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
May 16, 2025
Date of Report (Date of earliest event reported)
Prime Medicine, Inc.
(Exact name of registrant as specified in its charter)
Delaware | 001-41536 | 84-3097762 | ||
(State or other jurisdiction of incorporation) |
(Commission File Number) |
(I.R.S. Employer Identification No.) |
||
60 First Street Cambridge, MA |
02141 | |||
(Address of principal executive offices) | (Zip Code) |
(617) 465-0013
(Registrant’s telephone number, including area code)
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 |
Name of each exchange |
||
Common stock, par value $0.00001 per share | PRME | The Nasdaq Global 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 Rule12b-2 of the Securities Exchange Act of 1934 (§250.12b-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 5.02 | Departure of Directors or Certain Officers; Election of Directors; Appointment of Certain Officers; Compensatory Arrangements of Certain Officers. |
Departure of President, Chief Executive Officer and Principal Executive Officer
On May 19, 2025, Prime Medicine, Inc. (the “Company”) announced that Keith Gottesdiener, M.D. had resigned as President, Chief Executive Officer and principal executive officer of the Company, and as a member of the Board of Directors of the Company (the “Board”), as well as from all other officer and director positions he held with the Company and any of its subsidiaries, in each case effective as of the end of day on May 18, 2025 (the “Resignation”). Dr. Gottesdiener’s decision to resign from the Board was not the result of any disagreement with the Company on any matter relating to the operations, policies or practices of the Company.
In connection with the Resignation, Dr. Gottesdiener and the Company entered into a Separation Agreement (the “Separation Agreement”), pursuant to which Dr. Gottesdiener is entitled to receive severance benefits in accordance with the terms of his Amended and Restated Employment Agreement, dated July 7, 2022, as amended by the Amendment No. 1 to Employment Agreement, dated July 6, 2023, with the Company (as amended, the “Gottesdiener Employment Agreement”).
On the effective date of the Resignation, as contemplated by the Gottesdiener Employment Agreement, the Company will retain certain non-exclusive, limited consulting and advisory services of Dr. Gottesdiener for a period of up to one year from the effective date of the Resignation (the “Advisory Period”). During the Advisory Period, all of Dr. Gottesdiener’s outstanding equity awards will continue to vest in accordance with their terms. Additionally, on the effective date of the Resignation, the Company entered into a Consulting Agreement with KMG Strategic Consulting, LLC, a limited liability company managed by Dr. Gottesdiener, to provide for Dr. Gottesdiener’s continued consulting services to the Company, with the option, if mutually agreed, to extend such services beyond the one-year anniversary of the effective date of the Resignation (the “Consulting Agreement”).
The foregoing summaries of the Separation Agreement and Consulting Agreement do not purport to be complete and are qualified in their entirety by references to the full texts of the Separation Agreement and Consulting Agreement, copies of which the Company intends to file as exhibits to its Quarterly Report on Form 10-Q for the quarter ending June 30, 2025.
Appointment of Chief Executive Officer and Principal Executive Officer
In connection with the Resignation, on May 16, 2025, the Board appointed Allan Reine, M.D., the Company’s Chief Financial Officer and principal financial officer, as Chief Executive Officer and principal executive officer of the Company, in addition to continuing in his current role as principal financial officer of the Company, in each case effective as of May 19, 2025. The Board also appointed Dr. Reine to serve as a member of the Board as a Class II director to hold office until the Company’s annual meeting of stockholders to be held in 2027, until his successor is elected and qualified, or until his earlier death, resignation or removal, or until otherwise determined by the Board, effective as of May 19, 2025. In connection with Dr. Reine’s appointment to the Board, the Board determined that Dr. Reine is not independent under the applicable listing standards of the Nasdaq Stock Market LLC. Accordingly, Dr. Reine was not appointed to serve on any committees of the Board. Dr. Reine will not receive any additional compensation in connection with his service as a member of the Board.
In connection with Dr. Reine’s appointment as Chief Executive Officer, the Company entered into an Amended and Restated Employment Agreement (the “Reine Employment Agreement”), effective as of May 19, 2025, pursuant to which the Company has agreed to pay Dr. Reine an annual base salary of $665,000. Dr. Reine is also eligible to earn an annual target bonus of 60% of his annual base salary. During Dr. Reine’s employment, he will be eligible to participate in the Company’s equity compensation plans and employee benefit plans available to other employees of the Company. Upon the effective date of the Reine Employment Agreement, the Reine Employment Agreement will fully supersede the Employment Agreement, dated January 17, 2024, by and between the Company and Dr. Reine.
Pursuant to the Reine Employment Agreement, in the event Dr.
Reine is terminated by the Company without “Cause” or he resigns for “Good Reason” (as such terms are defined in the Reine Employment Agreement), in each case subject to the delivery of and compliance with a fully effective separation agreement that shall include, without limitation, a general release of claims, reaffirmation of applicable restrictive covenants and, in the Company’s discretion, a one year non-competition agreement, Dr. Reine will be entitled to (i) an amount equal to the sum of (A) twelve (12) months of his then-current base salary plus (B) 1.0 times his target annual bonus for the then current year, in each case subject to reductions by any amount received by him pursuant to a restrictive covenant agreement, and (ii) subject to Dr. Reine’s co-payment of premium amounts at the applicable active employees’ rate and proper election to continue COBRA health coverage, payment of the portion of the premium equal to the amount the Company would have paid to provide health insurance had he remained employed by us until the earliest of (A) twelve (12) months following his termination, (B) his eligibility for group medical plan benefits under any other employer’s group medical plan or (C) the end of his COBRA health continuation period. These amounts shall be paid out in substantially equal installments in accordance with the Company’s payroll practice over a period of twelve (12) months. In addition, subject to the delivery of the fully effective separation agreement, the bonus amount (if any) that Dr. Reine would have been paid if he had remained employed through the payment date, if such termination occurs on or after January 1 but before the date bonuses are paid for the prior year to the Company’s other executives, will be paid to Dr. Reine on the date the Company’s other executives receive their bonuses.
In the event Dr. Reine is terminated by the Company without “Cause” or he resigns for “Good Reason”, in each case within twelve (12) months following a “Change in Control” (as such terms are defined in the Reine Employment Agreement), subject to the delivery of and compliance with a fully effective separation agreement (as described above), Dr. Reine will be entitled to the following, in lieu of the benefits above: (i) a lump sum cash payment equal to the sum of (A) eighteen (18) months of his then-current base salary (or his base salary in effect immediately prior to the “Change in Control,” if higher) plus (B) 1.5 times his target annual bonus for the then current year (or target in effect immediately prior to the “Change in Control,” if higher), in each case subject to reductions by any amount received by him pursuant to a restrictive covenant agreement, (ii) subject to Dr. Reine’s co-payment of premium amounts at the applicable active employees’ rate and proper election to continue COBRA health coverage, payment of the portion of the premium equal to the amount the Company would have paid to provide health insurance had he remained employed by us until the earliest of (A) eighteen (18) months from the date of his separation, (B) his eligibility for group medical plan benefits under any other employer’s group medical plan or (C) the end of his COBRA health continuation period, and (iii) the bonus amount (if any) that Dr. Reine would have been paid if he had remained employed through the payment date, if such termination occurs on or after January 1 but before the date bonuses are paid for the prior year to the Company’s other executives. In addition, in the event Dr. Reine is terminated by us without cause or he resigns for good reason, in each case within eighteen (18) months following a “Change in Control,” all of the then-outstanding and unvested portion of his stock options and other stock-based awards that are subject solely to time-based vesting shall become fully vested and exercisable or non-forfeitable immediately as of the date of termination, with any such performance-based awards vesting at target.
Pursuant to the Reine Employment Agreement, the Board approved the grant of a stock option to purchase up to 2,000,000 shares of the Company’s common stock, par value $0.00001 per share (“Common Stock”), pursuant to the Company’s 2022 Stock Option and Incentive Plan (the “2022 Plan”) to Dr. Reine. The stock option award will have an exercise price equal to the closing price of the Company’s common stock on the Nasdaq Global Market on the date of grant. Twenty-five percent of the shares will vest on the one-year anniversary of the date of the grant and the balance will vest monthly in equal installments over the following thirty-six (36) months, subject to Dr. Reine’s continuous service. In addition, the Board approved the grant of a stock option to purchase up to 500,000 shares of Common Stock pursuant to the Plan to Dr. Reine. The stock option award will have an exercise price equal to the closing price of Common Stock on the Nasdaq Global Market on the date of grant and will vest upon the achievement of agreed milestones that will be set forth in the applicable equity agreement, subject to Dr. Reine’s continuous service.
