UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):
(Exact name of registrant as specified in its charter)
| (State or Other Jurisdiction of Incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
| (Address of Principal Executive Offices) | (Zip Code) |
Registrant’s telephone number, including area code:
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading |
Name of each exchange on which registered | ||
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
| Item 7.01. | Regulation FD Disclosure |
On January 8, 2024, Werewolf Therapeutics, Inc. (the “Company”) issued a press release to provide a business update and highlight the Company’s 2024 strategy outlook. A copy of the press release is furnished as Exhibit 99.1 hereto and is incorporated herein by reference. Also on January 8, 2024, the Company made publicly available on its website an updated corporate presentation. 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 Exhibits 99.1 and 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 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Press Release, dated January 8, 2024 | |
| 99.2 | Investor Presentation, dated January 2024 | |
| 104 | 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.
| WEREWOLF THERAPEUTICS, INC. | ||||||
| Date: January 8, 2024 | By: | /s/ Timothy W. Trost | ||||
| Timothy W. Trost | ||||||
| Chief Financial Officer and Treasurer | ||||||
Exhibit 99.1
Werewolf Therapeutics Provides Business Update and Highlights 2024 Strategic Outlook
- Prioritizing development of wholly owned clinical assets, WTX-124 and WTX-330; key updates from both INDUKINETM programs anticipated in 2024 -
- WTX-124: updated interim monotherapy dose-escalation data and initial combination dose escalation data from Phase 1/1b clinical trial expected in 1H 2024 -
- WTX-330: preliminary dose-escalation data from Phase 1 clinical trial expected in 2Q 2024 -
- Updated cash guidance provides runway through at least the first quarter of 2025 -
Watertown, Mass., January 8, 2024 – 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 provided a business update and outlined its strategic outlook and expected milestones for 2024.
Werewolf outlined the following objectives as the Company’s strategic priorities for 2024:
| 1. | Prioritize development of wholly owned clinical-stage programs – present data updates from WTX-124 and WTX-330 while advancing their clinical development. |
| 2. | Progress preclinical programs through IND-enabling work – demonstrate the breadth of Werewolf’s platform and portfolio opportunities. |
| 3. | Apply PREDATOR™ platform for non-core opportunities and external innovation – leverage Werewolf’s validated technical capabilities, preclinical programs and opportunities in inflammatory diseases. |
| 4. | Maintain disciplined spend – prudently allocate resources according to these priorities to optimize cash runway with continued focus on clinical development of lead programs. |
“2023 was an important year for Werewolf, highlighted by preliminary monotherapy data from our IL-2 program that offered proof of concept for WTX-124 and for our INDUKINE design more broadly,” said Daniel J. Hicklin, Ph.D., President and Chief Executive Officer of Werewolf. “In 2024, we expect to share progress from our wholly owned clinical programs, with updated monotherapy data and initial combination data from WTX-124 as well as our first look at WTX-330. In particular, for WTX-124, we hope to build upon the promising signals of antitumor activity and improved therapeutic index that we observed in the highest dose cohort presented at SITC.”
Dr. Hicklin continued, “In parallel, we expect to continue to progress our preclinical candidates through IND-enabling work to provide additional validation of the INDUKINE approach for novel targets, namely IL-21 and IL-18. Alongside this prioritization, we intend to seek partners who understand our unique conditional-activation expertise and protein engineering approach in areas beyond Werewolf’s core focus of oncology, such as inflammatory diseases, where we believe our approach is viable.”
Based on these strategic priorities, Werewolf has provided the following guidance for 2024:
WTX-124: a systemically delivered, conditionally activated Interleukin-2 (IL-2) INDUKINE molecule being developed as monotherapy or in combination with checkpoint inhibitors in multiple solid tumor types.
In November 2023, Werewolf presented first-in-human monotherapy data from the Phase 1/1b clinical trial of WTX-124 at the Society for Immunotherapy of Cancer’s (SITC) 38th annual meeting. The preliminary data established proof of concept for WTX-124 and for Werewolf’s INDUKINE design hypothesis. In the first half of 2024, Werewolf plans to:
| • | Report updated interim data from the monotherapy dose-escalation arm of the Phase 1/1b study; |
| • | Select a recommended dose for expansion (RDE) and initiate monotherapy dose expansion arms; and |
| • | Report initial data from the combination dose escalation cohorts of the Phase 1/1b study. |
WTX-330: a systemically delivered, conditionally activated Interleukin-12 (IL-12) INDUKINE molecule being developed in refractory and/or immunologically unresponsive tumors.
Werewolf continues to progress the Phase 1 clinical trial evaluating WTX-330 as a monotherapy in patients with immunotherapy insensitive or resistant advanced or metastatic solid tumors or non-Hodgkin lymphoma. In 2024, Werewolf plans to report initial data from the Phase 1 clinical trial in the second quarter of 2024.
Preclinical Portfolio: includes development candidates WTX-712 and WTX-518, INDUKINE molecules respectively targeting IL-21 and IL-18 for treatment of cancer, as well as numerous leads in discovery.
