UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 7.01. | Regulation FD Disclosure |
On June 1, 2024, Werewolf Therapeutics, Inc. (the “Company”) issued a press release announcing preliminary clinical data from the Company’s ongoing Phase 1/1b clinical trial evaluating WTX-124, its conditionally activated Interleukin-2 (“IL-2”) INDUKINE™ molecule. A copy of the press release is furnished as Exhibit 99.1 hereto and is incorporated herein by reference.
On June 3, 2024, the Company made available a presentation to be used with investors to discuss the clinical data from the Company’s Phase 1/1b clinical trial of WTX-124. A copy of the presentation is furnished as Exhibit 99.2 hereto and is incorporated herein by reference.
The information furnished under this Item 7.01, including Exhibit 99.1 and Exhibit 99.2, 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 a filing.
| Item 8.01. | Other Events. |
New Preliminary Data from Phase 1/1b Clinical Trial of WTX-124
On June 1, 2024, the Company announced new preliminary clinical data from the Company’s Phase 1/1b clinical trial evaluating WTX-124 in patients with locally advanced or metastatic solid tumors after checkpoint inhibitor therapy. The data was presented on June 1, 2024, in a poster session at the 2024 American Society of Clinical Oncology (“ASCO”) Annual Meeting.
The ongoing Phase 1/1b clinical trial is evaluating WTX-124 as a monotherapy and in combination with pembrolizumab in patients with immunotherapy sensitive advanced or metastatic solid tumors who have failed standard of care treatment, including checkpoint inhibitor therapy. The presentation at ASCO captured data as of a May 1, 2024 cutoff date from 47 heavily pretreated patients: 35 patients treated with at least one monotherapy dose of WTX-124, ranging from 1 mg to 28 mg; 12 patients treated with WTX-124 at doses ranging from 3 mg to 12 mg in combination with pembrolizumab.
Data as of the May 1, 2024, cutoff date are summarized as follows:
| • | WTX-124 as a monotherapy produced three objective clinical responses including one durable confirmed complete response and two partial responses in patients who are relapsed/refractory to immune checkpoint inhibitor therapy. |
| • | Responding patients had 100% regression of target lesions with responses occurring within the first two cycles of therapy and showing durability at the recommended dose for expansion (“RDE”). |
| • | Related treatment emergent adverse events were primarily mild to moderate in severity, manageable and reversible; no new safety signals were identified when WTX-124 was combined with pembrolizumab. |
| • | Analysis of paired tumor biopsies by NanoString suggests that WTX-124 robustly activated/expanded effector T cells preferentially over regulatory T cells. |
| • | Increased T cell activation signature for the combination suggests a potential for improved antitumor activity by combining WTX-124 with pembrolizumab. |
| • | WTX-124 was clinically active and generally well tolerated in patients, not all of whom would be eligible for treatment with approved high-dose IL-2 therapies based on age, indication or other factors. |
Based on these results, the Company has selected a WTX-124 monotherapy dose of 18 mg administered intravenously every two weeks, as the RDE to progress into the Phase 1b dose-expansion portion of the trial. The Company has thus far opened three expansion arms in advanced or metastatic renal cell carcinoma, cutaneous melanoma and cutaneous squamous cell carcinoma. The Company targets preliminary data from these expansion arms in the fourth quarter of 2024 or the first quarter of 2025. The Company also continues to dose-escalate WTX-124 in combination with pembrolizumab and expects to select an RDE to open the combination dose-expansion portion of the study in the third
quarter of 2024. In parallel, the Company also plans to engage regulators to discuss potential registrational pathways for WTX-124, including strategies for monotherapy accelerated approval in immune-checkpoint inhibitor relapsed/refractory indications.
In addition, on June 3, 2024, the Company announced that in the interval between the May 1, 2024 data cut-off for the ASCO data and June 3, 2024, it has observed in preliminary data clinical activity in two melanoma patients at the 12 mg combination dose level, one partial response and one near partial response (-29% target lesion reduction).
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Press Release, dated June 1, 2024. | |
| 99.2 | Investor Presentation, dated June 3, 2024. | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
Cautionary Note Regarding Forward-Looking Statements
Any statements in this Current Report on Form 8-K about the Company’s future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements are subject to substantial risks and uncertainties and actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include statements regarding the Company’s strategy, future operations, prospects, plans, objectives of management, the expected timeline regarding the clinical development of product candidates, including the announcement of data, the potential activity and efficacy of product candidates in preclinical studies and clinical trials, and the timing and outcome of planned meetings with regulatory authorities. The words “aim,” “anticipate,” “approach,” “believe,” “contemplate,” “continue,” “could,” “design,” “designed to,” “engineered,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “potential,” “predict,” “project,” “promise,” “should,” “target,” “will,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The Company may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: uncertainties inherent in the development of product candidates, including the conduct of research activities, the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical studies and clinical trials; the timing of and the Company’s ability to submit and obtain regulatory approval for investigational new drug applications; whether results from preclinical studies will be predictive of the results of later preclinical studies and clinical trials; whether interim or preliminary data from a clinical trial will be predictive of the results of the trial and future clinical trials; the Company’s ability to obtain sufficient cash resources to fund the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements; as well as the risks and uncertainties identified in the “Risk Factors” section of the Company’s most recent Form 10-Q filed with the Securities and Exchange Commission (“SEC”), and in subsequent filings the Company may make with the SEC. In addition, the forward-looking statements included in this Current Report on Form 8-K represent the Company’s views as of the date of this Current Report on Form 8-K. The Company anticipates that subsequent events and developments will cause its views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this Current Report on Form 8-K.
