# EDGAR Filing Document

**Accession Number:** 0001678660
**File Stem:** 0001193125-26-162620
**Filing Date:** 2026-4
**Character Count:** 40088
**Document Hash:** 98ab48c98e76bd58089746dd543aa95b
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001193125-26-162620.hdr.sgml**: 20260420

**ACCESSION NUMBER**: 0001193125-26-162620

**CONFORMED SUBMISSION TYPE**: 8-K

**PUBLIC DOCUMENT COUNT**: 41

**CONFORMED PERIOD OF REPORT**: 20260420

**ITEM INFORMATION**: Regulation FD Disclosure

**ITEM INFORMATION**: Other Events

**ITEM INFORMATION**: Financial Statements and Exhibits

**FILED AS OF DATE**: 20260420

**DATE AS OF CHANGE**: 20260420

**FILER**: 

**COMPANY DATA:**
- **COMPANY CONFORMED NAME:** Prelude Therapeutics Inc
- **CENTRAL INDEX KEY:** 0001678660
- **STANDARD INDUSTRIAL CLASSIFICATION:** PHARMACEUTICAL PREPARATIONS [2834]
- **ORGANIZATION NAME:** 03 Life Sciences
- **EIN:** 811384762
- **STATE OF INCORPORATION:** DE
- **FISCAL YEAR END:** 1231

**FILING VALUES:**
- **FORM TYPE:** 8-K
- **SEC ACT:** 1934 Act
- **SEC FILE NUMBER:** 001-39527
- **FILM NUMBER:** 26873290

**BUSINESS ADDRESS:**
- **STREET 1:** 175 INNOVATION BOULEVARD
- **CITY:** WILMINGTON
- **STATE:** DE
- **ZIP:** 19805
- **BUSINESS PHONE:** (302) 467-1280

**MAIL ADDRESS:**
- **STREET 1:** 175 INNOVATION BOULEVARD
- **CITY:** WILMINGTON
- **STATE:** DE
- **ZIP:** 19805

**FORMER COMPANY:**
- **FORMER CONFORMED NAME:** Prelude Therapeutics Inc.
- **DATE OF NAME CHANGE:** 20160630

?xml version='1.0' encoding='ASCII'? 8-K

### UNITED STATES

### SECURITIES AND EXCHANGE COMMISSION

#### Washington, D.C. 20549

### FORM 8-K

#### CURRENT REPORT

#### Pursuant to Section 13 or 15(d)

#### of the Securities Exchange Act of 1934

#### Date of Report (Date of earliest event reported): April 20, 2026

## Prelude Therapeutics Incorporated

#### (Exact Name of Registrant as Specified in its Charter)

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| | | |
|:---|:---|:---|
| **Delaware** | **001-39527** | **81-1384762** |
| **(State or other jurisdiction of**<br> **incorporation or organization)** | **(Commission**<br> **File Number)** | **(I.R.S. Employer**<br> **Identification No.)** |

---

---

| | |
|:---|:---|
| **175 Innovation Boulevard**<br> **Wilmington, Delaware** | **19805** |
| **(Address of principal executive offices)** | **(Zip Code)** |

---

#### Registrant's telephone number, including area code: (302) 467-1280

#### Not Applicable

#### (Former Name or Former Address, if Changed Since Last Report)
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:

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

---

| | | |
|:---|:---|:---|
| **Title of each class** | **Trading<br>Symbol(s)** | **Name of each exchange**<br> **on which registered** |
| Common Stock, $0.0001 par value per share | PRLD | Nasdaq Global Select Market |

---

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. ☐

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| | |
|:---|:---|
| **Item 7.01** | **Regulation FD Disclosure.**  |

---

On April 20, 2026, Prelude Therapeutics Incorporated (the "Company") issued a press release announcing the presentation of new preclinical data from its lead development candidate, PRT13722. A copy of the press release is attached as Exhibit 99.1 to this Current Report on Form 8-K.