Werewolf intends to progress these programs through IND-enabling work. In 2024, Werewolf plans to:
| • | Present preclinical data from WTX-712 in the first half of 2024. |
| • | Present preclinical data from WTX-518 in the first half of 2024. |
| • | Present preclinical data demonstrating the potential of INDUKINE molecules for inflammatory diseases by the fourth quarter of 2024. |
Cash Position and Financial Guidance:
Based on updated forecasting reflecting the Company’s streamlined development plans and careful cash management to date, Werewolf now expects that its cash and equivalents will be sufficient to fund its operational expenses and capital expenditure requirements through at least the first quarter of 2025.
About Werewolf Therapeutics:
Werewolf Therapeutics, Inc. is an innovative clinical-stage 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 product candidates, WTX-124 and WTX-330, are systemically delivered, conditionally activated Interleukin-2 (IL-2), and Interleukin-12 (IL-12) INDUKINE molecules for the treatment of solid tumors. WTX-124 is in development as a monotherapy and in combination with KEYTRUDA® (pembrolizumab) in multiple solid tumor types. WTX-330 is in development as a single agent in refractory and/or immunotherapy unresponsive or resistant advanced or metastatic solid tumors and non-Hodgkin lymphoma. To learn more visit www.werewolftx.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements that involve substantial risk 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, and objectives of management; the projection of the cash runway; the expected timeline for the preclinical and clinical development of product candidates and the availability of data from such preclinical and clinical development; the potential activity and efficacy of product candidates in preclinical studies and clinical trials; and the anticipated safety profile of product candidates; 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 and 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 preliminary data from a clinical trial will be predictive of the results of the trial and future clinical trials; the Company’s ability to manage cash resources and obtain additional 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.
Investor Contact:
Josh Rappaport
Stern IR
212.362.1200
Josh.rappaport@sternir.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 Corporate Overview | January 2024
Cautionary Statements This presentation contains forward-looking statements that involve substantial risks and important factors, including: uncertainties inherent in the development of product uncertainties. All statements, other than statements of historical facts, contained in this candidates, including the conduct of research activities, the initiation and completion of presentation, including statements regarding Werewolf Therapeutics, Inc.’s preclinical studies and clinical trials; uncertainties as to the availability and timing of (the “Company”) strategy, future operations, prospects, plans, objectives of results from preclinical studies and clinical trials; the timing of and the Company’s ability management, the projection of the cash runway, the expected timeline for the to submit and obtain regulatory approval for investigational new drug applications; preclinical and clinical development of product candidates and the availability of data whether results from preclinical studies will be predictive of the results of later from such preclinical and clinical development, the potential activity and efficacy of preclinical studies and clinical trials; whether preliminary data from a clinical trial will be product candidates in future preclinical studies and clinical trials, and the anticipated predictive of the results of the trial and future clinical trials; the Company’s ability to safety profile of product candidates, constitute forward-looking statements within the manage cash resources and obtain additional cash resources to fund the Company’s meaning of The Private Securities Litigation Reform Act of 1995. The words “aim,” foreseeable and unforeseeable operating expenses and capital expenditure “anticipate,” “approach,” “believe,” “contemplate,” “continue,” “could,” “design,” requirements, as well as the risks and uncertainties identified in the “Risk Factors” “designed to,” “engineered,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” section of the Company’s most recent Form 10-Q filed with the Securities and Exchange “objective,” “ongoing,” “plan,” “potential,” “predict,” “project,” “promise,” “should,” Commission (“SEC”) and in subsequent filings the