Prelude Therapeutics (NASDAQ: PRLD) details 2025 loss and cash runway to 2027
Rhea-AI Filing Summary
Prelude Therapeutics reported 2025 results showing reduced spending and a smaller loss while advancing its oncology pipeline. Revenue was
Net loss narrowed to
On the pipeline side, the FDA cleared the IND for lead JAK2V617F inhibitor PRT12396, with a Phase 1 trial in high-risk polycythemia vera and myelofibrosis anticipated to start in the second quarter of
Positive
- None.
Negative
- None.
Insights
Prelude cut its 2025 cash burn, extended runway to 2027, and advanced two key oncology programs toward the clinic.
Prelude Therapeutics combined tighter operating spend with incremental collaboration revenue in 2025. Revenue rose to
These changes narrowed net loss to
Strategically, FDA IND clearance for JAK2V617F inhibitor PRT12396 and planned 2026 IND and Phase 1 start for KAT6A degrader PRT13722 move both lead programs toward clinical proof of concept. The exclusive option agreement with Incyte on the JAK2V617F program and the expanded degrader payload collaboration with AbCellera underscore a partnering-led model. Future disclosures around the 2026 Phase 1 readouts and progress on degrader antibody conjugates and mCALR-targeted DACs will frame how effectively this pipeline translates into later-stage assets.
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
Securities registered pursuant to Section 12(b) of the Act:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 2.02 Results of Operations and Financial Condition.
On March 10, 2026, Prelude Therapeutics Incorporated (the "Company") issued a press release announcing its financial results for the year ended December 31, 2025. A copy of the press release is attached as Exhibit 99.1 to this Current Report on Form 8-K.
Item 7.01 Regulation FD Disclosure.
The Company has prepared investor presentation materials with information about the Company, which it intends to use as part of investor presentations. A copy of the investor presentation materials to be used by management for presentations is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
The information in this Current Report on Form 8-K and in Exhibits 99.1 and 99.2 attached hereto is being furnished, but shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (“Exchange Act”), and is not incorporated by reference into any filing of the Company under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, regardless of any general incorporation language in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
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Exhibit |
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Description |
99.1 |
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Press Release dated March 10, 2026 |
99.2 |
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Presentation |
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Cover Page Interactive Data File (embedded within the Inline XBRL Document) |
SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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PRELUDE THERAPEUTICS INCORPORATED
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Date: March 10, 2026 |
By: |
/s/ Bryant Lim |
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Bryant Lim |
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Chief Financial Officer and Chief Legal Officer |
Exhibit 99.1
Prelude Therapeutics Reports Full Year 2025 Financial Results and Provides Program Outlook for 2026
Received FDA clearance of Investigational New Drug application (IND) for PRT12396, mutant-selective JAK2V617F inhibitor in the first quarter of 2026
Phase 1 study of PRT12396 in patients with polycythemia vera and myelofibrosis anticipated to initiate by Q2 2026
Preclinical development and IND enabling studies for PRT13722, highly-selective oral KAT6A degrader underway, and the Company intends to file the IND for PRT13722 in mid-2026 with Phase 1 study initiation anticipated in the 2nd half of 2026
Current cash runway expected into second quarter of 2027 with $106 million in cash, cash equivalents, restricted cash and marketable securities as of December 31, 2025
WILMINGTON, Del., Mar. 10, 2026 (GLOBE NEWSWIRE) – Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today reported its financial results for the full year ended December 31, 2025 and provided an update on its R&D pipeline and other corporate developments.
“Since the announcement of our strategic shift in November of 2025, our team continues to operate with a clear focus on steady execution on our JAK2V617F inhibitor and KAT6 degrader programs, most recently evidenced by the timely clearance of the IND for PRT12396.” stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude. “We continue to remain on track to have both PRT12396 and PRT13722 in clinical development this year, which will position the Company for potential key data catalysts from both of these potentially differentiated modalities in 2027.”
Program Updates and Upcoming Milestones
Mutant selective JAK2V617F JH2 inhibitor program
JAK2V617F is the primary driver mutation responsible for disease progression in the majority of patients living with myeloproliferative neoplasms (MPNs). The mutation impacts approximately 95% of patients with polycythemia vera (PV), 60% of patients with essential thrombocythemia (ET) and 55% of patients with myelofibrosis (MF). Identifying JAK2 JH2 inhibitors that selectively target V617F+ cells has long been the goal for advancing the treatment of MPNs. Prelude has designed and identified novel allosteric inhibitors that bind into the JAK2 JH2 “deep pocket” where the V617F mutation resides. These candidates demonstrate mutant specific
Exhibit 99.1
inhibition in multiple preclinical models of MPNs. Prelude believes this approach may have the potential to reduce mutant allele burden, slow or even reverse disease progression, and transform treatment outcomes for MPN patients.
