On January 14, 2025 Parabilis Medicines (formerly Fog Pharmaceuticals), a clinical-stage biopharmaceutical company dedicated to creating extraordinary medicines for people living with cancer, reported updates from its targeted first-in-class oncology programs at the 43rd Annual J.P. Morgan Healthcare Conference in San Francisco (Press release, Parabilis Medicines, JAN 14, 2025, View Source [SID1234649732]).

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The presentation by Mathai Mammen, M.D., Ph.D., Chairman and CEO of Parabilis Medicines, highlighted recent advances in the Company’s versatile and tunable Helicon platform. This powerful peptide platform is capable of entering cells and potently and selectively binding proteins where small molecules cannot, drugging otherwise undruggable targets. Recent technical breakthroughs have led to an expanded range of powerful applications for Helicons across three main areas: functional inhibitors of intracellular protein-protein interactions, targeted protein degraders, and targeted radiopharmaceuticals. Additionally, the Company provided an update from its lead program, FOG-001, which is being evaluated in an ongoing Phase 1/2 study for microsatellite stable (MSS) colorectal cancer and other Wnt-pathway activated (WPAM+) solid tumors.

"We’ve made significant leaps forward in the last year in both experimental and data science technologies, propelling us toward an even deeper understanding and practical applications of the unique capabilities of Helicon peptide therapeutics," said Dr. Mammen. "Promising data from our ongoing Phase 1/2 trial show that FOG-001 is a bona fide β-catenin TCF4 inhibitor, confirming Helicons’ ability to target proteins previously considered undruggable in patients. FOG-001 could represent an expansive opportunity with the potential to provide benefit across multiple common cancer types, including colorectal cancer. We expect 2025 to be an eventful year, including the planned presentation of FOG-001 clinical results and the advancement of additional first-in-class pipeline programs including our ERG degrader for prostate cancer toward the clinic."

Program Updates and Expected 2025 Milestones

FOG-001

FOG-001 is the first and only direct inhibitor of β-cateninTCF4, which drives the vast majority of colorectal cancers and plays a significant role in several other cancer types. FOG-001 is currently being evaluated in a Phase 1/2 clinical trial (NCT05919264), and more than 60 patients with locally advanced or metastatic solid tumors have been dosed to date.

Early clinical data for FOG-001 confirm monotherapy antitumor activity with a manageable safety profile. Furthermore, paired biopsy transcriptomic and immunohistochemistry analyses have confirmed FOG-001’s in-tumor target engagement, eliciting important biological changes within the tumor microenvironment, including increased markers of inflammation, decreased markers of stemness, and increased markers of cellular differentiation. These clinical observations, coupled with preclinical data, provide a strong biological rationale for continued development of FOG-001 as a monotherapy and for evaluating multiple combination cohorts. Preliminary Phase 1/2 data are expected to be shared publicly in 2025.

ERG Degrader

The presentation also featured first-in-industry data demonstrating in vivo degradation of ERG, a longstanding high-value target in prostate cancer. ERG fusions have been implicated in 40-50% of all prostate cancer cases, and a Helicon-based targeted ERG degrader could provide a novel therapeutic option for patients with metastatic castrate-resistant prostate cancer (mCRPC). In vivo proof-of-concept data in preclinical models of prostate cancer showed robust activity with coincident ERG degradation confirmed by immunohistochemistry. The Company’s ERG degrader program is expected to advance into IND-enabling activities in 2025.

Radioligand Therapies

In May 2024, Parabilis Medicines and ARTBIO announced a collaboration to co-develop Helicon-enabled alpha radioligand therapies (HEARTs) incorporating the potential best-in-class isotope Lead-212 (also called 212Pb). The Company has identified multiple Helicons with sub-nanomolar affinity for the lead target. The collaboration continues to rapidly advance programs against multiple novel radioisotope targets.

About FOG-001

FOG-001 is an investigational first-in-class competitive inhibitor — and the only direct inhibitor — of β-catenin interactions with the T-cell factor (TCF) family of transcription factors, and is currently in clinical development. By directly targeting the β-cateninTCF4 protein-protein interaction, the most downstream node in the Wnt pathway, FOG-001 is intended to block the Wnt signaling pathway irrespective of the particular mutations driving disease.

FOG-001 combines key features that distinguish it from previously reported Wnt/β-catenin pathway modulators: FOG-001 acts inside the cell where it binds directly to the key oncogenic driver β-catenin; and FOG-001 blocks the Wnt pathway at the most downstream node, disrupting the interaction between β-catenin and the transcription factor TCF, thereby abrogating the signal transmission by which Wnt pathway mutations are believed to drive oncogenesis. FOG-001 is currently being evaluated in a first-in-human Phase 1/2 clinical trial in patients with locally advanced or metastatic solid tumors.

