Full Press Release Details
Presentation March 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 PM359 and PM577, including the ongoing Phase 1/2 trial of PM359 and the timing of the anticipated release of initial clinical data readout for p47phox CGD in 2025, and the timing for completion of IND-enabling studies for PM577; the
continued development and advancement of our AATD program, including the timing for completion of lead optimization and filing of an IND and/or CTA application in mid-2026; 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 Platform Discovery Platform Validation Clinical Validation Commercial Success Delivering the promise of Prime Editing Prime Editing Preclinical proof-of- Advance
first Prime Launch therapeutics. discovered in concept achieved in Editors into the clinic. Dr. David Liu's lab as multiple diseases. Progress multiple clinical next-generation gene Focused investment on programs. editing technology.
Proprietary delivery high value preclinical capabilities established. programs. Leverage platform modularity to accelerate pipeline expansion. Strategic collaborations to expand and accelerate. Reap the benefits of 2019 2020 - 2023 strategic
collaborations. 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+ PM359 for p47phox CGD: PM359 for p47phox CGD: PM359 for p47phox CGD: Announce initial clinical data Advance into pivotal study Report pivotal data; prepare from
Phase 1/2 trial for potential launch PM577 for Wilson's Disease: PM577 for Wilson's Disease: Prepare PM577 for Wilson's Disease: File IND and/or CTA in 1H 2026; Announce initial clinical data in 2027 for 2026 clinical entry,
advance initiate Phase 1 clinical trial additional mutations pre-clinically 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 Expand pipeline within priority focus Relaunch programs targeting areas and beyond neurological and other large indications Secure multiple additional strategic partnerships to accelerate our
pipeline and bolster our financial resources CGD = chronic granulomatous disease; AATD = Alpha-1 Antitrypsin Deficiency; CF = cystic fibrosis; IND = investigational new drug; CTA = clinical trial application 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 ) XCGD, CAR-T, Cystic Fibrosis XCGD = X-linked chronic granulomatous
disease; 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 12 Spacers Translocation Prime Editors and 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)
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 8
Our Pipeline: Aligned to Core Modular Platforms, With Additional
Programs Advancing as Potential Partnership Opportunities Modular Lead IND- Phase Indication Delivery Discovery Platform optimization enabling 1/2 phox p47 Chronic Granulomatous ex vivo Disease (CGD) HEMATOLOGY, X-linked CGD IMMUNOLOGY & ex vivo
(with PASSIGE ) ONCOLOGY 1 Ex vivo CAR-T ex vivo (with PASSIGE ) Wilson's Disease LNP LIVER Alpha-1 Antitrypsin Deficiency LNP (AATD) 2 Cystic Fibrosis LUNG LNP/AAV (including PASSIGE ) Prime Medicine is identifying opportunities to advance
its other programs, including neurological diseases, cell therapy, ocu lar diseases and hearing loss, in partnership or through internal efforts in the future. 1 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. 9 2 In January 2024, entered into an agreement with CF Foundation for up to $15 million to support development of Prime
Editors for Cystic Fibrosis. LNP = lipid nanoparticle; AAV = adeno-associated virus
Hematology, Immunology and Oncology | 10 10
Chronic Granulomatous Disease phox p47 CGD and XCGD Confidential | 11
Advancing Prime Editors for Chronic Granulomatous Disease (CGD), A
Disease of Significant Unmet Need Life threatening rare genetic disease, characterized by defective neutrophil function Disease Severity and Opportunity Presents in childhood; life expectancy at least 40 years Results in recurrent,
life-threatening infections - Difficult to eradicate - Frequent hospitalizations, IV antibiotics - Potentially deadly infections from normal exposures (gardening, swimming) Causes ongoing autoimmunity and inflammation - Deteriorating lung
function - Inflammatory bowel-like syndromes - Urinary and gastrointestinal obstruction Unmet Need Current treatment options We believe Prime Editing is - Lifelong anti-microbial therapy: ultimately fails due to evolution of antimicrobial
