UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
Current Report Pursuant to
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Securities Exchange Act of 1934
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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 (see General Instructions A.2. below):
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Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
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Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
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Securities registered pursuant to Section 12(b) of the Act:
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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 7.01. Regulation FD Disclosure.
On September 26, 2024, Mural Oncology plc (the “Company”) will hold its previously announced “Investor Day” event beginning at 10:00 a.m. ET. During the event, representatives of the Company will, among other things, discuss insights on the design of the Company’s late-stage clinical trials of nemvaleukin alfa, its investigational, engineered interleukin-2 cytokine, provide an update on expected timing for anticipated data readouts and other milestones and provide an overview of its interleukin-18 program. A copy of the press release relating to the Investor Day event is attached hereto as Exhibit 99.1 and a copy of the presentation slides to be used by the Company during the Investor Day event and webcast is attached hereto as Exhibit 99.2, both of which are incorporated by reference herein. A live webcast of the Investor Day event may be accessed by visiting the Investors & News section of the Company’s website at https://ir.muraloncology.com/events-and-presentations. A recording of the webcast will also be available on the Company’s website after the event. The information contained in, or that can be accessed through, the Company’s website is not a part of this filing.
The information contained under this Item 7.01 in this Current Report on Form 8-K, including Exhibit 99.1 and Exhibit 99.2, is being furnished herewith and shall not be deemed to be “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 such information 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 a filing.
Item 9.01 Financial Statements and Exhibits
(d) Exhibits
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99.1 |
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Press release issued by Mural Oncology plc on September 26, 2024. |
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99.2 |
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Cover Page Interactive Data File (embedded within the Inline XBRL document) |
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.
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Mural Oncology plc |
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Dated: September 26, 2024 |
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/s/ Maiken Keson-Brookes |
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Name: |
Maiken Keson-Brookes |
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Chief Legal Officer |
Exhibit 99.1
FOR IMMEDIATE RELEASE
Mural Oncology’s First Virtual Investor Day to Highlight Late-Stage Clinical Progress
Key data readouts for the company’s late-stage, potentially registrational trials of nemvaleukin are expected in late Q1/early Q2 2025 for platinum-resistant ovarian cancer and Q2 2025 for mucosal melanoma
Management team to provide additional information not previously disclosed related to nemvaleukin study design, statistical assumptions, and study execution
Clinicians to discuss treatment landscape of platinum-resistant ovarian cancer and mucosal melanoma, two indications with limited treatment options and poor outcomes for patients
IND submission for Mural’s IL-18 program planned forQ4 2025
WALTHAM, Mass and DUBLIN – September 26, 2024 – Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered cytokine therapies designed to address areas of unmet need for patients with a variety of cancers, will host a virtual Investor Day today beginning at 10 a.m. ET. Mural leadership will provide new clinical insight into the trial design, statistical assumptions, and progress of the company’s late-stage trials of nemvaleukin.
“Mural has the most advanced IL-2 program currently in development and we have made significant progress this year. We have a great deal of conviction around nemvaleukin, which is engineered to unlock the efficacy potential of high dose IL-2 for more patients, and we are pleased to share more details around our study designs and assumptions during today’s Investor Day,” said Caroline Loew, Ph.D., CEO of Mural Oncology. “There has also been significant interest in our IL-18 program and we announced today that we plan to submit an IND to the FDA for this program in Q4 2025. Together we believe these programs have the potential to be the next wave of much needed treatment options for cancer patients.”
ARTISTRY-7:
ARTISTRY-7 is a potentially registrational phase 3 trial comparing the combination of nemvaleukin and pembrolizumab versus investigator’s choice single agent chemotherapy in heavily pre-treated patients with platinum-resistant ovarian cancer (PROC), with a primary endpoint of overall survival (OS). Secondary endpoints include progression free survival, overall response rate, disease control rate, duration of response, time to response, CA-125 response, and treatment emergent adverse events. This four-arm trial also contains two smaller monotherapy arms to assess contribution of components.
PROC is an area of high unmet need, with few effective treatment options and poor survival. Nemvaleukin for the treatment of PROC has received Food & Drug Administration (FDA) Fast Track Designation.
Enrollment is complete, with a total of 456 patients (versus 448 planned), and approximately 187 patients in each of the two experimental arms.
Futility analyses are complete for both monotherapy arms:
Pembrolizumab (arm 2):
Nemvaleukin (arm 3):
No statistical comparisons will be performed on the pembrolizumab and nemvaleukin monotherapy arms; all analyses of these two arms will be descriptive.
ARTISTRY-7 Overall Survival Expectations and Rationale
Based on benchmarking against prior phase 3 trials in PROC, which had different eligibility criteria regarding the number of prior therapies, and the eligibility criteria of ARTISTRY-7 which allow for up to five prior lines of therapy in the platinum-resistant or refractory setting, protocol assumptions are:
ARTISTRY-7 Events and Statistics:
ARTISTRY-7 Timing:
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1 Edwards et al. “Comparison of toxicity and survival following intraperitoneal recombinant interleukin-2 for persistent ovarian cancer after platinum: twenty-four-hour versus 7-day infusion.” Journal of Clinical Oncology, November 1, 1997; Vlad et al. “A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer.” Cancer Immunology and Immunotherapy, February 2010.
ARTISTRY-6, Cohort 2:
ARTISTRY-6 cohort 2 is a potentially registrational single arm study of single agent nemvaleukin in patients with unresectable or metastatic mucosal melanoma. The trial’s primary endpoint is overall response rate evaluated per RECIST 1.1 by an independent central radiology review. Secondary endpoints include duration of response, time to response, disease control rate, progression-free survival, and safety.
Mucosal melanoma is a rare subtype of melanoma with poor prognosis and currently no approved treatment options. Nemvaleukin for the treatment of mucosal melanoma has received both FDA Fast Track Designation and Orphan Drug Designation.
Enrollment in this study is complete with 92 patients enrolled.
ARTISTRY-6, Cohort 2 Response Rate Assumptions and Rationale:
The target response rate is 25%. At this target, the lower bound of the 95% confidence interval will exceed a 15% response rate.
Mural believes that in this rare and highly aggressive tumor with poor outcomes even in the first line setting, demonstrating durable responses with a response rate of 20-25% would be meaningful for patients, and would support a discussion with the FDA regarding a potential BLA submission and potential accelerated approval.
A potential accelerated approval would require confirmatory evidence to be agreed with and later submitted to the FDA for conversion to a regular approval. Discussions with FDA on a potential confirmatory evidence package are ongoing.
ARTISTRY-6 Timing:
Mural Oncology’s IL-18 Program:
Mural plans to nominate a development candidate for its IL-18 program by the end of 2024 and intends to submit an Investigational New Drug (IND) Application to the FDA in Q4 2025.
Mural Investor Day Webcast Details:
Mural’s management team will be joined by three clinicians on the webcast to discuss the treatment landscape for PROC and mucosal melanoma, as well as nemvaleukin’s clinical proof of concept data.
The live webcast will begin at 10 a.m. followed by a Question & Answer session. To join the webcast, please visit https://ir.muraloncology.com/events-and-presentations.
A replay of the webcast will be available shortly after the conclusion of the meeting.
About Mural Oncology
Mural Oncology is leveraging its novel protein engineering platform to develop cytokine-based immunotherapies for the treatment of cancer. By combining our expertise in cytokine biology and immune cell modulation and our protein engineering platform, we are developing medicines to deliver meaningful and clinical benefits to people living with cancer. Our mission is to broaden the potential, and reach, of cytokine-based immunotherapies to improve the lives of patients. Our lead candidate, nemvaleukin, is currently in potentially registrational trials in mucosal melanoma and platinum-resistant ovarian cancer reading out in the first half of 2025. Mural Oncology has its registered office in Dublin, Ireland, and its primary facilities in Waltham, Mass. For more information, visit Mural Oncology’s website at www.muraloncology.com and follow us on LinkedIn and X.
