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Item 7.01 Regulation FD Disclosure.
On December 11, 2022, Cogent Biosciences, Inc., a Delaware corporation (the “Company”), issued a press release announcing positive updated clinical data from its ongoing Phase 2 APEX trial evaluating bezuclastinib in patients with advanced systemic mastocytosis. The Company will present the updated clinical data on a webcast on December 12, 2022 at 8:00 am ET. Copies of the press release and corporate presentation are attached as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.
The information in this Current Report on Form 8-K, including Exhibits 99.1 and 99.2 attached hereto, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| Exhibit No. | Description | |
| 99.1 | Press release issued by Cogent Biosciences, Inc. on December 11, 2022, furnished herewith. | |
| 99.2 | Cogent Biosciences, Inc. corporate presentation, furnished herewith. | |
| 104 | The cover page from the Company’s Current Report on Form 8-K formatted in Inline XBRL. | |
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 hereunto duly authorized.
| Date: December 12, 2022 | COGENT BIOSCIENCES, INC. | |||||
| By: | /s/ Evan D. Kearns | |||||
| Evan D. Kearns | ||||||
| Chief Legal Officer | ||||||
Exhibit 99.1
Cogent Biosciences Announces Positive Updated Clinical Data from Ongoing Phase 2 APEX Trial Evaluating
Bezuclastinib in Patients with Advanced Systemic Mastocytosis (AdvSM)
• 89% ORR in TKI-therapy naïve patients; 73% ORR in all evaluable patients with 27-week median follow-up
• Rapid and deep responses seen including first confirmed CR at 20 weeks; 77% of patients with at least 2 cycles of
treatment had complete clearance of bone marrow mast cell aggregates
• Favorable safety and tolerability profile with no related cognitive effects or reported intracranial bleeding events
• Cogent to host investor webcast Monday, December 12 at 8:00 a.m. ET
WALTHAM, Mass. and BOULDER, Colo., December 11, 2022 — Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today announced positive updated clinical data from its ongoing Phase 2 APEX clinical trial evaluating the selective KIT D816V inhibitor bezuclastinib in patients with advanced systemic mastocytosis (AdvSM). The data are being presented in an oral presentation at the 64th American Society of Hematology (ASH) Annual Meeting in New Orleans, LA.
“Advanced systemic mastocytosis is a rare and life-threatening disease,” said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and APEX clinical trial investigator. “Updated results from the APEX trial demonstrate rapid and deep responses with bezuclastinib while maintaining an impressive safety and tolerability profile.”
“We are very encouraged by the clinical profile that bezuclastinib has shown to date,” said Andrew Robbins, President and Chief Executive Officer at Cogent Biosciences. “We are especially excited that a growing body of data supports bezuclastinib’s differentiated safety and tolerability profile enabling therapeutic exposures that could support key differentiation for both AdvSM patients and non-advanced systemic mastocytosis patients.”
Updated Data from Ongoing Phase 2 APEX Clinical Trial
APEX is a global, open-label, multi-center, two-part Phase 2 clinical trial in patients with AdvSM evaluating the safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. As of the data cutoff date of October 26, 2022, 16 patients had been treated in Part 1 at one of four dose levels (50 mg BID, 100 mg BID, 200 mg BID or 400 mg QD). The median age of patients at study entry was 69 years (ranging from 33-87 years). Patients were enrolled with the following sub-types: three patients with aggressive systemic mastocytosis (ASM), 12 patients with systemic mastocytosis with associated hematologic neo-plasm (SM-AHN), and one patient with mast cell leukemia (MCL). Three patients had received prior avapritinib and midostaurin treatment.
Updated Safety Data
As of the cutoff date October 26, 2022, bezuclastinib was generally well-tolerated at all doses. The majority of adverse events were Grade 1/2 and occurred in no more than one patient. Grade 3 events reported as at least possibly related to bezuclastinib were neutropenia (2 patients), thrombocytopenia (1 patient), anemia (1 patient) and hypersensitivity/mediator flare (1 patient). Importantly, there were no related cases of cognitive impairment and no reported intracranial bleeding events, which have been associated with other KIT inhibitors. Limited low-grade edema was observed, and analysis of platelet counts in bezuclastinib-treated patients showed no trend in platelet reduction at any dose.
