UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): January 4, 2021
Prelude Therapeutics Incorporated
(Exact Name of Registrant as Specified in its Charter)
| Delaware | 001-39527 | 81-1384762 | ||
| (State or other jurisdiction of incorporation or organization) |
(Commission File Number) |
(I.R.S. Employer Identification No.) | ||
| 200 Powder Mill Road Wilmington, Delaware |
19803 | |||
| (Address of principal executive offices) | (Zip Code) | |||
Registrant’s telephone number, including area code: (302) 467-1280
Not Applicable
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading |
Name of each exchange | ||
| Common Stock, $0.0001 par value per share | PRLD | Nasdaq Global Select Market |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Item 2.02 Results of Operations and Financial Condition.
On January 4, 2020, Prelude Therapeutics Incorporated (the “Company”) filed a registration statement on Form S-1 (the “Registration Statement”) with the Securities and Exchange Commission (the “SEC”) in connection with a proposed public offering of shares of the Company’s common stock by the Company (the “Offering”), which contained information regarding the Company’s preliminary estimates of certain financial metrics for the three months and fiscal year ended December 31, 2020. In the Registration Statement, the Company disclosed that it expects to report that the Company had cash and cash equivalents of approximately $218.3 million as of December 31, 2020.
The Company’s audited financial statements for the fiscal year ended December 31, 2020 are not yet available. Accordingly, the preliminary financial metrics and results included in the Registration Statement are estimates subject to the completion of the Company’s financial closing procedures and any adjustments that may result from the completion of the audit of the Company’s financial statements. The preliminary results may differ materially from the actual results that will be reflected in the Company’s audited financial statements when they are completed and publicly disclosed.
In accordance with General Instruction B.2. of Form 8-K, the information in this Item 2.02 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 liability of that section, nor shall it be deemed incorporated by reference in any of the Company’s filings under the Securities Act of 1933, as amended (the “Securities Act”), whether made before or after the date hereof, regardless of any incorporation language in such a filing, except as expressly set forth by specific reference in such a filing.
Item 7.01 Regulation FD Disclosure.
The Company is furnishing its corporate presentation which it intends to use in conferences and meetings. The full copy of the Company’s corporate presentation is filed as Exhibit 99.1 hereto.
The information furnished in Exhibit 99.1 shall not be deemed “filed” for purposes of Section 18 of the Exchange Act or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any other filing under the Exchange Act or the Securities Act except as expressly set forth by specific reference in such a filing.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Corporate Presentation dated January 2021 | |
Forward-Looking Statements
This Current Report on Form 8-K contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995 and other federal securities laws. Any statements contained herein that do not describe historical facts, including, but not limited to, statements regarding the Company’s expected cash and cash equivalents as of December 31, 2020, are forward-looking statements that involve risks and uncertainties that could cause actual results to differ materially from those discussed in such forward-looking statements. Such risks and uncertainties include, among others, the risks identified in the Company’s filings with the SEC, including its Quarterly Report on Form 10-Q for the quarter ended September 30, 2020, filed with the SEC on November 10, 2020, the Registration Statement related to the Offering, and subsequent filings with the SEC. Any of these risks and uncertainties could materially and adversely affect the Company’s results of operations, which would, in turn, have a significant and adverse impact on the Company’s stock price. The Company cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made. The Company undertakes no obligation to update publicly any forward-looking statements to reflect new information, events or circumstances after the date they were made or to reflect the occurrence of unanticipated events.
SIGNATURES
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 thereunto duly authorized.
| PRELUDE THERAPEUTICS INCORPORATED | ||||||
| Date: January 4, 2021 | By: | /s/ Brian Piper | ||||
| Brian Piper | ||||||
| Chief Financial Officer | ||||||
Exhibit 99.1 Corporate January 2021 PresentationExhibit 99.1 Corporate January 2021 Presentation
Disclaimer This presentation contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: our plans to develop and commercialize small molecule therapies, our expectations about timing and ability to commence, enroll or complete clinical studies and to obtain regulatory approvals for PRT543, PRT811, PRT1419, PRT2527 and other candidates in development, the ability of our product candidates to treat various cancers, the ability to discover additional suitable candidates for regulatory approval, the potential impact of the COVID-19 pandemic and the sufficiency of our cash and cash equivalents to fund our operations. Any statements contained herein or provided orally that are not statements of historical fact may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by such terminology as ‘‘believe,’’ ‘‘may,’’ ‘‘will,’’ ‘‘potentially,’’ ‘‘estimate,’’ ‘‘continue,’’ ‘‘anticipate,’’ ‘‘intend,’’ ‘‘could,’’ ‘‘would,’’ ‘‘project,’’ ‘‘plan,’’ ‘‘expect’’ and similar expressions that convey uncertainty of future events or outcomes, although not all forward-looking statements contain these words. Statements, including forward-looking statements, speak only to the date they are provided (unless an earlier date is indicated). These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption “Risk Factors” in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission for the fiscal quarter ended September 30, 2020. 2Disclaimer This presentation contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: our plans to develop and commercialize small molecule therapies, our expectations about timing and ability to commence, enroll or complete clinical studies and to obtain regulatory approvals for PRT543, PRT811, PRT1419, PRT2527 and other candidates in development, the ability of our product candidates to treat various cancers, the ability to discover additional suitable candidates for regulatory approval, the potential impact of the COVID-19 pandemic and the sufficiency of our cash and cash equivalents to fund our operations. Any statements contained herein or provided orally that are not statements of historical fact may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by such terminology as ‘‘believe,’’ ‘‘may,’’ ‘‘will,’’ ‘‘potentially,’’ ‘‘estimate,’’ ‘‘continue,’’ ‘‘anticipate,’’ ‘‘intend,’’ ‘‘could,’’ ‘‘would,’’ ‘‘project,’’ ‘‘plan,’’ ‘‘expect’’ and similar expressions that convey uncertainty of future events or outcomes, although not all forward-looking statements contain these words. Statements, including forward-looking statements, speak only to the date they are provided (unless an earlier date is indicated). These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption “Risk Factors” in our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission for the fiscal quarter ended September 30, 2020. 2