On January 14, 2025 Adimab, LLC, the global leader in the discovery and engineering of fully human monoclonal and multispecific antibodies, reported that five therapeutic products containing molecules discovered or optimized by Adimab have been approved for commercial sale (Press release, Adimab, JAN 14, 2025, View Source [SID1234649731]). Adimab’s first partnered program to receive approval was Innovent’s TYVYT (sintilimab injection), which is currently marketed by Innovent and Lilly in China for seven cancer indications.

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Other commercial products containing molecules from Adimab include:

Innovent’s SINTBILO (tafolecimab injection), a PCSK9 program approved in China for the treatment of adult patients with primary hypercholesterolemia and mixed dyslipidemia.
IASO Bio’s FUCASO (equecabtagene autoleucel), a BCMA CAR-T program approved in China for the treatment of patients with multiple myeloma.
Invivyd’s PEMGARDA (pemivibart), a SARS-CoV-2 monoclonal antibody approved for prophylactic emergency use to prevent COVID-19 infection in the United States.
Checkpoint Therapeutic’s UNLOXCYT (cosibelimab) received BLA approval December 2024 in the United States for multiple myeloma.
There are 11 additional Adimab-associated programs that are currently in Phase II or Phase III (pivotal) trials. The total number of Adimab-associated clinical programs initiated by our partners has now reached 78.

"Helping our partners get new therapies on the market to treat patients has been our goal from day one," explained Ryan McGovern, Chief Financial Officer of Adimab. "Given our high number of currently-approved and late-stage programs, we made the decision in 2024 to move royalty rights on our more advanced assets into a separate business unit called Adimab Royalty Company (ARC), which provides a unique opportunity for investors interested in an advancing, diversified portfolio of royalty-bearing assets. The rapid clinical and commercial advancement of so many exciting therapies is driving the value of ARC in addition to validating our core business at Adimab, which remains focused on generating new therapeutic candidates for our partners."

"Therapeutic product development has many challenges, and it is truly meaningful when programs are approved and reach patients. Over time, we have succeeded in building a valuable, sustainable business because of our relentless focus on high-quality execution for our partners without the distraction and conflict of an internal development pipeline. Also critical to our success are our continuous investment in improving the Adimab platform, our discipline on the expense side, our highly talented and committed employees, and our supportive investor base," said Philip T. Chase, Chief Executive Officer of Adimab. "We have been a reliable collaborator since 2009 and those looking to discover protein-based therapeutics know that we will continue to be a dependable resource for years to come."

Adimab partners have exercised more than 115 commercial licenses to option rights to advance programs into clinical development. In 2024, 11 partners exercised commercial options including BMS, NextPoint, Regeneron, REGiMMUNE, SixPeaks Bio, Santa Ana Bio, Triveni Bio, and Werewolf, among others.

Technologies

Antibody Discovery: Adimab discovers therapeutic antibodies in IgG and VHH formats through our proprietary yeast-based technology. Adimab can utilize its fully human synthetic diversity as well as additional diversities from in vivo sources. Antibodies from Adimab have exquisite specificity and are utilized in a variety of modalities, including monoclonal and multispecific formats, CAR-Ts, ADCs, etc.

Engineering: Adimab has developed and refined its engineering capabilities over thousands of lead antibody optimization efforts. The process starts with one or more partner-selected lead antibodies with the goal of optimizing potency, specificity, and/or developability. In addition to Adimab-discovered antibodies, engineered antibodies can originate from outside sources, typically to fix undesirable properties of antibodies from in vivo and phage-based technologies. Adimab also applies its engineering expertise to cytokines, TCRs, and other proteins.

Multispecifics: Adimab has extensive bispecific and multispecific know-how and capabilities, including proprietary solutions for both Fc (HC:HC) and Fab (HC:LC) heterodimerization, to allow for the generation of numerous bispecific and multispecific product designs with excellent developability properties. Additionally, Adimab can perform common light chain and fragment-based discovery and engineering necessary for certain partner-desired formats.

T Cell Engagers: Adimab has a highly characterized suite of functional and diverse CD3 (both IgG and VHH binders) and CD28 antibodies to generate bi- and multi-specific T cell engagers. Adimab has partnered this program non-exclusively with more than 25 partners, to date.