Company may make with the SEC. In “target,” “will,” or “would,” or the negative of these terms, or other comparable addition, the forward-looking statements included in this presentation represent the terminology are intended to identify forward-looking statements, although not all Company’s views as of the date of this presentation. The Company anticipates that forward-looking statements contain these identifying words. The Company may not subsequent events and developments will cause its views to change. However, while the actually achieve the plans, intentions or expectations disclosed in these forward-looking Company may elect to update these forward-looking statements at some point in the statements, and you should not place undue reliance on these forward-looking future, it specifically disclaims any obligation to do so. These forward-looking statements statements. Actual results or events could differ materially from the plans, intentions should not be relied upon as representing the Company’s views as of any date and expectations disclosed in these forward-looking statements as a result of various subsequent to the date of this presentation. 2 | ©2024 WEREWOLF THERAPEUTICS
Who we are Our mission is to unlock the promise of cytokines as more effective immunotherapies We are a clinical-stage biopharmaceutical company developing next generation, conditionally activated cytokine therapies for the treatment of cancer and other serious diseases We have two investigational drugs in Phase 1 clinical trials Our headquarters and research facilities are located in Watertown, Massachusetts 3 3 | | © ©2024 2024 W WE ER RE EW WOL OLF F T TH HE ER RA AP PE EU UT TI IC CS S
Clinical-Stage Company with Compelling Portfolio of Innovative Cytokine Therapeutics Designed on a platform capable of addressing broad therapeutic applications in oncology and beyond Clinical Programs Key Catalysts Robust Pipeline Scalable Platform Financial Stability Cash and cash equivalents WTX-124 JZP898 PREDATOR™ WTX-124 of $130.1M (as of 9/30/2023) Ongoing enrollment in the IFNα INDUKINE licensed to Initial clinical data Platform provides runway through dose escalation stage of a Jazz Pharmaceuticals; demonstrated WTX-124 Capability for pipeline at least 1Q 2025 Phase 1/1b study as a Enrolling in Phase 1 trial monotherapy clinical expansion for a broad monotherapy and in activity and PoC for range of mechanisms and TM combination with INDUKINE design WTX-712 indications pembrolizumab IL-21 INDUKINE Anticipating additional Business development candidate monotherapy dose WTX-330 Development escalation data to inform WTX-518 Ongoing enrollment Broad portfolio of clinical RDE and opening of in the dose escalation IL-18 INDUKINE and preclinical stage assets expansion arms in 1H24 stage of a Phase 1 study as development candidate available for partnering a monotherapy 4 4 | | © ©2024 2024 W WE ER RE EW WOL OLF F T TH HE ER RA AP PE EU UT TI IC CS S
Overcoming Off-Target Toxicity has been a Key Challenge for Cytokine Therapy The Challenge: Our Solution: Off-Tumor Cytokine Toxicity Limits Conditionally Activated Therapeutic Index Immunotherapy Suboptimal Pharmaceutical Properties With Optimized Therapeutic Index Tumor Activated cytokine INDUKINEs (inactive cytokines) Activated cytokines Activated immune cells Toxicity Poor Clinical Outcomes Targeted Delivery to the On-Target Immune Tumor Microenvironment Activation 5 | ©2024 WEREWOLF THERAPEUTICS
PREDATOR Exposure Platform Half-life extension Selectivity Tumor activation Tunable, Tissue-targeted Therapeutics for Cancer Potency Native Cytokine and other Diseases INDUKINE molecules contain multiple Safety domains, each with a unique function that Peripheral inactivation can be ‘tuned’ for specific mechanisms and pharmaceutical properties necessary to treat disease 6 6 | | © ©2024 2024 W WE ER RE EW WOL OLF F T TH HE ER RA AP PE EU UT TI IC CS S
INDUKINE Molecules: Targeting Cytokine Activity to Diseased Tissue Healthy tissue Cytokine inactive INDUKINE design Tumor tissue Cytokine activation Immune cell activation High exposure of Tumor-selective INDUKINE molecule protease activation 7 | ©2024 WEREWOLF THERAPEUTICS
PREDATOR Platform: Disease Selective Protease (DSP) Substrate Screen Innovative Linker Discovery Approach to Address Protease Heterogeneity Across Diseases and Patients Disease Tissue Healthy Tissue • Highly diverse substrate library • Unique protease specificities Patients & Healthy Donors • Innovative screening approach • Substrates selected in the context of a globular protein • Screens possible with a variety of diseased tissues Library of novel protease substrates 8 | ©2024 WEREWOLF THERAPEUTICS