Prelude Therapeutics Vision Building a patient-focused precision oncology company Regulatory Strategy Efficient development path with potential for accelerated regulatory approvals Discovery Engine Powered by scientists with proven ability to deliver precision oncology medicines Commercial Approach Rapidly advancing potentially high value therapy candidates with a commitment to future patient access, awareness, and support Clinical Development Highly selected patient populations & cancers with significant unmet need 3Prelude Therapeutics Vision Building a patient-focused precision oncology company Regulatory Strategy Efficient development path with potential for accelerated regulatory approvals Discovery Engine Powered by scientists with proven ability to deliver precision oncology medicines Commercial Approach Rapidly advancing potentially high value therapy candidates with a commitment to future patient access, awareness, and support Clinical Development Highly selected patient populations & cancers with significant unmet need 3
Senior Management & Board of Directors Board of Directors Experienced. Proven. Focused. Paul Friedman, MD CEO Former CEO Mardi Dier Parsaclisib CFO Former CFO, CBO PhD Andrew Combs PhD MD, PhD Peggy Scherle David Mauro Victor Sandor, MD Chief Medical Officer EVP and Chief Scientific Officer Former Head of Chemistry CMO Kris Vaddi PhD David Bonita, MD Founder & General Chief Executive Officer Partner Founding Kelvin Neu, MD member Partner Baker Brothers Investments Deborah Morosini MD, MSW Brian Piper MBA Christopher Pierce MBA Kris Vaddi, PhD EVP and EVP and Chief Financial Officer Founder & Chief Executive Chief of Business Chief of Clinical Affairs Officer Operations 4Senior Management & Board of Directors Board of Directors Experienced. Proven. Focused. Paul Friedman, MD CEO Former CEO Mardi Dier Parsaclisib CFO Former CFO, CBO PhD Andrew Combs PhD MD, PhD Peggy Scherle David Mauro Victor Sandor, MD Chief Medical Officer EVP and Chief Scientific Officer Former Head of Chemistry CMO Kris Vaddi PhD David Bonita, MD Founder & General Chief Executive Officer Partner Founding Kelvin Neu, MD member Partner Baker Brothers Investments Deborah Morosini MD, MSW Brian Piper MBA Christopher Pierce MBA Kris Vaddi, PhD EVP and EVP and Chief Financial Officer Founder & Chief Executive Chief of Business Chief of Clinical Affairs Officer Operations 4
Prelude Therapeutics Corporate Highlights INDs approved in 3 years; 3 clinical stage molecules 3 Pipeline focused on differentiated and validated targets Highly productive target class • 1 IND filed each year in 2018, 2019, and 2020 • At least 1 additional IND anticipated in 2021 agnostic discovery engine • 1 IND planned every 12 – 18 months Multiple wholly owned programs with Lead programs, PRT543 & PRT811 (PRMT5) and PRT1419 (MCL1) target clinically validated mechanisms with fast-to-market potential differentiated product profile Compelling market opportunities Patient-inspired drug development, regulatory, and commercial strategies to address high unmet need across multiple tumor types Experienced leadership team with Deeply experienced employee base that has worked on multiple approved targeted agents marquee investors and board members 5Prelude Therapeutics Corporate Highlights INDs approved in 3 years; 3 clinical stage molecules 3 Pipeline focused on differentiated and validated targets Highly productive target class • 1 IND filed each year in 2018, 2019, and 2020 • At least 1 additional IND anticipated in 2021 agnostic discovery engine • 1 IND planned every 12 – 18 months Multiple wholly owned programs with Lead programs, PRT543 & PRT811 (PRMT5) and PRT1419 (MCL1) target clinically validated mechanisms with fast-to-market potential differentiated product profile Compelling market opportunities Patient-inspired drug development, regulatory, and commercial strategies to address high unmet need across multiple tumor types Experienced leadership team with Deeply experienced employee base that has worked on multiple approved targeted agents marquee investors and board members 5
Prelude Discovery and Development Approach Target Selection Discovery Engine Pipeline Methyltransferases Identify target mechanisms Kinases with compelling biological Novel rationale Intervention Points Degraders Leverage our advanced medicinal chemistry capabilities to create Chemical better product Leads Protein-Protein candidates Interactions Medicinal and Process Chemistry Pursue targets that drive Capabilities Focused Clinical Development cancers with high unmet Rapidly building synthetically complex Optimized for early clinical POC and rapid need molecules execution of pivotal trials Cancer Biology & Translational Expertise Deep understanding of oncogenic pathways with translational focus 6Prelude Discovery and Development Approach Target Selection Discovery Engine Pipeline Methyltransferases Identify target mechanisms Kinases with compelling biological Novel rationale Intervention Points Degraders Leverage our advanced medicinal chemistry capabilities to create Chemical better product Leads Protein-Protein candidates Interactions Medicinal and Process Chemistry Pursue targets that drive Capabilities Focused Clinical Development cancers with high unmet Rapidly building synthetically complex Optimized for early clinical POC and rapid need molecules execution of pivotal trials Cancer Biology & Translational Expertise Deep understanding of oncogenic pathways with translational focus 6