Dr. Reine has also entered into the Company’s standard form of director indemnification agreement, which was filed as Exhibit 10.7 to the Company’s Registration Statement on Form S-1/A filed on October 17, 2022.
There is no arrangement or understanding between Dr. Reine and any other person pursuant to which he was selected as an officer and director of the Company, and there are no family relationships between Dr. Reine and any of the Company’s directors or executive officers. There are no transactions to which the Company is a party and in which Dr. Reine has a direct or indirect material interest that would be required to be disclosed under Item 404(a) of Regulation S-K. Dr. Reine’s biography is set forth in the Company’s definitive proxy statement for its 2025 annual meeting of stockholders filed pursuant to Regulation 14A on April 22, 2025.
The foregoing summary of the Reine Employment Agreement does not purport to be complete and is qualified in its entirety by reference to the full text of the Reine Employment Agreement, a copy of which the Company intends to file as an exhibit to its Quarterly Report on Form 10-Q for the quarter ending June 30, 2025.
Item 7.01 | Regulation FD Disclosure. |
On May 19, 2025, the Company issued press releases titled “Prime Medicine Announces Breakthrough Clinical Data Showing Rapid Restoration of DHR Positivity After Single Infusion of PM359, an Investigational Prime Editor for Chronic Granulomatous Disease” and “Prime Medicine Announces Strategic Restructuring to Focus on Opportunities in Large Genetic Liver Diseases, Cystic Fibrosis, and Partnered Programs Alongside CEO Leadership Transition.” A copy of each press release is furnished as Exhibit 99.1 and Exhibit 99.2, respectively, to this Current Report on Form 8-K, which is incorporated herein by reference.
On May 19, 2025, the Company posted an updated corporate presentation to its website at https://investors.primemedicine.com/news-events. A copy of the corporate presentation is furnished as Exhibit 99.3 to this Current Report on Form 8-K, which is incorporated herein by reference. Reference to the Company’s website is for inactive textual reference only and the content of the website should not be deemed incorporated by reference into this Current Report on Form 8-K.
The information in Item 7.01 of this Current Report on Form 8-K, including Exhibit 99.1, Exhibit 99.2 and Exhibit 99.3 attached hereto, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 8.01 | Other Events. |
Appointment of Executive Chair
On May 16, 2025, the Board appointed Jeffrey Marrazzo, a member of the Board, as Executive Chair of the Board, in addition to his service as a director, effective as of May 19, 2025.
Pipeline Prioritization
On May 19, 2025, the Company announced a strategic restructuring, including the deprioritization of its Chronic Granulomatous Disease (“CGD”) programs, as well as a cost and workforce reduction to focus on its liver franchise and programs funded through external partnerships. The Company will focus its internal efforts on the development of in vivo programs for the treatment of Wilson’s Disease and Alpha-1 Antitrypsin Deficiency (“AATD”), two of the largest genetic liver diseases. The Company expects to file an investigational new drug (“IND”) and/or clinical trial application (“CTA”) for its Wilson’s Disease program in the first half of 2026 and for its AATD program in mid-2026; initial clinical data from both programs are expected in 2027.
The Company will also continue its in vivo Cystic Fibrosis program with support from the Cystic Fibrosis Foundation, and its efforts to develop Prime Edited CAR-T products for hematology, immunology and oncology in partnership with Bristol Myers Squibb. The Company is exploring options for the continued clinical development of PM359 external to the Company and ceasing further efforts in X-linked CGD. The Company believes PM359 has the potential to transform the care of p47phox CGD and is committed to working with urgency to identify an appropriate partner to help ensure this important therapy is delivered to patients. In addition, the Company will continue to pursue additional business development opportunities to accelerate innovation, ensure the broadest application of Prime Editing, and further bolster its financial resources.
CGD Data Update
On May 19, 2025, the Company announced positive initial data from the first patient dosed in its ongoing Phase 1/2 clinical study of PM359 in CGD. Preliminary results from the first patient demonstrated that PM359 was well-tolerated, showed rapid engraftment and restored NADPH oxidase activity to well above the threshold for clinical benefit, as measured by the dihydrorhodamine (“DHR”) assay. PM359 is being evaluated in a Phase 1/2, multinational, first-in-human trial designed to assess safety, biological activity and preliminary efficacy in adult and pediatric study participants.
Initial safety and efficacy data reported are from the first adult patient treated in the trial.
The first patient was treated with a single dose of PM359, administered by intravenous infusion. NADPH oxidase activity was measured by the DHR assay at baseline, Day 15 and Day 30. Treatment with PM359 led to complete restoration of NADPH oxidase activity in 58% of neutrophils by Day 15 and 66% of neutrophils by Day 30, significantly exceeding the anticipated minimum threshold for clinical benefit of 20%. Additionally, the patient experienced rapid engraftment of his autologous transplant following myeloablative conditioning. Engraftment was confirmed in neutrophils on Day 14 and in platelets on Day 19. Of note, this is nearly two-times faster than approved gene editing technologies, where median engraftment has been reported to occur on Days 27 and 35 across these same measures.
Treatment with PM359 was generally well-tolerated, with an acceptable safety profile. Adverse events (“AEs”) were generally consistent with AEs otherwise observed during myeloablative conditioning with busulfan. No serious AEs related to PM359 were reported as of the data cutoff.
Beam Arbitration
The Company is currently engaged in arbitration proceedings with Beam Therapeutics, Inc. regarding the parties’ collaboration and license agreement and the Company’s development of a product for the treatment of AATD. The arbitration remains in an early stage.
Cautionary Note Regarding Forward Looking Statements
This Current Report on Form 8-K contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the Company’s expectations regarding: the continued development and advancement of its AATD and Wilson’s Disease programs, including the timing of the filing of IND and/or CTA applications in mid-2026 and the first half of 2026, respectively, and the timing of initial data for both programs in 2027; the initiation, timing, progress, and results of its research and development programs, preclinical studies and future clinical trials, and the release of data related thereto; the collaboration with Bristol Myers Squibb and the intended and potential benefits thereof, including the receipt of potential milestone and royalty payments from commercial product sales, if any; the potential of Prime Editing to correct the causative mutations of diseases, including of AATD, Wilson’s Disease and CF; its expectations regarding the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; the potential of Prime Editing as a transformative gene editing technology and its ability to unlock opportunities across thousands of potential indications; and its ability to identify an external partner to deliver PM359 therapy in X-linked CGD to patients; its evaluation of potential business development opportunities, including its ability to execute and realize the anticipated benefits of any strategic alternatives it may pursue; the impact of the pipeline deprioritization; and its expectations regarding the arbitration proceedings with Beam Therapeutics, Inc. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements contained in this Current Report on Form 8-K, such as those related to arbitration proceedings with Beam, are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this Current Report on Form 8-K. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in the Company’s most recent Annual Report on Form 10-K for the year ended December 31, 2024, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent the Company’s views only as of today and should not be relied upon as representing its views as of any subsequent date. The Company explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements except as required by law.
Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
Exhibit No. |
Description | |
99.1 | Press Release issued by the Company on May 19, 2025, furnished herewith. | |
99.2 | Press Release issued by the Company on May 19, 2025, furnished herewith. | |
99.3 | Presentation, dated May 2025, furnished herewith. | |
104 | 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.