PRT12396, Prelude’s lead, mutant-selective JAK2V617F inhibitor received IND clearance from the U.S. Food and Drug Administration, as previously announced in February 2026 and anticipates initiating a Phase 1 study in the 2nd quarter of 2026.
The Phase 1 study of PRT12396 is an open-label, multi-center study in patients with high-risk PV and intermediate and high-risk MF.
The JAK2V617F inhibitor program is subject to an exclusive option agreement with Incyte announced in November 2025.
Highly selective KAT6A oral degrader program
KAT6 is an emerging and recently validated target in the treatment of ER+ breast cancer. Prelude discovered and is developing first-in-class, highly potent, highly selective and orally bioavailable KAT6A selective degraders. The Company has selected a development candidate and remains on track to file an IND in mid-2026 with phase 1 study initiation planned in the 2nd half of 2026. Prelude believes that selectively degrading KAT6A has the potential for improved efficacy, tolerability and combinability with other agents relative to non-selective inhibitors of KAT6A/B.
The Company presented initial preclinical data supporting this hypothesis at the AACR Annual Meeting 2025. The presentation can be found at Publications - Prelude Therapeutics.
Degrader payloads for next generation DACs
Prelude is leveraging our expertise in targeted protein degradation to discover and develop novel degrader payloads for use with next generation DACs. We have developed highly potent SMARCA2/4 and CDK9 degrader payloads optimized for efficacy, tolerability and developability when coupled to a wide range of different antibodies.
The Company has amended and expanded the scope of our existing DAC collaboration with AbCellera Biologics. This enables AbCellera to use our degrader payloads on additional undisclosed antibody targets of interest and also enables Prelude to utilize our degrader payloads in licensing arrangements with other potential partners. The Company’s payloads and corresponding payload-linkers are available for licensing to partners to expand the reach of this new technology.
We have recently published preclinical data demonstrating that next generation DACs using Prelude degrader payloads have potential for significantly better in vivo efficacy and tolerability compared to traditional cytotoxic ADCs when tested head-to-head in xenograft models. These data can be found at: Publications – Prelude Therapeutics
Exhibit 99.1
Mutated calreticulin (mCALR) DAC discovery program
Mutant CALR is a neoantigen presented on the cell surface of malignant myeloid cells but not normal cells and is found in approximately 25-35% of patients with MF and essential thrombocythemia (ET). Recently, a mCALR-targeted monoclonal antibody demonstrated robust clinical activity in high-risk ET patients. Prelude is exploring mCALR-targeted DACs using the Company’s proprietary degrader payloads as a differentiated approach for patients with CALR mutations. This early discovery program is wholly owned and controlled by Prelude.
The Company presented the preclinical data from the program at the European Hematology Association 2025 Congress in June and the American Society of Hematology (ASH) 67th Annual Meeting in December 2025. The presentations can be found at Publications – Prelude Therapeutics.
Upcoming Investor Conference
The Company will participate in the Citizens Life Sciences Conference taking place in Miami, FL. On Tuesday, March 10, 2026 at 3:25 PM ET, Kris Vaddi, Ph.D., Chief Executive Officer, Peggy Scherle, Ph.D., Chief Scientific Officer and Bryant Lim, Chief Financial Officer will participate in a fireside chat.
A live webcast of the fireside chat can be accessed here and on the Company’s website under Events and Presentations. The recording will be archived and available on the Company’s website for 90 days.
Full Year 2025 Financial Results
Cash, Cash Equivalents, Restricted cash and Marketable securities:
Cash, cash equivalents, restricted cash and marketable securities as of December 31, 2025 were $106.4 million. The Company anticipates that its existing cash, cash equivalents and marketable securities will fund Prelude’s operations into the second quarter of 2027.
Research and Development (R&D) Expenses:
For the year ended December 31, 2025, R&D expense decreased to $94.3 from $118.0 million for the prior year period. Included in the R&D expense for the year ended December 31, 2025 was $6.9 million of non-cash expense related to stock-based compensation expense, including employee stock options, compared to $12.1 million for year ended December 31, 2024. Along with the decrease in stock-based compensation expense, research and development expenses decreased due to a decrease in expense related to our discontinued clinical trials. Research and development expenses may fluctuate from period to period depending upon the stage of certain projects and the level of preclinical and clinical trial-related activities.