Updated Clinical Activity Data
As of the cutoff date of October 26, 2022, 11 patients were evaluable for response per the modified IWG-MRT-ECNM criteria, and 12 patients were evaluable for response using pure pathological response (PPR) criteria. Reported ORR per mIWG-MRT-ECNM criteria includes centrally adjudicated confirmed and unconfirmed CR, CRh, PR, and CI.
| • | 89% ORR in TKI therapy naïve patients, including 67% of patients achieving CR, CRh or PR, and 22% of patients achieving CR or CRh |
| • | 73% ORR in all patients, regardless of prior treatment |
| • | 75% ORR in all patients by PPR criteria, regardless of prior treatment |
Additionally, results of key markers of clinical activity were reported from 16 patients.
| • | 14/16 patients achieved ≥ 50% reduction in serum tryptase levels by central assessment |
| • | 85% median reduction in serum tryptase |
| • | Eight of these patients achieved reduction to <20 ng/mL |
| • | 13/13 patients with ≥2 cycles of treatment achieved ≥50% reduction in bone marrow mast cells by central review |
| • | 10 of these patients achieved complete clearance of bone marrow mast cell aggregates |
| • | 11/12 patients with baseline D816V mutation and ≥2 cycles of treatment achieved ≥50% reduction in KIT D816V variant allele fraction (VAF) by droplet digital polymerase chain reaction (ddPCR) |
Bezuclastinib Clinical Development
Based on the continued favorable safety and tolerability profile and clinical activity observed to date in the Phase 2 APEX clinical trial with bezuclastinib for patients with AdvSM, Cogent will continue enrolling patients in Part 1 of APEX to determine a recommended dose for use in Part 2 of the trial.
In addition, Cogent continues to actively enroll patients in SUMMIT, a Phase 2 clinical trial with bezuclastinib for patients with non-advanced systemic mastocytosis (NonAdvSM), and PEAK, a registrational randomized, open-label, global, Phase 3 clinical trial in patients with imatinib-resistant Gastrointestinal Stromal Tumors (GIST). Cogent plans to present initial clinical efficacy results from the PEAK lead-in study during the first half of 2023 and present initial clinical data from SUMMIT in the second half of 2023.
Webcast Information & ASH Poster
Cogent will host a webcast on December 12, 2022 at 8:00 a.m.ET (7:00 a.m. CT) to discuss today’s updated clinical data from the ongoing APEX trial. The live event can be accessed on the Investor page of Cogent’s website at investors.cogentbio.com. A replay of the webcast will be available approximately two hours after the completion of the event and will be archived for up to 30 days.
The ASH poster is available to registered conference attendees as well as on the Posters and Publications section of Cogent’s website at www.cogentbio.com/research.
About Cogent Biosciences, Inc.
Cogent Biosciences is a biotechnology company focused on developing precision therapies for genetically defined diseases. The most advanced clinical program, bezuclastinib, is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. KIT D816V is responsible for driving systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Exon 17 mutations are also found in patients with advanced gastrointestinal stromal tumors (GIST), a type of cancer with strong dependence on oncogenic KIT signaling. In addition to bezuclastinib, the Cogent Research Team is developing a portfolio of novel targeted therapies to help patients fighting serious, genetically driven diseases initially targeting FGFR2 and ErbB2. Cogent Biosciences is based in Waltham, MA and Boulder, CO. Visit our website for more information at www.cogentbio.com. Follow Cogent Biosciences on social media: Twitter and LinkedIn. Information that may be important to investors will be routinely posted on our website and Twitter.