Date: May 19, 2025
Prime Medicine, Inc. | ||
By: | /s/ Allan Reine |
|
Name: | Allan Reine, M.D. | |
Title: | Chief Executive Officer |
Exhibit 99.1
Prime Medicine Announces Breakthrough Clinical Data Showing Rapid Restoration of DHR Positivity
After Single Infusion of PM359, an Investigational Prime Editor for Chronic Granulomatous Disease
— First ever clinical data supporting safety and efficacy of Prime Editing in humans —
— Initial data from first patient dosed in Phase 1/2 trial finds single dose of PM359 led to 58% DHR positivity
by Day 15 and 66% by Day 30, well above levels believed to be potentially curative —
— Rapid engraftment observed in both neutrophils and platelets —
— Encouraging safety profile; no serious adverse events related to PM359 —
— Initiating efforts to explore continued clinical development opportunities for PM359 external to Prime Medicine —
Cambridge, Mass., May 19, 2025 – Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today announced positive initial data from the first patient dosed in its ongoing Phase 1/2 clinical study of PM359 in Chronic Granulomatous Disease (CGD). Preliminary results from the first patient demonstrated that PM359 was well-tolerated, showed rapid engraftment and restored NADPH oxidase activity to well above the threshold for clinical benefit, as measured by the dihydrorhodamine (DHR) assay.
CGD is a rare inherited disease that leads to recurrent, debilitating and often life-threatening infections. It is caused by mutations in genes, including NCF1, that encode proteins that form the NADPH oxidase complex, an enzyme that kills bacteria and fungi to control infection. PM359, an ex vivo Prime Edited autologous hematopoietic stem cell (HSC) product for the treatment of p47phox CGD and the first Prime Editor generated therapy to be administered in humans, is designed to correct the delGT mutation in NCF1, the most prevalent disease-causing mutation in the p47phox variant of CGD, thereby addressing its underlying pathophysiology. Prime Medicine estimates that CGD causative mutations occur in between one in 100,000 and one in 200,000 births in the United States, with approximately 25 percent of patients presenting with the p47phox form of the disease.
“We created prime editing five and a half years ago as a versatile, precise genome editing technology that in principle could correct almost all mutations known to cause genetic diseases,” said David Liu, Ph.D., Co-Founder of Prime Medicine and Richard Merkin Professor and Director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute of MIT and Harvard. “Today’s data represent a milestone in medicine, establishing that prime editing in a patient’s cells can correct a pathogenic mutation and can change the course of a life-limiting disease. I am thrilled by the implication of these results for the CGD patient community, and more generally for people living with genetic diseases.”
PM359 is being evaluated in a Phase 1/2, multinational, first-in-human trial designed to assess safety, biological activity and preliminary efficacy in adult and pediatric study participants. Initial safety and efficacy data reported today are from the first adult patient treated in the trial.
This patient was treated with a single dose of PM359, administered by intravenous infusion. NADPH oxidase activity was measured by the dihydrorhodamine (DHR) assay at baseline, Day 15 and Day 30. Treatment with PM359 led to complete restoration of NADPH oxidase activity in 58% of neutrophils by Day 15 and 66% of neutrophils by Day 30, significantly exceeding the anticipated minimum threshold for clinical benefit of 20%.
Additionally, this patient experienced rapid engraftment of his autologous transplant following myeloablative conditioning. Engraftment was confirmed in neutrophils on Day 14 and in platelets on Day 19. Of note, this is nearly two-times faster than approved gene editing technologies, where median engraftment has been reported to occur on Days 27 and 35 across these same measures.
Treatment with PM359 was generally well-tolerated, with an acceptable safety profile. Adverse events (AEs) were generally consistent with AEs otherwise observed during myeloablative conditioning with busulfan. No serious AEs related to PM359 were reported as of the data cutoff.
“The data reported today are important for two reasons. First, for people living with CGD, these results suggest Prime Editing may offer a reprieve from their disease, restoring NADPH oxidase function and, therefore, reducing the risk of acquiring a deadly infection or suffering from inflammation of the lung, liver or bowel,” said Mohammed Asmal, M.D., Ph.D., Chief Medical Officer of Prime Medicine. “We are grateful to our first patient and to his family and caretakers for their trust and participation in our trial.”
Dr. Asmal continued, “Second, these data answer key questions about Prime Editors, confirming their potential to be delivered safely and restore normal gene function. This reaffirms our conviction that Prime Editing will be the foundation of a new class of differentiated, one-time genetic therapies, and we look forward to advancing our broader pipeline of investigational programs, directed towards large genetic diseases that impact the liver and lung.”
Prime Medicine does not plan to independently advance its efforts in CGD. Prime Medicine is exploring options for the continued clinical development of PM359 external to the company and ceasing further efforts in X-linked CGD. Prime Medicine believes PM359 has the potential to transform the care of p47phox CGD and is committed to working with urgency to identify an appropriate partner to help ensure this important therapy is delivered to patients.
Going forward, Prime Medicine will focus its resources on advancing its in vivo liver franchise, where the Company is advancing programs to cure two of the largest genetic liver diseases, Wilson’s Disease and Alpha-1 Antitrypsin Deficiency (AATD). Prime Medicine will also continue its in vivo Cystic Fibrosis program with support from the Cystic Fibrosis Foundation, and its efforts to develop Prime Edited CAR-T products for hematology, immunology and oncology in partnership with Bristol Myers Squibb. In addition, Prime Medicine will continue to pursue additional business development opportunities to accelerate innovation, ensure the broadest application of Prime Editing, and further bolster its financial resources.
About PM359
PM359, Prime Medicine’s first product candidate within its hematology and immunology area of focus, targets the p47phox variant of CGD, a serious, life-threatening disease that presents in childhood. PM359 comprises autologous hematopoietic stem cells (HSCs) modified ex vivo using Prime Editors that have been designed to correct a high percentage of cells containing the disease-causing mutation. PM359 has received rare pediatric drug designation and orphan drug designation from the U.S. Food and Drug Administration.
About Chronic Granulomatous Disease (CGD)
Chronic granulomatous disease (CGD) is a rare inherited hematologic disorder characterized by susceptibility to severe, difficult-to-treat infections, and inflammatory/autoimmune complications. CGD is caused by mutations in any one of the subunits comprising the NADPH oxidase complex, which is required for phagocytic cells, in particular neutrophils, to destroy many invasive microorganisms. CGD causative mutations are estimated to occur between one in 100,000 and one in 200,000 births in the United States, and most children are diagnosed within the first three years of life. Beginning in childhood, patients with CGD develop infections from a range of both typical and unusual bacteria, fungi and mycobacteria. These infections may present in various organ systems, and protracted infections can lead to long-term organ damage and failure. In addition, patients have non-infectious inflammatory disease, most commonly presenting as inflammatory bowel disease, soft tissue granulomas, and strictures of the urinary or digestive tract. Undiagnosed or untreated, the infectious manifestations of CGD are rapidly fatal, with refractory or antimicrobial resistant infection the leading cause of mortality.
About Prime Medicine
Prime Medicine is a leading biotechnology company dedicated to creating and delivering the next generation of gene editing therapies to patients. The Company is deploying its proprietary Prime Editing platform, a versatile, precise and efficient gene editing technology, to develop a new class of differentiated one-time curative genetic therapies. Designed to make only the right edit at the right position within a gene while minimizing unwanted DNA modifications, Prime Editors have the potential to repair almost all types of genetic mutations and work in many different tissues, organs and cell types. Taken together, Prime Editing’s versatile gene editing capabilities could unlock opportunities across thousands of potential indications.
Prime Medicine is currently progressing a diversified portfolio of investigational therapeutic programs organized around our core areas of focus: liver, lung, and immunology and oncology. Across each core area, Prime Medicine is focused initially on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. Over time, the Company intends to maximize Prime Editing’s broad and versatile therapeutic potential, as well as the modularity of the Prime Editing platform, to rapidly and efficiently expand beyond the diseases in its current pipeline, potentially including additional genetic diseases, immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases, which collectively impact millions of people. For more information, please visit www.primemedicine.com.
© 2025 Prime Medicine, Inc. All rights reserved. PRIME MEDICINE, the Prime Medicine logos, and PASSIGE are trademarks of Prime Medicine, Inc. All other trademarks referred to herein are the property of their respective owners.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Prime Medicine’s beliefs and expectations regarding: the continued development and advancement of its AATD and Wilson’s Disease programs; the potential of Prime Editing to correct the causative mutations of diseases, including of AATD, Wilson’s Disease and CF; the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; the potential of Prime Editing as a transformative gene editing technology and its ability to unlock opportunities across thousands of potential indications; and its ability to identify an external partner to deliver PM359 therapy in X-linked CGD to patients.
Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: uncertainties related to Prime Medicine’s product candidates entering clinical trials; the authorization, initiation, and conduct of preclinical and IND-enabling studies and other development requirements for potential product candidates, including uncertainties related to opening INDs and obtaining regulatory approvals; risks related to the development and optimization of new technologies, the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the scope of protection Prime Medicine is able to establish and maintain for intellectual property rights covering its Prime Editing technology; Prime Medicine’s ability to identify and enter into future license agreements and collaborations; Prime Medicine’s expectations regarding the anticipated timeline of its cash runway and future financial performance; and general economic, industry and market conditions. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Prime Medicine’s most recent Annual Report on Form 10-K, as well as any subsequent filings with the Securities and Exchange Commission.
In addition, any forward-looking statements represent Prime Medicine’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Prime Medicine explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
Investor and Media Contacts
Gregory Dearborn
Prime Medicine
857-209-0696
gdearborn@primemedicine.com
Hannah Deresiewicz
Precision AQ
212-362-1200
hannah.deresiewicz@precisionaq.com
Exhibit 99.2
Prime Medicine Announces Strategic Restructuring to Focus on Opportunities in Large Genetic Liver
Diseases, Cystic Fibrosis, and Partnered Programs Alongside CEO Leadership Transition
— Initial positive data from Phase 1/2 clinical trial of PM359 in CGD provide clinical proof-of-concept for
Prime Editing as a transformative gene editing technology —
— On-track to file IND and/or CTA for Wilson’s Disease and AATD programs in 1H 2026 and mid-2026,
respectively; initial clinical data for both expected in 2027 —
— Allan Reine, M.D., CFO, to succeed Keith Gottesdiener, M.D., as CEO; Jeff Marrazzo, member of the Board
of Directors, named Executive Chair —
— Implementing cost cutting measures to significantly reduce cash needs in advance of key data inflection points —
Cambridge, Mass., May 19, 2025 – Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today announced a strategic restructuring, including the deprioritization of its Chronic Granulomatous Disease (CGD) programs, as well as a cost and workforce reduction to focus on its liver franchise and programs funded through external partnerships.
Prime Medicine is currently advancing in vivo programs to cure two of the largest genetic liver diseases, Wilson’s Disease and Alpha-1 Antitrypsin Deficiency (AATD), with initial clinical data from both programs expected in 2027. Prime Medicine will also continue its in vivo Cystic Fibrosis program with support from the Cystic Fibrosis Foundation, and its efforts to develop Prime Edited CAR-T products for hematology, immunology and oncology in partnership with Bristol Myers Squibb. In addition, Prime Medicine will continue to pursue additional business development opportunities to accelerate innovation, ensure the broadest application of Prime Editing, and further bolster its financial resources.
Also today, Prime Medicine announced that Keith Gottesdiener, M.D., has decided to step down as Chief Executive Officer (CEO) and a member of the Company’s Board of Directors, effective immediately. Allan Reine, M.D., Prime Medicine’s Chief Financial Officer (CFO), has been named CEO and member of the Board of Directors and Jeff Marrazzo, member of the Company’s Board of Directors, has been named Executive Chair.
“The first-in-human data for PM359 announced today represent a landmark moment for the industry and for our company, demonstrating the unequivocal power of Prime Editing to change patients’ lives, with a single dose of PM359 providing potentially curative benefit in a matter of weeks,” said Allan Reine, M.D., Chief Executive Officer of Prime Medicine. “These data also reinforce the critical importance of ensuring Prime Medicine is positioned to withstand the challenges of the current environment, so that we can one day deliver the tremendous promise of Prime Editing to address a wide spectrum of genetic diseases. I am humbled by the opportunity to lead Prime Medicine through this next chapter, and committed to operating with excellence, efficiency and financial discipline as we focus our efforts internally on our Wilson’s Disease and AATD programs, where, in the near-term, we have the potential to cure two of the largest genetic liver diseases.”
Pipeline Prioritization:
Prime Medicine will focus its internal efforts on the development of in vivo programs for the treatment of Wilson’s Disease and AATD, two of the largest genetic liver diseases. Prime Medicine expects to file an investigational new drug (IND) and/or clinical trial application (CTA) for its Wilson’s Disease program in the first half of 2026 and for its AATD program in mid-2026; initial clinical data from both programs are expected in 2027.
• | Wilson’s Disease: Wilson’s Disease is a rare and severe disorder caused by excess copper accumulation in the liver and brain that can lead to liver failure and neurocognitive decline and can be fatal without a liver transplant. There are currently no approved disease-modifying therapies for Wilson’s Disease, which affects more than 20,000 people in the United States and European Union. |
• | AATD: AATD is a progressive, genetic disorder caused by mutations in the SERPINA1 gene, which can result in both lung- and liver-related symptoms, including shortness of breath, wheezing, chronic cough and frequent chest colds, as well as jaundice, ascites, and cirrhosis. There are currently no disease-modifying or curative treatments approved for the approximately 200,000 people in the United States and European Union with AATD, of which 20,000-30,000 people are currently diagnosed. Many patients with AATD ultimately progress to liver failure or severe lung disease, eventually resulting in premature death. |
Prime Medicine will also continue its in vivo Cystic Fibrosis program with support from the Cystic Fibrosis Foundation, and its efforts to develop Prime Edited CAR-T products for hematology, immunology and oncology in partnership with Bristol Myers Squibb.
As announced in conjunction with initial data for PM359 this morning, Prime Medicine is exploring options for the continued clinical development of PM359 external to the company and ceasing further efforts in X-linked CGD. Prime Medicine believes PM359 has the potential to transform the care of p47phox CGD and is committed to working with urgency to identify an appropriate partner to help ensure this important therapy is delivered to patients.
Management and Corporate Update
Management Update:
The Board of Directors has appointed Dr. Reine, Prime Medicine’s CFO, as CEO and member of the Board of Directors, effective immediately. Additionally, Jeff Marrazzo, member of the Board of Directors, has been named as Executive Chair.
• | Dr. Reine is a seasoned executive with more than twenty years’ experience in the biotechnology industry. Prior to joining Prime Medicine in 2024, Dr. Reine was CFO at Foghorn Therapeutics and, before that, at Pieris Pharmaceuticals. Previously, Dr. Reine spent fifteen years as a healthcare investor managing various healthcare portfolios primarily focused on biotechnology and pharmaceutical companies. In addition, Dr. Reine started his career in biotechnology investment banking and sell-side research. Dr. Reine also serves as Chairman of the Board of ONK Therapeutics. |
• | Mr. Marrazzo joined the Prime Medicine Board of Directors in 2023. Prior to that, he founded and built Spark Therapeutics into the world’s first fully integrated, commercial gene therapy company, and successfully orchestrated its $4.8 billion sale to Roche in 2019. Under his leadership, Spark developed and launched LUXTURNA® for a rare blinding disorder, the first U.S. Food and Drug Administration (FDA)-approved gene therapy for a genetic disease in the U.S., developed BEQVEZ™, which was licensed to Pfizer and approved by the FDA for hemophilia B, and advanced multiple programs into Phase 3, including several which received Breakthrough Designation. |
“The selection of Allan as Prime Medicine’s next CEO is the result of thoughtful succession planning, designed to position the company for long-term success, while maintaining the culture of innovative thinking, scientific rigor and collaboration that has always defined the organization and that will continue to fuel its long-term growth,” said Mr. Marrazzo. “As a seasoned CFO, former investor and physician, Allan brings a combination of financial and scientific acumen, which will enable him to champion and advance Prime Medicine’s pipeline, while ensuring the company can successfully navigate the evolving market conditions. I look forward to working closely together as he assumes this new role.”
Mr. Marrazzo continued, “Since its discovery in 2019, Keith has been an incredible advocate for Prime Editing. He was early to recognize the transformative power of this new technology and built Prime Medicine to enable its rapid development. With the announcement of positive initial data for PM359, and the changes in the company as part of the strategic prioritization, today marks a natural time to transition leadership of Prime Medicine. On behalf of the Board, I thank Keith for his visionary leadership and wish him the very best in his next professional endeavor.”
Dr. Gottesdiener will continue to support Prime Medicine as a consultant for a period of one year.