A Balanced Portfolio of Clinical and Preclinical Drug Candidates PROGRAM INDICATIONS DISCOVERY IND-ENABLING PHASE 1 PHASE 2 RIGHTS Advanced or Metastatic Solid Tumors WTX-124 Monotherapy & in combination IL-12 INDUKINE Molecule with Pembrolizumab Advanced or Metastatic WTX-330 Solid Tumors and Lymphoma IL-12 INDUKINE Molecule Monotherapy Cancer Indications JZP898 Exclusive Global Rights IFNα INDUKINE Molecule Licensed to Jazz WTX-712 Cancer Indications IL-21 INDUKINE Molecule WTX-518 Cancer Indications IL-18 INDUKINE Molecule Novel INDUKINE Immuno-oncology Molecules Inflammatory Diseases 9 | ©2024 WEREWOLF THERAPEUTICS
WTX-124: Expanding the Utility of IL-2 Therapy Delivering IL-2 to the Tumor Microenvironment with Improved Safety and Therapeutic Index The Challenge Deliver the benefits of IL-2 therapy with less toxicity to a broader range of patients Potential WTX-124 Advantages and Opportunity • Delivery of IL-2 selectively to the TME to improve the therapeutic index • Potential for activity beyond approved indications for rhIL2 CD8 • IL-2 therapy with an improved therapeutic index could address an immediate unmet medical need for patients who have progressed on checkpoint therapy • Strong rationale for combination with checkpoint inhibitors in earlier lines of therapy Status • Enrolling patients in Phase 1 clinical trial both as a single agent and in combination with Pembrolizumab • Released preliminary clinical data at 2023 Society for Immunotherapy of Cancer Annual Meeting • Additional monotherapy dose escalation data, RDE declaration and opening of expansion arms anticipated 1H 2024 Abbreviations: TME-tumor microenvironment; RDE-recommended dose for expansion 10 | ©2024 WEREWOLF THERAPEUTICS
WTX-124 has an Improved Therapeutic Index Compared to Native IL-2 Full potency IL-2 is required for complete tumor regression in preclinical models; WTX-124 generates immune memory WTX-124 antitumor activity is substantially more potent WTX-124 activates long-term antitumor immune memory than non-alpha IL-2 INDUKINE in MC38 tumor model 2500 2000 1500 Vehicle WTX-124 (70μg/dose) 1000 Non-Alpha INDUKINE (700μg/dose) 500 0 MC38 Tumor Model Rechallenge 0 10 20 30 Tumor Naive MC38 CR Days after start of dosing 100 600 Improved therapeutic window compared to IL-2 cytokine 80 TW<4 400 60 Minimum Efficacious Dose Maximum Tolerated Dose 40 Naive mice 200 Mice previously treated 20 TW>20 with WTX-124 0 0 0 10 20 30 40 50 Days after implantation 0 20 40 60 IL-2 Dose (Nanomoles) Nirschl CJ et al., SITC 2023 Poster: Optimal Antitumor Immunity is Triggered by WTX-124, a Clinical Stage Conditionally Activated INDUKINE™ Molecule Abbreviations: TW-therapeutic window; CR-complete regression 11 | ©2024 WEREWOLF THERAPEUTICS Naive Effector Memory Naive Effector Memory 3 Tumor Volume (mm ) WTX-124 IL-2 3 Tumor Volume (mm ) % of Tetramer+ Cells
WTX-124 Delivers IL-2 Selectively to Tumor Tissue in Preclinical Models Robust expansion and activation of antitumor CD8+ T effector cells in the TME Plasma Tumor Plasma Tumor 1000 WTX-124 INDUKINE 1000 Free IL-2 100 100 WTX-124 dosed on 10 10 Day 1 and 4 (50 µg) 1 1 0.1 0.1 0.01 0.01 0 48 96 144 192 240 288 0 48 96 144 192 240 288 Time (Hour) Time (hr) Time (hr) Time (Hour) + + + + + Treg IFNγ TILs Draining Lymph Node Total CD8 T Cells CD8 Tetramer T Cells CD8 Tet /Treg Ratio ✱ ✱ ✱ ✱ 5 5 100 80 80 2.5×10 2×10 19.8x 100 * 13.2x 5 1.5×10 ** Vehicle 5 7.4x 80 80 2×10 ** 5 60 60 1×10 **** 4 WTX-124 5 5×10 60 1.5×10 60 40 40 4 1×10 5 40 1×10 40 ns 20 3 20 4 5×10 20 20 5×10 0 0 0 0 0 0 Nirschl CJ et al., Cancer Immunology Research 2022 10(5):581-596 Abbreviations: TIL-tumor infiltrating lymphocytes; TME-tumor microenvironment 12 | ©2024 WEREWOLF THERAPEUTICS Vehicle WTX-124 Vehicle WTX-124 Vehicle WTX-124 Vehicle WTX-124 Vehicle WTX-124 Vehicle WTX-124 CD8+ % Polyfunctional CD8+ % Polyfunctional nMolar Cells/Mg of Tissue nMolar Ratio CD4+ FoxP3+ % IFNγ+
First-In-Human Study of WTX-124 Monotherapy and in Combination with Pembrolizumab Patients with IO sensitive tumor types who have exhausted all SOC options or for whom SOC is not indicated Monotherapy/Combination Dose Expansion Monotherapy Dose Escalation Determination of Advanced or metastatic renal cell carcinoma 1 mg 3 mg 6mg 12 mg 18 mg TBD monotherapy enrolling n = 5 n = 5 n = 5 n = 5 MTD/RDE Advanced or metastatic cutaneous malignant melanoma Combination Dose Escalation Determination of WTX-124 in Combination Other advanced or metastatic IO sensitive combination therapy with Pembrolizumab tumor types TBD (enrollment ongoing) MTD/RDE Monotherapy and combination mTPI (Modified Toxicity Assessment of safety, Concurrent biomarker analysis to Trial therapy dose escalations Probability Interval) design pharmacokinetics, evaluate proof of mechanism and enrolled in parallel with MTD/RDE, biomarkers, tumor-selective conditional Details staggered start for combination Enrolling ~ 150 patients total ADA and efficacy activation 1H 2024: Additional monotherapy dose escalation data, RDE declaration and opening of expansion arms anticipated Abbreviations: MTD-maximum tolerated dose; RDE-recommended dose for expansion; ADA-anti drug antibody; IO-immuno-oncology; SOC-standard of care 13 | ©2024 WEREWOLF THERAPEUTICS