Forward Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the potential for bezuclastinib to become a best-in-class treatment option for patients with AdvSM, the potential for bezuclastinib to achieve therapeutic exposures that could support key differentiation for patients with both AdvSM and NonAdvSM, Cogent’s plans to continue enrolling patients in Part 1 of APEX to determine a recommended dose for use in Part 2 of the trial, Cogent’s plan to present initial clinical efficacy results from the PEAK lead-in study during the first half of 2023, and Cogent’s plan to present initial clinical data from SUMMIT in the second half of 2023. The use of words such as, but not limited to, “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” or “would” and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical results, the rate of enrollment in our clinical trials and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. We may not actually achieve the forecasts or milestones disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption “Risk Factors” in Cogent’s most recent Quarterly Report on Form 10-Q filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither we, nor our affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date hereof.
Contact:
Christi Waarich
Senior Director, Investor Relations
christi.waarich@cogentbio.com
617-830-1653
Exhibit 99.2 Updated Clinical Data from Apex Phase 2 Study of Bezuclastinib in Advanced Systemic Mastocytosis Investor Webcast December 12, 2022 Presented at American Society of Hematology Conference December 11, 2022
This presentation and the accompanying oral commentary contain forward-looking statements that involve risks, uncertainties and assumptions. If the risks or uncertainties ever materialize or the assumptions prove incorrect, our results may differ materially from those expressed or implied by such forward looking statements. All statements other than statements of historical fact could be deemed forward-looking, including, but not limited to, any statements of the plans, strategies, and objectives of management for future operations, including our clinical development and commercialization plans and timelines; any projections of financial information; any statement about historical results that may suggest trends for our business; any statement of expectation or belief regarding future events; potential markets or market size, technology developments, our clinical and research pipelines, clinical and pre-clinical data or the implications thereof, enforceability of our intellectual property rights, competitive strengths or our position within the industry; any statements regarding the anticipated benefits of our collaborations or other strategic transactions; and any statements of assumptions underlying any of the items mentioned. These statements are based on estimates and information available to us at the time of this presentation and are not guarantees of future performance. Actual results could differ materially from our current expectations as a result of many risks and uncertainties, including but not limited to, risks associated with: the potential impacts of raising additional capital, including dilution to our existing stockholders, restrictions our operations or requirements that we relinquish rights to our technologies or product candidates; business interruptions resulting from the coronavirus disease outbreak or similar public health crises, which could cause a disruption of the development of our product candidates and adversely impact our business; the success, cost, and timing of our product development activities and clinical trials; the timing of our planned regulatory submissions to the FDA for our product candidate bezuclastinib and feedback from the FDA as to our plans; our ability to obtain and maintain regulatory approval for our bezuclastinib product candidate and any other product candidates we may develop, and any related restrictions, limitations, and/or warnings in the label of an approved product candidate; the potential for our identified research priorities to advance our bezuclastinib product candidate; the ability to license additional intellectual property relating to our product candidates from third-parties and to comply with our existing license