UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):
(Exact Name of Registrant as Specified in its Charter)
|
|
|
|
|
||
|
|
|||||
(State or other jurisdiction of |
|
(Commission |
|
(I.R.S. Employer |
||
|
|
|
||||
|
||||||
(Address of principal executive offices) |
|
(Zip Code) |
||||
Registrant’s telephone number, including area code: (
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:
Securities registered pursuant to Section 12(b) of the Act:
|
|
|
|
|
Title of each class |
|
Trading |
|
Name of each exchange on which registered |
|
|
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
Item 2.02 Results of Operations and Financial Condition
On March 15, 2023, Prelude Therapeutics Incorporated (the "Company") issued a press release announcing its financial results for the year ended December 31, 2022. A copy of the press release is attached as Exhibit 99.1 to this report.
Item 7.01 Regulation FD Disclosure
The Company has prepared investor presentation materials with information about the Company, which it intends to use as part of investor presentations. A copy of the investor presentation materials to be used by management for presentations is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
Item 8.01 Other Events
The Company announced a clinical trial collaboration with BeiGene, for future evaluation of the Company's CDK9 inhibitor, PRT2527, in combination with BeiGene's BTK inhibitor, zanubrutinib, in hematologic malignancies. A copy of the press release is attached as Exhibit 99.3 to this report.
The information in this Current Report on Form 8-K and in Exhibits 99.1, 99.2, and 99.3 attached hereto is being furnished, but shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (“Exchange Act”), and is not incorporated by reference into any filing of the Company under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, regardless of any general incorporation language in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
|
|
|
Exhibit |
|
Description |
|
|
|
99.1 |
|
|
99.2 |
|
|
99.3 |
|
Press release issued by Prelude Therapeutics Incorporated regarding clinical trial collaboration |
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.
|
|
|
|
PRELUDE THERAPEUTICS INCORPORATED
|
|
|
|
|
Date: March 15, 2023 |
By: |
/s/ Laurent Chardonnet |
|
|
Laurent Chardonnet |
|
|
Chief Financial Officer |
Exhibit 99.1
Prelude Therapeutics Reports Full Year 2022 Financial Results and Provides Corporate Update
Four differentiated clinical compounds progressing through Phase 1 towards key data milestones
Eight abstracts accepted for presentation at the 2023 American Association for Cancer Research (AACR) Annual Meeting
Cash balance of $201.7 million as of December 31, 2022; runway remains unchanged through Q4 2024
Wilmington, DE – March 15, 2023 – Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today reported its financial results for the fiscal year ended December 31, 2022, and provided a corporate update.
“We made considerable progress in 2022, including the filing and acceptance of two new INDs for our next generation CDK4/6 inhibitor and our first-in-class, highly selective SMARCA2 degrader. Our current clinical pipeline consists of four differentiated and internally discovered molecules that effectively target and block key oncogenic pathways in both hematological malignancies and solid tumors. Prelude’s highly productive internal discovery engine continues to deliver novel molecules across multiple therapeutic classes, including significant advances in our research efforts focused on identifying an orally available SMARCA2 degrader,” stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude.
Jane Huang, M.D., President and Chief Medical Officer of Prelude stated, “Prelude's six preclinical and two clinical abstracts accepted for presentation at the upcoming AACR Annual Meeting reflect the productivity and success of our research and development efforts. Initial data from PRT2527 and PRT1419 demonstrate encouraging safety, favorable pharmacokinetic and pharmacodynamic profiles in solid tumors, and support continued advancement in hematological cancers. Looking ahead, our top priority for 2023 is to efficiently advance these compounds forward into proof-of-concept clinical studies and determine appropriate next steps for each program.”
“Our recently announced collaboration with BeiGene reflects our commitment to maximize the therapeutic value of combining our highly selective and potent CDK9 inhibitor, PRT2527, with BTK inhibitors in hematologic malignancies,” added Dr. Huang.
Program Updates and Upcoming Milestones
PRT2527- CDK9 Inhibitor Program
PRT2527 is a potent and selective small molecule that has the potential to avoid off target toxicity and achieve higher clinical activity than other CDK9 programs currently in development. The Company is currently advancing PRT2527 as monotherapy in both solid and hematological indications. The Company also intends to pursue the clinically validated approach of combining PRT2527 with approved BTK inhibitors, beginning with its recently announced clinical collaboration with BeiGene.
Key 2023 objectives for this program include:
PRT1419- MCL1 Inhibitor Program
Based on the Phase 1 dose escalation study in solid tumors, and safety measured by troponin levels and changes in ejection fraction, the Company is now advancing PRT1419 in hematologic malignancies as monotherapy. The Company also plans to study PRT1419 in combination with venetoclax and in combination with azacytidine.