Corporate Update:
Alongside the pipeline prioritization announced today, Prime Medicine is undertaking cost reduction measures and restructuring its team, including reducing its organizational headcount by approximately 25% percent. These initiatives are designed to significantly decrease Prime Medicine’s operating expenses and cash burn, reducing anticipated cash needs by almost half through 2027.
Dr. Reine added, “I am deeply grateful to the employees who will be impacted as part of this restructuring. They all contributed mightily to advancing Prime Editing from concept to clinic, and their efforts across research and development and broader company-building will serve as the foundation for our success for many years to come. Importantly, while today’s restructuring positions Prime Medicine to efficiently execute towards potentially transformative inflection points in Wilson’s Diseases and AATD, we remain unwavering in our long-term ambition to realize the full promise of Prime Editing for a wide spectrum of diseases.”
Also today, Prime Medicine announced that it recently engaged in binding arbitration proceedings with Beam Therapeutics, Inc. regarding the parties’ 2019 Collaboration and License Agreement (the “Agreement”) and specific to its AATD program. Prime Medicine is committed to honoring the terms of the Agreement, and confident that it has the rights to pursue AATD under the Agreement.
Based on its current plans, Prime Medicine continues to expect that its cash, cash equivalents and investments as of March 31, 2025 will be sufficient to fund its operations and capital expenditure requirements into the first half of 2026.
About Prime Medicine
Prime Medicine is a leading biotechnology company dedicated to creating and delivering the next generation of gene editing therapies to patients. The Company is deploying its proprietary Prime Editing platform, a versatile, precise and efficient gene editing technology, to develop a new class of differentiated one-time curative genetic therapies. Designed to make only the right edit at the right position within a gene while minimizing unwanted DNA modifications, Prime Editors have the potential to repair almost all types of genetic mutations and work in many different tissues, organs and cell types. Taken together, Prime Editing’s versatile gene editing capabilities could unlock opportunities across thousands of potential indications.
Prime Medicine is currently progressing a diversified portfolio of investigational therapeutic programs organized around our core areas of focus: liver, lung, and immunology and oncology. Across each core area, Prime Medicine is focused initially on a set of high value programs, each targeting a disease with well-understood biology and a clearly defined clinical development and regulatory path, and each expected to provide the foundation for expansion into additional opportunities. Over time, the Company intends to maximize Prime Editing’s broad and versatile therapeutic potential, as well as the modularity of the Prime Editing platform, to rapidly and efficiently expand beyond the diseases in its current pipeline, potentially including additional genetic diseases, immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases, which collectively impact millions of people. For more information, please visit www.primemedicine.com.
© 2025 Prime Medicine, Inc. All rights reserved. PRIME MEDICINE, the Prime Medicine logos, and PASSIGE are trademarks of Prime Medicine, Inc. All other trademarks referred to herein are the property of their respective owners.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Prime Medicine’s beliefs and expectations regarding: the continued development and advancement of its AATD and Wilson’s Disease programs, including the timing of the filing of IND and/or CTA applications in mid-2026 and 1H 2026, respectively, and the timing of initial data for both programs in 2027; the initiation, timing, progress, and results of its research and development programs, preclinical studies and future clinical trials, including the release of data related thereto; the potential of Prime Editing to correct the causative mutations of diseases, including of AATD, Wilson’s Disease and CF; the breadth of Prime Editing technology and the implementation of its strategic plans for its business, programs, and technology; the potential of Prime Editing as a transformative gene editing technology and its ability to unlock opportunities across thousands of potential indications; its ability to identify an external partner to deliver PM359 therapy in X-linked CGD to patients; its rights to pursue AATD using its approach in connection with the arbitration proceedings with Beam Therapeutics, Inc.; and its expected cash runway.
Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: uncertainties related to Prime Medicine’s product candidates entering clinical trials; the authorization, initiation, and conduct of preclinical and IND-enabling studies and other development requirements for potential product candidates, including uncertainties related to opening INDs and obtaining regulatory approvals; risks related to the development and optimization of new technologies, the results of preclinical studies, or clinical studies not being predictive of future results in connection with future studies; the scope of protection Prime Medicine is able to establish and maintain for intellectual property rights covering its Prime Editing technology; Prime Medicine’s ability to identify and enter into future license agreements and collaborations; Prime Medicine’s expectations regarding the anticipated timeline of its cash runway and future financial performance; and general economic, industry and market conditions. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Prime Medicine’s most recent Annual Report on Form 10-K, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Prime Medicine’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Prime Medicine explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
Investor and Media Contacts
Gregory Dearborn
Prime Medicine
857-209-0696
gdearborn@primemedicine.com
Hannah Deresiewicz
Precision AQ
212-362-1200
hannah.deresiewicz@precisionaq.com
Exhibit 99.3 Delivering on the promise of Prime Editing Corporate Presentation May 2025 1
Forward Looking Statements This presentation contains forward-looking statements of Prime Medicine, Inc. ( Prime , we or our ) within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. These forward-looking statements contain information about our current and future prospects and our operations, which are based on currently available information. All statements other than statements of historical facts contained in this presentation, including statements regarding our strategy, projects and plans are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “hope,” “intend,” “may,” “might,” “objective,” “opportunity,” “plan,” “predict,” “positioned,” “possible,” “potential,” “project,” “seek,” “should,” “strategy,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, express or implied statements about Prime’s beliefs and expectations regarding: the potential of Prime Editing to correct the causative mutations of diseases, including CGD, Wilson’s Disease, CF, and AATD; the continued development and advancement of its AATD and Wilson’s Disease programs, including the timing of the filing of IND and/or CTA applications in mid-2026 and 1H 2026, respectively, and the timing of initial data for both programs in 2027; the initiation, timing, progress and results of our research and development programs, preclinical studies and clinical trials, including the release of data; the safety profile of Prime Editing, our modular LNP, and our programs; our ability to launch therapeutics; the timing of, and our ability to achieve, clinical validation and sustained, long-term value creation; the modularity of the Prime Editing platform and the benefits thereof; the collaboration with Bristol Myers Squibb and the intended and potential benefits thereof, including the receipt of potential milestone and royalty payments from commercial product sales, if any; our expectations regarding the breadth of Prime Editing, including the potential of Prime Editing to address more than 90% of genetic diseases and to address non-genetic diseases; the continued development and optimization of various non-viral and viral delivery systems, including our universal liver-targeted LNP delivery approach; the scope of protection we are able to establish and maintain for intellectual property rights covering our Prime Editing technology; the implementation of our strategic plans for our business, programs and technology, including our ability to identify and enter into future license agreements and collaborations; regulatory developments in the United States and foreign countries; our ability to attract and retain key scientific and management personnel; our estimates of our expenses, capital requirements, and needs for additional financing; and our expectations regarding the anticipated timeline of our cash runway and future financial performance. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make due to a number of risks and uncertainties. These and other risks, uncertainties and important factors are described in the section entitled Risk Factors in our most recent Annual Report on Form 10-K, as well as any subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent our views only as of the date of this presentation and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, the occurrence of certain events or otherwise subject to any obligations under applicable law. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Certain information contained in this presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of this presentation, we have not independently verified, and make no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research and no reliance should be made on any information or statements made in this presentation relating to or based on such internal estimates and research. 2