About Nemvaleukin
Nemvaleukin alfa (nemvaleukin) is a novel, engineered cytokine designed to leverage antitumor effects of the IL-2 pathway while mitigating the hallmark toxicities that limit its use. Nemvaleukin selectively binds to the intermediate-affinity IL-2 receptor (IL-2R) and is sterically occluded from binding to the high-affinity IL-2R. Because of this molecular design, nemvaleukin treatment leads to preferential expansion of antitumor CD8+ T cells and natural killer cells, with minimal expansion of immunosuppressive regulatory T cells. Nemvaleukin is currently being evaluated in two potentially registrational late-stage trials.
About Mural Oncology’s IL-18 Program
IL-18 is a potent immune-stimulating cytokine, but its efficacy is blunted by IL-18 binding protein (IL-18BP), a high affinity decoy receptor that binds to, and neutralizes, IL-18, thereby rendering it ineffective. Native IL-18’s potency is also limited by its short half-life. Mural Oncology’s novel approach to protein engineering is designed to mitigate these issues. First, Mural introduced mutations to IL-18 that eliminate binding to IL-18BP while minimally impacting the native IL-18 structure. Second, it fused IL-18 to protein scaffolds which extend the half-life and increase IL-18’s exposure. Together, these have demonstrated more durable immunological effect in preclinical studies. Mural intends to nominate a development candidate for its IL-18 program by the end of this year and file an IND submission by the end of 2025.
Forward-Looking Statements
Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding: the company’s pipeline and development programs, including the expected timing of clinical updates from the ARTISTRY-6 and ARTISTRY-7 trials, the expected timing of preclinical updates, candidate nomination, and IND submission, including with respect to the Company’s IL-18 program, the potential of the company’s product candidates and programs to address unmet medical needs, and the continued progress of its pipeline and programs. Any forward-looking statements in this press release are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include, among others, the inherent risks and uncertainties associated with competitive developments, preclinical
development, clinical trials, recruitment of patients, product development activities and regulatory approval requirements; that preclinical or interim results and data from ongoing clinical studies of the company’s cytokine programs and product candidates may not be predictive of future or final results from such studies, results of future clinical studies or real-world results; future clinical trials or future stages of ongoing clinical trials may not be initiated or completed on time or at all; the company’s product candidates, including nemvaleukin, could be shown to be unsafe or ineffective; changes in the cost, scope and duration of development activities; the U.S. Food and Drug Administration may make adverse decisions regarding the company’s product candidates; and those other risks and uncertainties set forth in the company’s filings with the Securities and Exchange Commission (“SEC”), including its Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2024 and in subsequent filings the company may make with the SEC. All forward-looking statements contained in this press release speak only as of the date of this press release. The company anticipates that subsequent events and developments will cause its views to change. However, the company undertakes no obligation to update such forward-looking statements to reflect events that occur or circumstances that exist after the date of this press release, except as required by law.
Contact:
Katie Sullivan
katie.sullivan@muraloncology.com
2024 virtual investor day: Clinical insights & clinician discussion September 26, 2024 Exhibit 99.2
Forward-Looking Statements Certain statements set forth in this presentation constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. The words “anticipate,” “believe,” “expect,” “may,” “will” and similar expressions are intended to identify forward-looking statements. Forward-looking statements made in this presentation include, but are not limited to, statements concerning: the protein engineering capabilities of Mural Oncology plc (the “Company”); the potential therapeutic and commercial value, and anticipated safety profile, of the Company’s engineered IL-2, IL-12, and IL-18 cytokine programs and product candidates, including nemvaleukin alfa (“nemvaleukin”) as a cancer immunotherapy when used as monotherapy or in combination, and its broad potential utility across a wide array of tumor types and indications and its potential dosing optionality; the Company’s expectations regarding timelines and plans for the development of its engineered IL-2, IL-12, and IL-18 cytokines, including, for nemvaleukin, expectations related to ongoing clinical studies in the ARTISTRY development program, the ability of ongoing studies to support potential registration, and potential for expansion of the development program, including to explore novel combinations with other cancer treatments; the potential patient populations and market for the indications that the Company is pursuing; and the sufficiency of the Company’s existing cash resources for the period anticipated. You are cautioned that forward-looking statements are inherently uncertain. Although the Company believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual results may differ materially from those expressed or implied in the forward-looking statements due to various risks, assumptions and uncertainties. These risks, assumptions and uncertainties include, among others: the inherent risks and uncertainties associated with competitive developments, preclinical development, clinical trials, recruitment of patients, product development activities and regulatory approval requirements; preclinical or interim results and data from ongoing clinical studies of the Company’s cytokine programs and product candidates may not be predictive of future or final results from such studies, results of future clinical studies or real-world results; future clinical trials or future stages of ongoing clinical trials may not be initiated or completed on time or at all; the Company’s product candidates, including nemvaleukin, could be shown to be unsafe or ineffective; changes in the cost, scope and duration of development activities; the U.S. Food and Drug Administration (“FDA”) may make adverse decisions regarding the Company’s product candidates; and those risks, assumptions and uncertainties described under the heading “Risk Factors” in the Company’s filings with the Securities and Exchange Commission (“SEC”), including its Quarterly Report on Form 10-Q for the quarterly period ended June 30, 2024, and as may be updated in subsequent filings the Company may make with the SEC, which are available on the SEC’s website at www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the Company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this presentation.