Patient Demographics from Early Monotherapy Dose Escalation Cohorts (n=16) Prior lines of systemic therapy, Tumor type Demographics (including immunotherapy) AGE (years) Mean (SD) 66.9 (10.62) n (%) n (%) Median 66.0 Melanoma* 8 (50.0%) 1 2 (12.5%) SEX, n (%) Female 8 (50.0%) NSCLC 5 (31.3%) 2 4 (25.0%) Male 8 (50.0%) Renal Cell Carcinoma 2 (12.5%) 3 5 (31.2%) RACE, n (%) Black/African- 1 ( 6.2%) Cutaneous SCC 1 (6.3%) American ≥4 5 (31.2%) White 13 (81.2%) Unknown 2 (12.5%) • Enrollment of heavily pretreated patients with tumor types for which immunotherapy, including Proleukin, is indicated • All patients received prior immunotherapy and progressed • Nine patients (56.3%) developed immune-related adverse events while receiving prior immunotherapy *Includes patients with cutaneous, uveal and mucosal melanoma; all patients enrolled in Cohorts 1-4 previously progressed on standard-of-care immunotherapy regimens Note: Preliminary clinical data as of October 18, 2023, from 16 patients in an ongoing Phase 1/1b clinical trial. 14 | ©2024 WEREWOLF THERAPEUTICS
WTX-124 was Generally Well-Tolerated in the Outpatient Setting at Relevant Doses Sixteen patients in four dose escalation cohorts (1-12 mg IV Q2W) were evaluable for safety Frequency of related treatment-emergent AEs Key safety findings to date: Abdominal distension Abdominal pain Arthralgia • Drug related TEAEs: no Grade 3 or higher Asthenia Blister Bursitis • Arthralgias and fatigue were the most common C-reactive protein increased Chills Cough related TEAEs Decreased appetite Dehydration Dry skin • No vascular leak syndrome of any grade Dyspepsia Eosinophilia (adverse event common to HD IL-2) Erythema Fatigue Hair texture abnormal Headache • No evidence of cytokine release syndrome Hypoaesthesia Hypothyroidism Influenza like illness • No patient developed dose-limiting toxicity or Leukocytosis Muscular weakness treatment-related serious AE Myalgia Nasal congestion Nausea • No patient discontinued study drug due to Oedema peripheral Paraesthesia Photopsia treatment-related AE Pleuritic pain Pruritus Pyrexia Rash Rash erythematous Rash maculo-papular Respiratory tract congestion Abbreviations: TEAEs-treatment-emergent adverse events; HD-high dose; Sensitive skin Sinus congestion Q2W-once every two weeks Note: Preliminary clinical data as of October 18, 2023, from 16 patients in # Subjects an ongoing, open label Phase 1/1b clinical trial. 15 | ©2024 WEREWOLF THERAPEUTICS Adverse Events (PTI)
Plasma PK Data Show an Extended WTX-124 Half-Life with Low Free (Active) IL-2 Exposure Preliminary PK data validate INDUKINE design and support improved therapeutic index and safety profile of WTX-124 Cycle 1 PK profiles for WTX-124 and free (active) IL-2 compared to high-dose IL-2 Cmax (mean ± SEM) Key safety findings to date: • Dose-dependent increase in WTX-124 plasma exposure 210-fold • Low free (active) IL-2 levels (<1.6% of prodrug) during dosing WTX-124 • WTX-124 prodrug Cmax at 12 mg IV Q2W comparable to HD IL-2 • Free (active) IL-2 at 12 mg IV Q2W: ~210-fold lower than HD IL-2 • Preliminary WTX-124 half-life range: 1.86-5.79 days • Preliminary ADA data: 5/15 patients exhibited non-dose dependent, treatment-emergent ADA (4/5 are low titer) w/ no impact on repeat dose exposure Free (active) IL-2 • Data suggest wide therapeutic index consistent with INDUKINE hypothesis, continued dose escalation supported Abbreviations: HD-high dose; Q2W-once every two weeks 16 | ©2024 WEREWOLF THERAPEUTICS
Immunofluorescence Staining of Tumor Biopsies from Patients Treated with WTX-124 Tumor-specific expansion and activation of CD8 T cells and NK cells differentiate WTX-124 among next-gen IL-2 molecules 65yo F with melanoma (6mg) 50yo F with melanoma (12mg) 61yo F with uveal melanoma (6mg) Pre-treatment DAPI CD8 GRZB Granzyme B (GRZB) is one of the primary On-treatment markers of activated T cells % GRZB+/CD8+ % GRZB/CD8+ % GRZB+/NK % GRZB+/NK % GRZB+/CD8+ % GRZB+/NK 1.3X 2.3X 1.4X 1.5 15 25 25 40 20 1.6X 3.25X 2.4X 20 20 30 15 1.0 10 15 15 20 10 10 10 0.5 5 10 5 5 5 0.0 0 0 0 0 0 Pre On Pre On Pre On Pre On Pre On Pre On 17 | ©2024 WEREWOLF THERAPEUTICS % GRZB+ %GRZB+ %GRZB + %GRZB+ % GRZB+ % GRZB+