General and Administrative (G&A) Expenses:
For the year ended December 31, 2025, G&A expenses decreased to $22.4 million from $28.7 million for the prior year period. Included in general and administrative expenses for the year ended December 31, 2025, was $5.0 million of non-cash expense related to stock-based compensation expense, including employee stock options, compared to $9.2 million for year ended December 31, 2024. The decrease in general and administrative expenses was primarily
Exhibit 99.1
due to a decrease in stock-based compensation along with a decrease in employee-related expenses.
Net Loss:
For the year ended December 31, 2025, net loss was $99.5 million, or $1.29 per share compared to $127.2 million, or $1.68 per share, for the prior year period. Included in the net loss for the year ended December 31, 2025, was $11.9 million of non-cash expenses related to the impact of expensing share-based payments, including employee stock options due in part to fewer employees, as compared to $21.3 million for the same period in 2024.
About Prelude Therapeutics
Prelude Therapeutics is a leading precision oncology company developing innovative medicines in areas of high unmet need for cancer patients. Our pipeline features highly selective KAT6A degraders and JAK2V617F mutant selective inhibitors -- new approaches to clinically validated targets with transformative potential for patients. We are leveraging our expertise in targeted protein degradation to create and develop next generation degrader antibody conjugates (DACs) with novel payloads. We are on a mission to extend the promise of precision medicine to every cancer patient in need. For more information, visit preludetx.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude’s product candidates, the potential safety, efficacy, benefits and addressable market for Prelude’s product candidates, the expected timeline for clinical trial results for Prelude’s product candidates, and the sufficiency of Prelude’s cash runway into the second quarter of 2026. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The words “believes,” “anticipates,” “estimates,” “plans,” “expects,” “intends,” “may,” “could,” “should,” “potential,” “likely,” “projects,” “continue,” “will,” “schedule,” and “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are predictions based on the Company’s current expectations and projections about future events and various assumptions. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, clinical trial sites and our ability to enroll eligible patients, supply chain and
Exhibit 99.1
manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude's ability to fund development activities and achieve development goals, Prelude's ability to protect intellectual property, and other risks and uncertainties described under the heading "Risk Factors" in Prelude’s Annual Report on Form 10-K for the year ended December 31, 2024, its Quarterly Reports on Form 10-Q and other documents that Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof, except as may be required by law.
Exhibit 99.1
PRELUDE THERAPEUTICS INCORPORATED
STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
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Year ended December 31, |
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(in thousands, except share and per share data) |
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2025 |
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2024 |
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Revenue |
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$ |
12,140 |
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$ |
7,000 |
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Operating expenses: |
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Research and development |
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94,300 |
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117,995 |
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General and administrative |
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22,406 |
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28,719 |
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Total operating expenses |
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$ |
116,706 |
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$ |
146,714 |
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Loss from operations |
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(104,566 |
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(139,714 |
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Other income, net |
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5,068 |
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12,541 |
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Net loss |
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$ |
(99,498 |
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$ |
(127,173 |
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Per share information: |
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Net loss per share of common stock, basic and diluted |
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$ |
(1.29 |
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$ |