Highly Experienced Late-Stage Oncology Team Executive Team Caroline Loew, PhD CEO Vicki Goodman, MD CMO Maiken Keson-Brookes CLO Adam Cutler CFO Board of Directors Francis Cuss MB, BChir, FRCP Scott Jackson MBA – Chairman Caroline Loew PhD George Golumbeski PhD Sachiyo Minegishi MBA Benjamin Hickey MBA
Mural at a Glance Abbrev.: CM: cutaneous melanoma; IL-12: interleukin-12; IL-18: interleukin-18; MM: mucosal melanoma; OS: overall survival; PDR: preliminary data readout; PROC: platinum resistant ovarian cancer; RP2D: recommended phase 2 dose; TLR: topline results Subject to event accrual Subject to patient enrollment Phase 2/3 Late-Stage Trials: Cash Position: Preclinical Assets: Fully enrolled for ARTISTRY-7 (Phase 3, PROC) and ARTISTRY-6 cohort 2 (Phase 2, mucosal melanoma) Ongoing discussions with FDA on ARTISTRY-6 potential confirmatory evidence package RP2D for next generation dosing schedule underway in ARTISTRY-6, cohorts 3 & 4 (phase 2, cutaneous melanoma ) 4Q 2024: Candidate nominations for IL-18 and IL-12 4Q 2025: IL-18 IND submission Cash runway into 4Q 2025 Late Q1/Early Q2: Interim OS for ARTISTRY-71 Q2: TLR Cohort 2 of ARTISTRY-6 1H: PDR Cohort 3-mono of ARTISTRY-6 (Phase 2, CM)2 2H: PDR Cohort 4-combo of ARTISTRY-6 (Phase 2, CM)2 2025 CATALYSTS: Significant opportunity in 2 indications with limited available therapies and planned indication expansion Commercial Opportunity:
Nemvaleukin: Engineered to unlock the efficacy potential of High Dose IL-2 for more patients High dose (HD) IL-2 (PROLEUKIN©/aldesleukin) has proven curative potential in melanoma and RCC Extremely durable complete responses However toxic AE profile requires administration in an acute care setting, and severely limits use to the fittest patients Nemvaleukin is a novel, stable, immediately active fusion protein Elegantly engineered with an ‘alpha-non-alpha’ structure to mitigate HD IL-2’s toxicity Design also unlocks therapeutic effects through more selective expansion of cytotoxic CD8+ T cells and NK cells Comprehensive clinical dataset from Ph1/2 trial (ARTISTRY 1), including deep and durable responses Durable responses seen with monotherapy in post PD-1 cutaneous and mucosal melanoma Durable responses, including complete responses, seen in combination therapy with pembrolizumab in heavily pre-treated PROC patients1 Manageable AE profile allows administration in outpatient setting. No capillary leak syndrome observed Currently in two registrational studies – mono and combination therapy Data available on slide 15 of this presentation ARTISTRY-7 (combination therapy), ARTISTRY-6, cohort 2 (monotherapy)
Pipeline Overview: 2024-2025 Milestones Discovery Preclinical Phase 1 Phase 2 Phase 3 Indication Dosing Nemvaleukin (IV) Combination with Pembrolizumab (Potentially Registrational) Platinum Resistant Ovarian Cancer (PROC) (ARTISTRY-7) Nemvaleukin (IV) Monotherapy (Potentially Registrational) Mucosal Melanoma (ARTISTRY-6, Cohort 2) Nemvaleukin (LFIV) Monotherapy and Combination with Pembrolizumab Program Advanced Solid Tumors (ARTISTRY-3) 2024-2025 Milestones Interim OS readout projected in late 1Q/ early 2Q 20251 Phase 2 dose selected in 1Q 2024 IND submission Q4 2025 Top-line data readout projected in 2Q 2025 Candidate nomination projected in 2024 Mechanism IL-12 IL-18 Tumor-targeted self-assembling split IL-12 Engineered IL-18 Abbrev.: IL: interleukin; IV: intravenous; LFIV: less frequent IV dosing; OS: overall survival; IND: Investigational New Drug Cutaneous Melanoma (ARTISTRY-6, Cohort 3) Nemvaleukin (LFIV) Monotherapy Preliminary data readout projected in 1H 20252 Doses per 3-week cycle Subject to event accrual Subject to patient enrollment Nemvaleukin (LFIV) Combination with Pembrolizumab Cutaneous Melanoma (ARTISTRY-6, Cohort 4) Preliminary data readout projected in 2H 20252 5x 5x 2x 2x 5x 2x 2x
Today’s Agenda Nemvaleukin clinical proof of concept Monotherapy and combination therapy across broad range of solid tumors Unmet need in platinum-resistant ovarian cancer Current treatment options and gaps ARTISTRY-7 overview: PROC Trial design, powering assumptions, progress update Mucosal melanoma and the need for dedicated treatments Differences of disease and current standard of care ARTISTRY-6 overview: mucosal melanoma Trial design, powering assumptions, progress update Engineered IL-18 program Protein engineering and early data generation Conclusion and Q&A Ulka Vaishampayan, MD University of Michigan John Hays, MD, PhD The Ohio State University Vicki Goodman, MD Mural’s Chief Medical Officer Rich Carvajal, MD Northwell Health Cancer Institute Vicki Goodman, MD Mural’s Chief Medical Officer Jean Chamoun, PhD Mural’s Vice President, Research Caroline Loew, PhD and team
Ulka Vaishampayan, md University of michigan Nemvaleukin ALFA: CLINICAL PROOF OF CONCEPT
ARTISTRY-1: First-In-Human Trial of IV Nemvaleukin Global, Multicenter, Open-Label Phase 1/2 Trial Dose Expansion NCTO2799095 1. Patients from Parts A and B could roll over to Part C upon progression or stable disease (after > 4 cycles) on monotherapy 2. Nemvaleukin daily Q5D, then off treatment for 9 days (cycle 1) or 16 days (cycle 2+) 3. ORR assessed by investigator (RECIST v1.1) 4. Nemvaleukin 3 µg/kg/d in C1-C4, 6 µg/kg/d in C5-C7. PD-(L)1 approved/unapproved indication based on FDA prescribing information and may have changed over time Selection of RP2D, 6 µg/kg Part A: Dose Escalation1 Median Prior lines of therapy Part B Monotherapy Melanoma: 3 Part B Monotherapy RCC: 2 Part C Combination therapy: 3 Nemvaleukin 3 or 6 µg/kg IV2 + pembrolizumab 200 mg IV Part C: Combination Therapy RP2D: Nemvaleukin 6 µg/kg IV2 Part B: Monotherapy2 Advanced melanoma (n=47): CPI pretreated Advanced RCC (n=27): CPI naive or pretreated Objectives: safety and anti-tumor activity3 Objectives: safety and anti-tumor activity3 Select advanced tumor cohorts (N=166): Safety run-in, nemvaleukin 1 µg/kg + pembro (n=3) C4: Monotherapy rollover (n=43) C1: PD-(L)1 unapproved4: pretreated (n=42) C5: Melanoma: treatment naive (n=3) C2: PD-(L)1 approved4: CPI pretreated (n=26) C6: NSCLC: CPI relapsed (n=21) C3: PD-(L)1 approved4: CPI naive (n=26) C7: HNSCC: CPI naive (n=2) Abbrev.: C1-7: Cohorts 1-7; CPI: checkpoint inhibitor; HNSCC: head & neck squamous cell carcinoma; IV: intravenous; NSCLC: non-small cell lung cancer; ORR: overall response rate; PD-(L)1: programmed death (ligand) 1; RCC: renal cell carcinoma; RECIST: Response Evaluation Criteria In Solid Tumors; RP2D: recommended phase 2 dose
Clinical Pharamacodynamic Effects of Nemvaleukin are Distinct from HD IL-2, Preferentially Expanding Only Cytotoxic CD8+ T Cells and NK Cells Nemvaleukin data are from the 6 μg/kg cohort in Part A of ARTISTRY-1. For fold change plots, data are mean + SE (N=10). For time course plot, data are mean + SD (N=12). 1. Vaishampayan et al. Oral Abstract 2500 presented at ASCO 2022. 2. Bhatt et al. Poster P123 presented at SITC 2018. Abbrev: HD: high-dose; IL-2: interleukin-2; IV: intravenous; NK: natural killer; SD: Standard deviation; SE: Standard Error; TID: 3 times daily; Tregs: regulatory T cells Nemvaleukin: CD8+ T and NK cells preferentially expanded while Tregs remained suppressed Nemvaleukin1 High-Dose IL-22 High-dose IL-2 33 µg/kg IV TIDx5 Cycle 1 (14 days) Cycle 2 (21 days) 0 5 10 15 Day 25 30 35 40 0 500 1000 1500 2000 Absolute count (cells/L blood) 20 Total NK cells Total CD8+ T cells FOXP3+ Treg Immune cell expansion Cycles 1 – 2