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.
| WEREWOLF THERAPEUTICS, INC. | ||||||
| By: | ||||||
| Date: June 3, 2024 | /s/ Timothy W. Trost | |||||
| Timothy W. Trost | ||||||
| Chief Financial Officer and Treasurer | ||||||
Exhibit 99.1
Werewolf Therapeutics to Present Data from Ongoing Phase 1/1b Clinical Trial of
WTX-124 as Monotherapy and in Combination with Pembrolizumab in Solid Tumors
- WTX-124 was shown to be clinically active and generally well-tolerated in patients who were relapsed/refractory to immune checkpoint inhibitor therapy -
- Encouraging single agent clinical activity with three objective responses, including a durable confirmed complete response -
- Monotherapy recommended dose for expansion selected and expansion arms open for enrollment -
- Preliminary data on WTX-124 administered to patients in combination with pembrolizumab showed that the combination was generally well-tolerated with enhanced immune activation in tumors -
- Company to host webcast to review these data on Monday, June 3, 2024, at 8:00 am ET -
WATERTOWN, Mass., June 01, 2024 (GLOBE NEWSWIRE) — Werewolf Therapeutics, Inc. (the “Company” or “Werewolf”) (Nasdaq: HOWL), an innovative biopharmaceutical company pioneering the development of conditionally activated therapeutics engineered to stimulate the body’s immune system for the treatment of cancer, today announced new clinical data from the Phase 1/1b trial evaluating WTX-124, its conditionally activated Interleukin-2 (IL-2) INDUKINETM molecule, in patients with locally advanced or metastatic solid tumors after checkpoint inhibitor therapy. The data will be presented today, on June 1, 2024, in a poster session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, and in a webcast on June 3, 2024.
“Approved high-dose IL-2 (HD IL-2) has been known to be effective in creating durable responses for some patients, however the toxicity of the drug has meant that many patients are not eligible for the treatment,” said Justin Moser, M.D., WTX-124 study investigator and Associate Clinical Investigator, HonorHealth Research Institute, Scottsdale, AZ. “The emerging data from the Phase 1/1b clinical trial of WTX-124 suggest that we may potentially achieve durable objective responses with a favorable safety profile for patients in the outpatient setting, some of whom would not have been candidates for HD IL-2.”
“We are pleased to share these findings from our ongoing Phase 1/1b clinical trial of WTX-124 that build on the promise of our INDUKINE hypothesis that potent cytokine-based immunotherapies could address difficult-to-treat tumors while minimizing toxicities typical of IL-2 therapy,” added Randi Isaacs, M.D., Chief Medical Officer. “We have selected our recommended dose for expansion (RDE) and opened three monotherapy expansion arms in more homogenous and less heavily pre-treated populations to better assess clinical activity in each while we continue to explore additional doses in dose escalation. In addition, the combination of WTX-124 with pembrolizumab was generally well-tolerated, which alongside compelling biomarker activity, suggests the potential for combination efficacy. Altogether, these results reinforce our conviction in WTX-124 as a potential best-in-class IL-2 therapy, and we look forward to providing additional updates as the program progresses.”
The ongoing Phase 1/1b study is evaluating WTX-124 as a monotherapy and in combination with pembrolizumab in patients with immunotherapy sensitive advanced or metastatic solid tumors who have failed standard of care treatment, including checkpoint inhibitor therapy. The presentation at ASCO captures data from 47 heavily pretreated patients: 35 patients treated with at least one monotherapy dose of WTX-124, ranging from 1 mg to 28 mg; 12 patients treated with WTX-124 at doses ranging from 3 mg to 12 mg in combination with pembrolizumab.