Prelude Therapeutics Pipeline Discovery/ IND Worldwide Program Indications Phase 1 Phase 2 Phase 3 Upcoming Milestones Preclinical Enabling Rights Selected Solid Tumors • Expansion cohorts (incl. ACC, HRD+) 4Q2020/1H2021 PRT543* Selected Myeloid • Data presentation (PRMT5) Malignancies 2H2021 (incl. MF and MDS) • Expansion cohorts PRT811* GBM and CNS Metastatic 1H2021 (Brain Penetrant Cancers • Initial clinical data PRMT5) YE2021 Selected Hematological • Expansion cohorts PRT1419* Malignancies 2H2021 (MCL1) Selected Solid and PRT2527 • IND 2021 Hematological Malignancies (CDK9) Multiple Genomically PRT-SCA2 • IND 2021/2022 Selected Cancers (SMARCA2) - PRT-K4 Solid Tumors• IND-enabling 2021 (Kinase) Wholly owned patent portfolio covering composition of matter and method of * Currently in Phase 1 dose escalation 7 use patents. Prior to any possible extensions, PRT543 has IP coverage into at least H2 2038, while PRT811 and PRT1419 have coverage until at least 2039Prelude Therapeutics Pipeline Discovery/ IND Worldwide Program Indications Phase 1 Phase 2 Phase 3 Upcoming Milestones Preclinical Enabling Rights Selected Solid Tumors • Expansion cohorts (incl. ACC, HRD+) 4Q2020/1H2021 PRT543* Selected Myeloid • Data presentation (PRMT5) Malignancies 2H2021 (incl. MF and MDS) • Expansion cohorts PRT811* GBM and CNS Metastatic 1H2021 (Brain Penetrant Cancers • Initial clinical data PRMT5) YE2021 Selected Hematological • Expansion cohorts PRT1419* Malignancies 2H2021 (MCL1) Selected Solid and PRT2527 • IND 2021 Hematological Malignancies (CDK9) Multiple Genomically PRT-SCA2 • IND 2021/2022 Selected Cancers (SMARCA2) - PRT-K4 Solid Tumors• IND-enabling 2021 (Kinase) Wholly owned patent portfolio covering composition of matter and method of * Currently in Phase 1 dose escalation 7 use patents. Prior to any possible extensions, PRT543 has IP coverage into at least H2 2038, while PRT811 and PRT1419 have coverage until at least 2039
PRMT5 Programs 8PRMT5 Programs 8
PRMT5 Pathway Drives Oncogenesis and Resistance Regulates transcription of genes linked to cancer cell growth and proliferation Cell cycle genes Cancer metabolism Tumor suppressors Spliceosome Histones Oncogenes Proliferative signaling Transcription Factors PRMT5 inhibition can be leveraged to potentially treat a 9 broad range of solid tumors and hematologic malignancies PRMT5PRMT5 Pathway Drives Oncogenesis and Resistance Regulates transcription of genes linked to cancer cell growth and proliferation Cell cycle genes Cancer metabolism Tumor suppressors Spliceosome Histones Oncogenes Proliferative signaling Transcription Factors PRMT5 inhibition can be leveraged to potentially treat a 9 broad range of solid tumors and hematologic malignancies PRMT5
PRMT5 Regulates Drivers of DNA Damage Repair PRMT5 inhibition suppresses DNA repair gene expression & growth of HRD+ cell lines PRMT5 promotes DNA repair and cell survival 1000 POLD1 BRCA1 100 ATM CHEK2 RAD51 ATR 10 BRCA2 PRMT5 regulates multiple DNA repair genes 1 -4 -3 -2 -1 0 1 2 3 4 PRT543 - 0.25mM 125 MDA-MB-436 100 MDA-MB-468 BRCA1/2 RAD51/51D Ku80 75 50 25 DNA Repair 0 and Cell Survival 0.0001 0.001 0.01 0.1 1 10 PRT543 (mM) PRMT5 inhibition potentially drives synthetic lethality in 10 HRD+ cancers PRMT5 -Log (q-values) 10 Relative cell count (%)PRMT5 Regulates Drivers of DNA Damage Repair PRMT5 inhibition suppresses DNA repair gene expression & growth of HRD+ cell lines PRMT5 promotes DNA repair and cell survival 1000 POLD1 BRCA1 100 ATM CHEK2 RAD51 ATR 10 BRCA2 PRMT5 regulates multiple DNA repair genes 1 -4 -3 -2 -1 0 1 2 3 4 PRT543 - 0.25mM 125 MDA-MB-436 100 MDA-MB-468 BRCA1/2 RAD51/51D Ku80 75 50 25 DNA Repair 0 and Cell Survival 0.0001 0.001 0.01 0.1 1 10 PRT543 (mM) PRMT5 inhibition potentially drives synthetic lethality in 10 HRD+ cancers PRMT5 -Log (q-values) 10 Relative cell count (%)
PRMT5 Pathway Is Clinically Validated in Multiple Cancers by GSK'595 21% OR and mPFS of 11.2 mos observed with GSK'595 in Adenoid cystic carcinoma (ACC) Highly underserved cancer in which typical OR is <10% and PFS is 4 – 6 mos Objective responses reported in other cancers; currently in dose expansion phase in multiple tumors PRMT5 Inhibition Demonstrated Objective Responses Confirmed PR in ACC Source: GSK595, ESMO 2019 Siu, Lillian L., et al. Annals of Oncology 30.Supplement_5 (2019): mdz244. ACC offers potential fast-to-market opportunity for 11 Prelude PRMT5 inhibitors PRMT5PRMT5 Pathway Is Clinically Validated in Multiple Cancers by GSK'595 21% OR and mPFS of 11.2 mos observed with GSK'595 in Adenoid cystic carcinoma (ACC) Highly underserved cancer in which typical OR is <10% and PFS is 4 – 6 mos Objective responses reported in other cancers; currently in dose expansion phase in multiple tumors PRMT5 Inhibition Demonstrated Objective Responses Confirmed PR in ACC Source: GSK595, ESMO 2019 Siu, Lillian L., et al. Annals of Oncology 30.Supplement_5 (2019): mdz244. ACC offers potential fast-to-market opportunity for 11 Prelude PRMT5 inhibitors PRMT5
Prelude PRMT5 Program Optimized for a well-balanced and differentiated profile Differentiating Mechanism of Action Potency Selectivity Optimal Chemical Substrate Prelude compounds Space competitive are co-factor (SAM) Inhibitors (GSK) competitive inhibitors ADME Pharmaceutical properties Designed and synthesized >600 compounds to select 12 PRT543 and PRT811 for advancement PRMT5Prelude PRMT5 Program Optimized for a well-balanced and differentiated profile Differentiating Mechanism of Action Potency Selectivity Optimal Chemical Substrate Prelude compounds Space competitive are co-factor (SAM) Inhibitors (GSK) competitive inhibitors ADME Pharmaceutical properties Designed and synthesized >600 compounds to select 12 PRT543 and PRT811 for advancement PRMT5
PRT543 – Opportunity for Accelerated Development Path Potential best-in-class PRMT5 inhibitor Potential Rapid Path to Market Targets Selected Optimized Solid Tumors and PK Profile Phase 1 ongoing Differentiated Heme Malignancies PRMT5 Inhibitor Enrollment began in select High solid tumor expansion Strong oral bioavailability cohorts in 4Q2020 and expect Highly selective scientific rationale and long half-life to commence in select myeloid malignancies in early Highly potent Clinical PoC for target Differentiated safety 2021 and efficacy profile Potential for accelerated approval pathway 13 PRMT5PRT543 – Opportunity for Accelerated Development Path Potential best-in-class PRMT5 inhibitor Potential Rapid Path to Market Targets Selected Optimized Solid Tumors and PK Profile Phase 1 ongoing Differentiated Heme Malignancies PRMT5 Inhibitor Enrollment began in select High solid tumor expansion Strong oral bioavailability cohorts in 4Q2020 and expect Highly selective scientific rationale and long half-life to commence in select myeloid malignancies in early Highly potent Clinical PoC for target Differentiated safety 2021 and efficacy profile Potential for accelerated approval pathway 13 PRMT5
PRT543 – A Potent, Selective and Oral PRMT5 Inhibitor Candidate PRT543 is Highly-Selective Dose-Dependent PD Vs 36 methyltransferases in addition to a broad panel of Modulation of sDMA (symmetric dimethylation) is a receptors, transporters and channels direct measure of PRMT5 activity ~50% reduction in plasma sDMA correlates with efficacy in preclinical models PRT543 demonstrated optimized potency, dose-dependent 14 PD, and selectivity offering best-in-class potential PRMT5PRT543 – A Potent, Selective and Oral PRMT5 Inhibitor Candidate PRT543 is Highly-Selective Dose-Dependent PD Vs 36 methyltransferases in addition to a broad panel of Modulation of sDMA (symmetric dimethylation) is a receptors, transporters and channels direct measure of PRMT5 activity ~50% reduction in plasma sDMA correlates with efficacy in preclinical models PRT543 demonstrated optimized potency, dose-dependent 14 PD, and selectivity offering best-in-class potential PRMT5