Responses per RECIST v1.1 ARTISTRY-1: Nemvaleukin Demonstrated Durable Monotherapy Responses in Melanoma (Part B) Alla,b (n=46) Mucosal (n=6) Best overall response, n (%) CR 0 0 PR 6 (13.0)c 2 (33.3)d ORR, n (%) [95% CI] 6 (13.0) [4.9-26.3]c 2 (33.3) [4.3-77.8]d DOR in weeksd, Mean (SD) Median (range) 40.77 (55.6) c 16.75 (6.1-150.3) 78.2 (101.9)d 78.2 (6.1-150.3) a Excludes 1 patient who did not meet tumor-evaluable criteria. b Patients with mucosal, cutaneous, uveal, acral included in ‘All’. C Includes 4 confirmed PRs, 2 unconfirmed PRs, d 1 confirmed PR. e DOR for Part B only and does not include patients who rolled over to Part C; some patients may still be on treatment Data cut off Mar 27, 2023 Abbrev.: adj: adjuvant; ATEZO: atezolizumab; BIN: binimetinib; CBP: carboplatin; CI: confidence interval; COB: cobimetinib; CPI: checkpoint inhibitor; CR: complete response; DAB: dabrafenib; DCR: disease control rate (CR+PR+SD); DOR: duration of response; ENCO: encorafenib; FDA: US Food and Drug Administration; IPI: ipilimumab; MHRA: Medicines and Healthcare products Regulatory Agency; MV: melanoma vaccine; NA: not applicable; NIVO: nivolumab; ORR: overall response rate; PAC: paclitaxel; PD: progressive disease; PEMBRO: pembrolizumab; PR: partial response; SD: stable disease; TRAM: trametinib; TVEC: talimogene laherparepvec; VEM: vemurafenib. Data on file. All responders had been on prior CPI therapy and progressed FDA Orphan Drug and Fast Track designations, as well as MHRA’s ILAP Innovation Passport, granted in mucosal melanoma Data supported design of ARTISTRY-6 study
Case Study: 66-Year-Old Female with Urethral Melanoma (1 of 2) + per RECIST criteria Artistry-1 Data cut off Aug 2, 2023, EAP cut-off July 2024 Dx On-Study Benefits Prior Treatment Change in Target Lesions from Baseline+ Cycle 2 Stable Disease (SD): 8% increase Cycle 4 SD: 17% reduction Cycle 6-55 Partial Response (PR)+: 54% reduction at the time of study completion Dx w primary urethral mucosal melanoma in Apr 2017 Cystectomy & pelvic node dissection in Jun 2017 Melanoma Artistry 1: October 2019 – termination of study ( ~44 mo) Continuing treatment on EAP as of July 2024 (~57 months from Artistry-1 treatment start) Nemvaleukin therapy 6 µg/kg IV Nemvaleukin Adjuvant nivolumab (Sep 2017 – Sep 2018) Recurrence 8 months after treatment completion Most recent disease progression: Sep 2019 Notable treatment-related AEs Immune-related SAE: Grade 2 iritis/vitritis treated w steroid eye drops Grade 3 transient hypotension managed w fluids (SAE) Grade 3/4 Neutropenia Nemvaleukin Treatment Target Lesions (Axis mm) Non-Target Lesions Lymph Node Retroperitoneal (31) Lymph Node L iliac (18) Lymph node iliac Lymph node pelvic Lymph node Retroperitoneal M1
Case Study: 66-Year-Old Female with Urethral Melanoma (2 of 2): Target Lesion Shrinkage M1 EAP study Data cutoff July 2024 Mar 2020 Best response PR April 2017 66 y/o F dx of mucosal melanoma Sep 2017 – Sep 2018 Adjuvant nivolumab Nemvaleukin 6 μg/kg 2019 2018 2021 Sep 2019 Last documented PD 2020 Aug 2023 Ongoing PR (target lesions 54% at study completion) 1 of 2 target lymph node lesions SCREENING 10/9/2019 CYCLE 16 9/21/2021 (+~13 months) Oct 2019 – Aug 2023 (~44 months) EAP roll-over Jul 2024 Ongoing PR Artistry-1 Part B, melanoma cohort. Data cutoff Aug 2, 2023
ARTISTRY-1: Nemvaleukin Demonstrated Durable Monotherapy Responses in RCC (Part B) Responses per RECIST v1.1. CABO, cabozantinib; CPI, checkpoint inhibitor; CR, complete response; DCR, disease control rate (CR+PR+SD); DOR, duration of response; IPI, ipilimumab; mo, months; NIVO, nivolumab; ORR, overall response rate (CR+PR); PD, progressive disease; PR, partial response; RCC, renal cell carcinoma; SD, stable disease; SUN, sunitinib. RCC (n=22)a Best overall response, n (%) CR 0 PR 4 (18.2)b ORR, n (%) [95% CI] 4 (18.2) [5.2-40.3] Median DOR,c weeks (range) 15.6 (12.3-39.0) a N= 27 (56% received prior CPI), however 5 patients did not meet tumor-evaluable criteria bIncludes 3 confirmed PRs and 1 unconfirmed PR. cDOR is for Part B only and does not include rollover to Part C; some patients may still be on treatment. Clinically meaningful responses observed All responders had been on prior CPI therapy and progressed Vaishampayan U et al. Poster presented at the ASCO Meeting, Chicago, IL, June 3 - 7, 2022 Data cut off Oct 29, 2021 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 2 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 (2) (2) (5) (7) (2) (2) (2) (3) (3) (5) (2) (2) (1) (2) (1) (2) (3) (1) (1) (3) (1) (8) (2) (3) (1) (1) (5) Patients (prior lines of therapy) RCC patients with response Time on therapy (weeks) Patient Prior therapies 2: SUN, NIVO 63 ► 1: IPI/NIVO/(CABO or placebo) 24 (Part B), 23 ► (Part C) 1: IPI/NIVO 34 ► 1: IPI/NIVO 24 ► 1 2 3 4 1 3 4 2 Treatment ongoing Rollover to combination PR SD PD Duration of treatment (weeks) 6 mo 12 mo 18 mo
ARTISTRY-1: Nemvaleukin Combination Treatment with Pembrolizumab Demonstrated Durable Responses Data cut off Mar 27, 2023 1. DOR data cut off Sept 27, 2023 Abbrev.: BEV: bevacizumab; CBP: carboplatin; CDDP: cisplatin; CR: complete response; DOC: docetaxel; FDA: Food and Drug Administration; GEM: gemcitabine; mo: month; NIR: niraparib; PAC: paclitaxel; PCA: paclitaxel albumin; PD: progressive disease; PD-(L)1: programmed death (ligand) 1; PLD: pegylated liposomal doxorubicin hydrochloride; PR: partial response; PROC: platinum-resistant ovarian cancer; SD: stable disease; TAM: tamoxifen; TOP: topotecan; uPR: unconfirmed PR. Data on file. Best overall response n (%) PROC (n=14) CR 2 (14.3%) PR 2 (14.3)* ORR, n (%) 4 (28.6)* DOR in weeks 27.6-130.41 Cohort 1 * Includes 1 confirmed PR, 1 unconfirmed PR Of the 14 evaluable, investigator reported PROC patients, the median prior lines of ovarian cancer therapy was 5
Case Study: 48-Year-Old Female with High-Grade Serous Ovarian Cancer BEV=bevacizumab, CBP=carboplatin, CDDP=cisplatin, GEM=gemcitabine. Dx in Aug 2014 On-Study Benefits Prior Treatment High Grade Serous Ovarian Cancer Jan. 7, 2019 – termination of study (On treatment ~52 months)* Nemvaleukin + pembrolizumab therapy 3 µg/kg IV Nemvaleukin ARTISTRY-1 Treatment Target Lesions (Axis mm) Non-Target Lesions L common iliac lymph node (20) Retroperitoneal lymph node OC1 Data cut off Aug 2, 2023 PD-L1 status: TPS = 20% BRCA status: wild-type HRD status: Proficient TMB Intermediate MSS Platinum-Resistant Line Therapy Duration (mos) Best Response 1 CBP/TAXOL®/AVASTIN® 5 SD 2 CDDP/GEM 4.6 SD 3 CBP/DOXIL® 4.6 SD 4 ABRAXANE® 3.8 SD 5 CBP/TAXOTERE® 4.6 PR Nemvaleukin + Pembrolizumab Normalization of CA-125 tumor marker Change in Target Lesions from Baseline Cycle 2 Stable Disease (SD) Cycle 4 Partial Response+ (PR): 60% reduction Normalization of CA-125 Cycle 6 Confirmed PR+ Cycle 8 Complete Response (CR)+Ŧ: 60% reduction Cycle 10-52 Confirmed (CR)+Ŧ: 70% reduction Tolerated therapy well – no notable treatment-related AEs No SAEs reported Last dose of prior treatment Feb 22, 2018
Case Study: 83-Year-Old Female with High-Grade Serous Ovarian Cancer OC2 Dx Oct 2008 On-Study Benefits Prior Treatment High Grade Serous Ovarian Cancer Feb 2020 – April 2022 (On treatment ~26+ months) Nemvaleukin + pembrolizumab therapy 3 µg/kg IV Nemvaleukin ARTISTRY-1 Treatment Target Lesions (Axis mm) Non-Target Lesions R hemi-pelvic mass (97) R retroperitoneal nodule (34) None Data cut off Aug 2, 2023 PD-L1 status: unknown BRCA status: wild-type HRD status: unknown TMB status: unknown Micro-satellite unknown Platinum-Resistant Line Therapy Duration (mos) Best Response 1 CBP/TAXOL®/TAXOTERE® 4 Not Evaluable 2 CBP/ZJL/TAM/TAXOTERE® 6 CR Last dose of prior treatment Dec 7, 2018 Change in Target Lesions from Baseline Cycle 2 Stable Disease (SD): 6% reduction Cycle 4 Partial Response (PR)+: 55% reduction Cycle 6 Confirmed PR+: 68% reduction Cycle 8-22 PR+: 76-95% reduction Cycle 24-32 Complete Response (CR): 100% reduction > 80% decrease in target lesion in right pelvis D/C study due to pt death (due to colonic perforation not related to study treatment) Notable treatment-related AEs Grade 3 neutropenia +per RECIST criteria.