The Company has prepared investor presentation materials 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 8.01** | **Other Events.**  |

---

The Company will present preclinical data from its lead development candidate, PRT 13722, at the AACR Annual Meeting 2026 on April 20, 2026. Based on preclinical data, we believe PRT 13722 is a highly differentiated, first-in-class, orally bioavailable, potent and highly selective KAT6A degrader.

We observed the following in the preclinical data:

• PRT13722, by degrading KAT6A, drives more complete disruption of KAT6A regulatory pathways than dual KAT6A/B inhibitors, resulting in more robust depth and breadth of preclinical efficacy in hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2-) breast cancer (BC).

• PRT13722 drives durable complete tumor regressions in HR+/HER2- xenograft models (both endocrine therapy (ET) sensitive and experienced) at well-tolerated doses, as a monotherapy.

• PRT13722 is synergistic with ET, CDK4/6 inhibitors, and PI3Kα inhibitors, while maintaining monotherapy and combination activity across HR+ BC models, including estrogen receptor 1 mutated and acquired therapy-resistant cancer cells.

• PRT13722 has an improved preclinical hematological safety profile compared to prifetrastat, which may enable combinations with standard of care agents in HR+ BC.

PRT13722 is on track for an investigational new drug (IND) filing in mid-2026, and, pending IND clearance, initiation of a Phase 1 study is anticipated in the second half of 2026.

---

| | |
|:---|:---|
| **Item 9.01** | **Financial Statements and Exhibits.**  |

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(d) Exhibits

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| | |
|:---|:---|
| **Exhibit**<br> **Number** | **Description** |
| 99.1 | [Press Release dated April 20, 2026](d135229dex991.htm) |
| 99.2 | [Investor Presentation](d135229dex992.htm) |
| 104 | Cover Page Interactive Date File (embedded within the Inline XBRL Document) |

---

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#### 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.

---

| | | |
|:---|:---|:---|
|  | **PRELUDE THERAPEUTICS INCORPORATED** | **PRELUDE THERAPEUTICS INCORPORATED** |
| Date: April 20, 2026 | By: | /s/ BRYANT LIM |
|  |  | Bryant Lim |
|  |  | Chief Financial Officer and Chief Legal Officer |

---

## Exhibit 99.1

**Exhibit 99.1**![LOGO](g135229g0420064457589.jpg)

**Prelude Therapeutics Presents Preclinical Data from Development Candidate, PRT13722, a First-in-Class, Orally Bioavailable, Potent and Highly Selective KAT6A Degrader at American Association for Cancer Research (AACR) Annual Meeting 2026** 

*Data Demonstrate Potential for Differentiated Efficacy and Safety Profile, Including Complete Responses as Monotherapy in Multiple CDX and PDX Models of HR+/HER2- Breast Cancer* 

*Prelude Remains on Track to File Investigational New Drug (IND) Application by mid-2026 and to initiate clinical trial in 2H 2026* 

WILMINGTON, Del., Apr. 20, 2026 (GLOBE NEWSWIRE) – Prelude Therapeutics Incorporated (Nasdaq: PRLD), a precision oncology company, today announced the presentation of new preclinical data from its lead development candidate, PRT13722. PRT13722 is being developed for the treatment of hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2-) breast cancer (BC). Based on preclinical data, we believe PRT13722 is a highly differentiated, first-in-class, orally bioavailable, potent and highly-selective KAT6A degrader.

"These preclinical data further strengthen our hypothesis that developing a highly selective degrader specifically targeting KAT6A has the potential for further improvements of efficacy and importantly an improved hematological safety profile. We believe the efficacy and safety profile of PRT13722 will, in turn, enable meaningful combination approaches to existing standards of care," stated Peggy Scherle, Ph.D., Chief Scientific Officer of Prelude. "We remain on track to file an Investigational New Drug (IND) application for PRT13722 in the middle of this year and, pending clearance, enter the clinic in the second half of 2026."

"There remains a significant unmet need for new treatment options to further improve the standard of care in breast cancer," stated Edith A. Perez, M.D., Professor Emeritus at Mayo Clinic and strategic clinical advisor to Prelude. "New agents that show potential for relevant clinical efficacy and improved tolerability could enable alternative treatment strategies and novel combinations across multiple lines of therapy. It is important to follow the science as these promising new agents prepare to enter the clinic, including PRT13722."