PRT543 Demonstrated Broad Preclinical Activity JAK2V617F MPN Model Monotherapy Combination Oral administration of PRT543 as monotherapy and in combination with ruxolitinib led to significant decrease in spleen size in the JAK2VF bone marrow transplant model of MF. Data represent mean Ł SEM. Dotted line indicates mean spleen weight of WT transplanted mice. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. vehicle by Mann-Whitney U test. Dose-dependent activity as single agent and in combination 15 in heme and solid tumor models PRMT5PRT543 Demonstrated Broad Preclinical Activity JAK2V617F MPN Model Monotherapy Combination Oral administration of PRT543 as monotherapy and in combination with ruxolitinib led to significant decrease in spleen size in the JAK2VF bone marrow transplant model of MF. Data represent mean Ł SEM. Dotted line indicates mean spleen weight of WT transplanted mice. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. vehicle by Mann-Whitney U test. Dose-dependent activity as single agent and in combination 15 in heme and solid tumor models PRMT5
PRT543 Phase 1 Clinical Trial as of September 1, 2020 4Q2020 / Early 2021 Expansion cohorts Expansion Cohorts Dose Escalation in selected patients 35mg Adenoid Cystic Carcinoma (N~20) QD 50mg Recommended QD Homologous Recombination 35mg Expansion Dose Deficient (HRD+) Solid Tumors 5x/wk 8 45mg (N~20) BIW 7 22.5mg Solid Tumors with Spliceosome BIW 6 Mutations (N~20) 15mg BIW 5 40 mg 10mg TIW Recommended 4 BIW 40 mg Group A Myelofibrosis Monotherapy 5mg Expansion Dose BIW (N~20) BIW 3 Solid 20mg BIW Tumors 5 2 10mg Myelofibrosis and NHL BIW PRT543 + Ruxolitinib (N~20) 4 1 5mg BIW 3 Group B Myeloid Malignancies with MDS and 2 Spliceosome Mutations (N~20) Myelofibrosis 1 16 Potential for PoC in multiple cancers in 2021 PRMT5PRT543 Phase 1 Clinical Trial as of September 1, 2020 4Q2020 / Early 2021 Expansion cohorts Expansion Cohorts Dose Escalation in selected patients 35mg Adenoid Cystic Carcinoma (N~20) QD 50mg Recommended QD Homologous Recombination 35mg Expansion Dose Deficient (HRD+) Solid Tumors 5x/wk 8 45mg (N~20) BIW 7 22.5mg Solid Tumors with Spliceosome BIW 6 Mutations (N~20) 15mg BIW 5 40 mg 10mg TIW Recommended 4 BIW 40 mg Group A Myelofibrosis Monotherapy 5mg Expansion Dose BIW (N~20) BIW 3 Solid 20mg BIW Tumors 5 2 10mg Myelofibrosis and NHL BIW PRT543 + Ruxolitinib (N~20) 4 1 5mg BIW 3 Group B Myeloid Malignancies with MDS and 2 Spliceosome Mutations (N~20) Myelofibrosis 1 16 Potential for PoC in multiple cancers in 2021 PRMT5
PRT543 Phase 1 – Interim PK/PD Results Demonstrated Predictable Profile as of September 1, 2020 Dose-Proportional Increase in Exposure Dose-Dependent Decrease in Serum sDMA (Day 1) * PD Samples -72h post dose * * * * Serum was obtained from patients at various times following administration of PRT543 and analyzed for sDMA levels by Parameter 35 mg (5x) 50 mg QD LC/MS. The data are shown as % relative to pre-dose levels C (nM) 1976 2130 max T (h) 7 16 1/2 AUC (mM.h/wk) 96 243 Trough Level target based on Preclinical models PRT543 is currently in a dose range that provides target 17 coverage predicted based on preclinical models PRMT5PRT543 Phase 1 – Interim PK/PD Results Demonstrated Predictable Profile as of September 1, 2020 Dose-Proportional Increase in Exposure Dose-Dependent Decrease in Serum sDMA (Day 1) * PD Samples -72h post dose * * * * Serum was obtained from patients at various times following administration of PRT543 and analyzed for sDMA levels by Parameter 35 mg (5x) 50 mg QD LC/MS. The data are shown as % relative to pre-dose levels C (nM) 1976 2130 max T (h) 7 16 1/2 AUC (mM.h/wk) 96 243 Trough Level target based on Preclinical models PRT543 is currently in a dose range that provides target 17 coverage predicted based on preclinical models PRMT5
PRT543 Favorable Phase 1 Safety Profile as of September 1, 2020 Interim Safety data available for 41 patients 30 in Group A (solid tumors and NHL); 11 in Group B (myeloid malignancies) AE profiles similar between patient groups Primarily GI and manageable with standard treatments Diarrhea, nausea and fatigue Mostly Grade 1-2 Discontinuations: No patients discontinued study therapy due to adverse events Reversible thrombocytopenia is the most common hematological toxicity Dose limiting in solid tumor cohort at 50 mg QD No DLTs were seen at the 35mg QD dose; however, 3 of 5 patients experienced Grade 3 thrombocytopenia and were dose reduced to 35mg 5x weekly dose Only 1 of 8 patients has experienced Grade 3 thrombocytopenia at 35 mg 5x weekly dose 1 SAE related to study therapy (grade 4 thrombocytopenia) Platelets recovered to baseline levels after a one to two week drug holiday Deaths: No drug-related deaths reported, 9 deaths reported total on study PRT543 demonstrated good tolerability at doses up to 18 35 mg PRMT5PRT543 Favorable Phase 1 Safety Profile as of September 1, 2020 Interim Safety data available for 41 patients 30 in Group A (solid tumors and NHL); 11 in Group B (myeloid malignancies) AE profiles similar between patient groups Primarily GI and manageable with standard treatments Diarrhea, nausea and fatigue Mostly Grade 1-2 Discontinuations: No patients discontinued study therapy due to adverse events Reversible thrombocytopenia is the most common hematological toxicity Dose limiting in solid tumor cohort at 50 mg QD No DLTs were seen at the 35mg QD dose; however, 3 of 5 patients experienced Grade 3 thrombocytopenia and were dose reduced to 35mg 5x weekly dose Only 1 of 8 patients has experienced Grade 3 thrombocytopenia at 35 mg 5x weekly dose 1 SAE related to study therapy (grade 4 thrombocytopenia) Platelets recovered to baseline levels after a one to two week drug holiday Deaths: No drug-related deaths reported, 9 deaths reported total on study PRT543 demonstrated good tolerability at doses up to 18 35 mg PRMT5
PRT543 Preliminary Efficacy Data as of September 1, 2020 Group A (Solid Tumors) Thirteen patients have received doses ≥35 mg 5x/week and are response evaluable per RECIST 1.1: One patient demonstrated durable confirmed complete response (CR) in HRD+ high grade serous ovarian cancer Four patients demonstrated stable disease (including an additional patient with HRD+ ovarian cancer) Four patients showed progressive disease Seven patients remain on study, of whom four are awaiting their first response assessment Group B (Myeloid Malignancies) Eleven patients have enrolled into Group B (nine MF and two MDS) and all are evaluable for response assessments as per IWG criteria: One MF patient at the 20 mg b.i.w. dose level has demonstrated an objective response of clinical improvement and continues to receive therapy beyond one year to date A second MF patient at the 40 mg t.i.w. dose level demonstrated ~66% decrease in TSS Eight patients achieved a best response of SD; two additional patients remained on study for ~1 year 19 PRMT5PRT543 Preliminary Efficacy Data as of September 1, 2020 Group A (Solid Tumors) Thirteen patients have received doses ≥35 mg 5x/week and are response evaluable per RECIST 1.1: One patient demonstrated durable confirmed complete response (CR) in HRD+ high grade serous ovarian cancer Four patients demonstrated stable disease (including an additional patient with HRD+ ovarian cancer) Four patients showed progressive disease Seven patients remain on study, of whom four are awaiting their first response assessment Group B (Myeloid Malignancies) Eleven patients have enrolled into Group B (nine MF and two MDS) and all are evaluable for response assessments as per IWG criteria: One MF patient at the 20 mg b.i.w. dose level has demonstrated an objective response of clinical improvement and continues to receive therapy beyond one year to date A second MF patient at the 40 mg t.i.w. dose level demonstrated ~66% decrease in TSS Eight patients achieved a best response of SD; two additional patients remained on study for ~1 year 19 PRMT5
