IL-21

– Additional monotherapy dose-escalation data from ongoing Phase 1/1b clinical trial of WTX-124 expected to be presented in the first half of 2024 – – WTX-124 recommended dose for expansion (RDE), initiation of monotherapy dose expansion arms and initial combination dose-escalation data also expected in the first half of 2024 – – Preliminary data from Phase 1 clinical trial of WTX-330 expected in the second quarter of 2024 – – Updated cash guidance provides runway through at least the second quarter of 2025 – WATERTOWN, Mass., March 07, 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 provided a business update and reported financial results for the fourth quarter and full year ended December 31, 2023. “Werewolf made considerable progress in 2023, setting up 2024 as a year of execution across our pipeline,” said Daniel J. Hicklin, Ph.D., President and Chief Executive Officer of Werewolf. “In the first half of this year, we plan to present additional clinical data from our Phase 1/1b clinical trial of WTX-124, including updated monotherapy data and initial combination data, which we anticipate will build on the promising signals of antitumor activity and improved therapeutic index that we observed in the data presented at SITC last year. In addition, we plan to share data further demonstrating the performance of our platform in our preclinical programs at AACR. We also plan to share initial clinical data from WTX-330, our second clinical candidate, in the second quarter of 2024.” “Additionally, I would like to express my deep appreciation to Cindy Seidel-Dugan, Ph.D., Werewolf’s Chief Scientific Officer, who is retiring effective March 29, 2024, after a long and successful career in the biopharmaceutical industry. Cindy was a founding member of the Werewolf Executive Team and has been instrumental in establishing Werewolf’s innovative science, developing our INDUKINE technology, and shepherding our lead candidates through the discovery and IND-enabling process. We have benefited greatly from Cindy’s significant expertise, and the strong scientific leadership team she has built that will ensure continued success going forward. We wish Cindy the very best in her retirement.” Recent Highlights and Upcoming Milestones WTX-124: a systemically delivered, conditionally activated Interleukin-2 (IL-2) INDUKINE molecule being developed as monotherapy and in combination with pembrolizumab in multiple solid tumor types. In November 2023, at the Society for Immunotherapy of Cancer (SITC) 38th Annual Meeting, Werewolf presented first-in-human monotherapy data from the Phase 1/1b clinical trial of WTX-124. These preliminary data established proof of mechanism for WTX-124 and proof of concept for Werewolf’s INDUKINE design hypothesis.In the first half of 2024, Werewolf expects to present additional interim dose-escalation data from the monotherapy dose-escalation arm, nominate a recommended dose for expansion and initiate monotherapy dose expansion arms.Additionally, Werewolf continues to progress combination dose escalation cohorts of the Phase 1/1b clinical trial and plans to report initial clinical data from this arm in the first half of 2024. WTX-330: a systemically delivered, conditionally activated Interleukin-12 (IL-12) INDUKINE molecule being developed in refractory and/or immunologically unresponsive tumors. Werewolf is progressing Study WTX-330x2101, its Phase 1, multi-center, open-label clinical trial evaluating WTX-330 as a monotherapy in patients with immunotherapy insensitive or resistant advanced or metastatic solid tumors or non-Hodgkin lymphoma. Werewolf plans to report initial data from the Phase 1 study in the second quarter of 2024. Preclinical Portfolio: includes development candidates WTX-712 and WTX-518, INDUKINE molecules targeting IL-21 and IL-18, respectively, for treatment of cancer. Werewolf plans to present preclinical data from WTX-712 and WTX-518 at the 2024 AACR Annual Meeting on antitumor activity in the delivery of IL-21 or IL-18, respectively, to the tumor microenvironment in mouse tumor models. These programs are currently progressing through IND-enabling work. Abstract Number: 4078Title: WTX-712, a conditionally active IL-21 INDUKINETM molecule, induces a strong anti-tumor phenotype through a differentiated mechanismSession Date and Time: Tuesday, April 9, 2024, from 9:00 a.m. - 12:30 p.m.Abstract Number: 4074Title: Discovery of WTX-518, an IL-18 pro-drug that is conditionally activated within the tumor microenvironment and induces regressions in mouse tumor modelsSession Date and Time: Tuesday, April 9, 2024, from 9:00 a.m. - 12:30 p.m. Additional Updates: In January 2024, Werewolf appointed Michael Atkins, M.D., to its Board of Directors. Dr. Atkins has served as