Nemvaleukin’s Adverse Event Profile in ARTISTRY-1 Was Consistent with Our Expectations Based on its Mechanism of Action Dose expansion: monotherapy (Part B) and combination therapy (Part C) Data as of March 27, 2023 Administered on outpatient basis; most frequent AEs were manageable with supportive care AE profile consistent with nemvaleukin mechanism of action Monotherapy safety profile was similar to combination, with no additive toxicity Most frequently observed grade 3-4 TRAE: neutropenia1 Not associated with risk of serious infections or febrile neutropenia No capillary leak events reported in ART-1 TRAEs leading to discontinuation: 4% (monotherapy)2, 4% (combination)3 Includes neutropenia and neutrophil count decreased TRAEs leading to discontinuation in monotherapy were Gr3 failure to thrive, Gr3 bronchospasm, Gr2 ECG T wave abnormal, and Gr1 cardiac troponin increase TRAEs leading to discontinuation in combination were Gr5 starvation, Gr3 arthralgia, Gr3 fatigue, Gr3 pneumonia, and Gr2 cytokine release syndrome Part C includes patients who received nemvaleukin at 1, 3, or 6 µg/kg IV in combination with pembrolizumab 200 mg IV. Data as of Mar 27, 2023 . Data on file.
John hays, md, phd The ohio state university comprehensive cancer center Unmet need in platinum-resistant ovarian cancer
Platinum Resistant Ovarian Cancer (PROC) Ovarian cancer is the second most common gynecologic malignancy but most common cause of gynecologic cancer death in US (~20-25K cases per year) No commonly agreed upon early detection test 75% of patients diagnosed at advanced stage (Stage III-IV) Primary treatment is systemic chemotherapy/surgery ± maintenance therapy Clockwise from top left: Gonzales Martin et al N Engl J Med 2019;381:2391-2402; Monk et al JCO 2022; 40(34):3952-3964; Ray-Coquard et al N Engl J Med 2019;381:2416-2428; DiSilvestro et al JCO 2023 Jan 20;41(3):609-617 . 2023 Jan 20;41(3):609-617
What do we do when patients recur? Oronsky et al Med Onc 2017 Med Oncol 2017 Jun;34(6):10
Platinum Resistance Almost all patients who recur will become platinum resistant… Aurelia Chemotherapy w/wo bevacizumab Improved PFS but not OS Pujade-Loraine JCO 2014 May 1;32(13):1302-8
Antibody Drug Conjugates Two new approvals in last 2 years Mirvetuximab Sorevtansine (FRa) Trastuzumab Deruxtecan (HER2) What about the last 10 years? Moore et al Annals of Oncology Volume 32, Issue 6, June 2021, Pages 757-765 Meric Burnstam et al JCO 2024 Jan 1;42(1):47-58.
What about the last 10 years? Many agents tested: Immune therapy Checkpoint inhibitors (PD1/PD-L1, CTLA4, TIGIT, etc…) Novel antigen delivery/recognition (NY-ESO, CA125) Bispecific T-Cell Engagers (BiTE) CAR-T/TCR Underwhelming performance 10-15% RR for single agents Increased for combinations (e.g. PD-L1/CTLA4) but at increased toxicity cost
What About the Future? ADCs are great, but… Limited population with marker FRa high – 30-60% HER2 2/3+ – 30% IO therapy has promise but monotherapy has limitations Smart combinations are the way forward
Vicki goodman, md chief medical officer Artistry-7 overview
ARTISTRY-1: Nemvaleukin Combination Treatment with Pembrolizumab Demonstrated Durable Responses Data cut off Mar 27, 2023 1. DOR data cut off Sept 27, 2023 Abbrev.: BEV: bevacizumab; CBP: carboplatin; CDDP: cisplatin; CR: complete response; DOC: docetaxel; FDA: Food and Drug Administration; GEM: gemcitabine; mo: month; NIR: niraparib; PAC: paclitaxel; PCA: paclitaxel albumin; PD: progressive disease; PD-(L)1: programmed death (ligand) 1; PLD: pegylated liposomal doxorubicin hydrochloride; PR: partial response; PROC: platinum-resistant ovarian cancer; SD: stable disease; TAM: tamoxifen; TOP: topotecan; uPR: unconfirmed PR. Data on file. Best overall response n (%) PROC (n=14) CR 2 (14.3%) PR 2 (14.3)* ORR, n (%) 4 (28.6)* DOR in weeks 27.6-130.41 Cohort 1 * Includes 1 confirmed PR, 1 unconfirmed PR Of the 14 evaluable, investigator reported PROC patients, the median prior lines of ovarian cancer therapy was 5
ARTISTRY-7: Phase 3 / Potentially Registrational Study for Platinum-Resistant Ovarian Cancer Pembrolizumab may be administered up to 35 cycles. Investigational Nemvaleukin IV + Pembrolizumab versus Chemotherapy Key eligibility criteria Platinum-resistant/refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer At least 1L of systemic platinum therapy and ≤5L of systemic platinum-resistant therapy Prior bevacizumab treatment Measurable disease by RECIST v1.1 Randomization 3:1:1:3 Futility analysis completed for monotherapy arms Key Endpoints Primary outcome measure: Overall survival (OS) Secondary outcome measures: PFS, ORR, DCR, DOR, and TTR CA-125 response TEAEs Clinical trial and supply agreement with MSD (a tradename of Merck & Co., Inc. Rahway, NJ, USA) Conduct of trial is in association with The GOG Foundation, Inc. (GOG), the European Network of Gynaecological Oncological Trial groups (ENGOT), and the Asia-Pacific Gynecologic Oncology Trials Group (APGOT) Pembrolizumab dosing Nemvaleukin dosing a Alternative topotecan regimen: 1.25 mg/m2 on Days 1-5 of 21-d cycles b Response per RECIST v1.1 c Response per GCIG Arm 4 Investigator's Choice Single-Agent Chemotherapy PLD IV, 40 mg/m2 (Day 1 of 28-day cycle) Paclitaxel IV, 80 mg/m2 (Days 1, 8, 15, and 22 of 28-day cycle) Topotecan IV, 4 mg/m2 (Days 1, 8, and 15 of 28-day cycle) Gemcitabine IV, 1000 mg/m2 (Days 1 and 8 of 21-day cycle) 16 days nontreatment period 20 days nontreatment period Abbrev.: CA-125: cancer antigen-125; DCR: disease control rate; DOR: duration of response; GCIG: Gynecologic Cancer InterGroup; IV: intravenous; ORR: objective response rate; PFS: progression-free survival; PLD: pegylated liposomal doxorubicin; RECIST: Response Evaluation Criteria in Solid Tumors; TEAE: treatment-emergent adverse event; TTR: time to response Final Enrollment: 456 patients (vs 448 planned) Arm 1 Nemvaleukin IV 6 µg/kg + Pembrolizumab1 IV 200 mg Daily IV 21-day cycle Arm 2 Pembrolizumab1 IV 200 mg 21-day cycle Arm 3 Nemvaleukin IV 6 µg/kg Daily IV 16-day nontreatment period 21-day cycle 16-day nontreatment period 20-day nontreatment period