We are advancing Prime Editing to change the course of how diseases are treated. We aim to provide safe, effective and curative treatments, which offer lifelong benefit to patients. 3
Rapid Progress Since Inception: Prime Medicine is on the Cusp of Clinical Validation and Sustainable, Long-Term Value Creation Sustained Growth and Clinical Validation and Platform Validation Commercial Success Platform Discovery Focused Execution Delivering the promise of Prime Editing Prime Editing Preclinical proof-of- Breakthrough clinical data Progress multiple clinical discovered in concept achieved in from first-in-human study programs. Dr. David Liu’s lab as multiple diseases. of Prime Editor. next-generation gene Leverage platform modularity to Focused investment on editing technology. Proprietary delivery accelerate pipeline expansion. high value programs in capabilities established. large indications. Reap the benefits of Strategic collaborations to strategic collaborations. expand and accelerate. 2019 2020 - 2023 2024 - 2026 2027 - FUTURE 4
Prime Medicine is Entering a New Era of Gene Editing: Generating Clinical Data for Multiple Programs, Leveraging Platform Modularity 2025 2026 2027+ PM577 for Wilson’s Disease: PM577 for Wilson’s Disease: PM577 for Wilson’s Disease: Prepare for 2026 clinical entry, advance File IND and/or CTA in 1H 2026; Announce initial clinical data in 2027 additional mutations pre-clinically initiate Phase 1 clinical trial AATD: AATD: AATD: Prepare for 2026 clinical entry File IND and/or CTA mid-2026; Announce initial clinical data in 2027 initiate Phase 1 clinical trial Leverage business Advance additional Advance additional high-value development to accelerate high-value programs: programs: pipeline, extend reach • Share in vivo proof-of-concept data in • File IND and/or CTA for CF and CF and initiate IND-enabling studies initiate Phase 1 clinical trials Announced positive clinical data on • Expand pipeline within priority focus • Relaunch programs targeting PM359 in CGD, reinforcing our confidence areas and beyond neurological and other large in the promise of Prime Editing indications Secure multiple additional strategic partnerships to accelerate our pipeline and bolster our financial resources AATD = Alpha-1 Antitrypsin Deficiency; CF = cystic fibrosis; IND = investigational new drug; CTA = clinical trial application; CGD = chronic granulomatous disease 5
We Believe Prime Editing is the Only Gene Editing Technology That Can Edit, Correct, Insert and Delete DNA Sequences in Any Target Tissue Deletion / Insertion Correction p47 Chronic Granulomatous Disease (CGD) Prime Editing is designed with a Point Mutation Correction wide range of genome editing Wilson’s Disease, AATD capabilities and the ability to make Prime Editor edits of any size, from small base pair swaps to large, multi-kilobase Hotspot Correction REPLACEMENT Cystic Fibrosis, Retinitis inversions or insertions. This Pigmentosa (RHO adRP) provides tremendous flexibility to select the right approach for each indication and editing need. Repeat Excision Repeat expansion diseases Targeted Full Gene Insertion (PASSIGE ) CAR-T, Cystic Fibrosis AATD = Alpha-1 Antitrypsin Deficiency 6
Prime Editing Has Highly Differentiated Safety Profile: No Off-Target Activity Detected in Any Lead Program No detectable off-target deletions, No detectable double No detectable No detectable chromosomal translocations or strand breakage off-target edits bystander edits rearrangements Examples from CGD program used to support IND/CTA filings No large deletions or translocations observed in bone No off-target editing detected in healthy No Off-Target Edits detected 2 marrow engrafted Prime-Edited LT-HSCs vs. Cas-9 nuclease 1 human donor CD34+ cells with Prime Editing vs. Cas9 edited cells Indel Comparison of Translocation Prim 12 e E Spa dito cer rs a snd Cas9 Deletion Translocation 3 Positive Control 60 On-target (NCF1) 40 20 0 Genomic location 1 2 Analysis of edited CD34+ cells from CGD program: Targeted in vitro Analysis of 550 potential off-target sites of off-target editing. Data from in vivo analysis from mouse bone marrow 7 3 harvested 16 weeks after engraftment was complete. Cas9 nuclease-edited cells, generated by transfecting HEK293T with sgRNA targeting NCF1 and SpCas9 mRNA. CGD = chronic granulomatous disease; HSC = hematopoietic stem cell; IND = investigational new drug; CTA = clinical trial application SpCas9 Prime Editor Percent Indels (off-target sites)
Breakthrough Initial Clinical Data Shows PM359 Safely and phox Effectively Corrects Disease-Causing Mutation in p47 CGD Treatment with PM359 led to rapid engraftment and restoration of DHR positivity, well above minimum threshold for clinical benefit in single adult patient • Successful manufacturing from single mobilization • 18-year-old male tolerated myeloablative conditioning at fully therapeutic exposures with expected adverse events (transitory mucositis, pancytopenia) • No serious adverse events attributed to PM359 • Neutrophil engraftment confirmed on day 14, platelet engraftment on day 19; markedly faster than current autologous genetic therapy benchmarks (median of day 27 and day 35, respectively*) • Rapid recovery of NADPH oxidase activity rising to 66% as measured by DHR, ~3x therapeutic threshold Exploring continued clinical development opportunities for CGD external to Prime Medicine 8 *Source: CASGEVY label DHR = dihydrorhodamine, an assay to measure NADPH oxidase activity
Prime Editing Platform Modularity Accelerates and De-Risks Ongoing Efforts, Enables Rapid Generation of New Product Candidates Off-Target Assays Prime Editors Manufacturing Clinical Delivery Nonclinical Regulatory 9
Pipeline Focused on Value Creating Opportunities Modular Lead IND- Phase Indication Delivery Discovery Platform optimization enabling 1/2 Wilson’s Disease LNP LIVER Alpha-1 Antitrypsin Deficiency LNP (AATD) 1 Cystic Fibrosis LUNG LNP/AAV (including PASSIGE ) 2 IMMUNOLOGY & Ex vivo CAR-T ex vivo ONCOLOGY (with PASSIGE ) Prime Medicine is identifying opportunities to advance its other programs, including CGD, neurological diseases, cell therapy, ocular diseases and hearing loss, in partnership or through internal efforts in the future. 1 In January 2024, entered into an agreement with CF Foundation for up to $15 million to support development of Prime Editors for Cystic Fibrosis. 10 2 In September 2024, entered into a strategic research collaboration and license agreement with Bristol Myers Squibb to develop and commercialize multiple ex vivo T cell products in immunology and oncology. LNP = lipid nanoparticle; AAV = adeno-associated virus; CGD = chronic granulomatous disease
Liver | 11 11
Prime Medicine’s Liver Franchise: Aspiring to Cure Two of the Largest Genetic Liver Diseases, Enabled by Platform Modularity Wilson’s Disease Alpha-1 Antitrypsin Deficiency Current IND-enabling activities ongoing Final stages of lead optimization Status Rapidly IND and/or CTA on track for H1’26 IND and/or CTA anticipated in mid-2026 Advancing Targeted H1069Q, R778L E342K (Pi*Z Mutation), D341H (Little Rock*) Mutations 200,000 AATD patients in the US and EU Opportunity 20,000 WD patients in US and EU (20,000 to 30,000 patients diagnosed**) • Both programs use Prime Medicine's universal, proprietary liver LNP Modularity • Planning to leverage key learnings, regulatory frameworks and manufacturing synergies from Wilson's Disease program to potentially accelerate efforts and reduce costs in AATD and any follow-on liver programs • Achieved >70% hepatocyte editing using Prime Editors delivered with universal liver LNPs in humanized mice • Achieved >50% hepatocyte editing with surrogate, unoptimized Prime Editors delivered with universal liver LNP in NHPs*** Delivery • LNP was well tolerated in NHPs at clinically relevant doses and improved tolerability vs benchmark LNP WD = Wilson’s Disease; AATD = Alpha-1 Antitrypsin Deficiency; IND = investigational new drug; CTA = clinical trial application; LNP= lipid nanoparticle; NHP = non-human primate. *Little Rock is a rare 12 mutation in the SERPINA1 gene which leads to destabilization of the A1AT protein; **Based on the estimates of 10-15% of patients diagnosed; ***Preclinical studies using unoptimized surrogate Prime Editors for genetic diseases in NHP models