**Details on the poster presentation are as follows:** 

**Title: First-in-Class potent and selective oral KAT6A degrader development candidate, PRT13722, drives complete tumor regressions as a monotherapy with an improved preclinical hematological safety profile.** 

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**Abstract Control Number:** 7335

**Session Title:** Proximity-Induced Drug Discovery 2

**Session Start Time:** 4/21/2026 2:00 PM PT

**Location: Poster Section** 15

**Poster Board Number:** 20

**Presentation Number:** 5793

**Summary:** 

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• PRT13722 is a highly differentiated, first-in-class, orally bioavailable, potent and highly selective KAT6A degrader development candidate.

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• PRT13722, by degrading KAT6A, drives more complete disruption of KAT6A regulatory pathways than dual KAT6A/B
inhibitors, resulting in more robust depth and breadth of preclinical efficacy in HR+/HER2- breast cancer.

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• PRT13722 drives durable complete tumor regressions in HR+/HER2- xenograft models (both endocrine therapy (ET)
sensitive and experienced) at well-tolerated doses, as a monotherapy.

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• PRT13722 is synergistic with ET, CDK4/6 inhibitors, and PI3Kα inhibitors while maintaining monotherapy and
combination activity across HR+ BC models, including estrogen receptor 1 mutated and acquired therapy-resistant cancer cells.

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• PRT13722 has an improved preclinical hematological safety profile compared to prifetrastat, which may enable
combinations with standard of care agents in HR+ BC.

&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;• PRT13722 is on track for IND filing in mid-2026.

**Link to Poster Presentation:** <u>Publications - Prelude Therapeutics (preludetx.com</u>)

**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. PRT13722 remains on track for an IND filing in mid-2026 and subject to clearance, with Phase 1 study initiation planned in the 2<sup>nd</sup> 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 <u>Publications - Prelude Therapeutics</u>.

**Additional AACR Presentation** 

On April 18, 2026, Prelude's Sr. Director of Biology and Pharmacology, Koichi Ito, Ph.D. provided a lecture during an educational session entitled: ED08 – Chemistry to the Clinic Part 1 of 4: Next-Level Conjugates: Transforming Targeted Therapies. The title of the presentation is: "Beyond Conventional Payloads: Unlocking New Therapeutic Landscapes with Targeted Protein Degrader-Antibody Conjugates (DACs)"

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***About Prelude Therapeutics***

Prelude 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 timing of the IND filing for PRT13722 in mid-2026 and the initiation of a Phase 1 clinical study in the second half of 2026, the potential safety, efficacy, tolerability and combinability of PRT13722 with standard of care agents in HR+/HER2- BC, the addressable market for Prelude's product candidates, the potential for PRT13722 to achieve a differentiated profile relative to other approaches targeting KAT6, the expected timeline for clinical trial results for Prelude's product candidates, and the sufficiency of Prelude's cash runway. 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. Preclinical results described herein may not be predictive of clinical outcomes. 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 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, 2025, 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.

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**Investor Contact:**

Robert A. Doody, Jr.

Senior Vice President, Investor Relations

Prelude Therapeutics Incorporated

484.639.7235 <u>rdoody@preludetx.com</u>

## Exhibit 99.2

![Slide 1](g135229ex99_2s1g1.jpg)

Corporate Presentation April 2026 Exhibit 99.2

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![Slide 2](g135229ex99_2s2g1.jpg)

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). 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, 2025. This presentation also contains estimates and other statistical data made by independent parties and by us relating to product growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. This presentation concerns drugs that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration (the "FDA"). They are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are being investigated. Forward Looking Statements & Disclaimers

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![Slide 3](g135229ex99_2s3g1.jpg)

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 Experienced Leadership Team With Proven Track Record Charles Morris, MD Chief Medical Officer

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![Slide 4](g135229ex99_2s4g1.jpg)