Key 2023 objectives for this program include:
PRT3645-Next Generation CDK4/6 Inhibitor Program
PRT3645 is a highly selective and differentiated CDK4/6 inhibitor. PRT3645 is a CDK4 biased compound with tissue and brain penetration qualities, and has potential in multiple indications including gliomas, head and neck cancers and non-small cell lung cancer, in addition to HR+/HER2- and HR+/HER2+ breast cancers.
Key 2023 objective includes:
SMARCA2 Targeted Protein Degrader Program
PRT3789 is an IV administered, potent and highly selective SMARCA2 degrader. It is designed to achieve the requisite high selectivity for SMARCA2 over the isoform, SMARCA4, through a targeted protein degrader approach. PRT3789 is a first-in-class SMARCA2 candidate and is currently in Phase 1 clinical development in biomarker selected SMARCA4 mutant patients.
Prelude’s discovery team has also identified orally bioavailable SMARCA2 degraders.
Key objectives include:
Upcoming presentations
The following clinical abstracts will be presented at AACR 2023:
Presenter: Gerald Falchook
Presenter: Jason Henry
The following preclinical abstracts will be presented at AACR 2023:
Presenter: Anjana Agarwal
Presenter: Andrew Moore
Presenter: Michael Hulse
Presenter: Yue Zou
Presenter: Norman Fultang
Presenter: Koichi Ito
Corporate Update
On February 20, 2023, Bryant D. Lim, Esq., joined Prelude Therapeutics as Chief Legal Officer and Corporate Secretary. He has more than 20 years of experience in pharma and biotech, with expertise in business development, regulatory matters, fundraising and SEC reporting. Kris Vaddi, Ph.D. commented, “We are excited to welcome Bryant to Prelude and expand our leadership team to include his relevant expertise. Bryant is an excellent addition, helping us to move forward in our growth as a Company.”
Full Year 2022 Financial Results
About Prelude Therapeutics
Prelude Therapeutics is a clinical-stage precision oncology company developing innovative drug candidates targeting critical cancer cell pathways. The Company’s diverse pipeline is comprised of highly differentiated, potentially best-in-class proprietary small molecule compounds aimed at addressing clinically validated pathways for cancers with selectable underserved patients. Prelude’s pipeline includes four candidates currently in clinical development: PRT1419, a potent, selective inhibitor of MCL1, PRT2527, a potent and highly selective CDK9 inhibitor, PRT3645 a next generation CDK4/6 inhibitor, and PRT3789 an IV administered, potent and highly selective SMARCA2 degrader.
For more information, visit our website and follow us on LinkedIn and Twitter.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities, timing of availability and announcements of clinical results for PRT2527 and PRT1419, the timing of reporting expected findings related to PRT1419, PRT2527, PRT3645 and PRT3789, the potential benefits of Prelude’s product candidates and platform, and the sufficiency of cash and cash equivalents to fund operating expenses and capital expenditures through the fourth quarter of 2024. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, the impact of the COVID-19 pandemic on Prelude’s business, clinical trial sites, supply chain and manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude's ability to fund development activities and achieve development goals, Prelude's ability to protect intellectual property, and other risks and uncertainties described under the heading "Risk Factors" in documents Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.
PRELUDE THERAPEUTICS INCORPORATED
STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS
|
|
Year ended December 31, |
|
|||||
(in thousands, except share and per share data) |