ARTISTRY-7: Futility Criteria for Monotherapy Arms Smaller Single Agent Arms to Assess Contribution of Components Futility criteria for Arm 2: Based on Keynote-100 trial, where single agent pembro was evaluated in 376 patients with PROC with a response rate of 8% Futility in ARTISTRY-7 trial defined as <2 confirmed complete or partial responses in the first 12 patients enrolled This arm was closed to further enrollment for futility in August 2023 after enrolling 27 patients Arm 4 Investigator's Choice Single-Agent Chemotherapy PLD IV, 40 mg/m2 (Day 1 of 28-day cycle) Paclitaxel IV, 80 mg/m2 (Days 1, 8, 15, and 22 of 28-day cycle) Topotecan IV, 4 mg/m2 (Days 1, 8, and 15 of 28-day cycle) Gemcitabine IV, 1000 mg/m2 (Days 1 and 8 of 21-day cycle) 16 days nontreatment period 20 days nontreatment period Abbrev.: CA-125: cancer antigen-125; DCR: disease control rate; DOR: duration of response; GCIG: Gynecologic Cancer InterGroup; IV: intravenous; ORR: objective response rate; PFS: progression-free survival; PLD: pegylated liposomal doxorubicin; RECIST: Response Evaluation Criteria in Solid Tumors; TEAE: treatment-emergent adverse event; TTR: time to response Arm 1 Nemvaleukin IV 6 µg/kg + Pembrolizumab IV 200 mg Daily IV 21-day cycle Arm 2 Pembrolizumab IV 200 mg 21-day cycle Arm 3 Nemvaleukin IV 6 µg/kg Daily IV 16-day nontreatment period 21-day cycle 16-day nontreatment period 20-day nontreatment period Futility criteria for Arm 3: Based on two phase 2 trials using different doses and schedules of aldesleukin with consistent response rates of approx. 25%, including some patients with durable CRs1 At least 1 patient among first 24 enrolled to achieve ORR or SD for at least 3 months needed to continue enrollment Nemvaleukin single agent arm met the threshold to continue and enrolled a total of 55 patients 1. Edwards et al. “Comparison of toxicity and survival following intraperitoneal recombinant interleukin-2 for persistent ovarian cancer after platinum: twenty-four-hour versus 7-day infusion.” Journal of Clinical Oncology, November 1, 1997; Vlad et al. “A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer.” Cancer Immunology and Immunotherapy. February 2010.
ARTISTRY-7: Enrollment and Statistical Assumptions Arm 4 Investigator's Choice Single-Agent Chemotherapy PLD IV, 40 mg/m2 (Day 1 of 28-day cycle) Paclitaxel IV, 80 mg/m2 (Days 1, 8, 15, and 22 of 28-day cycle) Topotecan IV, 4 mg/m2 (Days 1, 8, and 15 of 28-day cycle) Gemcitabine IV, 1000 mg/m2 (Days 1 and 8 of 21-day cycle) 16 days nontreatment period 20 days nontreatment period Abbrev.: CA-125: cancer antigen-125; DCR: disease control rate; DOR: duration of response; GCIG: Gynecologic Cancer InterGroup; IV: intravenous; ORR: objective response rate; PFS: progression-free survival; PLD: pegylated liposomal doxorubicin; RECIST: Response Evaluation Criteria in Solid Tumors; TEAE: treatment-emergent adverse event; TTR: time to response Arm 1 Nemvaleukin IV 6 µg/kg + Pembrolizumab IV 200 mg Daily IV 21-day cycle Arm 2 Pembrolizumab IV 200 mg 21-day cycle Arm 3 Nemvaleukin IV 6 µg/kg Daily IV 16-day nontreatment period 21-day cycle 16-day nontreatment period 20-day nontreatment period Final Enrollment Across Experimental Arms: 374 patients enrolled (approximately 187 per arm) Enrollment stratified by PD-L1 expression levels, histological subtype, and choice of chemotherapy Overall Survival Expectations and Rationale: OS will be the only hypothesis tested endpoint, with alpha controlled at 2.5% (one sided) Expected OS benchmarked using several historical phase 3 trials: Studies differed in eligibility, particularly concerning lines of prior therapy, and with respect to our study Most allowed </= 3 prior lines of therapy and had median OS on chemo control arm between 8 and 13 months Protocol assumptions are a median OS of 10 months for chemotherapy arm and median OS of 14.3 months for Arm 1 (nemvaleukin + pembrolizumab) Final Enrollment ~187 ~187 27 55 456 patients
ARTISTRY-7 Interim Analysis Readout Expected Late Q1 or Early Q2 2025 Events: ~215 events for interim analysis estimated by late Q4 2024 or early Q1 2025 Data Readout: OS IA readout in late Q1 or early Q2 2025 EVENTS AND STATISTICS # of Events: Protocol specified interim analysis (IA) for overall survival (OS) will occur at 75% of events (~215 of 286 total events) Alpha Spend: Cumulative alpha spend at interim analysis is 1-sided, 0.0096 Hazard Ratio: Maximum hazard ratio for success is 0.727 (a 27.3% reduction in the risk of death1) TIMING 1. Assuming exactly 215 events
ARTISTRY-7 Interim Analysis (IA): Potential Outcomes 1 2a 2b IA Readout Q1 or early Q2 2025 Next Steps Hazard Ratio Meets Bar for Success Study Declared Positive File BLA for PROC in 2025 Decision to Continue to Final Analysis Decision to Terminate Study Hazard Ratio Not Met File BLA for PROC in 2026 Hazard Ratio Meets Bar for Success File BLA for PROC in 2026 Final analysis at ~286 events 85% power to demonstrate a 30% reduction in the risk of death, or target hazard ratio of 0.7 with cumulative alpha spend (1-sided, 0.025) Maximum hazard ratio for success at final OS: 0.7881 Clinically meaningful minimum median difference in OS of 2.7 months
RICH CARVAJAL, md Northwell health cancer institute MUCOSAL MELANOMA & THE NEED FOR DEDICATED TREATMENTS
Mucosal Melanoma: A Rare Melanoma Subtype Melanoma in Non-Sun Damaged Skin Melanoma in Sun Damaged Skin Acral Melanoma Mucosal Melanoma Conjunctival Melanoma 80% <10% <5% <2% <1% Uveal Melanoma <5%
The Clinical Heterogeneity of Mucosal Melanoma Carvajal RD et al. JNCCN 2012. Prasad et al. Head and Neck 2006. Head and Neck Mucosa (55%) Location Nasal Cavity, 49% Lateral nasal wall Turbinates Paranasal Sinuses, 10% Maxillary sinus Ethmoid sinus Oral Cavity, 41% Hard palate Upper alveolus Symptoms Sinonasal: Nasal obstruction, epistaxis, loss of smell, pain, proptosis, diplopia Oral Cavity: Bleeding, ulceration, discoloration, ill-fitting dentures Anorectal Mucosa (24%) Location Anal Canal, 33% Anorectal, 25% Rectal, 42% Symptoms Rectal bleeding, painful defecation, anorectal masses, “hemmorrhoids” Vulvovaginal Mucosa (18%) Location Vulvar, 90% Vaginal, 10% Symptoms Vulvar: Pruritis, bleeding, ulceration Vaginal: Vaginal discharge, dysparenuria, vaginal mass
CheckMate 172 (n=1008): OS with Nivolumab by Subtype Subtype n Median OS (mos) Non-Acral Cut Melanoma 723 25.3 (95% CI, 20.9 – 28.9) Ocular Melanoma 103 12.6 (95% CI, 10.2 – 15.1) Mucosal Melanoma 63 11.5 (95% CI, 6.4 – 15.0) Acral Melanoma 55 25.8 (95% CI, 15.1 – 30.6) Other 64 21.8 (95% CI, 9.8 – NR) Nathan et al, Eur J of Ca 2019.
