On August 7, 2024 Tango Therapeutics, Inc. (NASDAQ: TNGX), a clinical-stage biotechnology company committed to discovering and delivering the next generation of precision cancer medicines, reported its financial results for the second quarter ended June 30, 2024, and provided business highlights (Press release, Tango Therapeutics, AUG 7, 2024, View Source [SID1234645523]).

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"In the second quarter, we continued to advance the dose expansion portions of the TNG908 and TNG462 phase 1/2 clinical trials. We are progressing these molecules with the intent of remaining a leader in developing PRMT5 inhibitors for multiple cancers. We look forward to sharing a comprehensive clinical data update for the PRMT5 program later this year," said Barbara Weber, M.D., President and Chief Executive Officer of Tango Therapeutics. "In addition, we continue to advance TNG260 for cancers with STK11 loss-of-function mutations and patient enrollment is ongoing in the phase 1/2 clinical trial."

Recent Business Highlights

Pipeline Update

TNG908, a blood-brain barrier penetrant, MTA-cooperative PRMT5 inhibitor

Enrollment in the dose expansion portion of the TNG908 phase 1/2 clinical trial is ongoing. Expansion cohorts are being enrolled in MTAP-deleted solid tumors in glioblastoma (GBM), non-small cell lung and pancreatic cancers at 600 mg BID.
MTAP deletions occur in approximately 10%-15% of all human cancers, including 40% of GBM.
TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor

The dose expansion portion of the TNG462 phase 1/2 clinical trial is ongoing. Two doses are being evaluated (200 mg QD and 300 mg QD) in non-small cell lung and pancreatic cancer, as well as a histology-agnostic cohort enriched for cholangiocarcinoma, mesothelioma, sarcoma and bladder cancers.
TNG260, a first-in-class, highly selective CoREST complex inhibitor

The TNG260 phase 1/2 clinical trial is ongoing, evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG260 in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors with an STK11 loss-of-function mutation. To date, safety, tolerability and pharmacokinetic profiles are favorable.
STK11 mutations occur in approximately 15% of non-small cell lung, 15% of cervical, 10% of carcinoma of unknown primary, 5% of breast and 3% of pancreatic cancers.
Business Highlights

Gilead strategic collaboration

In June, Gilead licensed a drug discovery program for a $12.0 million license fee.
Upcoming Milestones

A comprehensive update of the PRMT5 program, including clinical data from the ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024.
Financial Results

As of June 30, 2024, the Company held $322.1 million in cash, cash equivalents and marketable securities, which the Company expects to be sufficient to fund operations into 2027.

Collaboration revenue was $7.8 million for the three months ended June 30, 2024, compared to $9.6 million for the same period in 2023, and $14.2 million for the six months ended June 30, 2024 compared to $15.4 million for the same period in 2023. Research costs incurred under the collaboration were lower during the three months ended June 30, 2024 which resulted in lower collaboration revenue amounts recognized.

License revenue was $12.1 million for the three and six months ended June 30, 2024, compared to $5.0 million for both the three and six months ended June 30, 2023. The increase is primarily due to licensing a drug discovery program to Gilead for $12.0 million during the second quarter of 2024.

Research and development expenses were $38.7 million for the three months ended June 30, 2024, compared to $28.7 million for the same period in 2023, and $76.7 million for the six months ended June 30, 2024 compared to $56.7 million for the same period in 2023. The change is due to increased spend related to the advancement of our clinical and preclinical programs and personnel-related costs to support our research and development activities.

General and administrative expenses were $10.8 million for the three months ended June 30, 2024, compared to $9.2 million for the same period in 2023, and $21.4 million for the six months ended June 30, 2024 compared to $17.2 million for the same period in 2023. The change was primarily due to increases in personnel-related costs.

Net loss for the three months ended June 30, 2024 was $25.6 million, or $0.24 per share, compared to a net loss of $20.7 million, or $0.23 per share, in the same period in 2023. Net loss for the six months ended June 30, 2024 was $63.5 million, or $0.58 per share, compared to a net loss of $48.7 million, or $0.55 per share, in the same period in 2023.