a member of Werewolf’s Scientific Advisory Board since August 2018 and has more than 30 years of experience in translational and clinical research, specializing in melanoma, kidney cancer, and cancer immunotherapy. Financial Results for the Fourth Quarter and Full Year 2023: Cash position: As of December 31, 2023, cash and cash equivalents were $134.3 million, compared to $129.3 million as of December 31, 2022. The Company also had restricted cash and cash equivalents of $21.2 million and $1.2 million as of December 31, 2023 and December 31, 2022, respectively. Based on updated forecasting the Company now expects that its existing cash and cash equivalents at December 31, 2023, and gross proceeds of $17.7 million under the at-the-market sales facility received from January 1, 2024 through March 1, 2024, will be sufficient to fund its operational expenses and capital expenditure requirements through at least the second quarter of 2025.Collaboration revenue: Collaboration revenue was $1.5 million for the fourth quarter of 2023, compared to $7.3 million for the same period in 2022, and $19.9 million for the full year 2023, compared to $16.4 million for the same period in 2022. Collaboration revenue consists of revenue recognized from the Company’s licensing agreement with Jazz Pharmaceuticals (Jazz) and includes fixed payments received from Jazz, plus costs incurred for research services to be reimbursed by Jazz.Research and development expenses: Research and development expenses were $9.6 million for the fourth quarter of 2023, compared to $15.9 million for the same period in 2022. Research and development expenses were $41.8 million for the full year 2023, compared to $53.8 million for the full year 2022.General and administrative expenses: General and administrative expenses were $4.8 million for the fourth quarter of 2023, compared to $4.6 million for the same period in 2022. General and administrative expenses were $18.7 million for the full year 2023, compared to $18.7 million for the full year 2022.Net loss: Net loss was $12.0 million for the fourth quarter of 2023, compared to $11.9 million for the same period in 2022. Net loss was $37.4 million for the full year 2023, compared to $53.8 million for the full year 2022. 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 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. Cautionary Note Regarding Forward-Looking StatementsThis 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. Werewolf Therapeutics, Inc.Consolidated Statements of Operations (unaudited)(amounts in thousands, except share and per share amounts) Three Months EndedDecember 31, Year EndedDecember 31, 2023 2022 2023 2022 Revenue: Collaboration revenue$1,501 $7,283 $19,943 $16,401 Operating expenses: Research and development 9,649 15,859 41,776 53,761 General and administrative 4,814 4,603 18,670 18,696 Total operating expenses 14,463 20,462 60,446 72,457 Operating loss (12,962) (13,179) (40,503) (56,056)Other income 959 1,249 3,135 2,246 Net loss$(12,003) $(11,930) $(37,368) $(53,810)Net loss per share, basic and diluted$(0.33) $(0.39) $(1.05) $(1.86)Weighted-average common shares outstanding, basic and diluted 36,570,280 30,734,797 35,646,572 28,863,935 Werewolf Therapeutics, Inc.Selected Consolidated Balance Sheet Data (unaudited)(amounts in thousands) December 31, 2023 December 31, 2022Cash and cash equivalents$134,343 $129,315 Working capital$118,992 $116,211 Total assets$174,833 $160,245 Total deferred revenue$1,340 $7,660 Total notes payable, net of discount and issuance costs$39,323 $— Total stockholders’ equity$111,374 $122,337 Investor Contact:Josh RappaportStern IR212.362.1200Josh.rappaport@sternir.com Media Contact:Amanda SellersVERGE Scientific Communications 301.332.5574asellers@vergescientific.com Company Contact:Ellen LubmanChief Business OfficerWerewolf Therapeuticselubman@werewolftx.com

IO-202 is a monoclonal antibody that targets leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), which can suppress immunity in solid tumours. Image Credit: crystal light / Shutterstock. The US Food and Drug Administration (FDA) has granted an orphan drug designation to Immune-Onc Therapeutics’ IO-202 for the treatment of a rare blood cancer – chronic myelomonocytic leukaemia (CMML). IO-202 had previously received a fast track designation from the US FDA as a treatment of relapsed or refractory (r/r) CMML in 2023. The therapy was also granted both orphan drug and fast track designations as a treatment for acute myeloid leukaemia (AML) by the FDA in 2020 and 2022, respectively. The orphan drug designations allow for an extended market exclusivity of seven years in the US and developmental incentives such as an exemption of FDA application fees and tax credits for qualified