Proprietary LNP–formulated Prime Editor is a Complex Multi-Component Drug Product Designed to Support Current and Future Liver Programs Ionizable LNP Modularity: • Nucleic acid encapsulation and endosomal escape Lipid 6 out of 8 components in the LNP are the same for liver programs* Helper • Stabilize and improve LNP pharmacokinetics Lipid• Facilitate membrane fusion and endosomal escape • Control particle size and stability PEG Lipids • Stealth coating reduces serum interactions and increases half-life • Improve intracellular delivery Cholesterol • Increase LNP stability Targeting • Proprietary GalNAc formulation to improve biodistribution of LNPs to hepatocytes Ligand PE mRNA* • Prime editor enzyme • pegRNA is disease and mutation specific pegRNA • ngRNA is disease and mutation specific; usage is dependent ngRNA on the Prime Editing strategy applied LNP = lipid nanoparticle; PEG = Polyethylene glycol; GalNAc = N-acetylgalactosamine; PE = Prime Editor; pegRNA = Prime Editing guide RNA; ngRNA = nicking guide RNA 13 *May require slight modifications to mRNA depending on disease context
Prime Medicine’s Modular LNP Dosed as a Single Administration in Cynomolgus Monkey (NHP) With Minimal, If Any Safety Concerns • Well-tolerated: no acute reactions, clinical observations, or body weight changes • Transient LFT elevations • No change in platelets, coagulation or blood count • No change in blood biochemistry • Minimal changes in IL6 levels • No other cytokine changes • No change in liver histopathology (H&E) • Animals healthy at 44 weeks • Benchmarked favorably against other LNPs in clinical development LNP = lipid nanoparticle; LFT = Liver Function Tests; H&E = hematoxylin and eosin 14
Wilson’s Disease Confidential | 15 15
Advancing Prime Editors for Wilson’s Disease: Disease Overview Large genetically defined disease well suited for Prime Editing Disease Severity and Opportunity Healthy Blood • Common liver and systemic disease presenting in teens to 20s • Leads to liver failure, neurocognitive decline and premature death Copper ceruloplasmin • Greater than 20,000 patients in US and Europe, 30-50% harboring H1069Q mutation CTR1 • R778L is the predominant mutation in Asian population ATP7B ATP7B Unmet Need Bile (fecal excretion) • Many patients die without liver transplant • No approved disease modifying therapies Wilson’s Blood (urinary excretion) • Current standard of care aims to prevent copper accumulation; options include Disease chelating agents and low copper diet Copper ceruloplasmin X Human Biology CTR1 ATP7B ATP7B • Autosomal recessive due to loss of function mutations in ATP7B X • Affects copper homeostasis, leading to toxic accumulation of copper in liver and brain Bile • Correction of 20-30% of hepatocytes may be curative 16
Prime Editor Efficiently Corrects the H1069Q Mutation Resulting in Liver Copper Reduction In Vivo Editing efficiency and copper reduction in fully humanized homozygous p.H1069Q ATP7B mouse model Efficient correction of the H1069Q PM577 drove 75% reduction in copper transversion mutation accumulation in the liver Prime has initiated IND-enabling activities planning for a H1’26 IND and/or CTA application(s) IND = investigational new drug; CTA = clinical trial application 17 * % Normalized to saline treated
Alpha-1 Antitrypsin Deficiency (AATD) Confidential | 18 18
Advancing Prime Editors for AATD: Disease Overview Disease Severity and Opportunity • AATD is an inherited genetic disorder that causes low levels of A1AT protein • Low levels of A1AT protein increases the risk of lung disease (emphysema) • Patients are also at risk of liver disease (cirrhosis) caused by mutant protein aggregation • Approximately 200,000 patients in the US and EU, ~10-15% of which are diagnosed today Unmet Need • Many patients progress to liver failure or severe lung disease, requiring transplant • Current standard of care includes chronic A1AT augmentation therapy for lung disease; no approved curative therapies • No approved treatments for liver disease Human Biology • Autosomal codominant disorder due to mutations in SERPINA1 gene We believe Prime Editing is uniquely • Lung: lack of functional A1AT leads to unrestricted neutrophil elastase activity, among well-suited to correct mutant A1AT other pathological changes (loss of function) • Liver: defective A1AT protein misfolding and accumulation (gain of function) protein to wild-type without the risk • 20-30% correction in hepatocytes could be curative of bystander edits 19 AATD = Alpha-1 Antitrypsin Deficiency; A1AT = alpha-1 antitrypsin
AATD Program Objective: Normalize A1AT Levels in PiZZ Genotype Patients to Healthy Human Levels 50 40 ` Normal human range 30 20 11uM is minimum threshold for benefit 10 0 Genotype MM MS SS MZ SZ ZZ NULLNULL Healthy Low Target patient Human Risk population** • Correcting circulating AAT protein to »20uM or more restores to healthy levels and predicted to prevent disease progression • 11uM is the current minimum level accepted by Regulators for replacement therapies • Decreased Z-AAT in the liver will potentially ameliorate the liver manifestations of AATD • Prime Editing corrects the mutation while leaving it under endogenous control *Taken from Vidal R, Blanco I, Casas F, et al. Arch Bronconeumol. 2006;42(12):645-59 and Ferrarotti I, Thun GA, Zorzetto M, et al. Thorax 2012; 67: 669–674; ** ZZ genotype contain Pi*Z mutation; Z-AAT = mutant A1AT protein. There are many genotypes (alleles) of the AATD gene. The M genotype is the most common and encodes for the normal (wild-type), fully functional AATD protein (M-AAT), and most people have the MM genotype (i.e., two, fully functional copies of the normal gene and normal AATD levels). The Z genotype (PI*Z mutation) encodes for a dysfunctional protein (Z-AAT) and patients with the ZZ genotype also have low levels of AATD, and develop the disease of AATD deficiency, with lung and liver manifestations. MZ heterozygotes serum A1AT levels are usually lower but sufficient, so they only carry some risk in the setting of other contributory factors. The S genotype is less common, and encodes for a protein that 20 is not fully functional; combinations of the S genotype (e.g., MS) are not usually associated with increased risk, others (e.g., SS) can carry low risk, while SZ have serum A1AT levels usually below the protective threshold value, putting people at increased risk of developing emphysema and chronic bronchitis. Serum A1AT Concentration (μM)
Prime Editor Efficiently Corrects the Mutation Resulting in M- AAT Protein Restoration In Vivo Efficient correction Restoration M-AAT Protein** AATD program in final stages of lead optimization; planning to file an IND and/or CTA in mid-2026 • Prime Editor restores AAT levels into healthy human range in fully humanized mouse model • Potential to correct mutated protein back to wild type (M-AAT) without bystander or off-target edits M-AAT = healthy A1AT protein; Z-AAT = mutant A1AT protein; IND = investigational new drug; CTA = clinical trial application 21 *Performed by LC-MS; **Analysis at day 7 Note: data generated with research LNP, positive control = healthy human serum
Lung | 22 22
Advancing Prime Editors for Cystic Fibrosis (CF), a Disease for Which There is No Curative Therapy Large genetically defined disease well suited for Prime Editing Disease Severity and Opportunity Healthy • Progressive, genetic disease that affects the lungs, pancreas and other organs, leading to premature death • Impacts close to 40,000 people in the United States, ~1,000 new cases diagnosed each year Unmet Need • Existing treatment options include airway clearance, inhaled medicines, pancreatic enzyme supplements, fitness plans and CFTR modulators for patients with specific mutations • No cure and existing treatments are ineffective for, or not tolerated by, approximately 15% Cystic Fibrosis of patients Human Biology • Autosomal recessive disorder caused by mutations in the CFTR gene, which cause CFTR protein to become dysfunctional • Dysfunctional CFTR reduces chloride and bicarbonate transport to epithelial lumen We believe Prime Editing-based approaches could eventually benefit more than 93% of all people with CF CFTR = cystic fibrosis transmembrane conductance regulator 23
Parallel Prime Editing Approaches to CF: Hotspot and PASSIGE In 2024, Prime Medicine entered into agreement with CF Foundation for up to $15 million to support development of Prime Editors for CF Hotspot PASSIGE Eight hotspot Prime Editors could address the “high unmet Potential to address nearly all CF patients with a single need” mutations; these same Prime Editors could address super exon insertion strategy >93% of all CF patients attB CFTR gene showing exons & introns* DNA donor + Bxb1 attP Super exon SA 3’ UTR Restoring CFTR function in Prime Edited cells under endogenous control CF = cystic fibrosis; attP = complimentary recognition sequence for attb; SA = splice acceptor; 3’ UTR = 3’ untranslated region; *Exons in gray introns in black; 24