Data as of the May 1, 2024, cutoff date are summarized as follows:
| • | WTX-124 as a monotherapy produced three objective clinical responses including one durable confirmed complete response (CR) and two partial responses (PRs) in patients who are relapsed/refractory to immune checkpoint inhibitor therapy. |
| • | Responding patients had 100% regression of target lesions with responses occurring within the first two cycles of therapy and showing durability at RDE. |
| • | Related treatment emergent adverse events (TEAEs) were primarily mild to moderate in severity, manageable and reversible; no new safety signals were identified when WTX-124 was combined with pembrolizumab. |
| • | Analysis of paired tumor biopsies by NanoString suggests that WTX-124 robustly activated/expanded effector T cells preferentially over Tregs. |
| • | Increased T cell activation signature for the combination suggests a potential for improved antitumor activity by combining WTX-124 with pembrolizumab. |
| • | WTX-124 was clinically active and generally well tolerated in patients, not all of whom would be eligible for HD IL-2 based on age, indication or other factors. |
These findings are summarized in a poster titled, “A phase 1/1b trial of the IL-2 prodrug WTX-124 in patients with locally advanced or metastatic solid tumors after checkpoint inhibitor therapy: Updated results of the monotherapy dose escalation and initial results of the combination therapy dose escalation with pembrolizumab.” The poster can be viewed in person from 9:00 am-12:00 pm CT on Saturday, June 1, 2024, on board number 102 and is available on the Company’s website at https://investors.werewolftx.com/news-and-events/scientific-resources.
Next Steps for WTX-124 Development
Based on these results, Werewolf has selected a WTX-124 monotherapy dose of 18 mg administered intravenously every two weeks (IV Q2W), as the RDE to progress into the Phase 1b dose-expansion portion of the trial. The Company has thus far opened three expansion arms in advanced or metastatic renal cell carcinoma, cutaneous melanoma and cutaneous squamous cell carcinoma. Werewolf also continues to dose-escalate WTX-124 in combination with pembrolizumab and expects to select an RDE to open the combination dose-expansion portion of the study in the third quarter of 2024. In parallel, the Company also plans to engage regulators to discuss potential registrational pathways for WTX-124, including strategies for monotherapy accelerated approval in immune-checkpoint inhibitor relapsed/refractory indications.
Webcast Details
Werewolf will host a webcast at 8:00 am ET on Monday, June 3, 2024, to review these clinical results presented at ASCO. Werewolf management will be joined by study investigator Justin Moser, M.D., Associate Clinical Investigator, HonorHealth Research Institute, Scottsdale, AZ, who will present the updated data. The event can be accessed live at https://investors.werewolftx.com/news-and-events/events. An archived replay will be available for approximately 90 days following the event.
About Werewolf Therapeutics
Werewolf Therapeutics, Inc., is an innovative biopharmaceutical company pioneering the development of therapeutics engineered to stimulate the body’s immune system for the treatment of cancer. We are leveraging our proprietary PREDATOR® platform to design conditionally activated molecules that stimulate both adaptive and innate immunity with the goal of addressing the limitations of conventional proinflammatory immune therapies. Our INDUKINE™ molecules are intended to remain inactive in peripheral tissue yet activate selectively in the tumor microenvironment. Our most advanced clinical stage product candidates, WTX-124 and WTX-330, are systemically delivered, conditionally activated Interleukin-2 (IL-2), and Interleukin-12 (IL-12) INDUKINE molecules, respectively, for the treatment of solid tumors. We expect to advance WTX-124 in multiple tumor types as a single agent and in combination with an immune checkpoint inhibitor and WTX-330 in multiple tumor types or Non-Hodgkin Lymphoma as a single agent. To learn more visit www.werewolftx.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this press release, including statements regarding Werewolf’s strategy, future operations, prospects, plans, objectives of management, the expected timeline regarding the clinical development of product candidates, including the announcement of data, the potential activity and efficacy of product candidates in preclinical studies and clinical trials, and the timing and outcome of planned meetings with regulatory authorities, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The words “aim,” “anticipate,” “approach,” “believe,” “contemplate,” “continue,” “could,” “design,” “designed to,” “engineered,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “potential,” “predict,” “project,” “promise,” “should,” “target,” “will,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The Company may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including: uncertainties inherent in the development of product candidates, including the conduct of research activities, the initiation and completion of preclinical studies and clinical trials; uncertainties as to the availability and timing of results from preclinical studies and clinical trials; the timing of and the Company’s ability to submit and obtain regulatory approval for investigational new drug applications; whether results
from preclinical studies will be predictive of the results of later preclinical studies and clinical trials; whether interim or preliminary data from a clinical trial will be predictive of the results of the trial and future clinical trials; the Company’s ability to obtain sufficient cash resources to fund the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements; as well as the risks and uncertainties identified in the “Risk Factors” section of the Company’s most recent Form 10-Q filed with the Securities and Exchange Commission (“SEC”), and in subsequent filings the Company may make with the SEC. In addition, the forward-looking statements included in this press release represent the Company’s views as of the date of this press release. The Company anticipates that subsequent events and developments will cause its views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this press release.
PREDATOR® is a registered trademark of Werewolf Therapeutics, Inc., Watertown, MA, USA.