WTX-124 Induced Dose-Dependent Changes in Immune Gene Expression Consistent with IL-2 Activity in the Tumor Microenvironment T-cell activation genes T-cell activation genes increased by ≥2.5-fold (172 genes) 102-004 (melanoma) – Cohort 3, 6 mg NanoString nCounter® 20 PanCancer immune panel 15 (770 genes) 6 genes ↑ ≥2.5X 10 A 5 0 Immune genes increased by ≥1.5-fold Cohort 1 Cohort 2 Cohort 3 Cohort 4 (1 mg) (3 mg) (6 mg) (12 mg) 111-001 (melanoma) – Cohort 4, 12 mg 379 20 15 53 genes ↑ ≥2.5X 10 B 5 B 0 117 A Note: Data presented for eight patients for whom on-treatment biopsies were available as of October 11, 2023 18 | ©2024 WEREWOLF THERAPEUTICS Number of genes Fold change Fold change CCL7 Tgfb2 IL1B Ctla4 CCL2 Zap70 THY1 Nfatc2 IL1R1 Icos IL7R Tlr4 IL6 Bcl2 TNFRSF8 Tlr6 CD274 Cd3d ITGAM Nfatc1 IL12RB1 Eomes ITGAX Btla PDCD1LG2 Rps6 CXCL12 Itk IFNB1 Egr1 TLR6 Pvr HAVCR2 Cd247 TLR4 Psen2 CCL11 Ccnd3 IL23A Cd3e IL25 Il7r IL21 Traf2 Anxa1 FUT7 CCL3 Jak2 IL15 Card11 CD40 Tigit IL10 Cd276 CD86 Il12rb2 SOCS1 Cd3g- CCR3 Ccl5 ADA Mapk8 Itga1 IFNG LCP1 Cxcr3 IL7 Traf6 IL13 Tnfsf13b Casp3 CCR2 IL18 Foxp3 VCAM1 Stat4 TNFSF14 Cd27 Spp1 CD1D IL13RA1 Il18r1 CCR5 Stat1 GZMB Stat5b IL2RA Il10 Map3k7 IL4R TNFSF13B Thy1 ANXA1 Lag3 CEBPB Lck Jak1 FAS Rel IL18R1 TNFSF4 Tap1 JAK3 Tcf7 Tnfrsf14 CXCL13 Gzmb Itk Tgfb1 Il15 Itgb2 Irf1 Ccr2 Cd4 Ada Pdcd1 Psmb10 Irf1 Pvr Mapk1
WTX-124 Demonstrated Monotherapy Antitumor Activity in Patients Refractory to ICI Therapy At 12 mg dose level, WTX-124 shrank treatment-refractory tumor metastatic deposits (3/5 patients) 2. Patient 102-006: unconfirmed PR (RECIST 1.1) 1. Patient 107-002: unconfirmed PR (RECIST 1.1) • 72-year-old man with cutaneous SCC who progressed on • 78-year-old man with melanoma who progressed on TM cemiplimab (Libtayo®); initial 8-week restaging CT scan nivolumab/relatlimab (Opdualag ) • Achieved a RECIST 1.1 partial response (PR; unconfirmed) showed uPR (>60% reduction in premaxillary target lesion) at the first restaging scan (8 weeks) after two cycles of Pretreatment On-treatment WTX-124 • Imaging studies (below) show complete resolution of a 1.4 cm target lesion in the liver • Stable non-target bone lesion in the T11 vertebral body PET-CT (pretreatment) CT (pretreatment) CT (on-treatment) 3. Patient 106-006 • 76-year-old man with refractory NSCLC with rapid necrosis of a large, visible scalp lesion after the first dose of study drug; mixed response, remained on study drug for 14 wks Abbreviation: ICI-immune checkpoint inhibitors; PR-partial response; SCC-squamous cell carcinoma; NSCLC-Non-small cell lung cancer Note: Preliminary clinical data as of November 1, 2023, from 16 patients in an ongoing, open label Phase 1/1b clinical trial. 19 | ©2024 WEREWOLF THERAPEUTICS
Proof of Mechanism for WTX-124 and Proof of Concept for INDUKINE Design Established Monotherapy WTX-124 administered in an outpatient setting has been well tolerated and has reached exposures associated with clinical responses in dose escalation Majority of patients treated would not have been eligible to receive HD IL-2 due to age, indication, or underlying organ function Among 16 patients treated with WTX-124 at doses up to 12 mg IV Q2W, there were no cases of vascular leak syndrome and no DLTs PK data showed extended prodrug exposure and low levels of free (active) IL-2 resulting in improved therapeutic index and opportunity for continued dose escalation WTX-124 administered at doses of 6-12 mg IV Q2W demonstrated CD8+ T cell and NK cell activation and antitumor activity (including 2 uPR at 12 mg) in multiple tumor types Additional interim data from monotherapy dose escalation and data informing RDE declaration expected to be reported in 1H 2024 Abbreviations: AE-adverse event; SAE-serious adverse event; DLT-dose limiting toxicity; HD-high dose; TME-tumor microenvironment; RDE-recommended dose for expansion; uPR-unconfirmed partial response; Q2W-once every two weeks Note: Based on preliminary clinical data as of November 1, 2023, from 16 patients in an ongoing, open label Phase 1/1b clinical trial. 20 | ©2024 WEREWOLF THERAPEUTICS