(1.68 |
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Weighted average common shares outstanding, basic and diluted |
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76,956,194 |
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75,805,840 |
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Comprehensive loss |
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Net loss |
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$ |
(99,498 |
) |
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$ |
(127,173 |
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Unrealized (loss) on marketable securities, net of tax |
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(27 |
) |
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(188 |
) |
Comprehensive loss |
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$ |
(99,525 |
) |
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$ |
(127,361 |
) |
Exhibit 99.1
PRELUDE THERAPEUTICS INCORPORATED
BALANCE SHEETS
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December 31, |
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(in thousands, except share and per share data) |
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2025 |
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2024 |
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Assets |
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Current assets: |
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Cash and cash equivalents |
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$ |
35,256 |
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$ |
12,474 |
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Marketable securities |
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67,958 |
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121,140 |
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Prepaid expenses and other current assets |
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2,478 |
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2,281 |
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Total current assets |
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105,692 |
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135,895 |
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Restricted cash |
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3,235 |
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4,044 |
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Property and equipment, net |
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5,113 |
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6,767 |
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Right-of-use asset |
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27,165 |
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28,699 |
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Prepaid expenses and other non-current assets |
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110 |
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110 |
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Total assets |
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$ |
141,315 |
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$ |
175,515 |
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Liabilities and stockholders’ equity |
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Current liabilities: |
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Accounts payable |
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$ |
3,983 |
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$ |
7,732 |
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Accrued expenses and other current liabilities |
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12,533 |
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15,209 |
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Deferred revenue |
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33,734 |
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— |
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Operating lease liability |
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2,744 |
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2,492 |
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Finance lease liability |
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— |
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208 |
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Total current liabilities |
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52,994 |
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25,641 |
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Deferred revenue, net of current portion |
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1,798 |
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— |
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Other liabilities |
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2,841 |
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3,090 |
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Operating lease liability |
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15,045 |
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15,325 |