Investor Contact:
Josh Rappaport
Precision AQ
212.362.1200
Josh.Rappaport@precisionaq.com
Media Contact:
Amanda Sellers
VERGE Scientific Communications
301.332.5574
asellers@vergescientific.com
Company Contact:
Ellen Lubman
Chief Business Officer
Werewolf Therapeutics
elubman@werewolftx.com
Exhibit 99.2 Shifting the Balance in Cytokine Therapeutics ASCO 2024 WTX-124 Phase 1/1b Clinical Trial Update Investor Webcast June 3, 2024 ©2024 WEREWOLF THERAPEUTICS
Cautionary Note Regarding Forward-Looking Statements and Disclaimer This presentation contains forward-looking statements that involve substantial risks and uncertainties inherent in the development of product candidates, including the conduct uncertainties. All statements, other than statements of historical facts, contained in this of research activities, the initiation and completion of preclinical studies and clinical presentation, including statements regarding Werewolf Therapeutics, Inc.’s trials; uncertainties as to the availability and timing of results from preclinical studies (the “Company”) strategy, future operations, prospects, plans, objectives of and clinical trials; the timing of and the Company’s ability to submit and obtain management, the expected timeline regarding preclinical and clinical development for regulatory approval for investigational new drug applications; whether results from product candidates, including the announcement of data, the potential activity and preclinical studies will be predictive of the results of later preclinical studies and clinical efficacy of product candidates in future preclinical studies and clinical trials, and the trials; whether interim or preliminary data from a clinical trial will be predictive of the timing and outcome of planned meetings with regulatory authorities, constitute results of the trial and future clinical trials; the Company’s ability to obtain sufficient forward-looking statements within the meaning of The Private Securities Litigation cash resources to fund the Company’s foreseeable and unforeseeable operating Reform Act of 1995. The words “aim,” “anticipate,” “approach,” “believe,” expenses and capital expenditure requirements, as well as the risks and uncertainties “contemplate,” “continue,” “could,” “design,” “designed to,” “engineered,” “estimate,” identified in the “Risk Factors” section of the Company’s most recent Form 10-Q filed “expect,” “goal,” “intend,” “may,” “might,” “objective,” “ongoing,” “opportunity,” “plan,” with the Securities and Exchange Commission (“SEC”) and in subsequent filings the “potential,” “predict,” “project,” “promise,” “should,” “target,” “will,” or “would,” Company may make with the SEC. In addition, the forward-looking statements included or the negative of these terms, or other comparable terminology are intended to in this presentation represent the Company’s views as of the date of this presentation. identify forward-looking statements, although not all forward-looking statements The Company anticipates that subsequent events and developments will cause its views contain these identifying words. The Company may not actually achieve the plans, to change. However, while the Company may elect to update these forward-looking intentions or expectations disclosed in these forward-looking statements, and you statements at some point in the future, it specifically disclaims any obligation to do so. should not place undue reliance on these forward-looking statements. Actual results or These forward-looking statements should not be relied upon as representing the events could differ materially from the plans, intentions and expectations disclosed in Company’s views as of any date subsequent to the date of this presentation. these forward-looking statements as a result of various important factors, including: 2 | ©2024 WEREWOLF THERAPEUTICS
3 • Introductory Remarks and Program Overview – Dan Hicklin, Ph.D., CEO • Walk-through of WTX-124 Data – Justin Moser, M.D. • Closing Remarks – Randi Isaacs, M.D., CMO Agenda • Q&A 3 | ©2024 WEREWOLF THERAPEUTICS
Overview of WTX-124 Program Objectives A cytokine prodrug engineered to improve the efficacy and tolerability of IL-2 The Challenge Approved high-dose IL-2 therapy (HD IL-2) with aldesleukin (Proleukin®) produces durable responses in patients with cutaneous melanoma and renal cell carcinoma, but its use is limited by severe toxicity TM Advantages of WTX-124, an IL-2 INDUKINE Molecule Novel prodrug engineered with enhanced pharmaceutical properties to selectively release a fully potent IL-2 in the tumor microenvironment to stimulate antitumor immunity with reduced toxicity Key Opportunities • Provide IL-2 therapy to patients ineligible for HD IL-2 based on age, performance status, and/or comorbidities • Address an urgent unmet medical need for patients relapsed/refractory to all SOC therapies including CPIs • Safely combine IL-2 therapy with SOC agents including CPIs in earlier lines of therapy • Explore the potential benefit of IL-2 therapy in other IO-sensitive solid tumor indications Abbreviations: SOC-standard of care; CPI-checkpoint inhibitors; IO-immunotherapy 4 | ©2024 WEREWOLF THERAPEUTICS