WTX-330: Leveraging the Potential of IL-12 Therapy The Challenge Develop a tolerable IL-12 therapy to stimulate innate and adaptive antitumor immune responses Potential WTX-330 Advantages and Opportunity • Delivery of IL-12 mechanism selectively to the TME with an improved therapeutic index • Potent preclinical antitumor activity in poorly immunogenic, anti-PD-1 therapy refractory tumors CD8 • Leverage IL-12 biology in the clinic to address mechanisms of checkpoint inhibitor resistance • Potential for multiple combination strategies to enhance anti-tumor activity Status • Phase 1 clinical trial actively enrolling • Release of initial data from Phase 1 clinical trial anticipated in 2Q 2024 Abbreviation: TME-tumor microenvironment 21 | ©2024 WEREWOLF THERAPEUTICS
IL-12 INDUKINE Delivers IL-12 Selectively to Tumor Tissue with an Improved Therapeutic Index Robust activation of antitumor CD8+ T effector cells and pleiotropic immune activation in the TME in preclinical models Tumor Peripheral Blood MC38 tumor model Vehicle 2000 ns ✱ ✱ mWTX-330 (7µg/dose) 60 16 Vehicle Vehicle mWTX-330 (43µg/dose) 1500 mWTX-330 14 mWTX-330 40 1000 12 20 10 500 0 8 0 0 5 10 15 20 25 30 Time (days) Vehicle WTX-124 mWTX-330 WTX-124 Therapeutic Window Differential Gene Signatures 5x ü Intratumoral IL-12 pathway activation Minimum Efficacious Dose 172 Maximum Tolerated Dose Recombinant ü Activation of multiple antigen Chimeric IL-12 presentation mechanisms 296 49x ü Th1 lineage skewing mWTX-330 122 ü Treg instability ü Increased chemokine expression 0 5 10 15 mWTX-330 IL-12 Dose (Nanomoles) -1 0 1 Nirschl CJ et al., Cancer Immunology Research, 1 July 2023; 11 (7): 962–977 Abbreviation: TME-tumor microenvironment 22 | ©2024 WEREWOLF THERAPEUTICS Vehicle mWTX-330 Vehicle mWTX-330 3 Tumor Volume (mm ) CD8+ % Polyfunctional CD8+ % Polyfunctional
IL-12 INDUKINE Inhibits Growth of Poorly Immunogenic EMT-6 Mouse Tumors Increased Clonality of Tumor Infiltrating CD8+ T Cells in preclinical models Efficacy in anti-PD-1 refractory EMT-6 tumors Increase of cross-presenting DCs in tumors Ratio Vehicle mWTX-330 3000 Vehicle 15 ** mWTX-330 anti-PD1 2000 10 5 1000 0 0 CD103 0 10 20 30 Days after start of dosing Increased TCR clonality of tumor infiltrating T cells Vehicle IL-12 INDUKINE 0.6 * Clone Rank #1 #2 0.4 #3 #4 #5 #6 0.2 #7 #8 #9 Vehicle IL-12 INDUKINE #10 0.0 Remaining DAPI PanCK CD3 CD8 Fraction of TCR repertoire represented by the top ten clones Nirschl CJ et al., Cancer Immunology Research, 1 July 2023; 11 (7): 962–977 23 | ©2024 WEREWOLF THERAPEUTICS Vehicle IL-12 INDUKINE Ve icle mWTX-330 h 3 Tumor Volume (mm ) Fraction of TCR Repertoire CD11b Clonality Index Score CD103+/CD11b+
First-In-Human Study of WTX-330 Evaluating Safety, Tolerability and Clinical Activity Monotherapy Dose Escalation Monotherapy Dose Expansion CPI-naïve relapsed or refractory advanced tumor indications (tumor types for which CPIs are not Relapsed/refractory Monotherapy approved, including NHL and mCRPC) advanced or metastatic expansion arms solid tumors failing SOC, to open after including immune determination CPI primary or secondary resistant relapsed checkpoint inhibitors of MTD/RDE or refractory advanced tumor indications Assessment of safety, MTD/RDE, CPI-unapproved and CPI-resistant Concurrent biomarker analysis on pharmacokinetics, biomarkers, indications supported by IL-12 blood and tumor tissue to evaluate Trial ADA and efficacy biology and preclinical data proof of mechanism and confirm Details differential activity based on Bayesian study design, n~75 conditional activation STATUS: Actively enrolling patients – preliminary data anticipated in 2Q 2024 Abbreviations: MTD-maximum tolerated dose; RDE-recommended dose for expansion; ADA-anti drug antibody; NHL-Non-Hodgkin lymphoma; mCRPC-metastatic castration-resistant prostate cancer; CPI-checkpoint inhibitor 24 | ©2024 WEREWOLF THERAPEUTICS
WTX-712: Expanding the Utility of IL-21 Therapy Potential WTX-712 Advantages and Opportunity • IL-21 distinctively leads to an effective anti-tumor response driven by activation and differentiation of multiple anti-tumor cell types including Tfh cells, B cells, and cytotoxic effector cells (CD8+ T cells, NK, and NKT cells) as well as inhibiting Tregs and promoting M1 macrophage function • IL-21 supports the generation and maintenance of lymphoid structures including TLS, which are increasingly recognized as critical for antitumor immunity • IL-21 cytokine therapy showed signs of clinical activity but has been limited by toxicity, suggesting an opportunity for approaches with an improved therapeutic index • Our preclinical data demonstrate a positive combination effect of WTX-712 with CPI • WTX-712 provides a differentiated anti-tumor immunity approach to common gamma-chain- cytokines, complementing our IL-2 INDUKINE WTX-124 Status • IND-enabling studies Abbreviations: TLS-tertiary lymphoid structure; CPI-checkpoint inhibitor 25 | ©2024 WEREWOLF THERAPEUTICS