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Total liabilities |
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72,678 |
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44,056 |
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Commitments (note 8) |
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Stockholders’ equity: |
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Voting common stock, $0.0001 par value: 487,149,741 shares authorized; 48,225,493 and 42,298,859 shares issued and outstanding at December 31, 2025 and 2024, respectively |
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5 |
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4 |
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Non-voting common stock, $0.0001 par value: 112,850,259 and 12,850,259 shares authorized at December 31, 2025 and 2024, respectively; 14,728,135 and 12,850,259 shares issued and outstanding at December 31, 2025 and 2024, respectively |
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1 |
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1 |
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Additional paid-in capital |
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751,684 |
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714,982 |
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Accumulated other comprehensive income |
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8 |
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35 |
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Accumulated deficit |
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(683,061 |
) |
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(583,563 |
) |
Total stockholders’ equity |
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68,637 |
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131,459 |
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Total liabilities and stockholders’ equity |
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$ |
141,315 |
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$ |
175,515 |
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Investor Contact:
Robert A. Doody, Jr.
Senior Vice President, Investor Relations
Prelude Therapeutics Incorporated
484.639.7235
rdoody@preludetx.com
Corporate Presentation March 2026 Exhibit 99.2
This presentation contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude’s product candidates and milestones, the potential safety, efficacy, benefits and addressable market for Prelude Therapeutic Incorporated's (the "Company") product candidates. Any statements contained herein or provided orally that are not statements of historical fact may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by such terminology as ‘‘believe,’’ ‘‘may,’’ ‘‘will,’’ ‘‘potentially,’’ ‘‘estimate,’’ ‘‘continue,’’ ‘‘anticipate,’’ “aim,” ‘‘intend,’’ ‘‘could,’’ ‘‘would,’’ ‘‘project,’’ ‘‘plan,’’ ‘‘expect’’ and similar expressions that convey uncertainty of future events or outcomes, although not all forward-looking statements contain these words. Statements, including forward-looking statements, speak only to the date they are provided (unless an earlier date is indicated). This presentation shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of securities of the Company in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction, or pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the Securities Act of 1933, as amended, and any other applicable securities laws. These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2024. Forward Looking Statements & Disclaimers
We are on a mission to extend the promise of precision medicine to every cancer patient in need Select the best modality to precisely target oncogenic mechanisms Strive for first- or best-in-class and anchor to patient unmet need Draw on decades of experience and proven leadership to drive innovation
Kris Vaddi, PhD Chief Executive Officer Andrew Combs, PhD Chief Chemistry Officer Sean Brusky, MBA Chief Business & Strategy Officer Peggy Scherle, PhD Chief Scientific Officer Bryant Lim, J.D. Chief Financial Officer, Chief Legal Officer, Secretary Dr. Victor Sandor, former CMO at Array BioPharma and current member of our Board of Directors, is serving as a senior medical advisor, providing strategic and operational leadership for our clinical development programs Experienced Leadership Team With Proven Track Records
PROGRAM POTENTIAL INDICATIONS DISCOVERY/ LEAD OPT. IND-ENABLING PHASE 1 PROGRAM INTEREST MILESTONES JAK2V617F Mutant Selective JH2 Inhibitors VF+ myeloproliferative neoplasms (MPNs) (MF, PV, ET) Phase 1 initiation anticipated in 2Q 2026 KAT6A Selective Degraders ER+ breast cancer, other malignancies Prelude wholly owned IND filing mid-2026 mCALR DAC CALR-mutated MPNs (ET, MF) Prelude wholly owned Oral abstract presented at ASH 2025 Degrader Payloads for DACs Broad utility across multiple indications . . . Additional Partnerships Prelude’s Pipeline & Discovery Engine JAK2, janus kinase 2; JH2, JAK2 homology domain 2 (pseudokinase regulatory domain); VF+, V617F mutated; MPNs, myeloproliferative neoplasms; MF, myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia; ER+, estrogen receptor positive; DAC, degrader antibody conjugate; mCALR = mutated calreticulin 1 - Exclusive option agreement with Incyte (Nov. 2025) 2 - DAC Discovery Collaboration with AbCellera (Nov. 2023, amended and expanded 2H 2025) Proprietary degrader payloads available for licensing to partners developing next generation DACs 1 2 PRT12396 PRT13722
