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Cytokine therapies targeting IL-18 and IL-12 have long been plagued with problems. Mural Oncology thinks its protein-engineering strategy may have solved them. It’s been a busy five months since cytokine therapy startup Mural Oncology landed its first big check after spinning out of Alkermes. Besides the usual new-business housekeeping, the company is in the midst of two potentially registrational late-stage studies for its lead clinical candidate. One candidate is an engineered interleukin-2 (IL-2) cytokine called nemvaleukin alfa. One trial pairs the drug with Merck & Co.'s Keytruda to treat ovarian cancer, while the second tests it as a monotherapy for mucosal melanoma.  “We’ve been focused very diligently on making sure that we deliver on these studies,” Caroline Loew, Ph.D., told Fierce Biotech Research in an interview. “Execution is going very well on those.”  But that’s not all. Mural has some potential new additions to the pipeline as well. During the annual meeting of the American Association for Cancer Research from April 5 to April 10, the company presented preclinical data on two new programs, one for a cytokine therapy that boosts interleukin-18 (IL-18) and another targeting IL-12.  “We’re really excited because it’s the first time that we have disclosed any data on these programs,” Loew said.  Both targets have generated a lot of interest in the cytokine therapy world. Simcha Therapeutics, Gilead and others are working on anti-cancer agents that target IL-18. Gilead also recently shelled out nearly $44 million for Xilio’s IL-12 drug. But no such drugs have FDA approval yet, partly because they’re difficult to develop in the first place.  While it’s still early days, Loew believes that Mural’s candidates have a good shot at performing well in the clinic, perhaps accomplished what others have not yet achieved.  “We’re confident that [our IL-18 therapy] is engineered with a really differentiated approach that will play out significantly in the clinic,” Loew said, adding later that she believes that the IL-12 molecule has the potential to be “best in class.”  IL-18-targeting cytokine therapies are very good at stimulating the immune system. But they’re held back by their affinity for a protein called IL-18 binding protein (IL-18PB), which neutralizes IL-18 and renders it ineffective. On top of that, the cytokines don’t stick around for long—their short half-life can make it difficult to achieve a lasting therapeutic effect.  Mural has built its way around these challenges. Scientists at the company altered IL-18’s structure to remove its affinity for IL-18PB without diminishing its potency, then attached protein scaffolds to it to increase its half-life. In one of its two AACR posters, Mural showed that its “enhanced” version of IL-18 stimulated an elevated, more sustained immune response in mice than did standard IL-18, a sign that it’s working as the company hoped.  For IL-12, Mural faced a different problem entirely. The cytokine is a powerful stimulator of the immune response and is known to have significant anti-tumor activity. It’s also very toxic.  “It has a very narrow therapeutic index,” Loew explained. “There’s a very tiny, specific amount that you can deliver before you get these toxicities. So the question is, how can you actually use this?”  To answer that, Mural researchers took what Loew described as a “Lego-like” approach. They split the cytokine into two inactive monomers, which they fused to antibody fragments directed at tumor antigens. These are administered one after another so they reach the tumor site separately, then fuse back together in its microenvironment. That way, they don’t assemble anywhere they shouldn’t, thus reducing IL-12’s toxic side effects.   “You’re creating the activity in the tumor, but you’re not creating any systemic toxicity,” Loew said. “It’s like science fiction.”  The second AACR poster showed that this sci-fi mechanism does indeed play out in the real world. In the tumors of mouse models, the researchers saw that the two subunits bound together and increased the release of inflammatory molecules within them—without any systemic adverse effects.  For both candidates, the most exciting aspect of the new AACR data is that the Mural’s protein-engineering strategy is ameliorating the issues that have held these types of drugs back from reaching their full potential, Loew said.  “As with nemvaleukin alfa, we are able to mitigate the issues and unveil the efficacy potential of those targets,” she said. Mural will nominate candidates for its IL-12 and IL-18 programs sometime this year, according to the company's Q4 report.  Mural may also have cracked the code when it comes to attracting female leaders. The company’s CEO, CMO and chief legal officer are all women—an unusual C suite for the industry. Women make up only a third of C-level positions at biotech companies, a 2023 survey of life sciences professionals showed.  “There are incredibly talented women who are now ready to take leadership roles—and who have been taking leadership roles—across biotechs and pharma,” Loew said. “I think it’s incredibly important in the recruitment process that leaders take time to explore diverse slates,” not only with regards to gender and other types of diversity as well, she added.  “When you’re systematic about doing that, that’s how you always ensure that you’ve brought the best leaders to the table,” Loew said. “In our case, they happen to be women.”  Loew has noticed that companies with a female leader tend to attract more of them. She theorized that having women at the helm signifies to other would-be women leaders that the firm’s culture will embrace them. “Part of that is that women are encouraged to maybe take a step-up role, to advance their own careers. They’re feeling supported by other women,” Loew said. “I feel proud to have been able to support women in their careers over the course of mine. It’s something we’ll continue to do.” 