Prime Medicine has Made Significant Progress Pursuing Five “High Unmet Need” Hotspot Mutations Phenotypic Restoration of CFTR in In vitro Prime Editor in Primary HBEs differentiated ALI culture CFTR VCL G542X Prime HOM Edited Efforts towards in vivo delivery to humanized mice and large animals using Prime’s LNP ongoing • We believe primary human lung progenitor data most predictive of in vivo efficacy • Comprehensive suite of assays in development to enable selection of development candidate and advance to IND enabling studies • Humanized mouse colonies, ferret and NHP colony established for in vivo optimization • Prime’s targeted modular lung LNP as well as alternative delivery system are being applied to accelerate CF hotspot editing in vivo LNP = lipid nanoparticle; NHP = non-human primate; CFTR = cystic fibrosis transmembrane conductance regulator; HBEs = human bronchial epithelial cells; ALI = air-liquid 25 interface
Immunology and Oncology | 26 26
Strategic License and Broad Collaboration Agreement with Bristol Myers Squibb (BMS) to Develop Prime Edited ex Vivo CAR-T Products First broad, multi-target collaboration advancing Prime Editing for the treatment of complex oncology and autoimmune indications • $110 million upfront • >$3.5 billion in potential milestones, including: Leadership in Prime Editing; PASSIGE ‒ $185 million in preclinical milestones technology may enable one-step, non- viral, multi-kilobase-size editing ‒ $1.2 billion in development milestones approach with no double-stranded breaks ‒ More than $2.1 billion in commercial milestones Global leader in cell therapy for ‒ Royalties on net sales hematology, immunology and oncology • Multiple targets in immunological diseases and cancer, beyond the genetic diseases in Prime Medicine’s internal pipeline Prime Medicine retains rights to advance certain target reagents designed under this collaboration for applications beyond ex vivo T cell products, including in vivo T cell and other cell therapy applications 27
CAR-T: PASSIGE and Multiplex Prime Editing is the Foundation of Prime Medicine’s Collaboration with BMS Platform modularity has potential to accelerate development of additional CAR-T Programs Existing Limitations Prime Editing Solution ✓ >80% integration efficiency of CAR, aimed at TRAC ꭗ Low payload integration efficiency locus to maintain endogenous control Multiplex ꭗ Constrained to limited number of knock-outs Engineering ✓ Capable of multiple edits done safely, each with a and limited single base pair changes full suite of functional modifications ✓ Precise on-target transgene integration ✓ Based on our extensive off-target evaluations in ꭗ Random or semi-random integration other settings, there is the potential for no Safety ꭗ High rate of translocations / chromosomal detectable off-target edits, translocations, or abnormalities unintended structural abnormalities in Prime- Edited CAR-T’s ꭗ Dependence on viral components✓ Entirely non-viral manufacturing process Manufacturing / Cost of Goods ꭗ Complicated by multi-step engineering✓ Single-step editing and integration TRAC = T-cell receptor alpha constant; Data presented at ASH, December 2022, ASGCT, May 2023 and ASH, December 2023 28
Beyond Precisely Inserting a Chimeric Antigen Receptor, We Can Simultaneously and Efficiently Multiplex Edit CAR-T Cells Prime Editors can be multiplexed to introduce multiple genomic modifications in CAR-T cells High efficiency multiplex editing of B2M and TRAC Maintained efficiency with five multiplex edits 100 100 SSi in ng glep leple le xx 80 80 100 Multiplex Multiplex 80 60 60 60 40 40 40 20 20 20 0 0 TRAC B2M Target 3 Target 4 Target 5 0 B2M TRAC B2M TRAC B2M = b2 macroglobulin; TRAC = T-cell receptor alpha constant 29 % Prime Editing % Prime Editing % Prime Editing % Singleplex Prime Editing
Corporate | 30 30
Beyond BMS, Business Development Will Continue to Play a Critical Role in Building Prime Medicine Prime Medicine remains active in sell-side business development, with the goal of accelerating our pipeline, bolstering our financial resources Partnering Strategy Current Relationships Within Our Core Within the Core BMS Enabled by Develop Prime Edited CAR-T products scientific leveraging PASSIGE and platform leadership in Outside Our Core gene editing and program CF Foundation advancement Funding to accelerate the development of Prime Editors for Cystic Fibrosis Enabling Innovation 31
Prime Medicine Holds Extensive, Foundational Intellectual Property for Prime Editing Technologies • Multiple configurations of RNA-templated gene editing - Prime Editor protein configurations: fusion, separate and split configurations - pegRNA configurations: fusion, split, separate and engineered configurations - Dual flap and dual guide RNA editing systems • Broad diversity of RNA-templated gene editing systems Seminal Prime Dual Flap Prime Editing PASSIGE System Editing Publication - Large variety of nucleic acid programmable DNA binding proteins - Extensive range of RNA-dependent DNA polymerases (reverse transcriptases) • PASSIGE: System using Prime Editing and recombinase to insert gene-sized DNA at chosen target location in genome - PASSIGE systems include various gene editing configurations and recombinases • Additional gene editing technology including DNA-dependent DNA PE4, PE5, PEmax Engineered pegRNAs pegRNA Enhancements polymerase editing • Program-specific patent filings for pipeline programs Prime Medicine holds 6 U.S. and 10 ex-U.S. issued patents - Numerous Prime-owned and in-licensed patent applications with broad coverage Improved Novel RT Proteins Novel PE Proteins recombinases filed worldwide - Pursuing aggressive filing strategy to cover technological advances pegRNA = Prime Editing guide RNA 32
Prime Medicine is the Leader in Gene Editing Positioned to Create Sustainable Value Through Pipeline Execution and External Partnerships 4 Potential to address more than 90% of genetic diseases and opportunities in non -genetic diseases The Leader in Prime 4 Pre-clinical efficacy across variety of target tissues leveraging various types of Prime Editing Editing 4 Comprehensive intellectual property position Platform 4 Fully integrated modular platform - pre-clinical, clinical, manufacturing, regulatory Modularity 4 Proprietary modular delivery systems within target tissues Oriented for 4 Advancing Prime Editing regulatory paradigms - streamlined development Growth Pipeline 4 PM577 in Wilson’s Disease IND and/or CTA expected in H1’26; AATD IND and/or CTA expected in mid-2026 Positioned 4 Strategically focused on programs in large genetic diseases, with clear path to value inflection and multi for Value billion-dollar opportunities Creation 4 BMS partnership to develop Prime Edited ex vivo CAR-T products Partnerships and BD 4 Cystic Fibrosis Foundation relationship and funding to advance Prime Editors for Cystic Fibrosis Potential 4 Additional business development to accelerate and expand pipeline Cash equivalents, investments and restricted cash of $158.3M as of 3/31/2025, cash runway into H1’26 AATD = Alpha-1 Antitrypsin Deficiency; IND = investigational new drug; CTA = clinical trial application 33
Appendix | 34 34
Prime Editing is Designed with a Wide Range of Genome Editing Capabilities Flexibility to select right approach for each indication based on editing need Small edits Mid-sized edits Large deletions Large insertions or Prime Editing (e.g., all 12 bp swaps, 1-bp to 20- (e.g., hotspot corrections, del up (e.g., multi-kb repeat excision, inversions Approach bp ins or del, combinations to 1-kb, ins up to 250 bp) exon del) (e.g., targeted multi-kb gene thereof) integration) Short Flap +++ Prime Editing Dual Flap ++ +++ +++ Prime Editing Long Flap ++ +++ ++ Prime Editing + + +++ PASSIGE = capable of the edit +/++/+++ = how fit Prime Medicine believes the technology is for making the edit, based on Prime Medicine’s internal assessment BP = base pair; KB = kilobase 35
PASSIGE Technology Enables Prime Editing to Insert Gene Sized Sequences Precisely, Potentially Addressing Large Markets PASSIGE: Prime-Assisted Site-Specific Integrase Gene Editing: One step non-viral multi-kilobase-size gene editing approach with no double-stranded breaks Where we are working today: Non-viral, multiplex-edited CAR-T therapies Cystic Fibrosis BMS collaboration (e.g., oncology and autoimmune diseases) X-Linked Chronic Granulomatous Disease (XCGD) Areas of opportunity:* Targeted whole gene replacement for Correct inversion bone marrow diseases mutations (e.g., Hereditary anemias, such as Fanconi (e.g., Hemophilia A) Anemia) Targeted whole gene replacement for rare In vivo protein factory Recombinase (e.g., GLA enzyme for Fabry’s disease) enzyme liver diseases (e.g., Phenylketonuria, Tyrosinemia) *Not part of Prime Medicine’s current pipeline 36