On August 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 and other immune-mediated conditions, reported a business update and provided financial results for the second quarter ended June 30, 2024 (Press release, Werewolf Therapeutics, AUG 8, 2024, View Source [SID1234645627]).

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"We believe the data recently presented from our WTX-124 and WTX-330 clinical programs displays the meaningful impact we can have on patients through our INDUKINE approach, and we are well positioned to advance both programs towards key inflection points in the coming quarters," said Daniel J. Hicklin, Ph.D., President and Chief Executive Officer of Werewolf. "We continue to focus on enrollment in these two clinical trials and look forward to providing additional clinical data updates as we look to address the unmet medical needs for cancer patients with late-stage disease."

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 June 2024, at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, Werewolf presented additional interim data from the monotherapy dose-escalation arm and preliminary dose-escalation data from the combination arm of its ongoing Phase 1/1b clinical trial of WTX-124. The updated data showcased that WTX-124 was clinically active and generally well-tolerated in patients, with highlights as follows as of the May 1, 2024, cutoff date:
◦WTX-124 as a monotherapy achieved three objective clinical responses, including one durable confirmed complete response and two partial responses in patients who were 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 Tregs.
◦WTX-124 was clinically active and generally well tolerated in patients, not all of whom would be eligible for high dose IL-2 based on age, indication or other factors.

•Werewolf has selected 18 mg administered intravenously every two weeks (IV Q2W) as the monotherapy RDE to progress into the Phase 1b dose expansion portion of the trial based on clinical activity and acceptable safety in the outpatient setting.
•Werewolf disclosed data that demonstrated that the combination of WTX-124 with pembrolizumab was generally well tolerated with biomarker activity supporting the potential for combination efficacy and clinical activity was observed in two melanoma patients at the 12 mg combination dose level.

•Dose escalation is ongoing for WTX-124 in combination with pembrolizumab, with updated data and opening of expansion arms anticipated in the second half of 2024.
WTX-330: a systemically delivered, conditionally activated Interleukin-12 (IL-12) INDUKINE molecule being developed in advanced or metastatic solid tumors.
•In June 2024, Werewolf announced initial safety and efficacy data from its ongoing Phase 1 clinical trial of WTX-330 in patients with advanced or metastatic solid tumors or Non-Hodgkin Lymphoma. The data demonstrated that administration of WTX-330 reached therapeutically relevant exposure levels of systemically delivered IL-12 prodrug, with highlights as follows as of the June 12, 2024, cutoff date:
▪Compared to previous IL-12 therapeutic strategies at 500 ng/kg, at the 0.024 mg/kg dose, WTX-330 demonstrated an approximately 23-fold higher systemic drug concentration of IL-12 prodrug delivered to patients in the outpatient setting, with low free IL-12 levels across all dose levels.
▪One patient with metastatic melanoma achieved an unconfirmed partial response when treated with 0.024 mg/kg WTX-330 IV Q2W. Two additional patients with microsatellite stable colorectal cancer were treated with 0.032 mg/kg WTX-330 IV Q2W and achieved Response Evaluation Criteria in Solid Tumors (RECIST) stable disease.
▪All patients exhibited mild to moderate treatment-related toxicities primarily associated with the first dose, with no Grade 4 or Grade 5 related adverse events. Two patients experienced reversible dose-limited toxicities at the 0.032 mg/kg dose level.
•Werewolf anticipates sharing additional results from the checkpoint inhibitor-resistant or -naïve relapsed or refractory advanced tumor patient expansion arms in the fourth 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 and an INDUKINE molecule delivering IL-10 for treatment of Irritable Bowel Disease.
•During the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2024, Werewolf presented two posters detailing progress of WTX-518 and WTX-712 preclinical programs, which the Company is progressing through investigational new drug application-enabling studies:
◦WTX-518: Demonstrated in vitro activity unimpeded by IL-18BP and selectivity that delivers active binding protein resistant (BPR) IL-18 to the tumor microenvironment, eliciting complete tumor regression in an MC38 mouse tumor model.
◦WTX-712: Demonstrated antitumor activity and tumor regression in the MC38 mouse tumor model. IL-21 was observed to achieve superior anti-tumor efficacy compared to IL-2 therapy in mouse tumor models that are highly resistant to anti-PD-1/PD-L1 treatment.
•During the American Association of Immunologists Meeting in May 2024, Werewolf presented a poster for its conditionally active IL-10 INDUKINE molecules for the treatment of inflammatory bowel disease.
◦Novel INDUKINE Molecules: Data demonstrated application of the Company’s PREDATOR platform in immune-mediated disease, indicating that IL-10 INDUKINE molecules were peripherally inactive and conditionally active in target tissue thereby preventing intestinal histological damage and inhibiting inflammatory cytokine production in mouse models of colitis.
Financial Results for the Second Quarter of 2024:
•Cash position: As of June 30, 2024, cash and cash equivalents were $135.3 million, compared to $139.2 million as of March 31, 2024. The Company believes its existing cash and cash equivalents as of June 30, 2024, will be sufficient to fund operational expenses and capital expenditure requirements through at least the first quarter of 2026.
•Collaboration revenue: Collaboration revenue was $1.1 million for the second quarter of 2024, compared to $8.1 million for the same period in 2023. Collaboration revenue consists of revenue recognized from the Company’s collaboration agreement with Jazz Pharmaceuticals (Jazz) and includes fixed payments received from Jazz, plus costs incurred for research services to be reimbursed by Jazz. As of June 30, 2024, Werewolf substantially completed its performance obligations under the collaboration agreement, so all remaining deferred revenue related to the collaboration agreement has been recognized.
•Research and development expenses: Research and development expenses were $15.3 million for the second quarter of 2024, compared to $9.6 million for the same period in 2023. The increase in research and development expenses was primarily due to the Company’s development efforts for WTX-124 and WTX-330, which continue to progress through their respective clinical trials, resulting in higher clinical trial costs and higher manufacturing costs to support those trials.
•General and administrative expenses: General and administrative expenses were $4.8 million for the second quarter of 2024, compared to $4.6 million for the second quarter of 2023.
•Net loss: Net loss was $17.2 million for the second quarter of 2024, compared to $5.1 million for the same period in 2023.