– Preliminary data from the WTX-124 monotherapy dose-escalation arm of the ongoing Phase 1/1b clinical trial provide compelling early evidence of dose-dependent anti-tumor and biomarker activity – – Safety data indicate WTX-124 is generally well tolerated through cohort 4 (12 mg), with a wide therapeutic index supportive of continued dose escalation – – Additional interim WTX-124 monotherapy data and recommended dose for expansion expected in the first half of 2024 – – Announcing the addition of WTX-518, a novel conditionally activated IL-18 INDUKINE™ molecule designed to promote activation of immune cells in the tumor microenvironment resulting in antitumor immunity, to Werewolf’s pipeline of preclinical development candidates – WATERTOWN, Mass., Nov. 14, 2023 (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 third quarter ended September 30, 2023. “Werewolf has made tremendous strides since last quarter, most notably with the presentation of promising first-in-human data from our lead clinical program, WTX-124. Preliminary data presented at SITC indicate that WTX-124 is well-tolerated and elicits monotherapy biomarker and clinical activity, including two patients with ongoing unconfirmed partial responses in the 12 mg cohort,” said Daniel J. Hicklin, Ph.D., President and Chief Executive Officer of Werewolf. “We look forward to sharing additional data to inform our recommended dose to proceed into monotherapy expansion arms in the first half of 2024. We are also pleased to announce the addition of WTX-518, an IL-18 INDUKINE molecule, as our newest pipeline candidate and expect to present preclinical data on this molecule in the first half of 2024.” 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 checkpoint inhibitor therapy in multiple solid tumor types. In November 2023, at the Society for Immunotherapy of Cancer (SITC) 38th Annual Meeting, Werewolf presented preliminary clinical data from the first four monotherapy dose escalation cohorts of Study WTX-124x2101, its Phase 1/1b, multi-center, open-label clinical trial evaluating WTX-124 in patients with immunotherapy sensitive advanced or metastatic solid tumors who have failed standard of care treatment, including checkpoint inhibitor therapy. The preliminary data established proof of mechanism for WTX-124 and proof of concept for Werewolf’s INDUKINE design, with highlights as follows, as of the data cut-off date of October 18, 2023: WTX-124 was generally well-tolerated across 16 patients, with no Grade 3 or higher treatment-related adverse events, no related serious adverse events and no evidence of vascular leak syndrome, at doses up to and including 12 mg.Early evidence of antitumor activity was observed in monotherapy dose escalation cohorts 3 (6 mg) and 4 (12 mg), including two patients with ongoing unconfirmed partial responses (PR) dosed at 12 mg. An additional patient dosed at 12 mg showed evidence of anti-tumor activity.These WTX-124 data are consistent with key INDUKINE pharmaceutical properties, including systemic delivery of the WTX-124 prodrug with preferential activation in the tumor microenvironment while preserving a wide therapeutic index supportive of continued dose escalation. Werewolf is progressing Study WTX-124x2101, and dose escalation is ongoing in both the monotherapy and combination therapy arms of the study. The Company expects to report additional interim data from monotherapy dose escalation cohorts, declaration of a recommended dose for expansion, and opening of the monotherapy expansion arms in the first half of 2024.In September 2023, Werewolf hosted a virtual event reviewing the IL-2 landscape and opportunity for WTX-124 among next-generation therapeutic approaches. The event featured key opinion leader in cytokines and cancer immunotherapy, Michael Atkins, M.D., William M. Scholl Professor and Vice Chair of the Department of Oncology at Georgetown University. 