|
2022 |
|
|
2021 |
|
||
Operating expenses: |
|
|
|
|
|
|
|
|
Research and development |
|
$ |
92,889 |
|
|
$ |
86,778 |
|
General and administrative |
|
|
30,651 |
|
|
|
26,957 |
|
Total operating expenses |
|
|
123,540 |
|
|
|
113,735 |
|
Loss from operations |
|
|
(123,540 |
) |
|
|
(113,735 |
) |
Other income, net |
|
|
8,102 |
|
|
|
2,041 |
|
Net loss |
|
$ |
(115,438 |
) |
|
$ |
(111,694 |
) |
Per share information: |
|
|
|
|
|
|
|
|
Net loss per share of common stock, basic and diluted |
|
$ |
(2.44 |
) |
|
$ |
(2.43 |
) |
Weighted average common shares outstanding, basic and diluted |
|
|
47,371,589 |
|
|
|
46,049,763 |
|
Comprehensive loss |
|
|
|
|
|
|
|
|
Net loss |
|
$ |
(115,438 |
) |
|
$ |
(111,694 |
) |
Unrealized gain (loss) on marketable securities, net of tax |
|
|
(981 |
) |
|
|
(711 |
) |
Comprehensive loss |
|
$ |
(116,419 |
) |
|
$ |
(112,405 |
) |
PRELUDE THERAPEUTICS INCORPORATED
BALANCE SHEETS
|
|
December 31, |
|
|||||
(in thousands, except share and per share data) |
|
2022 |
|
|
2021 |
|
||
Assets |
|
|
|
|
|
|
|
|
Current assets: |
|
|
|
|
|
|
|
|
Cash and cash equivalents |
|
$ |
30,605 |
|
|
$ |
31,828 |
|
Marketable securities |
|
|
171,123 |
|
|
|
259,405 |
|
Prepaid expenses and other current assets |
|
|
2,652 |
|
|
|
3,882 |
|
Total current assets |
|
|
204,380 |
|
|
|
295,115 |
|
Restricted cash |
|
|
4,044 |
|
|
|
4,044 |
|
Property and equipment, net |
|
|
4,908 |
|
|
|
3,929 |
|
Right-of-use asset |
|
|
1,792 |
|
|
|
1,707 |
|
Other assets |
|
|
5,376 |
|
|
303 |
|
|
Total assets |
|
$ |
220,500 |
|
|
$ |
305,098 |
|
Liabilities and stockholders’ equity |
|
|
|
|
|
|
|
|
Current liabilities: |
|
|
|
|
|
|
|
|
Accounts payable |
|
$ |
6,777 |
|
|
$ |
7,840 |
|
Accrued expenses and other current liabilities |
|
|
13,093 |
|
|
|
9,621 |
|
Operating lease liability |
|
|
1,832 |
|
|
|
1,740 |
|
Total current liabilities |
|
|
21,702 |
|
|
|
19,201 |
|
Other liabilities |
|
|
3,361 |
|
|
- |
|
|
Total liabilities |
|
|
25,063 |
|
|
|
19,201 |
|
Commitments |
|
|
|
|
|
|
|
|
Stockholders’ equity: |
|
|
|
|
|
|
|
|
Voting common stock, $0.0001 par value: 487,149,741 shares authorized; 36,496,994 and 36,200,299 shares issued and outstanding at December 31, 2022 and 2021, respectively |
|
|
4 |
|
|
4 |
|
|
Non-voting common stock, $0.0001 par value: 12,850,259 shares authorized; 11,402,037 and 11,402,037 shares issued and outstanding at December 31, 2022 and 2021, respectively |
|
|
1 |
|
|
1 |
|
|
Additional paid-in capital |
|
|
531,682 |
|
|
|
505,723 |
|
Accumulated other comprehensive income (loss) |
|
|
(1,692 |
) |
|
|
(711 |
) |
Accumulated deficit |
|
|
(334,558 |
) |
|
|
(219,120 |
) |
Total stockholders’ equity |
|
|
195,437 |
|
|
|
285,897 |
|
Total liabilities and stockholders’ equity |
|
$ |
220,500 |
|
|
$ |
305,098 |
|
Investor Contact:
Lindsey Trickett
Vice President, Investor Relations
240.543.7970
ltrickett@preludetx.com
Media Contact:
Helen Shik
Shik Communications
617.510.4373
Helen@ShikCommunications.com
Corporate Presentation March 2023 Exhibit 99.2
Forward Looking Statements 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, present data and clinical results or updates, and to obtain regulatory approvals for PRT1419, PRT2527, PRT3645, PRT3789, our oral SMARCA2 candidate 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). Certain data in this presentation are based on cross-study comparisons and are not based on any head-to-head clinical trials. Cross-study comparisons are inherently limited and may suggest misleading similarities or differences. This presentation shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction. These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2022.
