotherapy dose escalation and rapidly enrolling combination arms to support advancement of PRT3789 into next phase of development, initially in these two cancer types."

Dr. Vaddi continued, "Additional accomplishments for the quarter include the commencement of patient enrollment for our first-in-class, highly selective oral SMARCA2 degrader, PRT7732 in a biomarker selected phase 1 trial. With two highly differentiated SMARCA2 degraders in the clinic, we are well-positioned to build on our leadership in this novel and important therapeutic class and provide optionality for patients. We look forward to reporting our progress on both of these programs beginning early 2025."

Dr. Vaddi also added, "Other milestones for the quarter included presentation of first preclinical data from our Precision ADC program demonstrating the potential of SMARCA2/4 degrader as a potent and effective payload on multiple antibodies, as well as acceptance of interim clinical data in hematological malignancies of our potential best-in-class CDK9 inhibitor, PRT2527 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting in December."

Clinical Program Updates and Upcoming Milestones

PRT3789 – A first-in-class, highly selective, intravenous SMARCA2 Degrader

PRT3789 is designed to treat patients with a SMARCA4 mutation. Patients with SMARCA4-mutated cancer have a poor prognosis. This represents an area of high unmet medical need.

PRT3789 is in Phase 1 clinical development in patients with biomarker selected SMARCA4-mutated cancers. Enrollment remains on track, and the Company expects to conclude monotherapy dose escalation by year-end 2024 and identify a dose for advancement to registrational trials. In addition, enrollment of patients into back-fill cohorts enriched for NSCLC and SMARCA4 loss-of-function mutations is ongoing, as is enrollment of the combination with docetaxel cohort. The Company also initiated a Phase 2 clinical trial evaluating PRT3789 in combination with KEYTRUDA (pembrolizumab) in patients with SMARCA4-mutated cancers, per the previously announced collaboration with Merck (known as MSD outside of the US and Canada).

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Interim Phase 1 data presented at medical congresses in Q3 2024

The Company presented the first interim clinical data updates of the Phase 1 dose escalation study of PRT3789 in SMARCA4 mutated cancers at ESMO (Free ESMO Whitepaper) Congress 2024 and the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium. The presentations can be found at Publications – Prelude Therapeutics

As reported by investigators, PRT3789 was generally safe and well-tolerated at doses tested to date. Of the 26 advanced NSCLC or esophageal patients with Class 1 (loss of function) mutations who were evaluable for efficacy, RECIST confirmed partial responses (PRs) were observed in 4 patients (2 esophageal, 2 NSCLC). Of the 9 patients with Class 1 mutations treated at doses of 283 mg or higher, two had RECIST confirmed partial responses and both were NSCLC patients. Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations. Additional patients on-study demonstrated clinical benefit as measured by prolonged SD, including one advanced NSCLC patient who remains stable and on study having been treated for more than a year.

Initial observations of safety from evaluable patients in the PRT3789 plus docetaxel combination dose escalation arm of the trial were also presented. To date, PRT3789 in combination with docetaxel demonstrated an acceptable safety profile, with no dose limiting toxicities or study drug serious adverse events reported.

PRT7732 – A potent, highly selective and orally bioavailable SMARCA2 Degrader

PRT7732 is a highly selective and orally bioavailable SMARCA2 degrader. The Company initiated and enrolled our first patients in a phase 1 multi-dose escalation trial of PRT7732 (NCT06560645) in biomarker selected SMARCA4 mutated cancers.

Pfizer Ignite Collaboration

Prelude has entered into a collaboration agreement with Pfizer Ignite enabling streamlined access to Ignite services in support of Prelude’s SMARCA2 degrader development programs. Per Pfizer, Ignite is a service offering providing partners access to Pfizer’s significant resources, scale and expertise in developing potentially breakthrough medicines. Under the terms of the collaboration agreement, Prelude retains full ownership and global license rights to all of its programs.

Precision ADC with SMARCA2/4 dual degrader payload

Prelude is developing potent SMARCA2/4 dual degraders that robustly inhibit cancer cell growth and induce cell death across multiple cancer types. The Company presented the first preclinical data from its Precision ADC platform at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium in October. The data demonstrated potent activity of a SMARCA 2/4 degrader payload when conjugated to a range of commercially available antibodies, including PSMA, TROP2, C-MET, CEACAM5, and CD33. The SMARCA2/4 degrader payload conjugated to an anti-PSMA antibody demonstrated tumor regressions and significantly better in vivo efficacy compared to a traditional PSMA-targeted cytotoxic ADC in xenograft models of prostate cancer at well tolerated doses. The presentation can be found at Publications – Prelude Therapeutics.

PRT2527 – A potent and highly selective CDK9 Inhibitor

PRT2527 is a potent and highly selective CDK9 inhibitor that has the potential to avoid off-target toxicities observed with other less selective CDK9 inhibitors. The Company is currently advancing PRT2527 as monotherapy in both lymphoid and myeloid hematological malignancies, and in combination with zanubrutinib in B-cell malignancies.

PRT2527 is expected to complete monotherapy dose escalation in B-cell malignancies this year. Initiation of dose escalation in myeloid malignancies occurred in the first half of 2024. Interim phase 1 clinical data with potentially best-in-class CDK9 inhibitor, PRT2527 in hematological malignancies will be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2024.

Third Quarter 2024 Financial Results 

Cash, Cash Equivalents, and Marketable securities:

Cash, cash equivalents and marketable securities as of September 30, 2024 were $153.6 million. The Company anticipates that its existing cash, cash equivalents and marketable securities will fund Prelude’s operations into 2026. 

Research and Development (R&D) Expenses:

For the third quarter of 2024, R&D expense increased to $29.5 million from $26.3 million for the prior year period. Included in the R&D expense for the three months ended September 30, 2024 was $3.4 million of non-cash expense related to stock-based compensation expense, including employee stock options, compared to $3.3 million for three months ended September 30, 2023. Research and development expenses increased primarily due to an increase in our chemistry, manufacturing, and controls (CMC) costs supporting our pre-clinical and clinical programs. We expect our R&D expenses to vary from quarter to quarter, primarily due to the timing of our clinical development activities.

General and Administrative (G&A) Expenses:

For the third quarter of 2024, G&A expenses increased to $7.9 million from $7.1 million for the prior year period. Included in general and administrative expenses for the three months ended September 30, 2024, was $2.5 million of non-cash expense related to stock-based compensation expense, including employee stock options, compared to $3.4 million for three months ended September 30, 2023. General and administrative expenses increased primarily due to an increase in professional fees incurred to support our research and development efforts.

Net Loss:

For the three months ended September 30, 2024, net loss was $32.3 million, or $0.43 per share compared to $30.6 million, or $0.45 per share, for the prior year period. Included in the net loss for the quarter ended September 30, 2024, was $5.9 million of non-cash expenses related to the impact of expensing share-based payments, including employee stock options, as compared to $6.7 million for the same period in 2023.