On August 7, 2024 IDRx, Inc., a clinical-stage biopharmaceutical company dedicated to transforming cancer treatment with purpose-built precision therapies, reported the completion of an oversubscribed $120 million Series B Preferred Stock financing (Press release, IDRx, AUG 7, 2024, View Source [SID1234645522]). The financing was led by RA Capital Management, Commodore Capital, and Blackstone Multi-Asset Investing with additional new investors, including Rock Springs Capital and a U.S.-based healthcare-focused fund. Existing investors, including Andreessen Horowitz (a16z) Bio + Health, Casdin Capital, Nextech Invest Ltd. (on behalf of one or more funds managed by it), Forge Life Science Partners, co-founder Nick Lydon, Ph.D., and strategic partner Merck KGaA, Darmstadt, Germany also participated in the financing. Derek DiRocco, Ph.D., Partner at RA Capital Management, has joined the IDRx Board of Directors.

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IDRx plans to use the proceeds from the financing to support the ongoing Phase 1/1b StrateGIST 1 study of its lead product candidate IDRX-42, a potent, oral, highly selective KIT inhibitor targeting all major categories of activating and resistance mutations in patients with KIT-mutant GIST. Additionally, proceeds will be used to fund the expected initiation of the first pivotal study for IDRX-42 in patients with second-line GIST.

At the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, IDRx presented preliminary Phase 1 data from the ongoing Phase 1/1b StrateGIST 1 trial. The data support the best-in-class potential of IDRX-42 in patients with GIST. This included a 23% objective response rate (ORR) across all patients (median four prior lines of therapy) and a 43% ORR in second-line patients, including those with either or both ATP binding site and activation loop mutations, with a favorable tolerability profile consistent with use in front-line and second-line settings. IDRx is now enrolling patients in the Phase 1b portion of the trial. In addition, the U.S. Food and Drug Administration (FDA) has recently granted Fast Track designation to IDRX-42 for the treatment of GIST after disease progression on or intolerance to imatinib.

"We are thrilled to announce this financing, which includes support from a top-tier syndicate of investors and positions us to accelerate the development of IDRX-42 for a broad population of patients with GIST, including in the second-line and front-line settings, where patients haven’t seen a new treatment option in over 15 years," said Tim Clackson, Ph.D., Chief Executive Officer of IDRx. "IDRX-42 was designed to overcome the twin challenges of on-target treatment resistance and off-target driven adverse events, which limit the clinical benefit of currently available TKIs. We are extremely encouraged by the clinical data generated with IDRX-42 to date and are focused on rapidly advancing this potential new treatment option that could elevate the standard of care for GIST patients."

"RA Capital Management is excited to co-lead this round to support the advancement of IDRX-42 as a differentiated new treatment for GIST," said Derek DiRocco, Ph.D., Partner of RA Capital Management and board member of IDRx. "We have been extremely impressed by what the IDRx team has accomplished in a short time, and I look forward to contributing to IDRx’s future growth and success as the company prepares to execute on its late-stage clinical development activities for IDRX-42."

About GIST

GIST is the most common subtype of soft tissue sarcoma. Approximately 80% of cases arise from gain of function mutations in the KIT receptor tyrosine kinase, driving the malignancy through constitutive activation of aberrant signaling. Resistance mutations in KIT emerge in ~90% of patients treated with imatinib, the current standard of care for GIST. In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type.

About the StrateGIST 1 Study

StrateGIST 1 is an ongoing, open-label, first-in-human Phase 1/1b study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of IDRX-42 in patients with metastatic and/or surgically unresectable GIST after failure of imatinib and other approved drugs. The study is currently enrolling patients with documented pathogenic mutation in KIT or any platelet-derived growth factor receptor alpha (PDGFRA) mutation (other than PDGFRA exon 18) at sites in the U.S., United Kingdom, Belgium, The Netherlands, France, Germany, Italy, Spain, and South Korea. The Phase 1b portion has been initiated and includes four expanded exploratory cohorts based on defined lines of prior TKI therapy, including front line, second line, third line + (with standard approved TKIs only), and third line + (including investigational TKIs).