Prelude Therapeutics: Delivering Precision Medicines to Patients with Cancer Large Commercial Opportunities Diversified Pipeline Exceptional Team Well Capitalized Powerful R&D Engine
Prelude Discovery and Development Engine: Positioned to Succeed R&D ENGINE DIFFERENTIATED PROGRAMS APPROACH CDK9 MCL1 SMARCA2 CDK4/6 Target Mechanisms that drive meaningful benefit in patients with cancer Discover Optimized molecules that overcome the limitations of current treatments Translate Science into meaningful treatments for patients Internal Discovery Engine Clinical Development Expertise
Differentiated Programs with Transformative Potential for Patients with Cancer Potentially Best-in-Class Selectivity Potential to avoid off-target toxicity and higher clinical activity Potent and Selective Degrader Potential to address major unmet need in biomarker-selected patients Optimized PK Profile Potential for maximal target engagement and improved cardiac safety Highly Selective CDK4 Bias Potential for high tissue and brain penetration and better combinability CDK9 MCL1 SMARCA2 CDK4/6 Powerful Discovery Engine generating new INDs every 12-18 months
PROGRAM CANCER INDICATIONS DISCOVERY PHASE 1 PHASE 2/3 AREAS OF CLINICAL FOCUS CDK9 PRT2527 Selected solid and hematologic malignancies R/R MCL, CLL, Aggressive Lymphomas as Monotherapy or in Combination with BTKi MCL1 PRT1419 Selected hematologic malignancies and solid tumors CLL Post Ven/BTKi, AML in combo with Azacitidine/Venetoclax CDK4/6 PRT3645 Selected solid tumors HR+/HER2-, HR+/HER2+ Breast cancer treatment through multiple lines, GBM, H&N, NSCLC in combination with KRAS inhibitors SMARCA2 PRT3789 (IV) Multiple genomically- selected cancers SMARCA4 deleted NSCLC and Other cancers SMARCA2 (Oral) Multiple genomically- selected cancers SMARCA4 deleted NSCLC and Other cancers New Programs (Multiple targets) Selected solid and hematologic malignancies Solid Tumors Heme Malignancies Prelude Precision Oncology Pipeline: Diversified and Differentiated
Driving The Programs to Key Milestones and Value Creation PRT2527 PRT1419 PRT3645 SMARCA2 CDK9 MCL1 Next Generation CDK4/6 Present solid tumor data at AACR 2023 RP2D in solid tumors in early-2023 RP2D in hematological malignancies in 2H Present initial clinical data for hematological malignancies in 2H Present solid tumor data at AACR 2023 RP2D in hematological malignancies in 2H Present initial clinical data for hematological malignancies in 2H Present initial clinical data in 2H PROGRAM 2023 MILESTONES Initiate Phase 1 in 1Q Provide Clinical update 2H PRT3789
PRT2527 CDK9 Inhibitor
CDK9 Inhibition: Targeting Cancer by Regulating Oncogene Expression CDK9 regulates expression of several oncogenes that drive cancer cell growth and resistance (i.e. MYC, MYB, MCL1) Non-selective CDK9 inhibitors have demonstrated clinical activity in multiple tumor types but poor tolerability Improving the selectivity of CDK9 inhibitors may translate to better activity and safety SUPER ENHANCER RNA Pol II TSS MYC & MYB TARGET GENES mRNA CDK9
PRT2527: Potent and Highly Selective CDK9 Inhibitor Compound AZD4573 KB0742 VIP152** PRT2527 Biochemical* IC50 (nM) CDK9 1.9 483 16 0.95 Proliferation* IC50 (nM) 11 915 84 18 Plasma* IC50 (nM) 192 1056 923 196 Fold Selectivity CDK9 vs Other Isoforms CDK1 23x >20x 371x 73x CDK2 35x >20x 147x 340x CDK3 2x >20x 37x 35x CDK4 53x >20x 38x 250x CDK5 37x >20x >600x >1000x CDK6 79x >20x 296x >1000x CDK7 150x >20x >600x >1000x Highly Selective, ATP Competitive CDK9 Inhibitor >100x 100-10x <10x *Internal data; biochemical assay at 1 mM ATP, H929 CTG proliferation assay; **VIP151 was formerly BAY151 and licensed to Vincerx by Bayer
CDK9 inhibitor: PRT2527 Phase 1 Dose-Escalation Study in Advanced Solid Tumors Phase 1 dose escalation study of PRT2527 is ongoing and enrolling following tumor types Selected sarcomas displaying a gene fusion Castrate resistant prostate cancer HR+ HER2- breast cancer Non-small cell lung cancer Solid tumors with MYC amplification Nine patients have been treated in the first three dose levels (3, 6 and 12 mg/m2 I.V. weekly), with no dose-limiting toxicities and acceptable tolerability to date Dose-dependent inhibition of CDK9 transcription targets observed in PBMCs HR+ Hormone receptor positive; HER2- Human epidermal growth factor negative ClinicalTrials.gov Identifier: NCT05159518 ASH Annual Meeting 2022 Abstract No. 210