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 trial evaluating WTX-330 as a monotherapy in patients with immunotherapy insensitive or resistant advanced or metastatic solid tumors or non-Hodgkin lymphoma. Enrollment is ongoing in dose-escalation. Additional Updates: Werewolf is announcing the addition of WTX-518 as a pipeline candidate for preclinical development. WTX-518 is a conditionally activated IL-18 INDUKINE molecule in development for the treatment of cancer and is wholly owned by Werewolf. IL-18 is designed to promote activation of immune cells in the tumor microenvironment resulting in antitumor immunity. Werewolf expects to present preclinical data regarding this molecule in the first half of 2024.At SITC, Werewolf also presented five posters with preclinical and translational data supporting PREDATOR platform capabilities; pipeline programs, including both clinical candidates as well as WTX-712 (IL-21); and the potential of INDUKINE molecules as a complement to other anti-cancer approaches, such as checkpoint inhibitors and cell therapy. All posters are available at investors.werewolftx.com/news-and-events/scientific-resources. Financial Results for the Third Quarter of 2023: Cash position: As of September 30, 2023, cash and cash equivalents were $130.1 million, compared to $137.5 million as of June 30, 2023. The Company also had restricted cash and cash equivalents of $21.2 million as of September 30, 2023, and June 30, 2023, respectively. The Company expects that its existing cash and cash equivalents will be sufficient to fund its operational expenses and capital expenditure requirements through at least the fourth quarter of 2024.Collaboration revenue: Collaboration revenue was $5.9 million for the third quarter of 2023, compared to $5.0 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 $10.8 million for the third quarter of 2023, compared to $13.1 million for the same period in 2022. The decrease in research and development expenses was primarily due to a decrease in contract manufacturing costs associated with WTX-124 and WTX-330. The decline in contract manufacturing costs was partially offset by an increase in clinical trial costs for WTX-124 and WTX-330.General and administrative expenses: General and administrative expenses were $4.3 million for the third quarter of 2023, compared to $4.4 million for the same period in 2022. The decrease in general and administrative expenses was primarily due to a reduction in insurance premiums, which was offset in part by an increase in costs incurred to protect the Company’s intellectual property.Net loss: Net loss was $8.3 million for the third quarter of 2023, compared to $11.9 million for the same period in 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 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. 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 future operations, prospects, and plans; the projection of the cash runway; the expected timeline for the pre-clinical and clinical development of product candidates and availability of data from such pre-clinical and clinical development; and 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,” “believe,” “contemplate,” “continue,” “could,” “design,” “designed to,” “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 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. Werewolf Therapeutics, Inc.Condensed Consolidated Statements of Operations (unaudited)(amounts in thousands, except per share data) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2023 2022 2023 2022 Revenue: Collaboration revenue$5,897 $4,970 $18,442 $9,118 Operating expenses: Research and development 10,838 13,070 32,127 37,902 General and administrative 4,310 4,439 13,856 14,093 Total operating expenses 15,148 17,509 45,983 51,995 Operating loss (9,251) (12,539) (27,541) (42,877)Other income 966 596 2,176 997 Net loss$(8,285) $(11,943) $(25,365) $(41,880)Net loss per share, basic and diluted$(0.23) $(0.40) $(0.72) $(1.48)Weighted-average common shares outstanding, basic and diluted 35,654 29,764 35,335 28,233 Werewolf Therapeutics, Inc.Selected Condensed Consolidated Balance Sheet Data (unaudited)(amounts in thousands) September 30, 2023 December 31, 2022Cash and cash equivalents$130,058 $129,315Working capital$124,819 $116,211Total assets$176,386 $160,245Total deferred revenue$2,402 $7,660Total notes payable, net of discount and issuance costs$39,231 $—Total stockholders’ equity$112,443 $122,337 Investor Contact:Josh RappaportStern IR212.362.1200Josh.rappaport@sternir.com Media Contact:Peg RusconiVERGE Scientific Communicationsprusconi@vergescientific.com Company Contact:Ellen LubmanChief Business OfficerWerewolf Therapeuticselubman@werewolftx.com