Complex Targets: Certain membrane-obligate proteins (e.g., GPCRs and ion channels) are often poorly behaved outside their native membrane environment. For these targets, Adimab has developed proprietary in vitro and in vivo discovery workflows that rely solely on the target being expressed in its native membrane and without the need for antigen mimetics. The company has employed these workflows numerous times to generate robust panels of functional and specific antibodies to these classically difficult targets, which are then further extensively engineered with our yeast platform.

On January 14, 2025 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with RAS/MAPK pathway-driven cancers, reported it has exercised early the option to license from GenFleet Therapeutics VS-7375 (also known as GFH375), a potential best-in-class oral and selective KRAS G12D (ON/OFF) inhibitor (Press release, Verastem, JAN 14, 2025, View Source [SID1234649730]). In addition, the Company announced preliminary clinical data from the Phase 1 study being conducted by GenFleet in China.

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As previously announced by GenFleet, 26 patients have been treated with VS-7375 in a Phase 1 dose-escalation study being conducted in China. Both confirmed and unconfirmed partial responses have been observed, including patients with metastatic pancreatic cancer and advanced non-small cell lung cancer. In addition, six dose cohorts have been cleared with no dose-limiting toxicities (DLTs) observed. In the study, oral dosing of VS-7375 has achieved plasma levels in patients that correlate with efficacious exposures that induced deep tumor regressions across all preclinical KRAS G12D tumor models as presented in collaboration with GenFleet at the AACR (Free AACR Whitepaper) 2024 annual meeting.

Enrollment in the Phase 1 dose-escalation study in China is ongoing. Verastem remains on track to file a U.S. investigational new drug (IND) application for VS-7375 during the first quarter of 2025 and expects to initiate a Phase 1/2a study in mid-2025. The Companies expect to share updated preclinical and clinical data at upcoming medical meetings in mid-2025.

"Bringing VS-7375 formally into our pipeline allows us to leverage our scientific and development expertise in the RAS/MAPK-pathway to target KRAS G12D – the most prevalent KRAS mutation in human cancers," said Dan Paterson, chief executive officer at Verastem Oncology. "Our decision to exercise the option early for VS-7375 was based on the safety, pharmacokinetics and efficacy data to date in the Phase 1 study in China, which are in line with our expectations and, importantly, indicate that patients are generally achieving oral bioavailability with exposures that correlate with strong tumor regressions across KRAS G12D mutant preclinical models. We look forward to building on the work GenFleet has started in China to bring VS-7375 to the clinic in the U.S. in mid-2025."

In August of 2023, Verastem entered into a discovery and collaboration agreement with GenFleet to advance three oncology discovery programs targeting RAS pathway-driven cancers. The collaboration was designed with a risk-sharing structure and flexibility for Verastem to exclusively license up to three compounds selected for collaboration after the successful completion of pre-determined milestones in Phase 1 trials. Under the terms of the license for VS-7375, Verastem receives an exclusive global license to VS-7375 outside of the GenFleet markets of mainland China, Hong Kong, Macau, and Taiwan.

About VS-7375, an Oral KRAS G12D (ON/OFF) Inhibitor

VS-7375 is a potential best-in-class, potent, and selective oral KRAS G12D dual ON/OFF inhibitor. VS-7375 is the lead program from the Verastem Oncology discovery and development collaboration with GenFleet Therapeutics. GenFleet’s IND for VS-7375 (known as GFH375 in China) was approved in China in June 2024, and the first patient was dosed in a Phase 1/2 study in July 2024.

The Phase 1 portion of the study is being conducted in approximately 20 hospitals in China and will evaluate the safety and efficacy of VS-7375 in patients with advanced KRAS G12D mutant solid tumors. The Phase 1 study will determine the recommended Phase 2 dose (RP2D) and the Phase 2 will further evaluate the efficacy and safety of VS-7375 in patients with advanced solid tumors, such as pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

Preclinical data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2024 demonstrated oral bioavailability across preclinical species, strong anti-tumor activity as a single agent, and potent efficacy in an intracranial tumor model suggesting the potential to treat brain metastases.

KRAS G12D represents 26% of all KRAS mutations, making it the most prevalent KRAS mutation in human cancers. The KRAS G12D mutation occurs most commonly in pancreatic (37%), colorectal (12.5%), endometrial (8%) and non-small cell lung (5%) cancers. Currently, no therapies are approved by the U.S. Food and Drug Administration targeting KRAS G12D.