agreements and collaboration agreements; the ability and willingness of our third-party research institution collaborators to continue research and development activities relating to our product candidates; our ability to commercialize our products in light of the intellectual property rights of others; our ability to obtain funding for our operations, including funding necessary to complete further development and commercialization of our product candidates; the scalability and commercial viability of our manufacturing methods and processes; the commercialization of our product candidates, if approved; our plans to research, develop, and commercialize our product candidates; our ability to attract collaborators with development, regulatory, and commercialization expertise; our expectations regarding our ability to obtain and maintain intellectual property protection for our product candidates; among others. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to our business in general, see our periodic filings filed from time to time with the Securities and Exchange Commission. Unless as required by law, we assume no obligation and do not intend to update these forward- looking statements or to conform these statements to actual results or to changes in our expectations. All of Cogent Biosciences, Inc. (“Cogent”) product candidates are investigational product candidates and their safety and efficacy have not yet been established. Cogent has not obtained marketing approval for any product, and there is no certainty that any marketing approvals will be obtained or as to the timelines on which they will be obtained. Any data pertaining to Cogent product candidates is interim data and may include investigator-reported interim data for which Cogent has not yet independently reviewed the source data. The interim data may not be representative of the final results that may be obtained in the corresponding trials and results from earlier trials may not be representative of results obtained in later trial or pivotal trials. 2
Andrew Robbins Daniel J. DeAngelo, M.D., Ph.D. Jessica Sachs, M.D. President and Chief Executive Officer Chief of the Division of Leukemia Chief Medical Officer Dana-Farber Cancer Institute Introduction & Corporate Overview Andrew Robbins Introduction & Corporate Overview Review of Updated APEX Data with Bezuclastinib in Review of Initial APEX Data with Bezuclastinib in Advanced Dr. Daniel DeAngelo Dr. Daniel DeAngelo Advanced Systemic Mastocytosis (ASM) patients Systemic Mastocytosis (ASM) patients Andrew Robbins Andrew Robbins Presentation Summary Presentation Summary Andrew Robbins Q&A Dr. Jessica Sachs Dr. Daniel DeAngelo 3
Demonstrating differentiated profile as potential best-in-class selective KIT mutant inhibitor Building exciting portfolio of next-generation potent, selective kinase inhibitors Cash runway into 2025; $289.1 million as of September 30, 2022 4
Neurological Headache, brain fog, Disease Overview: Aggressive and life-threatening cognitive dysfunction, anxiety, depression form of systemic mastocytosis (SM) that is primarily driven by KIT D816V mutation and leads to Systemic 1,2 uncontrolled proliferation of mast cells (MC) Anaphylaxis • Subtypes: aggressive SM (ASM); SM with Cutaneous (skin) Flushing of the face/neck/chest, hives, associated hematologic neoplasm (SM-AHN); skin rashes, itching with or without 1 mast cell leukemia (MCL) rash • Based on subtype, the median overall survival 3,4 Gastrointestinal ranges from <6 months to 3-4 years Diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux disease Unmet Need Remains: Approved therapies with (GERD) associated dose-limiting toxicities • Reported toxicities for marketed therapies: Other nausea, vomiting, diarrhea, edema, intracranial Cardiovascular 5-7 Ear/Nose/Throat/Respiratory bleeding, cognitive effects Skeletal Gynecological Urinary References: 1Pardanani A. Am J Hematol. 2021;96(4):508-525. 2DeAngelo DJ et al. Nat Med. 2021;27(12):2183-2191. 3Ustun C et al. Haematologica. 2016;101(10):1133-1143. 4Lim K-H et al. Blood. 2009;113(23):5727-5736. 5AYVAKIT (avapritinib) [package insert]. Blueprint Medicines Corporation; 5 2021. 6Magliacane D et al., Transl Med UniSa. 2014;8:65-74. 7RYDAPT (midostaurin) [package insert]. Novartis Pharmaceuticals; 2021.