CDK9 Inhibitor: PRT2527 Phase 1 Studies in Solid Tumors and Hematologic Malignancies PRT2527 Solid Tumors N=11 PRT2527 MYC Amplified or Overexpressed Solid Tumors, Prostate Cancer N=15 Solid Tumors Dose dependent increases in exposure and target engagement observed in Phase 1 Clinical MYC and MCL1 depletion to levels consistent with tumor regression in preclinical models Generally well tolerated Dose Confirmation Dose Escalation PRT2527 Monotherapy Aggressive B cell lymphomas (multiple types), follicular lymphoma, CLL/SLL/Richters, MCL PRT2527 N=30 Hematologic Malignancies ASH 2022 preclinical oral presentation CDK9 as a target externally validated in aggressive lymphoma and other heme malignancies Dose Confirmation Dose Escalation ClinicalTrials.gov Identifier: NCT05159518 Solid Tumor data at AACR 2023 RP2D in hematological malignancies 2H 2023 Initial clinical data in 2H 2023 ClinicalTrials.gov Identifier: NCT05665530
CDK9 Inhibitor Differentiation and Market Opportunity Potential for Improved Safety Based on Best-in-Class Kinome Selectivity PRT2527 is a highly potent CDK9 inhibitor with best-in-class kinome selectivity compared to competitor compounds Optimized PK profile to maximize therapeutic window Well-tolerated in GLP preclinical studies at doses exceeding those required for efficacy High levels of inhibition of CDK9 dependent genes in Phase 1 Market Opportunity CDK9 inhibitors in CLL, Mantle cell lymphoma, and DLBCL may address areas of high unmet need CDK9 MCL1 SMARCA2 CDK4/6
PRT2527: Broad Potential Addressing areas of High Unmet Need 1. SEER Cancer Stat Facts: https://seer.cancer.gov/statfacts/html/clyl.html; 2. Gena Kanas, et. al. Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe 3. CancerMPact® Treatment Architecture, Non-Hodgkin US, 4. CancerMPact® Treatment Architecture, Chronic Lymphocytic Leukeimia, US, 5. CLL Patient Based Forecast, Datamonitor Healthcare Broad Opportunity: ~125K patients treated annually(US): CLL, MCL and DLBCL1,2,3,4,5 Limited Treatment Options: >50% of High Risk CLL, MCL and DLBCL patients are refractory/relapsed within 1 year after 2L Treatment 2,3
PRT1419 MCL1 Inhibitor
MCL1 inhibition: Targeting Cancer Cell Survival MCL1 is a member of the BCL2 family of inhibitors of apoptosis Established resistance mechanism to the BCL2 inhibitor Venetoclax Prolonged depletion of MCL1 is undesirable and may be associated with cardiac toxicity Optimizing the PK profile of an MCL1 inhibitor may maximize the therapeutic window Mechanism
PRT1419 is Potent MCL1 Inhibitor with Demonstrated Preclinical Activity as Monotherapy and in Combination Monotherapy Combination Robust monotherapy activity also seen in models of DLBCL & MM Proliferation IC50 (nM) Whole Blood IC50 (nM) AMG176 150 1800 AZD5991 31 320 MIK665 4.5 430 PRT1419 80 210 Prelude compounds are competitive inhibitors of BIM binding
PRT1419 Does Not Cause Cardiac Injury in Preclinical Toxicology Studies Doses: 0.3, 1, 3 and 6 mg/m2; once weekly Linear increases in exposure No troponin elevations observed at any doses, even high dose which covered EC90 for 24h No histopathological evidence of cardiac injury Pharmacokinetics Pharmacodynamics
MCL1 inhibitor: PRT1419 Phase 1 Study in Hematologic Malignancies PRT1419 Monotherapy AML/MDS/CMML CLL/SLL FL/MZL/MCL N=24-30 PRT1419 Combination PRT1419+Aza: AML/MDS/CMML PRT1419+Ven: AML/MDS/CMML PRT1419+Ven: MCL N=24-30 In the solid tumor PRT1419 dose escalation Phase 1, 26 patients have been treated and 15 patients @ RP2D No cardiac toxicity seen @ RP2D as measured by ejection fraction decline/troponin elevation Solid tumor data to be presented 1H 2023 Upregulation of MCL1 is a mechanism of resistance to BCL2 inhibition, particularly in CLL and AML; Strong preclinical hypothesis in heme1 Dose Confirmation Dose Escalation ClinicalTrials.gov Identifier: NCT05107856 RP2D in heme monotherapy expected 2H 2023 Initial clinical data in 2H 2023 1 Ong et al. Cancer Drug Resist 2022;5:380-400
MCL1 Inhibitor Differentiation and Market Opportunity Optimized PK Profile to Achieve Desired Target Engagement MCL1 CDK9 SMARCA2 CDK4/6 PRT1419 is a highly potent and selective MCL1 inhibitor Designed to have a PK profile with high clearance to provide desired target engagement with improved safety No cardiotoxicity or troponin changes in GLP preclinical studies at doses exceeding those required for efficacy No evidence of cardiotoxicity in the solid tumor Phase 1 at the recommended Phase 2 dose Market Opportunity AML, MDS, CLL, MCL patients need additional treatment options