International Real World Data Experience (n = 545) Dimitriou F et al. Ann Oncol, 2022. Data on patients from 25 centers in Australia, Europe, USA and Asia Median follow-up of 31 months (95% CI, 17-54) Progression-Free Survival Overall Survival
Most Recent FDA Approvals by Indication Cutaneous Melanoma Lifileucel (February 2024) Basal Cell Ca Cemiplimab (Feb 2021) Merkel Cell Ca Retifanlimab (March 2023) cSCC Pembrolizumab (June 2019) Acral Melanoma None Mucosal Melanoma None Uveal Melanoma Hepzato Kit (Aug 2023) FDA Approvals for Melanoma and Cutaneous Malignancies
Completed Clinical Trials in Mucosal Melanoma Setting Study Phase n Treatment Arm(s) Results Neoadjuvant Mao et al, ASCO 2023 2 19 Lenvatinib + Pembro 32% path RR in resected population (n=15) Lian et al, Ann Oncol 2024 2 29 Toripalimab + Axitinib 33% path RR in resected population (n=24) Adjuvant Lian et al, JCO 2013 2 189 Obs vs HDI vs Cis/TMZ RFS and OS improved with Cis/TMZ vs Obs or HDI Lian et al, ASCO 2018 3 204 HDI vs Cis/TMZ Primary Endpoint of RFS reached (15.5 vs 9.5 mos) in favor of chemo Lian et al, Ann Oncol 2022 2 145 Toripalimab vs HDI Similar RFS (13.6 vs 13.9 mos) and more favorable safety profile in favor of toripalimab Metastatic Sheng et al, JCO 2019; Li S, JITC 2022 1B 33 Toripalimab + Axitinib 48% ORR in chemo-naive patients (n=29); PFS 7.5 mos Nomura et al, Int J Clin Onc 2020 2 20 Nivolumab ORR 23.5% (n=17); PFS 12 mos; 1 yr OS rate 50% Yan et al, JCO 2021 2 114 Carbo/Taxol +/- Bev Primary Endpoint of PFS reached in favor of bevacizumab (4.8 vs 3.0 mos); OS 13.6 vs 9 mos in favor of bev Mao L, Clin Cancer Res 2022 2 43 Atezolizumab + Bev ORR 45%, median PFS 9.2 mos, median OS not reached Zhao L, JITC 2024 2 32 Camrelizumab + Apatinib ORR 43%, PSF 8 months
Limited Guidelines Available to Guide Management Smith HG et al. Eur J Cancer, 2020. NCCN Guidelines, Head and Neck Cancers. Nenclares et al. Eur J Cancer, 2020. Sinonasal and Oral Cavity Melanoma Anorectal and Vulvovaginal Melanoma
How do we manage advanced disease? Appropriate clinical trial if available CPI as SOC front-line therapy Targeted therapy as next line if actionable alteration present Carbo/Taxol/Bev Other chemotherapy regimens
Summary Mucosal melanoma is a rare melanoma subset with a distinct biology and a particularly poor prognosis There is no proven effective therapy in the perioperative or metastatic settings Only limited efforts are ongoing that are focused on developing novel therapies specifically for mucosal melanoma This patient population represents a significant unmet medical need
Vicki goodman, md chief medical officer Artistry-6 overview
Systematic Literature Review of Outcomes and Treatments in Post-Anti-PD-(L)1 Advanced Mucosal Melanoma Systematic Literature Review (SLR) conducted to identify interventional and real-world (RW) studies assessing treatments and clinical outcomes in patients with advanced mucosal melanoma who have previously been treated with anti-PD-(L)1 therapy TREATMENT OVERVIEW Four of the 11 RW studies reported ORR Each study contained 4-16 patients Patients received a variety of agents, including single agent and combination CPIs, kinase inhibitors, and combo CPI/kinase inhibitors ORR ranged from 0-25%, the latter in a sample size of 4 In the RW studies, post anti-PD-(L)1 treatments included checkpoint inhibitors (e.g., ipilimumab, and/or anti-PD-[L]1 rechallenge), cytotoxic agents, targeted therapies, radiation therapy, best supportive care, and treatments used off label such as tyrosine kinase inhibitors No cell therapy was reported in the RW studies In the interventional study, the reported post anti-PD-(L)1 treatment was lifileucel monotherapy, a tumor-infiltrating lymphocytes cell therapy 11 RW studies 1 interventional study ORR 0% to 25.0% RW ORR Outcomes in Patients with Mucosal Melanoma Post Anti-PD-(L)1 1 interventional study included 12 patients treated with lifileucil, a treatment with severe limitations, with a response rate of 50%
Responses per RECIST v1.1 ARTISTRY-1: Nemvaleukin Demonstrated Durable Monotherapy Responses in Melanoma (Part B) Alla,b (n=46) Mucosal (n=6) Best overall response, n (%) CR 0 0 PR 6 (13.0)c 2 (33.3)d ORR, n (%) [95% CI] 6 (13.0) [4.9-26.3]c 2 (33.3) [4.3-77.8]d DOR in weeksd, Mean (SD) Median (range) 40.77 (55.6) c 16.75 (6.1-150.3) 78.2 (101.9)d 78.2 (6.1-150.3) a Excludes 1 patient who did not meet tumor-evaluable criteria. b Patients with mucosal, cutaneous, uveal, acral included in ‘All’. C Includes 4 confirmed PRs, 2 unconfirmed PRs, d 1 confirmed PR. e DOR for Part B only and does not include patients who rolled over to Part C; some patients may still be on treatment Data cut off Mar 27, 2023 Abbrev.: adj: adjuvant; ATEZO: atezolizumab; BIN: binimetinib; CBP: carboplatin; CI: confidence interval; COB: cobimetinib; CPI: checkpoint inhibitor; CR: complete response; DAB: dabrafenib; DCR: disease control rate (CR+PR+SD); DOR: duration of response; ENCO: encorafenib; FDA: US Food and Drug Administration; IPI: ipilimumab; MHRA: Medicines and Healthcare products Regulatory Agency; MV: melanoma vaccine; NA: not applicable; NIVO: nivolumab; ORR: overall response rate; PAC: paclitaxel; PD: progressive disease; PEMBRO: pembrolizumab; PR: partial response; SD: stable disease; TRAM: trametinib; TVEC: talimogene laherparepvec; VEM: vemurafenib. Data on file. All responders had been on prior CPI therapy and progressed FDA Orphan Drug and Fast Track designations, as well as MHRA’s ILAP Innovation Passport, granted in mucosal melanoma Data supported design of ARTISTRY-6 study
Cohort 2 of ARTISTRY-6: Phase 2 - Potentially Registrational Trial of Nemvaleukin in Mucosal Melanoma https://clinicaltrials.gov, NCT04830124 Key eligibility criteria 1 Unresectable and/or metastatic mucosal melanoma Patient has received anti–PD(L)-1 ± anti–CTLA-4 therapy No more than 1 prior systemic therapy Measurable disease per RECIST v1.1 ECOG PS 0-1 Key endpoints Primary: ORR per RECIST v1.1 (by independent central review) Key secondary: DOR, PFS, DCR, TTR per RECIST v1.1 (by independent central review) a With the exception of Cycle 1, which is 14 days (daily IV for 5 days + 9 days nontreatment), all cycles are 21 days3 Cohort 2 Mucosal melanoma (N=90) Nemvaleukin IV 6 µg/kg QDx5 Monotherapy 21-day cyclea 16-day nontreatment period Daily IV Abbrev.: CTLA-4: cytotoxic T-lymphocyte–associated antigen 4; DCR: disease control rate; DOR: duration of response; ECOG PS: Eastern Cooperative Oncology Group performance status; IV: intravenous; ORR: objective response rate; PD-(L)1: programmed death (ligand) 1; PFS: progression-free survival; RECIST: Response Evaluation Criteria in Solid Tumors; TTR: time to response ARTISTRY-6 also includes Cohorts 1, 3, and 4 which are designed to explore alternative dosing regimens of nemvaleukin, both as a monotherapy and in combination with pembrolizumab, in cutaneous melanoma Nemvaleukin dosing Final Enrollment: 92 patients