About IDRX-42

IDRX-42 is a potent, oral, highly selective KIT inhibitor targeting all major categories of activating and resistance mutations in patients with KIT-mutant GIST (including variants in exons 9, 11, 13 and 17). In preclinical studies, IDRX-42 demonstrated superior antitumor activity compared to imatinib, the current first-line of therapy, in GIST human xenograft models expressing mutations in KIT exons 9 and 11. In xenograft models expressing secondary resistance mutations in KIT exon 13 or 17, IDRX-42 treatment resulted in potent and dose-dependent antitumor activity superior to the second-line standard of care agent, sunitinib. IDRX-42 is currently being evaluated in StrateGIST 1, a first-in-human Phase 1/1b study. IDRX-42 was granted Orphan Drug designation by the FDA for the treatment of GIST.

On August 7, 2024 Agenus Inc. (NASDAQ: AGEN), a leader in developing novel immunological agents to treat various cancers, reported the publication of a seminal study in the prestigious Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), detailing the novel mechanism of action and effectiveness of botensilimab, an investigational, novel multifunctional anti-CTLA-4 antibody, in various treatment-resistant cancers (Press release, Agenus, AUG 7, 2024, View Source [SID1234645521]).

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The paper, entitled "Botensilimab, an Fc-Enhanced Anti-CTLA-4 Antibody, Is Effective Against Tumors Poorly Responsive to Conventional Immunotherapy," highlights several key findings:

Demonstrated Activity Across Multiple Cancers: Botensilimab has shown increased activity in multiple treatment-resistant cancers, including those that have progressed on prior checkpoint inhibitors.
Fc-Enhanced Design for Multifunctional Immune Activation: Unlike traditional anti-CTLA-4 antibodies, botensilimab’s Fc-enhanced design allows it to leverage multiple immune-activating mechanisms simultaneously. This includes enhanced T cell priming, reduction of intratumoral regulatory T cells, and activation of antigen-presenting cells, leading to a robust anti-tumor response.
Activity Independent of Conventional Limitations: Botensilimab shows clinical activity regardless of factors that typically limit conventional immunotherapy efficacy, such as tumor neoantigen burden and FcγRIIIA genotype. This broadens its potential applicability across diverse patient populations.
Remodeling the Tumor Microenvironment: The antibody uniquely remodels the tumor microenvironment, transforming "cold" tumors that are currently unresponsive to immune therapies into "hot" immunologically active tumors. This is achieved by reducing regulatory T cells and increasing T cell inflammation gene signatures within the tumor microenvironment.
Promise in Difficult-to-Treat Cancers: Botensilimab demonstrates significant promise in treating over nine difficult-to-treat cancers, including microsatellite stable colorectal cancer and may extend clinical benefits to patient populations historically unresponsive to conventional immune checkpoint inhibitors.
"We are thrilled to share these groundbreaking findings with the scientific community," said Dhan Chand, PhD, lead author and Vice President of Research at Agenus. "The compelling preclinical and clinical evidence generated with botensilimab reveal an actionable pathway to improve treatment outcomes and extend survival to patient populations historically unresponsive to conventional immune checkpoint inhibitors."

This paper underscores the potential of botensilimab to overcome some of the most challenging hurdles in cancer treatment, offering new hope to patients with limited options. Agenus is committed to advancing this promising therapy through further clinical development and regulatory pathways to ensure rapid and broad patient access.

About Cancer Discovery

Cancer Discovery publishes high-impact, peer-reviewed articles describing major advances in research and clinical trials. As the premier cancer information resource, the Journal also presents Review Articles, Perspectives and Commentaries, News stories, and Research Watch summaries of important journal articles to its readers to keep them informed about the latest findings in the field. Topics span the spectrum of cancer research and medicine from the laboratory to the clinic and epidemiologic studies.

About Botensilimab

Botensilimab is an investigational human Fc-enhanced CTLA-4 blocking antibody designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to "cold" tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and investigational therapies. Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses.

Approximately 1,100 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational PD-1 antibody, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit www.clinicaltrials.gov with the identifiers NCT03860272, NCT05608044, NCT05630183, and NCT05529316.