PRT1419: MCL1 Inhibitor Offers Potential Benefit for Patients with Poor Outcomes 1. SEER, https://seer.cancer.gov/statfacts/html/clyl.html; 2,3,4, CancerMPact® Treatment Architecture, * MDS number represents annual incident patients, treated patient number may be higher. Broad Opportunity: ~95K patients treated annually(US): CLL, AML, MDS 1,2,3,4 Outcomes for relapsed / refractory patients are poor: >50% of CLL, High Risk MDS and Unfit AML patients are refractory/relapsed within 1 year after second relapse2,3,4
PRT3645 Next Generation CDK4/6 Inhibitor
Next Generation CDK4/6 Inhibition: Targeting Cancer Through Cell Cycle Regulation Mechanism Validated mechanism with approval of Next Generation CDK4/6 inhibitors in HR+ breast cancer Resistance mechanism to other targeted therapies including KRAS G12C inhibitors Current CDK4/6 inhibitors limited by poor tolerability and lack broad tissue penetration Next generation CDK4/6 inhibitor with improved tolerability and tissue penetrance could translate into activity in areas of unmet need beyond HR+ breast cancer Sequential use of Next Generation CDK4/6 inhibitors in breast cancer may also improve outcomes
PRT3645 – Highly Selective Next Generation CDK4/6 Inhibitor Bias towards CDK4 over CDK6 Compound Palbociclib Abemaciclib PRT3645 Biochemical* IC50 (nM) CDK4 25 5 3 Proliferation* IC50 (nM) 52 70 47 Phospho-Rb* IC50 (nM) 28 30 16 Fold Selectivity CDK4 vs Other Isoforms CDK6 1x 6x 5x CDK1 >500x >500x >500x CDK2 >500x 173x >500x CDK3 >500x 212x >500x CDK5 >500x >500x >500x CDK7 >500x >500x >500x CDK9 209x 59x >500x >500x 500-50x 50-5x <2x *Internal data; biochemical assay at 1 mM ATP, MCF7 CTG proliferation assay; MCF7 pRB Highly Selective, ATP Competitive
Next Generation CDK4/6 inhibitor PRT3645 Improved Tissue Penetration and Robust Activity in Preclinical Models PRT3645 demonstrates higher brain penetration than approved CDK4/6 inhibitors PRT3645 shows robust activity in vivo as monotherapy and in combination U87 glioblastoma model MCF7 breast cancer model
Novel Combinations to Extend the Potential of CDK4/6 Inhibition Beyond ER+ Breast Cancer H2122 NSCLC Model DFBM-355 PDX model of ER+/HER2+ Breast Cancer PRT3645 significantly enhances the activity of KRAS G12C inhibitor in NSCLC models and with HER2 kinase inhibitor in ER+/HER2+ BC models
Next Generation CDK4/6 Inhibitor: PRT3645 Phase 1 Study in Solid Tumors A differentiated and highly brain penetrant Next Generation CDK4/6 inhibitor Potential to extend the reach of CDK4/6 inhibition beyond HR+ breast cancers, for which the first generation CDK4/6 inhibitors were approved PRT3645 Biomarker enriched patients with select tumor types including sarcomas, mesothelioma, gliomas, head and neck cancers and non-small cell lung cancer, in addition to breast cancer with or without brain metastases Dose Escalation and Confirmation ClinicalTrials.gov Identifier: NCT05538572 Initial clinical data in 2H 2023 RP2D in solid tumors in 2H 2024
Next Generation CDK4/6 Inhibitor Differentiation and Market Opportunity Deep Tissue Penetration with Potential for Activity in Areas of Unmet Need PRT3645 is a highly potent and selective Next Generation CDK4/6 inhibitor Optimized to demonstrate deep tissue penetration including brain penetrance Improved metabolic profile to allow for combination treatment in diseases beyond breast cancer Reduced toxicity in preclinical GLP studies with potential for improved tolerability in the clinic Market Opportunity: Breast cancer patients may benefit from sequential CDK4/6 inhibitors treatment There are estimated to be 65,000 breast cancer patients treated with CDK4/6 inhibitors in 2023 in the U.S. Other solid tumors (lung cancer, glioma, HER2+ breast cancer) may demonstrate activity in combination MCL1 CDK9 SMARCA2 CDK4/6
PR3789 SMARCA2 Degrader
Targeting SMARCA2 (BRM): Leveraging Synthetic Lethality The chromatin remodeling (SWI/SNF) complex is frequently mutated in cancer making it a potential therapeutic target Activity of the SWI/SNF complex requires either SMARCA4 (BRG1) or SMARCA2 (BRM) Loss of SMARCA4 (BRG1) through mutation leads to dependency on SMARCA2 (BRM) Subsets of solid tumors express SMARCA4 (BRG1) mutations Selectively inhibiting SMARCA2 (BRM) offers an attractive approach to target SMARCA4 (BRG1) mutant tumors Mechanism
Indication Any SMARCA4 Mutation1 NSCLC 10.0% Esophageal 8.0% Gastric (stomach adeno) 8.3% Skin (invasive and in situ melanoma)* 21.0% Endometrial (uterine corpus) 13.3% Squamous cell lung 7.7% Urinary (bladder) 9.0% Colorectal 6.0% Pancreatic 2.9% Melanoma (invasive) 8.7% SMARCA4 Mutations in NSCLC: An Opportunity with No Approved Therapies SMARCA4 Prevalence across selected Solid Tumors 1.cBioPortal; FoundationCore; 2.SMARCA4 LOF mutations included homozygous missense, hotspot mutations with LOF, and damaging mutations; 3.SEER 2022; Globocan; * Source: American Cancer Society – Cancer Facts & Figures 2022 Fernando et al. Nature Communications 2020 SMARCA4 Deletion – A Novel Biomarker for NSCLC Targets for Approved Drugs