ARTISTRY-6 Cohort 2: Assumptions on Final Data Cohort 2 of ARTISTRY-6 study expected to provide the most robust clinical dataset in advanced mucosal melanoma to date Primary analysis will occur when all patients have a minimum follow up of at least 6 months Target response rate: 25% We believe a response rate of 20-25% would be meaningful for patients and would support discussion with FDA around Biologics License Application (BLA) submission Trial designed so that at 25% response rate, lower bound of 95% confidence interval will exceed a 15% response rate Intend to discuss data with FDA in advance of BLA submission Potential accelerated approval with confirmatory evidence to be later submitted for conversion to regular approval Regulatory filing may be deferred if ARTISTRY-7 study continues to final analysis, pending the final outcome Abbrev.: BLA: Biologics License Application
Jean Chamoun, phD VICE PRESIDENT, RESEARCH Engineered il-18 program
Activates NK cells and antigen-experienced CD8+ T cells Restores activity in dysfunctional T cells Matures dendritic cells (DCs) IL-18R IL-18R MYD88 IL-18 Suppressed activity IL-18R IL-18R IL-18 IL-18BP IL-18BP IL-18BP overexpressed in the TME IL-18BP binds strongly to IL-18 minimizing it’s signaling IL-18 rapidly cleared from circulation Limited Application IL-18 is a Potent Stimulator of Innate and Adaptive Immunity, but with Key Limitations IL-18 Attractive Biology IL-18 Challenges
Mural Solution: Engineer an IL-18 with Optimized Characteristics NK / CD8+ T / DCs IL-18R IL-18R IL-18v IL-18BP IL-18BP-rich TME Engineer an active IL-18 molecule unaffected by IL-18BP presence Engineer an IL-18 with and extended half-life Optimize the IL-18 potency to fit its newly engineered profile Enhanced Anti-Tumor Activity Mural's Oncology IL-18: Engineered to Deliver a More Sustained Immune Response
--No Binding-- IL-18 huMOv1 IL-18 huMOv2 No Binding of Mural Oncology Variants to IL-18BP Broad Range of Potency Enhanced Pharmacokinetics Native HuIL-18 tight binding to IL18-BP No binding of MOV to IL18-BP huMOv1/2/3- human Mural Oncology variants IL18BP-resistant, half-life enhanced Preclinical Studies Demonstrated Enhanced Pharmacokinetics with an Optimized Potency and Maximal Resistance to IL-18BP Inhibition
Enhanced Pharmacokinetic Extended Pharmacodynamic muMOv1-mouse Mural Oncology variant IL18BP-resistant, half-life enhanced Mural’s Approach Achieves Intended Half-Life and Associated Pharmacodynamics Effects
Complete Responses and Survival Improvement Seen in Mural’s IL-18 Mouse Ortholog Variant Agent Dose (mg/kg) % TGI* Day 21 Complete Response Day 50 Probability of Survival Day 50 muMOv1 2.56 86% 2/10 40% muMOv1 5.12 93% 4/10 50% muMOv1 7.68 92% 5/10 50% *%TGI = % tumor growth inhibition, calculated before 1st animal in vehicle reached endpoint muMOv1- IL18BP-resistant, half-life enhanced mouse ortholog of Mural human variant The combination of IL-18BP resistance and half-life enhancement achieved desired effect
Key Takeaways: IL-18 Mural’s fit-for-purpose approach successfully engineered an IL-18 molecule with the desired profile: Maximal resistance to IL18-BP binding Enhance half-life compared to native IL-18 Optimized potency Clearly demonstrated desired efficacy with mouse ortholog variant IND filing by Q4 of 2025
CAROLINE LOEW, pHd WHY MURAL & WHY NOW?
Mural at a Glance Abbrev.: CM: cutaneous melanoma; IL-12: interleukin-12; IL-18: interleukin-18; MM: mucosal melanoma; OS: overall survival; PDR: preliminary data readout; PROC: platinum resistant ovarian cancer; RP2D: recommended phase 2 dose; TLR: topline results Subject to event accrual Subject to patient enrollment Phase 2/3 Late-Stage Trials: Cash Position: Preclinical Assets: Fully enrolled for ARTISTRY-7 (Phase 3, PROC) and ARTISTRY-6 cohort 2 (Phase 2, mucosal melanoma) Ongoing discussions with FDA on ARTISTRY-6 potential confirmatory evidence package RP2D for next generation dosing schedule underway in ARTISTRY-6, cohorts 3 & 4 (phase 2, cutaneous melanoma ) 4Q 2024: Candidate nominations for IL-18 and IL-12 4Q 2025: IL-18 IND submission Cash runway into 4Q 2025 Late Q1/Early Q2: Interim OS for ARTISTRY-71 Q2: TLR Cohort 2 of ARTISTRY-6 1H: PDR Cohort 3-mono of ARTISTRY-6 (Phase 2, CM)2 2H: PDR Cohort 4-combo of ARTISTRY-6 (Phase 2, CM)2 2025 CATALYSTS: Significant opportunity in 2 indications with limited available therapies and planned indication expansion Commercial Opportunity:
Key Takeaways: ARTISTRY-7 Trial Design Assumptions and Progress Fully enrolled with 456 patients (versus 448 planned), with approximately 187 patients per experimental arm Futility analysis complete for monotherapy arms: Pembrolizumab monotherapy arm reached futility (defined as <2 confirmed CR or PR in the first 12 patients) in August 2023 after enrolling 27 patients Nemvaleukin arm required at least 1 patient among the first 24 to achieve a response or SD for at least 3 months to continue; this arm continued to enroll a total of 55 patients Design assumptions on overall survival endpoint, with alpha controlled at 2.5% (one sided): Chemo arm: estimated median OS of 10 months Nemva + pembro arm: estimated median OS of 14.3 months Projected readout on 75% of events in late Q1 or early Q2 2025
Key Takeaways: ARTISTRY-6 Cohort 2 Trial Assumptions and Progress Cohort 2 or ARTISTRY-6 study expected to provide the most robust clinical dataset in advanced mucosal melanoma to date Fully enrolled with 92 patients Target response rate: 25% Response rate of 20-25% would be meaningful for patients and would support discussion with FDA around Biologics License Application (BLA) Trial designed so that at 25% response rate, lower bound of 95% confidence interval will exceed a 15% response rate Potential for accelerated approval, and discussions with FDA on potential confirmatory evidence package ongoing Regulatory filing may be deferred if ARTISTRY-7 study continues to final analysis, pending the final outcome of ARTISTRY-7 Projected readout in Q2 2025
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