Durable Confirmed CR in HRD+ High Grade Serous Ovarian Cancer Patient History Diagnosed in 2014 with tumor origin in fallopian tube Seven prior lines of therapy including PARPi Enrolled in 35mg, 5X/week; currently ongoing Based on genomic analysis of archival tumor tissue, HRD+ Mutations in genes involved in DNA damage response (ATR, RAD51D, BRCA1) Plans to confirm HRD status in validated clinical assay One target lesion per RECIST and CA125 level of 37.8 U/mL at baseline Baseline Patient Response RECIST CR at first follow up tumor assessment with associated drop in CA-125 level to 2.6 U/mL A second follow up scan performed 8 weeks after first follow up confirmed the CR and CA-125 measured 4.6 U/mL A third follow up scan performed at 24 weeks demonstrated continued CR and CA-125 measured 3.3 U/mL Patient has received 9 months of study therapy as of December 16, 2020 and Week 8 remains in CR Commencement of select solid tumor expansion cohorts began in 4Q2020 and additional solid tumor and myeloid 20 malignancies cohorts expected to begin in early 2021 PRMT5Durable Confirmed CR in HRD+ High Grade Serous Ovarian Cancer Patient History Diagnosed in 2014 with tumor origin in fallopian tube Seven prior lines of therapy including PARPi Enrolled in 35mg, 5X/week; currently ongoing Based on genomic analysis of archival tumor tissue, HRD+ Mutations in genes involved in DNA damage response (ATR, RAD51D, BRCA1) Plans to confirm HRD status in validated clinical assay One target lesion per RECIST and CA125 level of 37.8 U/mL at baseline Baseline Patient Response RECIST CR at first follow up tumor assessment with associated drop in CA-125 level to 2.6 U/mL A second follow up scan performed 8 weeks after first follow up confirmed the CR and CA-125 measured 4.6 U/mL A third follow up scan performed at 24 weeks demonstrated continued CR and CA-125 measured 3.3 U/mL Patient has received 9 months of study therapy as of December 16, 2020 and Week 8 remains in CR Commencement of select solid tumor expansion cohorts began in 4Q2020 and additional solid tumor and myeloid 20 malignancies cohorts expected to begin in early 2021 PRMT5
PRT543 Clinical Update as of December 16, 2020 Phase 1 clinical trial of PRT543 has enrolled 61 patients (42 with advanced solid tumors, one with NHL, 11 with MF, and seven with MDS) Overall safety profile unchanged from the September 1, 2020 data cutoff and consistent between both Groups A and B Majority of drug related adverse events continue to be grade 1-2 with anemia and thrombocytopenia being the most common grade 3-4 adverse events 24 SAEs have been reported amongst 11 patients, with 3 individual SAEs deemed drug related Thrombocytopenia remains only dose-limiting toxicity No patients have discontinued study due to adverse events ACC expansion cohort initiated at a dose/schedule of 35mg 5x weekly, with opportunity for intra- patient dose adjustment Both 25mg QD and 50mg 5x weekly doses/schedules explored in the escalation phase, which may enable a dose titration algorithm in expansion Enrollment into additional solid tumor and myeloid malignancies cohorts is planned in early 2021 21 PRMT5PRT543 Clinical Update as of December 16, 2020 Phase 1 clinical trial of PRT543 has enrolled 61 patients (42 with advanced solid tumors, one with NHL, 11 with MF, and seven with MDS) Overall safety profile unchanged from the September 1, 2020 data cutoff and consistent between both Groups A and B Majority of drug related adverse events continue to be grade 1-2 with anemia and thrombocytopenia being the most common grade 3-4 adverse events 24 SAEs have been reported amongst 11 patients, with 3 individual SAEs deemed drug related Thrombocytopenia remains only dose-limiting toxicity No patients have discontinued study due to adverse events ACC expansion cohort initiated at a dose/schedule of 35mg 5x weekly, with opportunity for intra- patient dose adjustment Both 25mg QD and 50mg 5x weekly doses/schedules explored in the escalation phase, which may enable a dose titration algorithm in expansion Enrollment into additional solid tumor and myeloid malignancies cohorts is planned in early 2021 21 PRMT5
PRT543 Offers Broad Opportunity Across Tumor Types US Market Opportunity Tumor Types ACC: 10-15,000 patients Scientific Rationale Ovarian: 63% of ovarian tumors HRD+ TNBC: 55% of TNBC tumors HRD+ Adenoid Cystic Carcinoma Transcriptional Prostate: 25% of mCRPC tumors HRD+ HRD+ Tumors (Ovarian, TNBC, Others) Regulation Splicing Uveal Melanoma: 2,000 patients annually Uveal Melanoma Dysregulation Synthetic MF: ~12,000 intermediate/high risk patients Myeloid Malignancies Lethality MDS: 10,000 patients annually (Myelofibrosis and MDS) 22 PRMT5PRT543 Offers Broad Opportunity Across Tumor Types US Market Opportunity Tumor Types ACC: 10-15,000 patients Scientific Rationale Ovarian: 63% of ovarian tumors HRD+ TNBC: 55% of TNBC tumors HRD+ Adenoid Cystic Carcinoma Transcriptional Prostate: 25% of mCRPC tumors HRD+ HRD+ Tumors (Ovarian, TNBC, Others) Regulation Splicing Uveal Melanoma: 2,000 patients annually Uveal Melanoma Dysregulation Synthetic MF: ~12,000 intermediate/high risk patients Myeloid Malignancies Lethality MDS: 10,000 patients annually (Myelofibrosis and MDS) 22 PRMT5
PRT811 – Expanding PRMT5 Opportunity into CNS Cancers Only clinical stage brain-penetrant PRMT5 inhibitor Differentiated Targeting GBM and Potential Rapid Brain-Penetrant CNS Metastatic Optimized Path to Market PRMT5 Inhibitor Brain Cancers PK Profile Phase 1 ongoing High target High and sustained engagement in the brain exposure in Anticipated expansion brain and preclinical Highly selective preclinical studies in GBM and PCNSL activity 1H 2021 Highly potent 23 PRMT5PRT811 – Expanding PRMT5 Opportunity into CNS Cancers Only clinical stage brain-penetrant PRMT5 inhibitor Differentiated Targeting GBM and Potential Rapid Brain-Penetrant CNS Metastatic Optimized Path to Market PRMT5 Inhibitor Brain Cancers PK Profile Phase 1 ongoing High target High and sustained engagement in the brain exposure in Anticipated expansion brain and preclinical Highly selective preclinical studies in GBM and PCNSL activity 1H 2021 Highly potent 23 PRMT5