PROGRAM POTENTIAL INDICATIONS DISCOVERY IND-ENABLING PHASE 1 PROGRAM INTEREST ANTICIPATED MILESTONES JAK2V617F Mutant Selective JH2 Inhibitors VF+ myeloproliferative neoplasms (MPNs) (MF, PV, ET) Phase 1 now enrolling 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

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![Slide 5](g135229ex99_2s5g1.jpg)

Our Investment Thesis Centers on Advancing Highly Differentiated Approaches to Clinically Validated Targets JAK2V617F (PRT12396) Mutant Selective Inhibitors Potentially transformative JAK2V617F allosteric JH2 inhibitor with potential to reduce mutant allele burden and modify the course of disease progression in patients with myeloproliferative neoplasms (MPNs) KAT6A (PRT13722) Highly Selective Oral Degrader Potentially first-in-class KAT6A degrader with absolute selectivity over KAT6B – a differentiated modality and profile with potential to become a backbone therapy in the treatment of ER+ breast cancer mCALR DAC Next Generation Precision DAC Potentially first-in-class mutated Calreticulin (mCALR) DAC (Degrader Antibody Conjugate) that is equipotent on all CALR mutations and >100x more potent compared to current lead clinical stage CALR antibody

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![Slide 6](g135229ex99_2s6g1.jpg)

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 Currently approved JAK inhibitors, like ruxolitinib (Jakafi®), while effective, equally inhibit both WT and V617F-mutated (VF+) JAK2, leading to dose limiting thrombocytopenia and anemia and do not alter disease progression JAK2V617F selective inhibitors target VF+ progenitor cells while sparing normal bone marrow function and offer the potential for disease modification and to 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

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![Slide 7](g135229ex99_2s7g1.jpg)

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 JH1 Catalytic Domain Confidential

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![Slide 8](g135229ex99_2s8g1.jpg)

PRT12396 is a JAK2V617F Mutant Selective JH2 Inhibitor with Disease Modifying Potential in MPNs \*\*\* p<0.001 by Mann-Whitney U test >200X selectivity over JAK1 and TYK2 and clean profile in KinomeSCAN™ panel of >450 kinases Selective anti-proliferative effects in JAK2VF MPN cells with minimal impact on JAK2WT cells Significant reduction in splenomegaly and normalization of pathogenic cytokines in vivo, equivalent to or better than ruxolitinib in MPN models at well-tolerated doses Isoform selectivity over JAK1/TYK2 Selective inhibition mutant cells in vitro Efficacy in MPN models in vivo BaF3 model ASH Annual Meeting 2025 oral presentation (access here)

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![Slide 9](g135229ex99_2s9g1.jpg)

No evidence of WT JAK2 inhibition in 2-week rat toxicology study at low and mid doses that provide efficacious exposures Reduction in neutrophils and reticulocytes observed only at high dose, consistent with plasma exposure approaching WT JAK2 IC50 AUC exposures required for efficacy are 10X lower than those associated with bone marrow suppression (reticulocyte inhibition) PRT12396 Demonstrates ~10X Therapeutic Window In Vivo – Potential to Overcome the Limitations of First Generation JAK2 Inhibitors Dotted lines represent proliferation IC50 values from SET2 (VF) and UT-7 (WT) 7-day proliferation assay Reticulocyte Inhibition Only at High Dose, with Full Recovery by Day 15 Efficacy AUC is 10X Lower Than Toxicity AUC Plasma Exposures at Low/Mid Doses Remain Below WT JAK2 IC50 ASH Annual Meeting 2025 oral presentation (access here) Confidential

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![Slide 10](g135229ex99_2s10g1.jpg)

PRT12396 – Phase 1 Study in MF and PV Cohorts in Parallel – Now Enrolling IND Cleared in January 2026 MF 2026 2027 2028 2029 Phase 1 Expansion Cohorts Phase 1 (MF & PV) 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 MF & PV 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) MPNs, myeloproliferative neoplasms; MF, myelofibrosis; PV, high risk polycythemia vera; CHR, complete hematologic response; DL, dose level PV DL(n) (N=3-6) DL1 (N=3-6) DL2 (N=3-6) Illustrative