PRT3789: Potent and Selective SMARCA2 Degrader with In Vivo Activity Robust Tumor Growth Inhibition of SMARCA4 mutated but not WT Xenograft Significant Degradation of SMARCA2 Protein but not SMARCA4 in Preclinical Models SMARCA4 mutant SMARCA4 WT PRT3789 PRT3789 Vehicle Low Dose Mid Dose High Dose SMARCA2 SMARCA4 LAMIN B1 SMARCA2 SMARCA4 LAMIN B1 Male Female
SMARCA2 Degrader: PRT3789 Phase 1 Study in Solid Tumors SMARCA2 inhibition has the greatest potential in patients with SMARCA4 deficient cancers, including approximately 10-20% of all non-small cell lung cancers SMARCA2 degradation to be evaluated in Phase 1 Study population: advanced, recurrent, or metastatic disease, with loss of SMARCA4 due to truncating mutation and/or deletion Biomarker selected by local NGS or IHC in tumor tissue or blood HR+ and HER2-negative or HR+ and HER2+breast cancer Recurrent GBM (IDH wild type) or CDKN2A/B homozygous deleted IDH-mutant astrocytoma KRAS-mutant NSCLC CDK pathway alternation in any of the following tumor types: malignant mesothelioma, HPV-negative HNSCC (including oral cavity, oropharynx, hypopharynx, and larynx), sarcoma, or NSCLC ClinicalTrials.gov Identifier: NCT05538572 PRT3789 Solid Tumors with loss of SMARCA4 Backfill: up to 10 participants with a minimum of 6 NSCLC participants with loss of SMARCA4 Dose Escalation and Confirmation IND cleared Q4 2022 Clinical update expected 2H 2023 ClinicalTrials.gov Identifier: NCT05639751
SMARCA2 Differentiation and Market Opportunity Potential First-in-Class SMARCA2 (BRM) Targeted Protein Degrader PRT3789 is a first-in-class SMARCA2 Degrader Potent and selective over the related isoform, SMARCA4, through a targeted protein degrader approach Improved tolerability compared to non-selective SMARCA2 inhibition Robust efficacy in SMARCA4 mutant preclinical models, providing clear patient selection strategy in the clinic Market Opportunity: 70,000 patients with SMARCA4 mutation in the US/EU5 SMARCA2 CDK4/6 MCL1 CDK9
PRT3789: Large Pan-Tumor Unmet Need in Patients with SMARCA4 Mutation Broad Opportunity: Improvement vs SoC: Most common 2L mNSCLC regimen offers minimal benefit and significant toxicity 4 SMARCA 4 Degrader offers: First in Class Treatment Option in patients with no approved drugs mPFS ~ 4.5 months docetaxel + ramucirumab NSCLC ~40% 1. Fernando, T.M., Piskol, R., Bainer, R. et al. Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients..https://doi.org/10.1038/s41467-020-19402-8; 2. https://www.mycancergenome.org/content/gene/smarca4/ 3. US SEER Database 4. CancerMPact® Treatment Architecture, NSCLC – Non Driver Mutation. CRC ~18% Urinary ~13% NSCLC ~40% CRC ~18% Urinary ~13% Distribution of Patients with SMARCA4 mutation by Tumor, based on study of ~130k patients1,2,3
Prelude Therapeutics: Key Takeaways and Reasons to Invest Current cash runway expected through Q4 2024 Potentially first-in-class SMARCA2 degrader program with a significant lead over competitors and offers transformational potential for the company Opportunity to drive programs to key inflection points in the next 12 – 24 months Emerging clinical data on CDK9 and MCL-1 programs demonstrate the potential for class-leading opportunities Deep clinical pipeline with unique and potentially best-in-class or first-in-class molecules
Experienced Management Team: Proven Track Records Andrew Combs, PhD Executive Vice President and Head of Chemistry Peggy Scherle, PhD Chief Scientific Officer Jane Huang M.D. President and Chief Medical Officer Kris Vaddi, PhD Founder & Chief Executive Officer Laurent Chardonnet, MBA Chief Financial Officer Bryant Lim, J.D. Chief Legal Officer and Corporate Secretary
Exhibit 99.3
Prelude Therapeutics Announces Clinical Trial Collaboration with BeiGene to Evaluate PRT2527 in Combination with Zanubrutinib in Hematologic Cancers
WILMINGTON, Del. – March 15, 2023 – Prelude Therapeutics Incorporated (Prelude) (Nasdaq: PRLD), a clinical-stage precision oncology company, today announced a clinical trial collaboration with BeiGene, for future evaluation of its investigational CDK9 inhibitor, PRT2527, in combination with BeiGene’s BTK inhibitor, zanubrutinib, in hematologic malignancies.