On August 7, 2024 Halda Therapeutics, a biotechnology company developing a novel class of cancer therapies called RIPTACTM (Regulated Induced Proximity TArgeting Chimeras) therapeutics, reported the publication of data demonstrating proof-of-mechanism and pharmacology of a RIPTAC therapeutic, published in the peer-reviewed journal Cell Chemical Biology (Press release, Halda Therapeutics, AUG 7, 2024, View Source [SID1234645520]). The manuscript entitled, "Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Heterobifunctional Small Molecule Strategy for Cancer Selective Therapies," describes the creation of a chemical biology model of RIPTAC therapeutics and illustrates the mechanism of action of this novel drug modality to enable selective killing of cancer cells.

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RIPTAC therapeutics are heterobifunctional small molecules that work by a novel "hold and kill" mechanism, bringing together two proteins, a tumor-specific protein and a protein with essential function, resulting in abrogation of the essential cell function, and subsequently, cancer cell death. This unique pharmacology does not require the target protein to be the driver of the cancer, unlike the majority of precision oncology medicines that rely on an oncogene driver as the target protein. In addition, the novel mode of action of RIPTAC therapeutics is designed to overcome the known bypass mechanisms of resistance that evolve during a course of therapy, a common limitation of today’s precision oncology medicines, thereby opening the potential for their use in both late and early stages of cancer treatment.

"We are excited to share data demonstrating the mechanism of action of RIPTAC molecules, as well as how the protein proximity paradigm can be extended into direct cancer cell killing," said Kanak Raina, PhD, lead author and Head of Biology at Halda. "Insights gained from the detailed interrogation of this chemical biology model have provided Halda with a robust foundation that has resulted in our pipeline of RIPTAC therapeutics for major cancers."

The publication details several chemical biology approaches using a model with a HaloTag‑FKBP target protein to dissect the mechanism of action and pharmacology of RIPTAC molecules. Key findings from the study include:

RIPTAC therapeutics demonstrated selective anti-proliferative activity in cells expressing the target protein.
A ternary complex formed by the target protein, the RIPTAC molecule, and a pan-essential protein abrogated the function of the essential protein selectively in target-expressing cells, causing cell death.
Several different pan-essential cellular proteins were shown to be amenable for selective cancer cell killing when incorporated into RIPTAC ternary complexes.
Halda’s scientific founder, Craig Crews, PhD, Professor of Molecular, Cellular, and Developmental Biology at Yale University, is an author on the paper in Cell Chemical Biology and is a pioneer of induced proximity biology that has led to the vision and invention of heterobifunctional drugs. Professor Crews commented, "RIPTAC therapeutics address a shortcoming shared by most current precision medicines for cancer, namely, the reliance on oncogenic driver proteins which can result in drug resistance in a large percentage of patients. The RIPTAC modality offers a new oral, selective, and widely applicable cancer cell-killing mechanism that can overcome drug resistance and can be used in advanced cancer where resistance has emerged, as well as in early stage disease where the tumor-specific protein is expressed."

On August 7, 2024 Invenra’s collaboration partner, Exelixis, Inc. (NASDAQ: EXEL) reported the initiation of the dose-escalation stage of the first-in-human phase 1 clinical trial of XB010 in patients with locally advanced or metastatic solid tumors (Press release, Invenra, AUG 7, 2024, View Source [SID1234645519]).

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XB010, an antibody-drug conjugate (ADC) consisting of a monomethyl auristatin E payload conjugated to a monoclonal antibody targeting the tumor antigen 5T4, is the first custom ADC generated through Exelixis’ biotherapeutics collaboration network. XB010 was constructed using Catalent’s SMARTag site-specific bioconjugation platform, and its 5T4-targeting mAb was discovered in collaboration with Invenra.

Exelixis further announced that the dose-escalation stage of their phase 1, global, open-label study will evaluate XB010 as a single agent and in combination with pembrolizumab to inform the cohort-expansion stage. The expansion cohorts are designed to further assess the tolerability and activity of monotherapy and of the combination in specific indications.