On January 14, 2025 Vistagen (Nasdaq: VTGN), a late clinical-stage company dedicated to pioneering neuroscience based on nose-to-brain neurocircuitry, reported positive results from an exploratory Phase 2A study of PH284 in cancer cachexia (Press release, VistaGen Therapeutics, JAN 14, 2025, View Source [SID1234649729]). PH284 is an investigational pherine nasal spray differentiated from all current treatments for the loss of appetite associated with chronic disorders, such as cancer. In the study, PH284 demonstrated higher mean subjective feeling of hunger as compared to placebo and appeared safe and well-tolerated with an adverse event profile similar to placebo in a population compromised by terminal cancer.

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"We are highly encouraged by the potential of PH284 to improve the quality of life for those challenged by the debilitating impacts of cancer cachexia," stated Shawn Singh, President and Chief Executive Officer of Vistagen. "Loss of appetite from cancer and other illnesses not only negatively impacts overall health and quality of life, but can also reduce the effectiveness of critical therapies, such as chemotherapy in cancer patients. PH284 is our fifth novel investigational pherine, each supported by positive Phase 2 or later clinical data and placebo-like tolerability, underscoring the breadth, diversity and potential of our neuroscience pipeline to address multiple significant unmet needs."

The previously unreported double-blind, placebo-controlled exploratory Phase 2A study was designed to evaluate the efficacy, safety, and tolerability of intranasal administration of PH284 in female patients diagnosed with cachexia (induced by chronic loss of appetite) due to terminal cancer (n=40). PH284 nasal spray (0.4 µg/50 µL) was administered intranasally, one spray in each nostril (total daily dose = 3.2µg), four times daily before meals (breakfast, mid-morning snack, lunch, and dinner). From Day 1 through Day 4, all subjects were administered placebo 30 minutes prior to each meal. Beginning on Day 5 through Day 11 subjects were randomized in a 1:1 fashion to receive either PH284 or placebo.

Efficacy

Patients measured Subjective Feeling of Hunger (SFH) ten minutes before each meal. PH284, as compared to placebo, induced a cumulative effect on mean SFH scores, with scores increasing from breakfast to lunch and lunch to dinner throughout the treatment period. Specifically, prior to dinner on Day 7 of treatment, PH284 subjects reported a 71% improvement in SFH versus baseline, while placebo subjects reported a less than 1% improvement.

Safety and Tolerability

No unusual changes in body weight were observed in either the PH284 or placebo groups, though on average, there was a small gain in body weight for PH284 versus a small loss in placebo. PH284 demonstrated no serious adverse events, and adverse events reported for the PH284 group were similar to those reported in the placebo-treated group. All the adverse events reported were attributed to the underlying medical condition (cancer) and were not deemed to be related to the administration of PH284 or placebo.

About Cachexia

Cachexia, also known as wasting syndrome, is a complex metabolic syndrome that causes a gradual loss of muscle and body weight. Cachexia is associated with chronic diseases like cancer, AIDS, heart failure, chronic obstructive pulmonary disease (COPD), anorexia nervosa, multiple sclerosis, tuberculosis, and anemias. The current definition of cancer cachexia is a loss of 5% or more of body weight over the preceding six months, accompanied by any of a handful of other symptoms, including fatigue and reduced strength. According to the National Cancer Institute, cachexia is estimated to occur in up to 80% of people with advanced cancer, depending on the type of cancer and how well they respond to cancer treatment. Cachexia is thought to directly cause up to 30% of cancer deaths, often because of heart or respiratory failure related to muscle loss. Maintaining nutritional support and alleviating cachexia has the potential to improve the underlying condition of cancer. Currently, there are no effective medical interventions or approved drugs proven to alleviate cachexia.

This previously unreported Phase 2A exploratory study of PH284 was sponsored by Pherin Pharmaceuticals (Pherin), now a wholly owned subsidiary of Vistagen, and conducted at the National Institute of Oncology (INCAN) and National Institute of Nutrition (INNSZ) in Mexico City, Mexico, in 2005. Vistagen gained access to the results of this study in connection with its acquisition of Pherin in February 2023. Hector Burges, MD, former Director, Institute of Nutrition; Marcos Cano Guardiana, MD, Associate Professor, National Institute of Oncology, Mexico City; and Ricardo Plancarte Sanchez, MD, Head of the Pain Clinic, Institute of Oncology, Mexico City, served as the Principal Investigators of the study.

About PH284

PH284 is an investigational neuroactive pherine nasal spray with a novel, rapid-onset potential mechanism of action (MOA) that is fundamentally differentiated from the MOA of all current treatments for the loss of appetite associated with chronic disorders, such as cancer or heart disease. PH284 is thought to act by regulating olfactory to mediobasal-hypothalamus neural circuits involved in appetite control. PH284 has demonstrated an excellent safety profile in all clinical trials completed to date. Vistagen is currently evaluating the potential path forward for PH284, including an assessment of completed studies and studies we believe are necessary to support a U.S. Investigational New Drug application for potential further Phase 2 clinical development of PH284 for the treatment of cachexia.