1 Systemic Mastocytosis: Estimated prevalence in the U.S. is 20,000–30,000 patients NonAdvSM Significant unmet medical need Comprises upwards of for clinically active, well- 1 90% of all cases of SM tolerated treatment options for this patient population AdvSM 1 Coltoff A, Mascarenhas J., 2019. 6
• Oral, selective, and type I tyrosine kinase inhibitor (TKI) with potent activity against KIT D816V, an activation loop mutation • Preclinically, highly active with specificity for mutations in KIT exons 9, 11, 17, and 18 1 • Spares closely related kinases, has minimal brain penetration, and favorable PK properties – Inhibition of closely related kinases have been linked to off-target toxicities, such as bleeding, edema, and 2, 3 pleural effusions Kinase Inhibition Profile of Clinical Stage and Approved KIT D816V Agents; Cell IC (nM) 50 KIT V560G/D816V Compound (HMC 1.2) WT KIT PDGFRα PDGFRβ CSF1R FLT3 KDR Bezuclastinib 14 121 > 10,000 > 10,000 > 10,000 > 1000 > 1000 Avapritinib 13 114 53 10 249 305 > 1000 BLU-263 6 355 21 6 161 345 > 1000 References: 1Guarnieri A. et al. Abstract P257 Molecular Cancer Therapeutics, 2021. 20(12_Supplement), P257-P257. 2Giles FJ et al, Leukemia. 7 2009;23(10):1698-1707. 3Liu S, Kurzrock R. Seminars in Oncology. 2015;42(6):863-875
Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM) 1 2 3 Daniel J. DeAngelo , MD, PhD; Vinod Pullarkat , MD, MRCP; Miguel Piris-Villaespesa , MD; Tracy I. 4,5 4,5 6 7 8 George , MD; Jay L. Patel , MD; Celalettin Ustun , MD; Prithviraj Bose , MD; LouAnn Cable ; Jessica 8 8 8 8 8 8 Sachs , MD; Liangxing Zou , Lei Sun , PhD; Amanda Pilla , Benjamin Exter , PharmD; Hina A. Jolin , 4 PharmD; Tsewang Tashi , MD 1 2 Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, Massachusetts; City of Hope Medical Center, Hematology and Hematopoietic Cell 3 4 Transplantation, Duarte, CA; Hospital Universitario Ramón y Cajal, Madrid, Spain; Huntsman Cancer Institute, University of Utah, Division of Hematology & 5 6 Hematologic Malignancies, Salt Lake City, UT; ARUP Laboratories, Salt Lake City, UT; Rush University Medical Center, Division of Hematology, Oncology, and 7 8 Cell Therapy, Chicago, Illinois; The University of Texas MD Anderson Cancer Center, Houston, TX; Cogent Biosciences, Inc., Waltham, MA
Primary Endpoint • Dose Optimization: Incidence of AEs/SAEs, laboratory changes, PK, biomarkers, ORR • Expansion: ORR (confirmed CR, CRh, PR and CI) per mIWG-MRT-ECNM and assessed by Central Response Review Committee Other Endpoints • Safety/Tolerability: Incidence of AEs leading to dose modification, changes in Patient Reported Outcomes (PROs) • Efficacy: DOR, TTR, PFS, OS, pure pathologic response • PK/PD: plasma concentration of bezuclastinib, serum tryptase, KIT D816V burden 9 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Hybrid Congress; New Orleans, LA, 11 Oct 2022: Publication Number: 626
• 16 patients enrolled; median age: 69 years; Range: 33-87 Total 50mg BID 100mg BID 200mg BID 400mg QD (N=16) (N=4) (N=3) (N=4) (N=5) Male, n (%) 13 (81) 3 (75) 3 (100) 3 (75) 4 (80) ECOG PS 0-1, n (%) 14 (88) 4 (100) 3 (100) 4 (100) 3 (60) AdvSM Subtype per Central Eligibility Review, n (%) ASM 3 (19) 1 (25) 0 (0) 0 (0) 2 (40) SM-AHN 12 (75) 3 (75) 2 (67) 4 (100) 3 (60) MCL 1 (6) 0 (0) 1 (33) 0 (0) 0 (0) ∫ Prior therapy for AdvSM, n (%) Treatment Naïve* 11 (69) 3 (75) 2 (67) 3 (75) 3 (60) Avapritinib 3 (19) 0 (0) 1 (33) 1 (25) 1 (20) *Patients who have received Midostaurin 3 (19) 0 (0) 1 (33) 1 (25) 1 (20) no prior SM directed KIT D816V in Whole Blood, Positive, n (%) 14 (88) 4 (100) 3 (100) 3 (75) 4 (80) therapies ∫ Additional therapies 10.6 14.3 7.98 