PRT811 – A Potent, Selective and Brain Penetrant PRMT5 Inhibitor Candidate PRT811 is a Potent Equivalent Potency and 100-fold SAM-Competitive PRMT5 Inhibitor Higher Brain Exposure vs GSK’595 Highly selective vs 36 methyl transferases in addition to a GSK’595 PRT811 broad panel of receptors, transporters and channels Mean Mean Plasma concentration 2.50 2.02 μmol/L Brain concentration 0.722 4.11 μmol/kg Brain/plasma ratio 0.0293 2.26 % Control < 1% > 60% > 80% PRT811 has high oral bioavailability, high brain exposure, and 24 no dose-limiting toxicities to date PRMT5PRT811 – A Potent, Selective and Brain Penetrant PRMT5 Inhibitor Candidate PRT811 is a Potent Equivalent Potency and 100-fold SAM-Competitive PRMT5 Inhibitor Higher Brain Exposure vs GSK’595 Highly selective vs 36 methyl transferases in addition to a GSK’595 PRT811 broad panel of receptors, transporters and channels Mean Mean Plasma concentration 2.50 2.02 μmol/L Brain concentration 0.722 4.11 μmol/kg Brain/plasma ratio 0.0293 2.26 % Control < 1% > 60% > 80% PRT811 has high oral bioavailability, high brain exposure, and 24 no dose-limiting toxicities to date PRMT5
PRT811 – Strong Activity Demonstrated in GBM Models GBM Orthotopic Model - sDMA PRT811 in GBM Model PRT811 Inhibited Tumor Growth PRT811 Decreased sDMA Levels in Orthotopic Brain Tumor in GBM Model Model Vehicle PRT811 We believe PRT811 is uniquely positioned to potentially 25 treat PRMT5 sensitive CNS cancers PRMT5PRT811 – Strong Activity Demonstrated in GBM Models GBM Orthotopic Model - sDMA PRT811 in GBM Model PRT811 Inhibited Tumor Growth PRT811 Decreased sDMA Levels in Orthotopic Brain Tumor in GBM Model Model Vehicle PRT811 We believe PRT811 is uniquely positioned to potentially 25 treat PRMT5 sensitive CNS cancers PRMT5
PRT811 Phase 1 Clinical Trial as of September 1, 2020 Anticipated 1H2021 Dose Escalation* Expansion Cohorts Recommended Expansion cohorts Expansion Dose 200mg In selected patients QD 120mg Glioblastoma QD (N~20) 60mg QD 5 Primary CNS Lymphoma 30mg 4 QD (N~20) 15mg Advanced Solid 3 QD Tumors 2 Glioma PCNSL 1 * (2 wks on/1 wk off) 21 day cycles 26 Potential PoC in CNS cancers in 2021 PRMT5PRT811 Phase 1 Clinical Trial as of September 1, 2020 Anticipated 1H2021 Dose Escalation* Expansion Cohorts Recommended Expansion cohorts Expansion Dose 200mg In selected patients QD 120mg Glioblastoma QD (N~20) 60mg QD 5 Primary CNS Lymphoma 30mg 4 QD (N~20) 15mg Advanced Solid 3 QD Tumors 2 Glioma PCNSL 1 * (2 wks on/1 wk off) 21 day cycles 26 Potential PoC in CNS cancers in 2021 PRMT5
PRT811 Phase 1 Interim Results Demonstrated Dose-Dependent PK as of September 1, 2020 PRT811 Pharmacokinetic Profile Day 1 M 1ean 1 5 mg 5 mg (n=3) M 3ean 3 0 mg 0 mg (n=3) 60 mg Mean 60 mg (n=3) 1000.0 Dose-dependent exposure 120 mg Mean 120 mg (n=4) 200 mg Mean 200 mg (n=4) Dose-dependent sDMA Inhibition; ~50% at IC50 200 mg dose 100.0 No unexpected AEs or drug-related SAEs 10.0 Dose escalation ongoing 1.0 0 2 4 6 8 10 12 Time, h PRT811 offers the potential to achieve desired levels of 27 PRMT5 inhibition in tissues including brain PRMT5 Plasma Concentration, nMPRT811 Phase 1 Interim Results Demonstrated Dose-Dependent PK as of September 1, 2020 PRT811 Pharmacokinetic Profile Day 1 M 1ean 1 5 mg 5 mg (n=3) M 3ean 3 0 mg 0 mg (n=3) 60 mg Mean 60 mg (n=3) 1000.0 Dose-dependent exposure 120 mg Mean 120 mg (n=4) 200 mg Mean 200 mg (n=4) Dose-dependent sDMA Inhibition; ~50% at IC50 200 mg dose 100.0 No unexpected AEs or drug-related SAEs 10.0 Dose escalation ongoing 1.0 0 2 4 6 8 10 12 Time, h PRT811 offers the potential to achieve desired levels of 27 PRMT5 inhibition in tissues including brain PRMT5 Plasma Concentration, nM
Confirmed PR in Glioblastoma Multiforme Patient History Diagnosed with recurrent GBM and originally treated with surgery and chemoradiation with Temodar in July 2019 Patient has not been treated with steroids or Avastin, and clinical status is stable Presented with progressive disease in June 2020 Enrolled in 200 mg (q.d. two weeks on/one week off) in July 2020 Patient’s tumor is: IDH1+ MGMT unmethylated Baseline One target lesion per RANO (response assessment in neuro-oncology) measuring 23 mm x 10 mm Study Follow-Up In September 2020, at patient’s first follow-up MRI evaluation (week 7) lesion measured 13 mm x 6 mm (66% reduction) Follow-up MRI at week 18 confirmed a partial response (PR) per RANO criteria and an improved regression of 77% from baseline Patient has received 5 months of study therapy as of December 16, 2020 and remains in PR and is clinically stable Week 7 28 PRMT5Confirmed PR in Glioblastoma Multiforme Patient History Diagnosed with recurrent GBM and originally treated with surgery and chemoradiation with Temodar in July 2019 Patient has not been treated with steroids or Avastin, and clinical status is stable Presented with progressive disease in June 2020 Enrolled in 200 mg (q.d. two weeks on/one week off) in July 2020 Patient’s tumor is: IDH1+ MGMT unmethylated Baseline One target lesion per RANO (response assessment in neuro-oncology) measuring 23 mm x 10 mm Study Follow-Up In September 2020, at patient’s first follow-up MRI evaluation (week 7) lesion measured 13 mm x 6 mm (66% reduction) Follow-up MRI at week 18 confirmed a partial response (PR) per RANO criteria and an improved regression of 77% from baseline Patient has received 5 months of study therapy as of December 16, 2020 and remains in PR and is clinically stable Week 7 28 PRMT5
PRT811 Clinical Update as of December 16, 2020 Phase 1 clinical trial of PRT811 has enrolled 24 patients (eight with GBM and 16 with advanced solid tumors) Overall safety profile unchanged from the September 1, 2020 data cutoff Four patients have each experienced one SAE, none of which attributed to study therapy No dose limiting toxicities have been observed One patient discontinued study therapy due to transient Grade 2 nausea 300mg QD dose cohort currently ongoing Remain on track to complete the dose escalation phase 1H21 and initiate expansion phase in cancers including GBM, PCNSL, and CNS metastatic solid tumors in the second half of 2021 29 PRMT5PRT811 Clinical Update as of December 16, 2020 Phase 1 clinical trial of PRT811 has enrolled 24 patients (eight with GBM and 16 with advanced solid tumors) Overall safety profile unchanged from the September 1, 2020 data cutoff Four patients have each experienced one SAE, none of which attributed to study therapy No dose limiting toxicities have been observed One patient discontinued study therapy due to transient Grade 2 nausea 300mg QD dose cohort currently ongoing Remain on track to complete the dose escalation phase 1H21 and initiate expansion phase in cancers including GBM, PCNSL, and CNS metastatic solid tumors in the second half of 2021 29 PRMT5