WTX-124: Summary of Data to Date Establishes potential for a best-in-class IL-2 therapy SITC - Nov 2023 ASCO - June 2024 Updated monotherapy and initial combination Initial monotherapy dose-escalation data; dose-escalation data; 47 patients (1-28 mg) 16 patients (1-12 mg) • Monotherapy antitumor activity further demonstrated • Generally well tolerated by IO-refractory patients in the – durable complete response in patient with CSCC outpatient setting, many ineligible for HD IL-2 based on (earlier PR) age, comorbidities, or indication • 100% target lesion reduction noted in responding • Wide therapeutic index established demonstrating patients proof of concept for the INDUKINE platform • Data support selection of monotherapy RDE and • Demonstrated Teff cell activation and monotherapy opening of expansion arms clinical activity (2 PRs at 12 mg dose level) • Combination dose escalation data demonstrated a • Proof of concept established for WTX-124 favorable safety profile with strong biomarker signals supportive of combination antitumor activity Abbreviations: PR-partial response; CSCC-cutaneous squamous cell carcinoma; RDE-recommended dose for expansion; IO-immunotherapy; ICI-immune checkpoint inhibitor Note: SITC data as of November 1, 2023; ASCO data as of May 1, 2024, each for an ongoing, open label Phase 1/1b clinical trial. 5 | ©2024 WEREWOLF THERAPEUTICS
Justin Moser, MD Associate Clinical Investigator HonorHealth Research Institute 6 6 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
WTX-124 FIH Study Monotherapy Expansion Arms are now Open and Enrolling Forty-seven patients have received at least one dose of WTX-124 (35 in monotherapy, 12 in combination) Monotherapy/Combination Dose Expansion MONOTHERAPY DOSE ESCALATION Determination Advanced or metastatic renal cell of WTX-124 IV 28 mg TBD 23 mg Q2W RDE/ carcinoma n =3 18 mg n =1 MTD as a 12 mg n =9 6 mg Open n =11 monotherapy 3 mg Open Advanced or metastatic cutaneous n =4 1 mg n =4 n =3 melanoma Advanced or metastatic cutaneous COMBINATION THERAPY DOSE ESCALATION squamous cell carcinoma Determination of WTX-124 IV (monotherapy only) 18 mg TBD Q2W RDE/MTD in combination 12 mg n =TBD 6 mg n =4 with pembrolizumab IV Q6W 3 mg Other advanced or metastatic IO- n =4 Open n =4 sensitive tumor types TBD mTPI-2 (Modified Toxicity Monotherapy and combination Tumor biopsies obtained on Assessment of safety, efficacy, Trial Probability Interval 2) study therapy dose escalations enrolled treatment to evaluate PD pharmacokinetics, design; enrolling ~160 patients in parallel with staggered start for biomarkers supporting proof of Details biomarkers, and ADA with IO-sensitive tumors combination mechanism Abbreviations: FIH-first in human; IV-intravenous; Q2W-once every two weeks; Q6W-once every six weeks; RDE-recommended dose for expansion; MTD-maximum tolerated dose; TBD-to be determined; IO-immunotherapy; ADA-antidrug antibody; PD-pharmacodynamic Note: Preliminary clinical data as of May 1, 2024, of an ongoing, open label Phase 1/1b clinical trial. Monotherapy expansion arms opened and enrolling as of May 20, 2024. 7 | ©2024 WEREWOLF THERAPEUTICS
WTX-124 Phase 1 Patient Population was Heterogeneous and Heavily Pretreated All 47 patients (monotherapy, combination) progressed on standard-of-care ICI regimens Demographics Tumor Types Prior Therapies All prior lines of therapy Enrollment restricted to solid tumor n (%) indications for which immunotherapy AGE (years) Mean (SD) 63.9 (10.9) 1 10 (21.3%) with ICIs is standard-of-care 2 11 (23.4%) Median 65.0 n (%) 3 15 (31.9%) Melanoma* 24 (51.1%) SEX, n (%) Female 20 (42.6%) ≥4 11 (23.4%) NSCLC 8 (17.0%) Renal cell carcinoma 4 (8.5%) Male 27 (57.4%) Prior lines of immunotherapy Cutaneous SCC 2 (4.3%) n (%) Black/African- RACE, n (%) 2 (4.3%) GEJ adenocarcinoma 1 (2.1%) American 1 20 (42.6%) Hepatocellular 1 (2.1%) 2 15 (31.9%) White 39 (83.0%) Urothelial (bladder) 1 (2.1%) 3 9 (19.1%) Other/ 6 (12.7%) Other 6 (12.8%) Unknown ≥4 3 (6.4%) *Includes patients with cutaneous, mucosal and uveal melanoma. Abbreviations: ICI-immune checkpoint inhibitor; NSCLC-non-small cell lung cancer; SCC-squamous cell carcinoma; GEJ-gastroesophageal junction Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 8 | ©2024 WEREWOLF THERAPEUTICS