Our Investment Thesis Centers on Advancing Two Programs – Both Representing Highly Differentiated Approaches to Clinically Validated Targets KAT6A Highly Selective Oral Degraders JAK2V617F Mutant Selective Inhibitors First-in-class KAT6A degraders, with absolute selectivity over KAT6B – a differentiated modality and selectivity profile with potential to become a backbone therapy in the treatment of ER+ breast cancer Potentially transformative JAK2V617F allosteric JH2 inhibitors with potential to reduce mutant allele burden and modify the course of disease progression in patients with myeloproliferative neoplasms (MPNs)
JAK2V617F is the Primary Driver Mutation Leading to Activated JAK-STAT Signaling, Uncontrolled Proliferation, and Disease Progression in MPNs The JAK-STAT pathway mediates growth factor signaling, most notably: Thrombopoietin receptor for platelet production Erythropoietin receptor for red blood cell production The JAK2V617F mutation leads to growth factor-independent hyperactivation of JAK-STAT pathway and uncontrolled myeloid and erythroid proliferation Inhibition of wildtype JAK2 causes anemia and thrombocytopenia and current JAK inhibitors, like ruxolitinib (Jakafi®), while effective, equally inhibit both WT and V617F-mutated (VF+) JAK2 JAK2 JH2 inhibitors that selectively target VF+ progenitor cells have potential to reduce mutant allele burden, modify disease progression, and transform treatment outcomes for MPN patients Jakafi® is a registered trademark of Incyte Corporation Jakafi® Campbell P.J. and Green A.R. N Engl J Med 2006;355:2452-2466
A JAK2V617F Mutant Selective Inhibitor Could Become a Disease Modifying Option for the Majority of MPN Patients and Represents an Expansive Opportunity Essential Thrombocythemia (ET) Polycythemia Vera (PV) JAK2 V617F Mutated ~95% JAK2 V617F Mutated ~60% CALR Mutated MPL mutation Nonmutated Nonmutated ~78,500 ~142,000 Est. # of U.S. Patients with JAK2V617F Mutation ~228,500 Primary Myelofibrosis (PMF) JAK2 V617F Mutated ~55% CALR Mutated MPL mutation Nonmutated ~8,000 Sources: NCI SEER Database (accessed Dec 2024), Leukemia & Lymphoma Society Facts & Figures; F. Passamonte et.al., “Clinical Significance of JAK2 V617F Mutant Allele Burden”; Haematologica 2009 Jan;94(1):7–10
Prelude Scientists Recently Discovered the First Known JAK2 Inhibitors That Bind in the JAK2 JH2 “Deep Pocket” Where the V617F Mutation Resides Prelude JAK2 JH2 Inhibitors Bind into the “Deep Pocket” Adjacent to V617F Mutation Allosteric JH2 Regulatory Domain vs Catalytic Domain
Global sales of ruxolitinib (Jakafi® /Jakavi®) alone grew to over $4.5B in 20241,2 Continuing strong sales growth for ruxolitinib in PV First generation JAK inhibitors have delivered transformative efficacy for MF patients Highly effective at reducing symptoms and spleen size However, toxicities from wild-type activity limit ability to reach maximal efficacy Ruxolitinib is the only JAK inhibitor approved in PV (2L only) and none are approved in ET Prelude’s JAK2V617F mutant selective inhibitors demonstrate: Potent and selective reduction in JAK2V617F cells in vitro compared to WT cells Improved efficacy, reduced toxicity, and rapid reduction of mutant alleles in vivo Potential for transformative efficacy and disease modification in PV, ET and MF JAK2V617F Mutant Selective Inhibitors Are Highly Differentiated From 1st Generation JAK Inhibitors in a Large and Growing Market 1 - Incyte Pharmaceuticals (Q4 2024 Financial Results and Corporate Update Presentation, February 10, 2025); Jakafi is a registered trademark of Incyte 2 - Novartis Pharmaceuticals (Full Year 2024 Product Sales, Accessed August 2025; Jakavi is a registered trademark of Novartis First Public Disclosure of Preclinical Data on Prelude’s JAK2V617F Program Presented at ASH 2025
JAK2V617F Program1: Phase 1 Study Design (Illustrative) MF 2026 2027 2028 2029 Phase 1 Expansion Cohorts Phase 1 (MF & hrPV) First Look at Spleen/Symptoms/CHR Mutant Allele Burden Phase 1a Dose Escalation Expansion Cohorts DL(n) (N=3-6) DL1 (N=3-6) DL2 (N=3-6) Expansion in hrPV & MF at Dose OBJECTIVE CHR rate, durability (24 week) and molecular response rate (allele burden reduction) Spleen and symptom benefit Data generation in preparation for first registrational trial(s) 1 - Subject to exclusive option agreement with Incyte (announced November 2025) MPNs, myeloproliferative neoplasms; MF, myelofibrosis; hrPV, high risk polycythemia vera; CHR, complete hematologic response; DL, dose level hrPV DL(n) (N=3-6) DL1 (N=3-6) DL2 (N=3-6)
Exclusive option agreement with Incyte (announced November 2025) Option Agreement With Incyte Provides Significant Capital to Further Advance Our JAK2V617F and KAT6A Programs