PRT811 Expands PRMT5 Opportunity into CNS Cancers US Market Opportunity Tumor Types Scientific Rationale 10,000 patients annually Glioblastoma Multiforme Transcriptional Regulation Splicing Primary CNS Lymphoma ~2,000 -~2,500 patients annually Dysregulation PRMT5i-sensitive subset of 200,000 CNS Synthetic CNS Metastatic Disease metastatic patients annually Lethality 30 PRMT5PRT811 Expands PRMT5 Opportunity into CNS Cancers US Market Opportunity Tumor Types Scientific Rationale 10,000 patients annually Glioblastoma Multiforme Transcriptional Regulation Splicing Primary CNS Lymphoma ~2,000 -~2,500 patients annually Dysregulation PRMT5i-sensitive subset of 200,000 CNS Synthetic CNS Metastatic Disease metastatic patients annually Lethality 30 PRMT5
MCL1 Program 31MCL1 Program 31
Prelude MCL1 Program Dysregulated MCL1 expression occurs frequently in cancer MCL1 is a member of BCL2 family of proteins involved in blocking cell death proteins MCL1 is a validated bypass and resistance mechanism for venetoclax (BCL2 inhibitor) and TKIs Currently active competitor compounds are IV candidates Challenging medicinal chemistry target that requires disruption of protein-protein interaction 32 Significant opportunity in post-venetoclax setting MCL1Prelude MCL1 Program Dysregulated MCL1 expression occurs frequently in cancer MCL1 is a member of BCL2 family of proteins involved in blocking cell death proteins MCL1 is a validated bypass and resistance mechanism for venetoclax (BCL2 inhibitor) and TKIs Currently active competitor compounds are IV candidates Challenging medicinal chemistry target that requires disruption of protein-protein interaction 32 Significant opportunity in post-venetoclax setting MCL1
PRT1419: Oral Differentiated Clinical-Stage MCL1 Inhibitor Candidate Targeting Selected Optimized PK Potential Rapid Heme Cancers Profile Maximizes Path to Market MCL1 Inhibitor Therapeutic Robust activity in Potent Window Phase 1 dose preclinical models with escalation ongoing once weekly dosing Selective High oral bioavailability, Anticipated expansion Synergistic with Oral permeability and in MDS/AML with venetoclax intrinsic clearance Venetoclax/Aza 33 MCL1PRT1419: Oral Differentiated Clinical-Stage MCL1 Inhibitor Candidate Targeting Selected Optimized PK Potential Rapid Heme Cancers Profile Maximizes Path to Market MCL1 Inhibitor Therapeutic Robust activity in Potent Window Phase 1 dose preclinical models with escalation ongoing once weekly dosing Selective High oral bioavailability, Anticipated expansion Synergistic with Oral permeability and in MDS/AML with venetoclax intrinsic clearance Venetoclax/Aza 33 MCL1
PRT1419: Potential Leading Oral MCL1 Inhibitor Assay AMG176 AZD5991 MIK665 PRT1419 Highly Potent Binding to MCL1 Proliferation IC (nM) 150 31 4.5 80 50 Whole Blood IC (nM) 1800 320 430 210 50 Prelude compounds -6 Caco-2 (x10 cm/s) 6 <0.1 0.2 11 are competitive inhibitors of BIM binding Human Hepat. Cl (%HBF) 42 ND ND 71 Solubility at pH 7.4 (mg/mL) 13 ND ND >1000 Route of Administration IV IV IV Oral/IV PRT1419 is a potent oral MCL1 inhibitor candidate with no 34 preclinical evidence of cardiac toxicity MCL1PRT1419: Potential Leading Oral MCL1 Inhibitor Assay AMG176 AZD5991 MIK665 PRT1419 Highly Potent Binding to MCL1 Proliferation IC (nM) 150 31 4.5 80 50 Whole Blood IC (nM) 1800 320 430 210 50 Prelude compounds -6 Caco-2 (x10 cm/s) 6 <0.1 0.2 11 are competitive inhibitors of BIM binding Human Hepat. Cl (%HBF) 42 ND ND 71 Solubility at pH 7.4 (mg/mL) 13 ND ND >1000 Route of Administration IV IV IV Oral/IV PRT1419 is a potent oral MCL1 inhibitor candidate with no 34 preclinical evidence of cardiac toxicity MCL1
PRT1419 Demonstrated Preclinical Activity as Monotherapy and in Combination Monotherapy Combination Dose-dependent activity with tumor regression at once- 35 weekly, oral dosing in hematological tumor models MCL1PRT1419 Demonstrated Preclinical Activity as Monotherapy and in Combination Monotherapy Combination Dose-dependent activity with tumor regression at once- 35 weekly, oral dosing in hematological tumor models MCL1
PRT1419: Clinical Trial Program Phase 1 Initiated in 2H2020 2021 Current Dose Escalation Expansion Cohorts Expansion cohorts in selected patients Recommended AML (N~20) Expansion Dose AML or MDS 4 PRT1419 + Venetoclax or Aza (N~20) Group A 3 High Risk MDS (N~20) AML and 2 High Risk MDS 1 Recommended Multiple Myeloma (N~20) 4 Expansion Dose Group B 3 NHL (B or T cell Lymphoma) (N~20) NHL & 2 Myeloma 1 36 Phase 1 escalation cohorts underway MCL1PRT1419: Clinical Trial Program Phase 1 Initiated in 2H2020 2021 Current Dose Escalation Expansion Cohorts Expansion cohorts in selected patients Recommended AML (N~20) Expansion Dose AML or MDS 4 PRT1419 + Venetoclax or Aza (N~20) Group A 3 High Risk MDS (N~20) AML and 2 High Risk MDS 1 Recommended Multiple Myeloma (N~20) 4 Expansion Dose Group B 3 NHL (B or T cell Lymphoma) (N~20) NHL & 2 Myeloma 1 36 Phase 1 escalation cohorts underway MCL1
PRT1419 Clinical Update as of December 16, 2020 Phase 1 clinical trial of PRT1419 has enrolled four patients with various hematological malignancies No adverse events above Grades 1 or 2 and no serious adverse events have been observed Currently enrolling AML and high-risk MDS patients into the second dose escalation cohort (200mg 1x weekly) 37 MCL1PRT1419 Clinical Update as of December 16, 2020 Phase 1 clinical trial of PRT1419 has enrolled four patients with various hematological malignancies No adverse events above Grades 1 or 2 and no serious adverse events have been observed Currently enrolling AML and high-risk MDS patients into the second dose escalation cohort (200mg 1x weekly) 37 MCL1
Preclinical Programs CDK9, SMARCA2 38Preclinical Programs CDK9, SMARCA2 38
Prelude CDK9 Program CDK9 phosphorylates RNA Pol II and regulates transcription Regulates expression of several immediate early genes driving oncogenesis and resistance (i.e. MYC, MYB, MCL1) Non-selective CDK9 inhibitors have demonstrated clinical activity in multiple tumor types but poor tolerability Lack of selectivity and potency vs other CDK9s is believed to contribute to low therapeutic window Highly-selective CDK9 inhibitors believed to have broad 39 applicability in hematological and solid malignancies CDK9Prelude CDK9 Program CDK9 phosphorylates RNA Pol II and regulates transcription Regulates expression of several immediate early genes driving oncogenesis and resistance (i.e. MYC, MYB, MCL1) Non-selective CDK9 inhibitors have demonstrated clinical activity in multiple tumor types but poor tolerability Lack of selectivity and potency vs other CDK9s is believed to contribute to low therapeutic window Highly-selective CDK9 inhibitors believed to have broad 39 applicability in hematological and solid malignancies CDK9