WTX-712 has an Improved Therapeutic Index Compared to Native IL-21 Tumor selective activity results in robust anti-tumor immune activation in preclinical studies WTX-712 antitumor activity in MC38 tumor model with an WTX-712 treatment transforms the tumor microenvironment improved therapeutic window compared to IL-21 cytokine Control WTX-712 2000 Vehicle TW= 3 IL-21-HLE WTX-712 (375μg) WTX-712 (750μg) 1500 WTX-712 (1200μg) TW= 16 1000 WTX-712 500 0 5 10 15 20 25 IL-21 Dose (nM) 0 0 10 20 30 Minimum Efficacious Dose (MED) DNA CD8 CD4 Macrophages Mono/Neutrophils GZMB Maximum Tolerated Dose (MTD) Days after start of dosing CD8 T Cells Expressing Effector Molecules WTX-712 specifically induces IFNγ in the tumor Granzyme B+ IFNγ+ M1/M2 Macrophage Ratio Tumor Serum 60 30 ✱✱✱✱ 8 2000 100 ✱✱✱ ✱ 80 1500 6 60 1000 40 20 40 500 4 20 LLOQ 20 10 0 0 0 4 8 12 24 48 72 96 120 168 0 4 8 12 24 48 72 96 120 168 2 Time (Hrs) Time (Hrs) 0 0 0 Vehicle WTX-712 Vehicle WTX-712 Vehicle WTX-712 TM Sullivan JM et al., AACR 2023 Poster: Generation of IL-21 INDUKINE Molecules for the Treatment of Cancer TM Sullivan JM et al., SITC 2023 Poster: Development of WTX-712, a Conditionally Active IL-21 INDUKINE Molecule for the Treatment of Cancer 26 | ©2024 WEREWOLF THERAPEUTICS IFNγ Level (pg/mL) 3 Tumor Volume (mm ) IFNγ Level (pg/mL) % of CD8 T cells % of CD8 T cells % of CD45 Ratio
WTX-518: Overcoming the Limitations of IL-18 Therapy Potential WTX-518 Advantages and Opportunity • IL-18 activates innate (strong NK activator) and adaptive immune cells promoting production of IFN-γ from antigen experienced T cells and favoring Th1 differentiation of naïve T cells • IL-18 activity is heavily regulated by the decoy protein IL- 18BP, which when overcome, can promote effective antitumor immunity but with an increased risk of IL-18 Improved antitumor activity of BPR IL-18 mediated toxicity INDUKINE in MC38 tumor model 2000 • The design of WTX-518 uniquely eliminates the ability of IL-18BP to inhibit IL-18 and 1500 systemically delivers IL-18 prodrug for conditional activation within the TME, providing optimal antitumor immunity with an improved therapeutic window 1000 • IL-18 and IL-12 synergize to drive T cell activation and release of IFN-γ. WTX-518 500 complements our current portfolio already containing WTX-330 (IL-12 INDUKINE). 0 0 10 20 30 Day Status Vehicle BPR IL-18 INDUKINE • IND-enabling studies Wild-Type IL-18 INDUKINE Abbreviations: TME-tumor microenvironment; BPR-binding protein resistant 27 | ©2024 WEREWOLF THERAPEUTICS 3 Tumor Volume (mm )
Oncology-focused INDUKINE PREDATOR Therapeutics Platform • Additional proinflammatory mechanisms • Cell-based therapies • mRNA therapies Non-Oncology INDUKINE Werewolf’s innovative PREDATOR Therapeutics • Inflammation Platform offers value creation through • Other diseases pipeline expansion and partnering opportunities Expanding Conditional-Activation Technology to New Modalities • Targeted antibodies, T cell engagers, ADCs • Cell-based therapies • Disease-specific linkers 28 | ©2024 WEREWOLF THERAPEUTICS
Shifting the Balance WTX-124 WTX-330 in Cytokine Therapeutics Phase 1 Phase 1/1b • Two lead programs in Phase 1 development Clinical Trial Clinical Trial are wholly owned by Werewolf in Advanced and in Advanced Metastatic • Collaboration is central to our growth strategy and Metastatic Solid Tumors with Jazz global partnership on JZP898 Solid Tumors and Lymphoma PREDATOR Platform: Value Deep Pipeline Strong Cash Position Creation Engine Approximately $130.1M in cash and cash JZP898, an IFNα INDUKINE molecule, in clinical Our protein engineering technology optimizes development by Jazz Pharmaceuticals equivalents (as of September 30, 2023) the design of conditionally activated cytokine WTX-712, an IL-21 INDUKINE molecule, in Financial runway through at least therapeutics (INDUKINE molecules) to diseased preclinical development for the treatment of 1Q 2025 with opportunity for multiple value- tissues. cancer enhancing catalysts in the near term Opportunity to pursue non-cancer indications WTX-518, an IL-18 INDUKINE molecule, in Approximately 36.19M shares outstanding such as inflammatory diseases. preclinical development for the treatment of (as of November 10, 2023) cancer 29 | ©2024 WEREWOLF THERAPEUTICS
Experienced Leadership Daniel J. Hicklin, PhD Randi E. Isaacs, MD Chulani Karunatilake, PhD Chief Medical Officer President and CEO Chief Technology Officer Ellen Lubman, MBA Cynthia Seidel-Dugan, PhD Tim Trost, CPA Chief Business Officer Chief Scientific Officer Chief Financial Officer 30 | ©2024 WEREWOLF THERAPEUTICS
Thank You! 31 | ©2024 WEREWOLF THERAPEUTICS