Our Investment Thesis Centers on Advancing Two Programs – Both Representing Highly Differentiated Approaches to Clinically Validated Targets KAT6A Highly Selective Oral Degraders JAK2V617F Mutant Selective Inhibitors First-in-class KAT6A degraders, with absolute selectivity over KAT6B – a differentiated modality and selectivity profile with potential to become a backbone therapy in the treatment of ER+ breast cancer Potentially transformative JAK2V617F allosteric JH2 inhibitors with potential to reduce mutant allele burden and modify the course of disease progression in patients with myeloproliferative neoplasms (MPNs)
KAT6 is an emerging, clinically-validated target in ER+ breast cancer A KAT6A/B dual inhibitor (PF-07248144, prifetrestat) has initiated a pivotal phase 2/3 trial in combination with fulvestrant, after progression on a CDK4/6 inhibitor1 Limited monotherapy activity, but compelling efficacy in combo with fulvestrant in post-CDK4/6 inhibitor setting in a broad (unselected) population of ER+ BC1 Clinically relevant safety observations including grade 3/4 neutropenia and dysgeusia are challenging and may limit dosing to maximal benefit in combination with SoC treatments (e.g., CDK4/6 inhibitors)1 Prelude’s KAT6A selective degrader program aims to differentiate based on: Efficacy as monotherapy or in combination Potential for lower risk of hematological toxicity and neutropenia Improved combinability and synergy with other agents (e.g., oral SERDs, AIs, CDK4/6s, PI3Kas) Prelude’s lead (PRT13722) is in IND-enabling studies and on track for IND filing in mid-2026 1 - P LoRusso, et al., Dose optimization of PF-07248144, a first-in-class KAT6 inhibitor, in patients (pts) with ER+/HER2− metastatic breast cancer (mBC): Results from phase 1 study to support the recommended phase 3 dose (RP3D) ASCO 2025 Annual Meeting, J Clin Oncol 43, 1020 (2025) Prelude’s Oral KAT6A Selective Degrader Program
KAT6 Landscape is Evolving, But Most Others Are Pursuing Inhibitor Approaches Pfizer Clinical Candidate PF-07248144 (prifetrastat) Clinical PoC in combination with fulvestrant for ER+ BC Advancing to Ph2/3 registrational trial Olema, Menarini and BeOne Starting Ph1 with chemotypes very similar to Pfizer All are KAT6A/B dual inhibitors Ideaya, Pfizer KAT6A/B and KAT7 cross-selective inhibitors KAT7 inhibition may play a role beyond ER+ BC Others Multiple research-stage programs globally Prelude is the first KAT6A selective degrader* poised to enter the clinic in 2026 Company Asset Program Status KAT(X) Inhibitor Pfizer PF-07248144 (prifetrastat) Ph2/3 KAT6A/B Inhibitor Olema, Aurigene OP-3136 Ph1 KAT6A/B Inhibitor Menarini, Insilico MEN2312 Ph1 KAT6A/B Inhibitor BeOne BG-75202 Ph1 KAT6A/B Inhibitor Pfizer PF-08032562 Ph1 KAT6A/B/7 Inhibitor Ideaya IDE251 IND KAT6A/B/7 Inhibitor Others Multiple Research / Preclinical KAT6A/B Inhibitors * Based on recent patent and literature search (as of March 1, 2026) Prelude PRT13722 IND-enabling KAT6A Degrader
Early-stage ER+ BC (adjuvant, neo-adjuvant) Selective KAT6A Degradation Represents a Differentiated Approach Versus KAT6A/B/(7) Inhibition With Significantly Broader Commercial Potential KAT6A/B/(7) Inhibitors Pfizer, BeOne, Olema, Ideaya, Menarini, Others 1L ER+/HER2- mBC 2L/3L+ r/r ER+/HER2- mBC Current SoC1 Limited monotherapy efficacy reported to date with KAT6A/B inhibitors KAT6B-mediated neutropenia may limit combinability with SoC agents used in the frontline setting (e.g., CDK4/6s, PI3Kas, etc.) KAT6A Selective Degrader First-in-class opportunity: Only KAT6 degrader approaching clinical development Potential for best-in-class monotherapy and combination efficacy KAT6A selectivity may contribute to lower neutropenia and improve combinability Fulvestrant + CDK4/6i Targeted therapies Chemotherapy Aromatase Inhibitors + CDK4/6 inhibitors Future: Oral SERDs, next gen CDK2/4/6s, targeted therapies, ADCs, others Endocrine therapy / AIs Future: Oral SERDs, others $42B total market by 2033 2 1 - NCCN Treatment Guidelines for Invasive Metastatic and Early Stage Breast Cancer (v5.2025) 2 - Vision Research Reports; "Estrogen Receptor Positive Breast Cancer Treatment Market Forecast 2024-2033. ER+ BC Treatment Market Size | Companies
PRT13722: Our Lead KAT6A Selective Degrader Development Candidate Prelude Data on File PRT13722: Highly Potent KAT6A Degrader in Preclinical Models Absolute kinetic selectivity for KAT6A over KAT6B (>1000-fold) Global proteomics demonstrates highly selective KAT6A degradation Excellent oral PK across species Compelling in vivo efficacy as monotherapy in multiple models Reduced effect on neutrophils in preclinical models Non-GLP DRF studies complete IND-enabling studies underway Absolute Degradation Selectivity (KAT6A vs KAT6B) ZR-75 Breast Cancer CDX Model Compelling In Vivo Efficacy (Complete Regressions) PRT13722 PRT13722 PRT13722
PRT13722 demonstrates dose-dependent efficacy, driving tumor regressions at low oral doses in preclinical models Well-tolerated with no observed body weight loss in preclinical models PRT13722 Monotherapy Drives Tumor Regressions in the Challenging T47-D Breast Cancer Model with Improved Efficacy Over Prifetrestat + Fulvestrant Combination Significant TGI as Monotherapy vs. prifetrestat + fulvestrant Tumor Regressions Observed at Low Doses TGI, tumor growth inhibition; PO, orally administered; QD, once daily; BID, twice daily; CRD, clinically relevant dose; Veh, vehicle Prelude Data on File Vehicle PRT13722, 0.3 mg/kg, PO QD PRT13722, 0.3 mg/kg, PO BID PRT13722, 3.0 mg/kg, PO QD PRT13722 Monotherapy prifetrestat + fulvestrant