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![Slide 11](g135229ex99_2s11g1.jpg)

Exclusive option agreement with Incyte (announced November 2025) Option Agreement With Incyte Provides Significant Capital to Further Advance Our JAK2V617F and KAT6A Programs

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![Slide 12](g135229ex99_2s12g1.jpg)

Our Investment Thesis Centers on Advancing Highly Differentiated Approaches to Clinically Validated Targets JAK2V617F (PRT12396) Mutant Selective Inhibitors Potentially transformative JAK2V617F allosteric JH2 inhibitor with potential to reduce mutant allele burden and modify the course of disease progression in patients with myeloproliferative neoplasms (MPNs) KAT6A (PRT13722) Highly Selective Oral Degrader Potentially first-in-class KAT6A degrader with absolute selectivity over KAT6B – a differentiated modality and profile with potential to become a backbone therapy in the treatment of ER+ breast cancer mCALR DAC Next Generation Precision DAC Potentially first-in-class mutated Calreticulin (mCALR) DAC (Degrader Antibody Conjugate) that is equipotent on all CALR mutations and >100x more potent compared to current lead clinical stage CALR antibody

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![Slide 13](g135229ex99_2s13g1.jpg)

Selective KAT6A Degradation Could Represent a Differentiated Approach Versus KAT6A/B/(7) Inhibition With Potential for Broader Application Early-stage ER+ BC (adjuvant, neo-adjuvant) KAT6A/B/(7) Inhibitors Pfizer, BeOne, Olema, Ideaya, Menarini, Others 1L ER+/HER2- mBC 2L/3L+ ER+/HER2- mBC Current SoC1 Monotherapy efficacy reported to date with KAT6A/B inhibitors (11% ORR) KAT6B-mediated neutropenia may limit combinability with SoC agents used in the frontline and early-stage settings (e.g., CDK4/6i, PI3K⍺i, etc.) KAT6A Selective Degrader Only KAT6A degrader nearing the clinic Potential for best-in-class monotherapy and combination efficacy KAT6A selectivity may lower neutropenia and enable broad combinability ET +/- CDK4/6 inhibitors ADCs, Targeted Tx ET +/- CDK4/6 inhibitors ET + PI3K⍺ inhibitors +/- CDK4/6i (PIK3CAm) ET +/- CDK4/6 inhibitors Future SoC2 Oral SERDs, CDK2/4 inhibitors, pan-mutant PI3K⍺ inhibitors, ADCs, and other targeted therapies in development 1 - NCCN Treatment Guidelines for Invasive Metastatic and Early Stage Breast Cancer (v5.2025); 2 - clinicaltrials.gov, investor presentations (multiple) ET: Endocrine Therapy, inclusive of SERMs (e.g., tamoxifen), SERDs (e.g., fulvestrant), and aromatase inhibitors (e.g., letrozole, anastrozole, exemestane)

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![Slide 14](g135229ex99_2s14g1.jpg)

KAT6 is a clinically validated mechanism in ER+ breast cancer A KAT6A/B dual inhibitor, prifetrastat is now in pivotal phase 3 trials in combination with fulvestrant, after progression on a CDK4/6 inhibitor1 Demonstrated compelling efficacy in post CDK4/6 inhibitor setting in a broad population of ER+ BC1 Clinically relevant safety observations including dysgeusia and grade 3/4 neutropenia are challenging and may limit dosing to maximal benefit in combination with SoC treatments (e.g., CDK4/6 inhibitors)1 Our KAT6A program aims to demonstrate a superior clinical profile Optimal efficacy Lower hematological toxicity Improved combinability profile with other agents (e.g., oral SERDs, AIs, CDK4/6is, PI3K⍺is) ER+ breast cancer treatment market is projected to reach $42B by 20332 Most common type of breast cancer, representing 70% of all cases 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) 2 - Vision Research Reports; "Estrogen Receptor Positive Breast Cancer Treatment Market Forecast 2024-2033. ER+ Breast Cancer Treatment Market Size \| Companies Prelude's First-In-Class Oral KAT6A Selective Degraders