27.85 7.18 ‡ included PEG interferon-α, Median KIT D816V VAF, % (range) (0.02-47.18) (0.02 – 37.4) (7.04 – 32.28) (8.7 – 47.18) (0.93 – 13.48) cladribine, hydroxyurea, azacytidine, decitabine, 30 45 70 20 30 Median Bone Marrow MC Burden, % (range) brentuximab vedotin, and (7-80) (20-70) (30-80) (7-30) (10-80) other 178 334 253 97 232 ‡ Includes patients with Median Serum Tryptase, ng/mL (range) (50-1578) (169-605) (144-1578) (67.9-121) (50-370) positive KIT D816V Data as of: 26Oct2022 10 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: Publication Number: 626
Treatment Related Adverse Events in > 10% Patients and all Related SAEs ‡ TKI Prior ‡ Therapy TKI Total Naïve Exposure 50 mg BID 100 mg BID 200 mg BID 400 mg QD (n=16) (n=13) (n=3) (n=4) (n=3) (n=4) (n=5) Preferred Term All grade Grade ≥3 All grade All grade All grade All grade All grade All grade Hair color changes 4 (25) 0 2 2 0 2 1 1 ^ Taste disorder 4 (25) 0 3 1 1 0 1 2 ∫ Neutropenia 4 (25) 2 (13) 4 0 1 1 1 1 ‡ Edema peripheral 3 (19) 0 1 2 0 0 1 2 SM-directed therapy with midostaurin and avapritinib Thrombocytopenia 3 (19) 1 (6) 3 0 0 1 0 2 ^ Includes pooled Nausea 2 (13) 0 1 1 0 1 0 1 preferred terms of terms of Taste disorder and Dysgeusia Fatigue 2 (13) 0 1 1 1 0 1 0 ∫ Includes pooled preferred Vomiting 2 (13) 0 1 1 0 1 0 1 terms of Neutropenia, Anemia 2 (13) 1(6) 0 2 0 1 1 0 Neutrophil count decreased, Hypersensitivity and WBC decreased 1 (6) 1(6) 1 0 0 0 0 1 # # (mediator flare) Serious adverse event • The majority of TEAEs were of low grade with one related SAE and no related Grade 4 events • No related cognitive effects or bleeding events reported • The majority of hematological TEAEs were of low grade, reversible and did not require dose modification • No discontinuations with 3 patients dose reduced due to TEAEs; one re-escalated to randomized dose Data as of: 26Oct2022 11 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: Publication Number: 626
9 All patients in Apex were required to have platelet count ≥50 x 10 /L for 2 weeks prior to the first dose of study drug *Two patients excluded: (1) due to presence of essential thrombocythemia at baseline; (1) no post-baseline assessment Data as of: 26Oct2022 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: Publication Number: 626 12
– Serum Tryptase • 88% of patients achieved a ≥ 50% reduction • 85% median reduction • 50% achieved levels <20 ng/mL – Bone Marrow MC Burden • 100% of patients with at least 2 cycles of treatment achieved a ≥ 50% reduction a Three patients excluded: no post-baseline assessment available • 77% achieved complete clearance of mast cell aggregates by central review – KIT D816V VAF • 92% of patients with at least 2 cycles of treatment achieved a ≥ 50% reduction b Four patients excluded: (2) KIT D816V negative at baseline; (2) no post-baseline assessment available Data as of: 26Oct2022 13 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: Publication Number: 626
Part 1 Dose Optimization (n=16) • Patients inevaluable (n=2) • n=1 no measurable C-finding at baseline • n=1 received confounding concomitant medication mIWG-MRT-ECNM response evaluable population (n=14) • Patients excluded (n=3) • n=2 off study prior to first response timepoint • n=1 ongoing; has not reached first response timepoint Centrally assessed for mIWG-MRT-ECNM (n=11) 14