Inhibition of BTK is an active therapeutic approach in several B cell malignancies and the combination of CDK9 inhibition with BTK inhibition has demonstrated, in recent data publications, synergistic clinical efficacy over BTK inhibition alone; hence, there is a strong rationale for studying the combination in patients with certain hematologic malignancies.
“The opportunity to combine Prelude’s potent, selective and potentially best-in-class CDK9 inhibitor with BeiGene’s next-generation highly efficacious and tolerable BTK inhibitor, zanubrutinib, reflects our commitment to bringing the most promising options to patients,” said Jane Huang, MD, President and Chief Medical Officer, Prelude Therapeutics.
Under terms of the clinical trial collaboration agreement, BeiGene will provide zanubrutinib to Prelude, and Prelude will retain all global operational, development and commercialization rights and responsibilities for PRT2527.
About PRT2527
PRT2527 was designed to be a potent and selective Cyclin-dependent kinase 9, or CDK9, inhibitor. In preclinical studies, PRT2527 was shown to reduce MCL1 and MYC protein levels and was highly active in preclinical models at well-tolerated doses. PRT2527 has demonstrated high potency and kinase selectivity which may offer improved efficacy and safety compared to less selective CDK9 inhibitors, allowing for rapid development in combinations. PRT2527 is currently being studied as monotherapy in a Phase 1 dose-escalation study in advanced solid tumors, as well as in relapsed/refractory hematologic malignancies.
About Prelude Therapeutics
Prelude Therapeutics is a clinical-stage precision oncology company developing innovative drug candidates targeting critical cancer cell pathways. Prelude’s diverse pipeline is comprised of highly differentiated, potentially best-in-class and first-in-class proprietary small molecule compounds aimed at addressing clinically validated pathways for cancers with selectable underserved patients. Prelude’s pipeline includes four candidates currently in clinical development: PRT1419, a potent, selective inhibitor of MCL1, PRT2527, a potent and highly selective CDK9 inhibitor, PRT3645, a next-generation CDK4/6 inhibitor, and PRT3789 a first-in-class SMARCA2/BRM protein degrader.
For more information, visit our website and follow us on LinkedIn and Twitter.
About zanubrutinib
Zanubrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Zanubrutinib was specifically designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared
to other approved BTK inhibitors, zanubrutinib has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.
Zanubrutinib is supported by a broad clinical program which includes more than 4,700 subjects in 35 trials in more than 30 geographies. To date, zanubrutinib (BRUKINSA®) is approved in over 60 markets, including the United States, China, the European Union, Great Britain, Canada, Australia, South Korea, Iceland, Norway and Switzerland.
About BeiGene
BeiGene is a global biotechnology company that is developing and commercializing innovative and affordable oncology medicines to improve treatment outcomes and access for far more patients worldwide. With a broad portfolio, we are expediting development of our diverse pipeline of novel therapeutics through our internal capabilities and collaborations. We are committed to radically improving access to medicines for far more patients who need them. Our growing global team of more than 9,000 colleagues spans five continents, with administrative offices in Beijing, China; Cambridge, U.S.; and Basel, Switzerland. To learn more about BeiGene, please visit www.beigene.com and follow us on Twitter at @BeiGeneGlobal.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities, timing of availability and announcements of clinical results for PRT2527, the timing of reporting expected findings related to PRT2527, the potential benefits of Prelude’s product candidates, alone or in combination, and the sufficiency of cash and cash equivalents to fund operating expenses and capital expenditures into the fourth quarter of 2024. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, the impact of the COVID-19 pandemic on Prelude’s business, clinical trial sites, supply chain and manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude's ability to fund development activities and achieve development goals, Prelude's ability to protect intellectual property, and other risks and uncertainties described under the heading "Risk Factors" in documents Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.
Investor Contact:
Lindsey Trickett
Vice President, Investor Relations
240.543.7970
ltrickett@preludetx.com
Media Contact:
Helen Shik
Shik Communications
617.510.4373
Helen@ShikCommunications.com