clinical testing. The fast track designations enable earlier interactions with the FDA for the pursuit of accelerated approval. The status also opens chances of rolling reviews. IO-202 is a monoclonal antibody that targets leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), which can suppress immunity in solid tumours. It also mediates the T-cell suppression and infiltration of AML cells. It is being investigated as a monotherapy and in combination with chemotherapy, azacytidine, along with targeted therapy AbbVie /Genentech’s Venclexta (venetoclax), in a Phase I trial (NCT04372433). The study is expected to enrol approximately 106 patients with either r/r AML or r/r CMML. It is expected to conclude in 2026, as per ClinicalTrial.gov. See Also: Harmony wins orphan drug tag for pitolisant to treat Prader-Willi syndrome United Therapeutics sues FDA over handling of Liquidia’s NDA A second Phase I trial (NCT05309187) investigating IO-202 in combination with a PD-1 immune checkpoint inhibitor, MSD’s Keytruda (pembrolizumab) is also currently underway. The study enrolled approximately 200 patients with advanced solid tumours and is expected to be completed in April. Monoclonal antibodies have been identified as a key innovation area for cancer therapy by GlobalData, with multiple companies investing to develop antibody therapies for various indications. In December 2023, AbbVie partnered with BigHat Biosciences to identify and develop antibody therapies in oncology and neuroscience indications. GlobalData is the parent company of Pharmaceutical Technology . Almirall is developing an interleukin-21 (IL-21)-hindering monoclonal antibody, NN-8828, for the treatment of immune-inflammatory dermatological ailments. The company acquired the therapy from Novo Nordisk last week for an undisclosed upfront payment and will be entitled to developmental and commercial milestones, as well as tiered royalties on future global sales.

Pictured: Novo Nordisk's corporate headquarters in Denmark/iStock, Ole Schwander Spanish pharma Almirall announced Monday that it has licensed Novo Nordisk’s anti-IL-21 monoclonal antibody NN-8828, which it plans to develop as a treatment for immune inflammatory dermatological diseases and has first-in-class potential. Almirall is looking to “accelerate the development” of NN-8828 with an eye towards eventually debuting the candidate on the global market for “key dermatological diseases,” according to Monday’s announcement. Under the licensing agreement, Novo will receive an undisclosed upfront payment and will be entitled to developmental and commercial milestones, as well as tiered royalties on future global sales. The licensing agreement will allow Almirall to “explore the innovative approach of IL-21 blockage as a possible new pathway to effectively treat a range of dermatological diseases,” CSO Karl Ziegelbauer said in a statement. The pharma, headquartered in Barcelona, Spain, is focused on medical dermatology. NN-8828 is a monoclonal antibody that targets and binds the IL-21 cytokine with high affinity. IL-21 is a key player in the inflammatory cascade and has been implicated in various immune-based skin diseases, including atopic dermatitis, psoriasis, pemphigus and Sjögren's syndrome. By blocking IL-21 signaling, NN-8828 can potentially inhibit the underlying mechanisms of these diseases providing “a promising option for the treatment of inflammatory and autoimmune skin disorders,” according to Almirall. Before punting the candidate over to Almirall, Novo had trialed NN-8828 up to Phase II in non-dermatological conditions. In January 2013, the Danish pharma announced that it was discontinuing the development of NN-8828 in rheumatoid arthritis after the candidate delivered a middling performance in a Phase IIa study. NN-8828 met its primary endpoint of significantly lowering disease activity versus placebo but “the magnitude of the treatment effect did not warrant further development,” according to Novo. The Danish drugmaker continued assessing NN-8828 in other inflammatory diseases, such as Crohn’s disease and systemic lupus erythematosus, but ultimately exited the inflammation space entirely in September 2014. Now part of Almirall’s holdings, NN-8828 joins a pipeline of promising dermatology therapies anchored by lebrikizumab, which is currently undergoing regulatory review in the European Union for the treatment of atopic dermatitis. Almirall licensed the European rights for lebrikizumab from Dermira in June 2019. Eli Lilly acquired Dermira in January 2020. Also under review in the EU is Almirall’s efinaconazole, an investigational treatment for the fungal infection onychomycosis and sarecycline, meant to treat acne. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.