KAT6A Selective Degraders Show Potential for Lower Bone Marrow Toxicity in Preclinical Models Compared to KAT6A/B Dual Inhibitors Neutrophils Day 5 Dose Response of CFU-GM Low Dose High Dose High Dose Low Dose KAT6A degrader KAT6A degrader Ex vivo and in vivo studies with early KAT6A selective degrader tool compounds showed limited effects on neutrophils in contrast to dual KAT6A/B inhibitors or degraders; in non-GLP toxicology studies, PRT13722 was well tolerated with no dose dependent impact on neutrophils observed 1 1 - Impact on neutrophils and other hematologic safety parameters to be further assessed as part of on-going 28 day toxicology studies with PRT13722 Prelude Data on File
Prelude is advancing a first-in-class, highly selective KAT6A degrader (PRT13722) with broad potential to become a new backbone therapy in the treatment of ER+ breast cancer PRT13722 has potential to achieve best-in-class efficacy relative to dual KAT6A/B inhibitors PRT13722 has completed dosing in non-GLP toxicology studies and was well tolerated, supporting potential to differentiate further based on overall safety and broad combinability with other agents On track for IND filing in mid-2026 with phase 1 start expected in 2H 2026 KAT6A Selective Degrader Program Summary
Degrader Antibody Conjugates (DACs) Represent the Next Generation of ADCs For a review of ADCs, see Fu, Z., Li, S., Han, S. et al. Sig Transduct Target Ther 7, 93 (2022). Precision DACs enable improved selectivity in two ways Antibodies target tumor-specific cell surface antigens sparing healthy cells, and Targeted Protein Degraders address critical proteins in validated biological pathways Potential to deliver both improved efficacy and improved tolerability Property Traditional ADC Precision DAC Potency Antibody Selectivity Payload Selectivity PD Marker - Payload Non-Genotoxic X X X Targeted Protein Degrader (TPD) Payload Model of Precision DAC (DAR 4 example)
Prelude’s Degrader Payloads: Engineered to Improve Efficacy, Tolerability and Developability Compared to Traditional Cytotoxic Payloads Payload Rationale DAC Properties Prelude Degrader Payload-Linkers Efficacy Tolerability Developability Exceptional Potency (pM) Allows low DAR; Catalytic effect SMARCA2/4 Dual Degraders (VHL- and CRBN- based) CDK9 Degraders Permeable Enable localized bystander effect Non-Permeable Limit off-target toxicity from payload diffusion Highly stable E3 Ligase binder Long t1/2 in vivo; Stable drug substance Prodrug Lower risk of cleavage in plasma High Clearance Rapid clearance in plasma Non-Genotoxic Indications beyond cancer Prelude’s Degrader Payloads Have the Potential to Deliver Novel DACs with Improved Efficacy and Therapeutic Index or
Mutated Calreticulin (mCALR) Represents a Promising Target for Next Generation DACs Mutant CALR is a neoantigen presented on the cell surface of malignant cells but not normal cells and is found in 25-35% of patients with Myelofibrosis (MF) and ET SMARCA2/4 and CDK9 degraders are both highly active in CALR mutated MPN cell lines and can be used as payloads for mCALR-targeted DACs mCALR-targeted DACs, delivering Prelude’s degrader payloads to disease-initiating clones have the potential to be first-in-class, disease modifying therapies Primary Myelofibrosis (PMF) Essential Thrombocythemia (ET) Polycythemia Vera (PV) JAK2 V617F Mutated ~95% MPL mutation MPL mutation Nonmutated Nonmutated mCALR is emerging as a clinically validated target in MPNs with disease modifying potential Nonmutated ~5,000 ~32,500 N/A Est. # of US Pts. with CALR Mutation Sources: NCI SEER Database (accessed Dec 2024), Leukemia & Lymphoma Society Facts & Figures; J.How et. al., Mutant calreticulin in myeloproliferative neoplasms, Blood (2019) 134 (25): 2242–2248 JAK2 V617F Mutated ~95% JAK2 V617F Mutated ~60% JAK2 V617F Mutated ~55% CALR Mutated ~35% CALR Mutated ~25%
CALR x SMARCA2/4 DACs Demonstrate Robust and Selective Tumor Growth Inhibition and Improved Potency vs. Antibody Alone in CALR Mutant Cells >68x Selective Cytotoxicity in vitro SMARCA2/4 Degrader Robust Tumor Growth Inhibition in vivo Fultang N., et al., EHA2025 Oral Abstract, 12 June 25; Discovery Of First-in-class Precision ADCs Targeting Mutant Calreticulin For The Treatment Of MPNs. (Link) 1 - Abstract now available: ASH Annual Meeting & Exposition - Hematology.org CALR x SMARCA2/4 DAC CALR x SMARCA2/4 DAC 100x Better Potency DAC Naked Ab
Executive Summary Lead JAK2V617F mutant selective inhibitor (PRT12396) IND accepted and on track for Phase 1 study initiation in 2Q 20261 First-in-class KAT6A selective degrader (PRT13722) on track to enter the clinic in 2026 with clear path to differentiation in ER+ breast cancer market Novel approaches to clinically-validated targets (e.g., mCALR) poised to deliver differentiated pipeline candidates beyond JAK2 and KAT6 Current cash runway expected into second quarter of 2027 with $106 million in cash, cash equivalents, restricted cash and marketable securities as of December 31, 2025 1 - Subject of exclusive option agreement with Incyte (announced November 2025)
Thank You Contact Us: Robert Doody SVP, Investor Relations rdoody@preludetx.com
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