WTX-124 was Generally Well Tolerated as a Monotherapy in the Outpatient Setting Treatment-related adverse events were primarily mild to moderate including at clinically active doses Key Safety Findings: Frequency of related TEAEs • Most frequent related TEAEs occurring in were arthralgia, fatigue, pruritis more than and eosinophilia one patient • Majority of related TEAEs were Grade 1 and 2 N=35 patients were treated • Grade 3 TEAEs at ≥18 mg were with WTX-124 manageable, reversible monotherapy (1-28 mg IV • No Grade 4 or 5 related TEAEs Q2W) and evaluable for • No evidence of vascular leak safety syndrome, ≥ Grade 2 cytokine release syndrome, or infusion reactions • No recurrence to date of irAEs that had previously occurred on Adverse event preferred terms Number of subjects ICI therapy Abbreviations: TEAEs-treatment-emergent adverse events; HD-high dose; IV-intravenous; Q2W-once every two weeks; irAEs-immune related adverse events; ICI-immune checkpoint inhibitor Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 9 | ©2024 WEREWOLF THERAPEUTICS
No New Safety Signals were Observed for WTX-124 Combined with Pembrolizumab Addition of pembrolizumab did not change the character of related adverse events Frequency of related TEAEs occurring more than once for patients at 3-12 mg WTX-124 monotherapy (N=19) or combination therapy (N=12) • Majority of related TEAEs for combination therapy were mild to moderate • Combination therapy did not show an increase in the frequency and/or severity of TEAEs seen with WTX-124 monotherapy (e.g., arthralgia, rash, pruritis, fatigue, eosinophilia) Number of subjects Abbreviation: TEAEs-treatment-emergent adverse events Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 10 | ©2024 WEREWOLF THERAPEUTICS Adverse events (preferred terms)
WTX-124 Demonstrated Monotherapy Antitumor Activity at Doses ≥12 mg Durable CR (8+ months) in a patient with CSCC; PRs in patients with melanoma and GEJ cancer Cutaneous SCC (12 mg) * NSCLC (1 mg) Melanoma (6 mg) Melanoma (18 mg) NSCLC (3 mg) NSCLC (18 mg) NSCLC (12 mg) Gastroesophageal junction (18 mg) Melanoma (12 mg) *Patient being followed off Melanoma (12 mg) Melanoma (12 mg) study drug Renal cell carcinoma (18 mg) Melanoma (1 mg) Hepatocellular carcinoma (12 mg) Note that patients could be Uveal melanoma (12 mg) treated beyond progression Renal cell carcinoma (6 mg) (PD) if clinically indicated. Mucosal melanoma (28 mg) Urothelial/bladder (18 mg) Uveal melanoma (6 mg) Patient ongoing Renal cell carcinoma (1 mg) Melanoma (28 mg) NSCLC (12 mg) Mucosal melanoma (18 mg) Mucosal melanoma (3 mg) Basal cell carcinoma (12 mg) Melanoma (18 mg) NSCLC (3 mg) Abbreviations: CR-complete response; PR-partial response; CSCC-cutaneous squamous cell carcinoma; NSCLC-non-small cell lung cancer; GEJ-gastroesophageal junction Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 11 | ©2024 WEREWOLF THERAPEUTICS
Complete Regression of Target Lesions in Patients Responding to WTX-124 Three patients had objective responses and an additional seven had stable target lesions at potential RDE doses (n=16) *Metastatic lymph node target lesion normalized in size (<1 cm) * * Abbreviations: RDE- recommended dose for expansion; BCC-basal cell carcinoma, NSCLC-non-small cell lung cancer, HCC-hepatocellular carcinoma, RCC-renal cell carcinoma, GEJ-gastroesophageal junction tumor, CSCC-cutaneous squamous cell cancer Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 12 | ©2024 WEREWOLF THERAPEUTICS
Responses at Target Lesions Occurred Rapidly and were Durable at Potential RDE Doses All three objective responses to WTX-124 monotherapy occurred within two cycles (~8 weeks) *Metastatic lymph node target lesion normalized in size (<1 cm) Gastroesophageal junction * tumor (18 mg) Cutaneous squamous cell Melanoma (12 mg) carcinoma (12 mg) Abbreviations: RDE- recommended dose for expansion Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 13 | ©2024 WEREWOLF THERAPEUTICS
June 2023: PET-CT at time of September 2023: Baseline CT Confirmed Complete Response (CR) Ongoing at 8+ progression on cemiplimab performed at study entry Months in a Patient with ICI-Refractory Cutaneous SCC T NT 72-year-old man with metastatic cutaneous SCC who progressed on RT/cetuximab and had no response to four doses (12 weeks) of ® cemiplimab (Libtayo ; anti-PD-1) – panel a Initiated treatment with 12 mg WTX-124 IV Q2W three months after discontinuing cemiplimab a b Baseline CT showed a 2.6 cm premaxillary target lesion (T) and a non- target lesion (NT) extending into the pterygopalatine fossa – panel b November 1, 2023: First November 30, 2023: Confirmatory restaging CT at 8 weeks PET-CT at 12 weeks WTX-124 TREATMENT RESPONSE • 3 weeks: On-treatment biopsy of target lesion showed no tumor • 8 weeks: restaging CT showed a partial response (PR) with a 62% decrease of target lesion, no increase of non-target lesion – panel c • 12 weeks: confirmatory PET-CT showed a complete metabolic response of target/non-target lesions, consistent with a CR – panel d Patient tolerated therapy well with only Grade 2 arthralgias, Grade 2 rash WTX-124 treatment stopped at 21 weeks in the setting of confirmed CR c d (ongoing at 8+ months) Abbreviations: IO-immunotherapy; SCC-squamous cell carcinoma; IV-intravenous; Q2W-once every two weeks; CT-computed tomography scan; PET-positron emission tomography Note: Preliminary clinical data as of May 1, 2024, for an ongoing, 14 | ©2024 WEREWOLF THERAPEUTICS open label Phase 1/1b clinical trial.