PRT2527: Potent and Highly Selective CDK9 Inhibitor Candidate Compound Dinaciclib AZD4573 PRT2527 Highly Selective CDK9 Inhibitor Biochemical IC (nM) CDK9 4.4 1.9 0.95 50 Candidate 11 18 Proliferation IC (nM) 50 192 196 WB IC (nM) 50 CDK1 98x 23x 73x CDK2 7x 35x 340x Prelude compounds CDK3 0.5x 2x 35x are ATP competitive Fold Selectivity CDK9 vs inhibitors CDK4 13x 53x 250x Other Isoforms CDK5 17x 37x >1000x CDK6 59x 79x >1000x CDK7 34x 150x >1000x <10x 100-10x >100x PRT2527 demonstrated improved potency and kinase 40 selectivity relative to competitor compounds in preclinical studies CDK9PRT2527: Potent and Highly Selective CDK9 Inhibitor Candidate Compound Dinaciclib AZD4573 PRT2527 Highly Selective CDK9 Inhibitor Biochemical IC (nM) CDK9 4.4 1.9 0.95 50 Candidate 11 18 Proliferation IC (nM) 50 192 196 WB IC (nM) 50 CDK1 98x 23x 73x CDK2 7x 35x 340x Prelude compounds CDK3 0.5x 2x 35x are ATP competitive Fold Selectivity CDK9 vs inhibitors CDK4 13x 53x 250x Other Isoforms CDK5 17x 37x >1000x CDK6 59x 79x >1000x CDK7 34x 150x >1000x <10x 100-10x >100x PRT2527 demonstrated improved potency and kinase 40 selectivity relative to competitor compounds in preclinical studies CDK9
CDK9 Inhibitor Candidate: PRT2527 Improved Selectivity Potent in Vitro Activity PRT2527 Sustained Regressions at Well-Tolerated Doses in Vivo PRT2527 (nM) pSer2RNAP2 MV4-11 (AML) MCL1 1500 Vehicle AZD PRT2527 AZD4573 Myc 1000 Caspase Actin 500 79% 96% 0 8 11 14 17 20 23 Days post inoculation 41 PRT2527 IND expected to be filed in 2021 CDK9 3 Tumor Volume (mm )CDK9 Inhibitor Candidate: PRT2527 Improved Selectivity Potent in Vitro Activity PRT2527 Sustained Regressions at Well-Tolerated Doses in Vivo PRT2527 (nM) pSer2RNAP2 MV4-11 (AML) MCL1 1500 Vehicle AZD PRT2527 AZD4573 Myc 1000 Caspase Actin 500 79% 96% 0 8 11 14 17 20 23 Days post inoculation 41 PRT2527 IND expected to be filed in 2021 CDK9 3 Tumor Volume (mm )
SMARCA2 Targeted Degrader Program SMARCA4 and SMARCA2 Regulate Chromatin Loss of SMARCA4 Leads to Accessibility and Gene Expression SMARCA2 Dependency Breast cancer Missense Pancreatic cancer Non-missense Loss of SMARCA4 Ovarian cancer Deep deletion Small cell lung cancer Lung squamous cell carcinoma Head and neck squamous cell carcinoma Esophageal/gastric cancer Colon adenocarcinoma Bladder cancer Uterine/Endometrioid adenocarcinoma Skin cancer/melanoma Lung adenocarcinoma 0 5 10 15 % of SMARCA4 mutation Opportunity to target 10 – 12% NSCLC with SMARCA4 42 deletions SMARCA2SMARCA2 Targeted Degrader Program SMARCA4 and SMARCA2 Regulate Chromatin Loss of SMARCA4 Leads to Accessibility and Gene Expression SMARCA2 Dependency Breast cancer Missense Pancreatic cancer Non-missense Loss of SMARCA4 Ovarian cancer Deep deletion Small cell lung cancer Lung squamous cell carcinoma Head and neck squamous cell carcinoma Esophageal/gastric cancer Colon adenocarcinoma Bladder cancer Uterine/Endometrioid adenocarcinoma Skin cancer/melanoma Lung adenocarcinoma 0 5 10 15 % of SMARCA4 mutation Opportunity to target 10 – 12% NSCLC with SMARCA4 42 deletions SMARCA2
Prelude Discovered Selective sub-nM SMARCA2 Degraders Prelude SMARCA2 Degraders Sub-Nanomolar Potency for Highly Selective for SMARCA2 SMARCA2 Degradation Replicate Genetic Synthetic Degradation Lethality PRT1003361 Cont. vs PRT2835 120 7 SMARCA2 100 6 80 PBRM1 5 60 4 40 3 SMARCD1 FEM1B 20 Degradation SMARCB1 2 IC50: 0.76nM 0 1 -20 0 0.01 1 100 10000 -2 -1 0 1 2 Conc(nM) Log2 FC vs 2835 Lead optimization in progress – IND-enabling anticipated in 43 the first half of 2021 SMARCA2 %inhibition -Log(P-value)Prelude Discovered Selective sub-nM SMARCA2 Degraders Prelude SMARCA2 Degraders Sub-Nanomolar Potency for Highly Selective for SMARCA2 SMARCA2 Degradation Replicate Genetic Synthetic Degradation Lethality PRT1003361 Cont. vs PRT2835 120 7 SMARCA2 100 6 80 PBRM1 5 60 4 40 3 SMARCD1 FEM1B 20 Degradation SMARCB1 2 IC50: 0.76nM 0 1 -20 0 0.01 1 100 10000 -2 -1 0 1 2 Conc(nM) Log2 FC vs 2835 Lead optimization in progress – IND-enabling anticipated in 43 the first half of 2021 SMARCA2 %inhibition -Log(P-value)
Prelude Therapeutics Projected Milestones H1 H2 H1 H2 2020 2021 Upcoming Milestones Expansion cohorts PRT543 (PRMT5) PRT543 4Q2020/1H2021 Phase 1 Expansion Phases (N=~160) Data presentation 2H2021 PRT811 (Brain-penetrant PRMT5) PRT811 Expansion cohorts 1H2021 Initial clinical data 2H2021 Phase 1 Expansion Phase (N=~60) PRT1419 (MCL1) PRT1419 Expansion cohorts 2H2021 Phase 1 Expansion (N=100) PRT2527 (CDK9) IND 2021 IND Target SMARCA2 IND 2021/2022 IND-Enabling 44Prelude Therapeutics Projected Milestones H1 H2 H1 H2 2020 2021 Upcoming Milestones Expansion cohorts PRT543 (PRMT5) PRT543 4Q2020/1H2021 Phase 1 Expansion Phases (N=~160) Data presentation 2H2021 PRT811 (Brain-penetrant PRMT5) PRT811 Expansion cohorts 1H2021 Initial clinical data 2H2021 Phase 1 Expansion Phase (N=~60) PRT1419 (MCL1) PRT1419 Expansion cohorts 2H2021 Phase 1 Expansion (N=100) PRT2527 (CDK9) IND 2021 IND Target SMARCA2 IND 2021/2022 IND-Enabling 44
Financial Highlights Cash and Cash Equivalents $218.3 million as of December 31, 2020 (unaudited) Includes $166.6 million net proceeds raised in September 2020 IPO Shares Outstanding 43.7 million shares voting and non-voting common stock as of September 30, 2020 55.5 million shares fully diluted 45Financial Highlights Cash and Cash Equivalents $218.3 million as of December 31, 2020 (unaudited) Includes $166.6 million net proceeds raised in September 2020 IPO Shares Outstanding 43.7 million shares voting and non-voting common stock as of September 30, 2020 55.5 million shares fully diluted 45
Prelude Therapeutics Corporate Highlights INDs approved in 3 years; 3 clinical stage molecules 3 Pipeline focused on differentiated and validated targets Highly productive target class • 1 IND filed each year in 2018, 2019, and 2020 • At least 1 additional IND anticipated in 2021 agnostic discovery engine • 1 IND planned every 12 – 18 months Multiple wholly owned programs with Lead programs, PRT543 & PRT811 (PRMT5) and PRT1419 (MCL1) target clinically validated mechanisms with fast-to-market potential differentiated product profile Compelling market opportunities Patient-inspired drug development, regulatory, and commercial strategies to address high unmet need across multiple tumor types Experienced leadership team with Deeply experienced employee base that has worked on multiple approved targeted agents marquee investors and board members 46Prelude Therapeutics Corporate Highlights INDs approved in 3 years; 3 clinical stage molecules 3 Pipeline focused on differentiated and validated targets Highly productive target class • 1 IND filed each year in 2018, 2019, and 2020 • At least 1 additional IND anticipated in 2021 agnostic discovery engine • 1 IND planned every 12 – 18 months Multiple wholly owned programs with Lead programs, PRT543 & PRT811 (PRMT5) and PRT1419 (MCL1) target clinically validated mechanisms with fast-to-market potential differentiated product profile Compelling market opportunities Patient-inspired drug development, regulatory, and commercial strategies to address high unmet need across multiple tumor types Experienced leadership team with Deeply experienced employee base that has worked on multiple approved targeted agents marquee investors and board members 46