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![Slide 15](g135229ex99_2s15g1.jpg)

KAT6A: An Emerging Target in the Treatment of ER+/HER2- Breast Cancer 1 - White J, et al. Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy. Trends Pharmacol Sci 45 (3): 243-254 (2024). 2 - Sharma S, et al. Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer. Cell Chem Biol 30 (10):1191-1210 (2023). KAT6 is a histone acetyltransferase that epigenetically regulates chromatin accessibility1-2 The KAT6A complex regulates estrogenic, cell cycle, MYC, and other oncogenic pathways1-2 KAT6A and KAT6B are mutually exclusive paralogs, with KAT6A being the primary driver of oncogenesis1-2 KAT6A (8p11) is frequently amplified in breast, lung, and other cancers1-2

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PRT13722: Our KAT6A Selective Degrader Development Candidate Absolute selectivity for KAT6A over KAT6B (>1000-fold) based on both degrader kinetics and proteomics Excellent oral PK across species enabling once-daily oral dosing Compelling in vivo efficacy as monotherapy in ER+ BC models, both KAT6A amplified/non-amplified Compelling in vivo efficacy in combo with SoC ET, CDK4/6, PI3K⍺ agents Reduced effect on neutrophils in multiple preclinical models IND filing on track for mid-2026 Absolute Degradation Selectivity (KAT6A vs KAT6B) In Vitro1 KAT6A Amplified ER+/HER2- Breast Cancer CDX Model (ZR-75-1) Dosed with PRT13722\* Compelling Monotherapy Efficacy Including Complete Regressions In Vivo1 1 - AACR 2026 poster presentation (access here); CRR = Complete Response Rate; \*When denoted with an asterisk, PRT13722\* indicates data shown is with the racemic mixture of PRT13722. à 63% CRR à 100% CRR Global Proteomics

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Well-tolerated over treatment duration of 80 days with no observed body weight loss in animals PRT13722 compared to prifetrastat with >50-fold lower AUC at efficacious doses PRT13722 Monotherapy Drives Durable Tumor Regressions in the More Challenging T47-D Model with Improved Efficacy Over prifetrastat + fulvestrant in Combination AACR 2026 poster presentation (access here) 1 - Mice harboring T47-D xenografts were treated with the racemic mixture of PRT13722\*; effects on tumor growth are shown. Better Efficacy as Monotherapy vs. prifetrastat + fulvestrant in Combination1 Durable Tumor Regressions Observed at Low Doses (Tumors Below Baseline >2.5 months)1 PRT13722\*, 3 mg/kg, PO, QD Class Treatment % Tumors Regressed Mono-Tx prifetrastat, 1 mg/kg 0% PRT13722, 1 mg/kg 50% PRT13722\*, 3 mg/kg 75% + ET prifetrastat, 1 mg/kg + fulvestrant 13% PRT13722, 1 mg/kg + fulvestrant 88% Fulvestrant (25 mg/kg, SC, QW+LD)

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PRT13722 achieved 100% complete response as a monotherapy in ER+/HER2- xenografts derived from a patient with recurrent disease following treatment with chemotherapy and tamoxifen Responses persisted following cessation of treatment No significant body weight loss observed in animals at either dose level PRT13722 Monotherapy Eradicates Tumors in Post-Tamoxifen Patient-Derived Xenografts (PDX) AACR 2026 poster presentation (access here); Off-tx indicates treatment cessation Treatment Mouse % CRR PRT13722 3 mg/kg, PO, QD 100% (8/8) PRT13722 10 mg/kg, PO, QD 100% (8/8) Tumors at endpoint; CRR = complete response rate (no detectable tumor) PRT13722 Achieved Complete Responses in ST353 PDX Model