July 2023: Baseline PET-CT at July 2023: Baseline CT shows the Partial Response (PR) in a Cutaneous Malignant time of progression on Opdualag 1.4 cm target liver lesion Melanoma Patient with Secondary ICI Resistance 78-year-old man with metastatic BRAF wild type cutaneous melanoma who discontinued adjuvant nivolumab due to toxicity, then progressed on nivolumab/relatlimab (Opdualag ; anti-PD-1, anti-LAG3; panel a) as first line therapy for metastatic disease (best overall response PR) Initiated treatment with 12 mg WTX-124 IV Q2W T a b Baseline CT (panel b) showed a 1.4 cm liver target lesion (T) and a T11 vertebral non-target lesion (NT). A lesion in the right humerus was September 2023: First restaging demonstrated on PET-CT - panel d Patient also had complete CT at 8 weeks shows complete resolution of a right upper humeral resolution of target liver lesion WTX-124 TREATMENT RESPONSE metastasis on PET-CT • 5 weeks: target lesion biopsied at baseline could not be reidentified July 2023 November 2023 for repeat biopsy • 8 weeks: restaging CT showed a 100% reduction of target lesion and no increase of non-target lesion, consistent with a PR – panel c • 16 weeks (CT): target lesion remained absent, but non-target T11 bone lesion increased. New lesions identified in sternum and periportal lymph nodes – not shown d c • 16 weeks (PET-CT): Right humeral bone lesion present at baseline had completely resolved – panel d Abbreviations: IO-immunotherapy; IV-intravenous; Q2W-once every two weeks; CT-computed tomography; PET-positron emission tomography Note: Preliminary clinical data as of May 1, 2024, for an ongoing, 15 | ©2024 WEREWOLF THERAPEUTICS open label Phase 1/1b clinical trial.
Partial Response (PR) in a Gastroesophageal Junction Tumor Patient with Secondary ICI Resistance October 2023: 63-year-old man with a metastatic gastroesophageal junction (GEJ) Baseline CT adenocarcinoma who previously progressed on FOLFOX/nivolumab and shows a 1.6 cm nivolumab/BMS986253 (anti-IL-8). BOR for each line was SD. mesenteric lymph node Initiated treatment with 18 mg WTX-124 IV Q2W three months after target lesion discontinuing nivolumab/BMS986253. Baseline CT showed a 1.6 cm mesenteric lymph node target lesion and four lymph node non-target lesions. TREATMENT RESPONSE January 2024: First restaging CT • 3 weeks: metastatic L axillary lymph node biopsied at baseline could at 8 weeks not be reidentified shows a 56% reduction of • 8 weeks: restaging CT showed a 56% reduction of target lesion mesenteric (complete normalization to <1 cm) and no increase of non-target lymph node lesions, consistent with a PR target lesion (normalization • 16 weeks: ongoing response observed at target lesion. Progression of size to <1 cm) seen at one of four non-target lymph nodes, per radiology report. Patient discontinued WTX-124 but has neither progressed nor needed any additional anticancer therapy for 3 months. Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label 16 | ©2024 WEREWOLF THERAPEUTICS Phase 1/1b clinical trial.
PK Data Continue to Demonstrate Proof of Concept for the INDUKINE Strategy Data support the improved safety profile and therapeutic index of WTX-124 compared to HD IL-2 Cycle 1 PK profiles for WTX-124 and free IL-2 compared to Preliminary PK findings: high-dose IL-2 Cmax (mean ± SEM) • WTX-124 dosed at 18 mg IV Q2W has a ~1.5-fold higher Cmax than HD IL-2 • Peak free IL-2 exposure after WTX-124 18 mg is ~136-fold lower than HD IL-2 • Across all dose levels, free IL-2 levels are very low (<1.6% of prodrug exposure) ~136-fold • WTX-124 PK is approximately dose- proportional up to 18 mg IV Q2W • Repeat dosing does not cause accumulation of WTX-124 or free IL-2 • ADA are transient, primarily low titer, and have no apparent impact on repeat dose exposure • Pembrolizumab did not affect WTX-124 PK Abbreviations: PK-pharmacokinetics; HD-high dose; IV-intravenous; 17 | Q2W-once every two weeks; ADA-anti-drug antibody ©2024 WEREWOLF THERAPEUTICS Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial.