Response mIWG-MRT-ECNM Response Criteria* Pure Pathological Response Criteria Assessment ✓ Absence of neoplastic MC aggregates in bone ✓ Absence of neoplastic MC aggregates marrow in bone marrow ✓ Serum tryptase ≤ 20 ng/mL✓ Serum tryptase < 20 ng/mL Complete Remission (CR) ✓ Remission of peripheral blood counts✓ Remission of peripheral blood counts ✓ Complete resolution of all mIWG C-findings ✓ Reduction of neoplastic MC in bone marrow ✓ Reduction of neoplastic MC in bone by ≥ 50% marrow by ≥ 50% Partial Remission (PR) ✓ Reduction of serum tryptase by ≥ 50%✓ Reduction of serum tryptase by ≥ 50% ✓ Resolution of ≥ 1 mIWG C-finding ✓ Resolution of ≥1 mIWG C-finding in the Not a part of PPR Criteria Clinical Improvement (CI) absence of CR, CRh, PR, or PD *confirmed response duration must be ≥ 12 weeks 15
mIWG-MRT-ECNM mIWG-MRT-ECNM per CRRC β Best Response, n (%) * Total per CRRC Assessment Assessment ‡ ‡ (confirmed and unconfirmed) (n=11) (TKI Therapy Naïve) (Prior TKI Exposure) (n=9) (n=2) *3 patients pending confirmation Overall response rate of response are included: (2) PR; (1) CR in patients diagnosed with SM- † CR + CRh + PR + CI 8 (73) 8 (89) 0 (0) AHN β mIWG-evaluable patients who CR + CRh + PR 6 (55) 6 (67) 0 (0) have at least one post-baseline Complete Response (CR + CRh) 2 (18) 2 (22) 0 (0) assessment are included ‡ SM-directed therapy with Partial Response (PR) 4 (36) 4 (44) 0 (0) midostaurin and avapritinib † Clinical Improvement (CI) 2 (18) 2 (22) 0 (0) Primary endpoint of Apex study Stable Disease (SD) 3 (27) 1 (11) 2 (100) PPR per Investigator PPR per Investigator Assessment Total Assessment α ‡ (Prior TKI Therapy) Best Response, n (%) ‡ (n=12) (TKI Therapy Naïve) (n=2) (n=10) α PPR-evaluable patients who have Overall response rate (CR + PR) 9 (75) 7 (70) 2 (100) at least one post-baseline assessment are included. Complete Response (CR) 3 (25) 3 (30) 0 (0) ‡ SM-directed therapy with Partial Response (PR) 6 (50) 4 (40) 2 (100) midostaurin and avapritinib Stable Disease (SD) 3 (25) 3 (30) 0 (0) • Median duration on treatment = 27 weeks (range: 0.3-40) • First confirmed CRh by mIWG documented as early as 8 weeks and first confirmed CR as early as 20 weeks Data as of: 26Oct2022 16 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: Publication Number: 626
1 a Prior avapritinib and midostaurin. Discontinued due to disease progression b Discontinued after 2 doses of study treatment due to investigator decision (femur fracture) Includes confirmed and unconfirmed responses Data as of: 26Oct2022 17 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: Publication Number: 626
Data as of: 26Oct2022 DeAngelo D,. et al. American Society of Hematology (ASH) 2022 Annual Meeting; New Orleans, LA, 11 Oct 2022: 18 Publication Number: 626
• The highly potent and selective TKI bezuclastinib was generally well-tolerated across all dose levels and continues to demonstrate a differentiated safety profile – No related cognitive effects or bleeding events reported – Limited effect of bezuclastinib on platelet counts in patients, supported by preclinical data • Treatment with bezuclastinib resulted in encouraging early signs of clinical activity demonstrated across all dose levels – mIWG-MRT-ECNM: 89% overall response rate (CR + CRh + PR + CI) in TKI therapy-naïve patients and 73% in all patients at median follow up of 27 weeks • First confirmed CRh by mIWG as early as 8 weeks and first confirmed CR as early as 20 weeks – 88%, 92%, and 100% of patients with available data achieved a 50% reduction in serum tryptase, KIT D816V VAF, and bone marrow MC burden, respectively • Enrollment to Part 1 is ongoing 19
Demonstrating differentiated profile as potential best-in-class selective KIT mutant inhibitor Building exciting portfolio of next-generation potent, selective kinase inhibitors Cash runway into 2025; $289.1 million as of September 30, 2022 20
Q&A
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