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PRT13722 Demonstrates Potential for Lower Bone Marrow Toxicity in Preclinical Models Compared to KAT6A/B Dual Inhibitors Ex Vivo Dose Response of CFU-GM LD KAT6A degrader KAT6A selective degraders show limited effects on neutrophils in contrast to dual KAT6A/B inhibitors, supporting potential for improved safety profile and combinability Prelude Data on File; CFU-GM, Colony-Forming Unit-Granulocyte/Macrophage, myeloid progenitor cells found in bone marrow; LD, low dose; HD, high dose; CD, clinical dose \*Study conducted with racemic mixture of PRT13722; AACR 2026 poster presentation (access here) In Vivo Neutrophil Assessment (Day 5) KAT6A degrader Plot of In Vivo Efficacy vs. Impact on Neutrophils (PRT13722 vs. prifetrastat) HD HD LD CD

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PRT13722 Demonstrates Synergistic Potential in Combination with Current SoC Agents (ET, CDK4/6i, PI3Kαi) In Vivo Deeper monotherapy and combination efficacy H2H vs. prifetrastat at clinical doses Excellent in vivo efficacy in combination with fulvestrant (ET), alpelisib (PI3Kαi) and abemaciclib (CDK4/6i) No dosing holidays, body weight loss, mortality, or adverse clinical signs, alone or in combination AACR 2026 poster presentation (access here) prifetrastat Current Standard of Care Agents fulvestrant (ET/SERD) abemaciclib (CDK4/6i) alpelisib (PI3Kαi) PRT13722 1 mg/kg

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Prelude is advancing a potenial first-in-class, highly selective oral KAT6A degrader (PRT13722) with potential to become a new backbone therapy in the treatment of ER+/HER2- breast cancer PRT13722 has potential to achieve more robust efficacy relative to KAT6A/B/(7) inhibitors PRT13722 was well-tolerated, supporting potential to differentiate further based on overall safety and combinability with other agents On track for IND filing in mid-2026 with Phase 1 study start expected in 2H 2026 KAT6A Selective Degrader Program Summary

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Our Investment Thesis Centers on Advancing Highly Differentiated Approaches to Clinically Validated Targets JAK2V617F (PRT12396) Mutant Selective Inhibitors Potentially transformative JAK2V617F allosteric JH2 inhibitor with potential to reduce mutant allele burden and modify the course of disease progression in patients with myeloproliferative neoplasms (MPNs) KAT6A (PRT13722) Highly Selective Oral Degrader Potentially first-in-class KAT6A degrader with absolute selectivity over KAT6B – a differentiated modality and profile with potential to become a backbone therapy in the treatment of ER+ breast cancer mCALR DAC Next Generation Precision DAC Potentially first-in-class mutated Calreticulin (mCALR) DAC (Degrader Antibody Conjugate) that is equipotent on all CALR mutations and >100x more potent compared to current lead clinical stage CALR antibody

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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 degraders are 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 for a differentiated approach for mCALR+ MPNs 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%

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Precision Degrader Antibody Conjugates (pDACs) Represent Next Generation 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 TPDs Remain an Under-represented Payload Class\* \*Data source: Morris, J. Beacon ADC by HansonWade. "Analyzing the ADC Boom: Landscape Review." World ADC (San Diego). November 2024. Denotes Payload MOA for clinical stage assets currently in development at time of analysis.

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Prelude Discovered mCALR x SMARCA2/4 DACs With Robust and Selective in vitro and in vivo Activity and ~100x Improved Potency 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. (access here); Reis, et al. Blood. 2024;144(22):2336 CALR x SMARCA2/4 DAC CALR x SMARCA2/4 DAC DAC Naked Ab ~100x Better Potency

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Executive Summary Lead JAK2V617F mutant selective inhibitor (PRT12396) IND cleared and Phase 1 study enrollment underway1 Potentially first-in-class KAT6A selective degrader (PRT13722) on track to enter the clinic in 2026 with a path to differentiation in ER+/HER2- breast cancer market Novel approaches to clinically-validated targets (e.g., mCALR) poised to deliver differentiated pipeline candidates beyond JAK2 and KAT6A 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)

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Thank You Contact Us: Robert Doody SVP, Investor Relations rdoody@preludetx.com