WTX-124 Caused Dose Dependent Increases in Intratumoral T-cell Activation by NanoString Top 40 Key insights from tumor upregulated biomarkers: T-cell activation genes across all • Largest changes seen at 18 mg monotherapy (monotherapy) and 12 mg dose levels (combination) • Upregulation of GRZB and IL2RA signify enhanced effector T cell function • Treg genes including FOXP3 and TNFRSF4 did not increase with dose • Data suggest preferential activation and expansion of effector T cells over Tregs • No observed carry-over effect from prior checkpoint inhibitors based on Treg genes distinct NanoString signature for monotherapy vs. combination at 3 and 6 mg Note: Data presented for patients for whom on-treatment biopsies were available as of May 1, 2024. 18 | ©2024 WEREWOLF THERAPEUTICS
T-cell Inflamed Tumor Microenvironment Associated with WTX-124 Clinical Activity Findings in baseline tumor biopsies were consistent with the known mechanism of action of IL-2 Baseline biopsies showed trends toward greater Fresh tumor biopsies acquired prior to starting WTX-124 treatment CD8+ T cell density in patients with PR/CR/SD CD8 GRZB versus those with PD (multiplexed IF) DESeq2 analysis of NanoString data showed that responders have a unique baseline signature Tumor: Cutaneous SCC Melanoma RCC Cemiplimab Opdualag Pembrolizumab/axitinib Prior IO: (1° resistance) (2° resistance) (2° resistance) WTX-124 12 mg (DL4) 12 mg (DL4) 18 mg (DL4) dose: Biopsied Complete regression Complete regression 8.5% increase lesion: RECIST CR (confirmed) PR (non-confirmed) SD (awaiting confirmation) Abbreviations: PR-partial response; CR-complete response; SD-stable disease; PD-progressive disease; CSCC-cutaneous squamous cell carcinoma; RCC-renal cell carcinoma; IO-immunotherapy; DL-dose level 19 | ©2024 WEREWOLF THERAPEUTICS Note: Based on biopsies and preliminary clinical data available as of May 1, 2024.
Summary of Data from Ongoing WTX-124 Phase 1/1b Study Safety Clinical Activity • Generally well tolerated in the outpatient setting • Objective responses at monotherapy doses ≥12 mg • No evidence of vascular leak syndrome, cytokine • Confirmed, durable CR in patient with CSCC release syndrome (≥Grade 2) or infusion reactions • Two PRs in patients with melanoma, • Majority of related TEAEs were Grade 1-2 (all gastroesophageal junction tumor were reversible) • 100% regression of target lesions in responding patients • No related Grade 4 or 5 TEAEs • Dose-dependent expansion and activation of effector T • No new safety signals when combined with cells in the tumor microenvironment, further enhanced pembrolizumab with combination therapy WTX-124 has monotherapy antitumor activity in patients refractory to SOC ICI regimens and no new safety signals when combined with pembrolizumab at clinically active doses Abbreviations: TEAE-treatment-emergent adverse events; IV-intravenous; Q2W-once every two weeks; CR-complete response; CSCC- cutaneous squamous cell carcinoma; PR-partial response; Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. 20 | ©2024 WEREWOLF THERAPEUTICS
Randi Isaacs, MD Chief Medical Officer Werewolf Therapeutics, Inc. 21 21 | | ©2024 WEREWOLF THERAPEUTICS ©2024 WEREWOLF THERAPEUTICS
Preliminary WTX-124 Clinical Data Demonstrate Potential for a Best-in-class IL-2 Therapy ü Monotherapy activity demonstrated in heavily pretreated patients who were refractory to all SOC therapies including checkpoint inhibitors ü Clinical activity observed in patients ineligible for approved HD IL-2 therapy ü WTX-124 18 mg IV Q2W was selected as the monotherapy RDE based on clinical activity and outpatient safety profile ü Combination with pembrolizumab was generally well-tolerated with AE profile similar to monotherapy ü Increased T cell activation signature for the combination suggests a potential for improved antitumor activity by combining WTX-124 with pembrolizumab ü Opportunity to explore activity of monotherapy or combination therapy in IO-sensitive indications beyond melanoma and renal cell carcinoma and in earlier lines of therapy Abbreviations: SOC-standard of care; HD-high dose; IV-intravenous; Q2W-once every two weeks; RDE-recommended dose for expansion; AE-adverse event; IO-immunotherapy Note: Preliminary clinical data as of May 1, 2024, for an ongoing, open label Phase 1/1b clinical trial. Monotherapy expansion arms opened and enrolling as of May 20, 2024. ©2024 WEREWOLF THERAPEUTICS 22 |
WTX-124 program next steps ü WTX-124 dose of 18 mg IV Q2W has been selected as recommended dose for expansion (RDE) ü Monotherapy expansion arms in advanced or metastatic renal cell carcinoma (n=20), cutaneous melanoma (n=20), and cutaneous squamous cell carcinoma (n=10) now open for enrollment ü Dose escalation continuing for WTX-124 combination with pembrolizumab; selection of RDE and opening of combination expansion arms expected in 3Q24 ü Next potential milestone in 4Q24/1Q25 • Evaluation of monotherapy clinical activity in more homogeneous, less heavily pre-treated patient populations • FDA meeting to discuss potential registration pathways, including strategy for monotherapy accelerated approval in ICI relapsed/refractory indications Abbreviations: IV-intravenous; Q2W-once every two weeks; ICI-immune checkpoint inhibitor ©2024 WEREWOLF THERAPEUTICS 23 |
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