uniquely well-suited to address resistance multiple forms of CGD - Allogeneic HSCT is only curative option: complicated by GvHD, graft failure, limited availability IV = intravenous; HSCT = hematopoietic stem cell transplant; GvHD = graft vs. host
Prime Medicine's CGD Franchise Covers Vast Majority of Patient
Population Leveraging modular elements from across the PM359 program, including the IND filing, CMC work and clinical trial, to accelerate advancement of XCGD program phox PM359 for p47 CGD X-linked CGD Program Current Initial data from Phase 1/2
clinical trial expected in 2025 Preclinical development ongoing Status Rapidly Leveraging modular elements of PM359 program to inform IND cleared in April 2024, within 30 days of submission and accelerate advancement Advancing Targeted delGT
mutation in NCF1 Greater than 90% of mutations in the CYBB gene Mutations Approach Short Flap Prime Editing PASSIGE 2 Approximately 25% of CGD Patients Approximately / of CGD Patients Opportunity 3 CGD = chronic granulomatous disease; IND =
investigational new drug 13
PM359: Preclinical Data Support Advancement for the Treatment of
Chronic Granulomatous Disease Maintenance of >85% of corrected patient long-term HSCs with complete restoration of NADPH oxidase in neutrophils observed Engraftment Editing Efficiency Phenotypic Correction Prime Edited LT-HSCs showed complete
Long-term engrafted HSCs carried precise Human neutrophils showed full engraftment in vivo correction of NCF1 correction of NADPH oxidase activity ex 100 100 vivo 100 100 100 100 80 80 80 80 80 80 60 60 60 60 60 60 40 40 40 40 40 40 20% minimal 20
20% 20 1 20 20 20 threshold 20 minimal 1 threshold 0 0 00 0 0 Prime Mock Prime Mock Prime M Mock ock Prime Healthy Prime Mo Moc ck k Prime Edited Mock Prime Edited Edited Edited Edited Edited Edited Edited Donor Edited Edited Edited CGD Patient
Human blood reconstitution by Prime Editing LT-HSCs Edited LT-HSC derived neutrophils had normal enzymatic activity (NADPH oxidase) 1 HSC = hematopoietic stem cell; LT-HSC = long term HSC; DHR = dihydrorhodamine; * normalized to
healthy donor control. Minimal threshold for patient benefit per Marciano BE, Zerbe CS, 14 Falcone EL, et al. X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. J Allergy Clin Immunol. 2018;141(1):365-371.
doi:10.1016/j.jaci.2017.04.035. Data presented at ASGCT and ESGCT 2023 Bone Marrow Chimerism Bone Marrow Chimerism + (% human CD45 ) (% human CD45+) % corrected cells % corrected cells % positive DHR* DHR oxidation (%) % positive DHR*
PM359: Clinical Trial Enrolling, Initial Clinical Data in 2025 PM359 is
comprised of autologous HSCs modified ex vivo using Prime Editing Cohort 1: Pivotal Trial* n=2-3, age 18 Cohort 2: n=2-3, ages 12-17 Cohort 3: n=2-3, ages 6-11 Initial clinical data (2025) Safety / engraftment Editing rate in
HSCs DHR as a measure of NADPH oxidase activity 15 HSC = hematopoietic stem cell; DHR = dihydrorhodamine *Pending alignment with FDA
PASSIGE has Potential to Treat X-linked CGD (XCGD) 'All in
one' delivery of PASSIGE reagents for CYBB gene replacement in CD34+ cells has potential to treat >90% of X-linked CGD patients PASSIGE reagents designed to precisely insert healthy CYBB gene sequence at prespecified site in the
patient's CYBB locus CYBB locus healthy CYBB gene Exon 1 Exon 2 (exon2-13) STOP CODON Healthy CYBB gene sequence under control of the PASSIGE demonstrated high multiplex editing efficiency endogenous CYBB regulatory elements phox
Potential synergies to accelerate leveraging p47 CGD program Predicted low risk of off-target editing Validated CGD assays and HSC models established for PM359 are applicable to X-CGD CGD = chronic granulomatous disease; X-CGD = X-linked CGD
Ex vivo CAR-T BMS Collaboration Confidential | 17 17
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 18
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 Low
payload integration efficiency locus to maintain endogenous control Multiplex 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 Random or semi-random integration other settings, there is the potential for no Safety
High rate of translocations / chromosomal detectable off-target edits, translocations, or abnormalities unintended structural abnormalities in Prime- Edited CAR-T's Dependence on viral components Entirely non-viral
manufacturing process Manufacturing / Cost of Goods 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,
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 20 % Prime Editing % Prime