On January 14, 2025 BostonGene, a leading provider of AI-driven molecular and immune profiling solutions, and Georgetown University’s Lombardi Comprehensive Cancer Center reported a collaboration to explore the effectiveness of immune system profiling to monitor patients with gastrointestinal (GI) cancers receiving combinations of immunotherapy and anti-VEGF inhibitors in the microscopic residual disease (MRD) setting (Press release, BostonGene, JAN 14, 2025, View Source [SID1234649728]).

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Currently, surveillance for GI cancer patients having undergone curative-intent procedures relies on radiologic imaging and non-specific lab tests with poor sensitivity, often detecting relapse only after it has advanced. Biomarkers, such as circulating tumor DNA (ctDNA), have emerged as non-invasive blood tests with the ability to identify the earliest signs of cancer relapse, or MRD. This multi-institution feasibility study aims to identify high-risk patients with GI cancers who have completed standard of care curative-intent therapies but have MRD in the surveillance setting, defined by detectable ctDNA but no evidence of radiographic relapse. These high-risk patients are then treated with combination of atezolizumab (immune checkpoint blockade) and bevacizumab (anti-VEGF therapy) while assessing ctDNA serially for MRD clearance. The study aims to obtain pilot data on ctDNA as a new tool to detect early signals of therapeutic efficacy within months of starting treatment.

Immune system profiling, a non-invasive blood-based tool can detect unique and specific cancer-driven changes in a patient’s immunity often not detected by conventional methods. In this trial, the investigators hope to characterize the baseline and on-treatment changes in the peripheral blood immune profiles of patients with MRD receiving immunotherapy. Evaluating peripheral blood immune profiles as predictive biomarkers is promising in the MRD setting where tumor biopsies are not feasible and systemic immune surveillance is relevant in eradicating micrometastases.

The pioneering study will explore immune system profiling as a new predictive marker of therapeutic response. By tracking immune system profiling and ctDNA trends post-treatment, it aims to generate pilot data on immune system profiling’s feasibility in guiding treatment and improving outcomes in GI cancer patients.

"We need new approaches for improving outcomes for patients with gastrointestinal cancers," said principal investigator John L. Marshall, MD, director of the Ruesch Center for the Cure of GI Cancers at Georgetown Lombardi. "If we can validate immune system profiling as a reliable early marker of MRD, it would be a pivotal step towards enhancing early detection, optimizing treatment strategies, and ultimately preventing relapse." Marshall treats patients at MedStar Georgetown University Hospital.

"If we can demonstrate feasibility of enrolling patients and clearing ctDNA with immunotherapy in this pilot study, it could lead to future validation studies of novel therapeutics in the MRD setting and ctDNA as a surrogate for survival with the hopes of expediting drug discovery in the adjuvant and post-adjuvant settings," said co-principal investigator Reetu Mukherji, MD, assistant professor of medicine at Georgetown and co-writer of the study. "Additionally, our study will incorporate correlative science to study the yet unknown peripheral blood immune profiles of patients with MRD using the BostonGene peripheral blood profiling assay. Most ICI biomarkers studied to date are based on molecular or immune profiling of tumor tissue or molecular testing of ctDNA. However, liquid immunoprofiling is an emerging technology that holds ICI biomarker promise and warrants further study. This study has the potential to identify novel predictive biomarkers and hopefully one day transform current approaches to improve survival rates for patients who have undergone curative treatment."

Marshall and Mukherji both treat patients at MedStar Health, Georgetown’s academic health system partner.

Using advanced molecular and immune profiling capabilities, BostonGene will characterize each patient’s immune environment, providing detailed insights into how immune system profiling trends correlate with therapeutic outcomes. This analysis will facilitate the identification of predictive biomarkers, potentially informing future clinical applications of immune system profiling for MRD monitoring. By utilizing advanced multiomic data analysis and immune system profiling technology, BostonGene will also deliver essential insights into how a patient’s immune changes during and after therapy.

"We are excited to collaborate with Georgetown Lombardi," said Nathan Fowler, MD, Chief Medical Officer at BostonGene. "Our expertise in molecular and immune profiling, combined with immune system analysis, has the potential to revolutionize how MRD is detected and managed in GI cancers. By providing critical insights into immune system dynamics, we empower clinicians to make more informed, timely treatment decisions, thereby improving patient outcomes and reducing relapse rates."