On June 27, 2024 AbbVie (NYSE: ABBV) reported the acquisition of Celsius Therapeutics, Inc. ("Celsius"), a privately held biotechnology company pioneering new therapies for patients with inflammatory disease (Press release, AbbVie, JUN 27, 2024, View Source [SID1234644583]). Celsius’ lead investigational asset is CEL383, a potential first-in-class anti-TREM1 antibody that has completed a Phase 1 clinical study for the treatment of IBD.

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TREM1 has been identified as a key disease driver gene in IBD, where it is expressed on inflammatory monocytes and neutrophils. In these cell types and others, TREM1 is upstream of multiple known inflammatory pathways and acts as an amplifier of inflammation.

"Given the potential relevance of TREM1 as a key driver of inflammation and pathology in IBD and other conditions, we are eager to advance the development of CEL383 with a goal of helping more patients with IBD achieve remission," said Kori Wallace, M.D., Ph.D., vice president, global head of immunology clinical development, AbbVie.

"AbbVie shares our excitement about the potential of TREM1 inhibition for patients with inflammatory disease," said Tariq Kassum, M.D., chief executive officer, Celsius. "I’d like to thank the Celsius team for their relentless efforts in the discovery of CEL383. We look forward to the further development of this promising program, which we hope will offer a new approach to the treatment of IBD."

Under the terms of the agreement, AbbVie has acquired all outstanding Celsius equity for $250 million in cash, subject to certain customary adjustments.

About CEL383
CEL383 is an investigational antibody directed towards TREM1. In preclinical assays, CEL383 has been shown to inhibit TREM1 signaling, reducing the levels of multiple inflammatory mediators of high clinical relevance in inflammatory conditions. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, single ascending dose study evaluating the safety, tolerability and pharmacokinetics of CEL383 in healthy volunteers has concluded (NCT05901883).

Advisors
AbbVie’s legal advisor was Covington & Burling LLP. Celsius’ financial advisor was Centerview Partners LLC and Goodwin Procter LLP served as legal advisor.

On June 27, 2024 Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, reported plans to expand its ongoing Phase 1 clinical trial to include two combination cohorts evaluating EO-3021 for the treatment of advanced gastric or gastroesophageal junction cancer (Press release, Elevation Oncology, JUN 27, 2024, View Source [SID1234644584]). Following recently signed clinical supply agreements with Eli Lilly and Company (Lilly) and GSK, respectively, Elevation Oncology will evaluate EO-3021 in combination with ramucirumab, a VEGFR2 inhibitor, in second-line patients and in combination with dostarlimab, a PD-1 inhibitor, in the front-line setting. The Company expects to initiate dosing in the combination portion of the Phase 1 trial by year-end 2024.

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"EO-3021 has the potential to change the treatment paradigm for tumors that express Claudin 18.2, including a majority of gastric and gastroesophageal junction adenocarcinomas," said Valerie Malyvanh Jansen, M.D., Ph.D., Chief Medical Officer of Elevation Oncology. "Based on safety data from preclinical and clinical trials, we believe EO-3021 benefits from a differentiated safety profile and will be readily combinable. We also know that combination-based regimens are a mainstay of cancer care, and that the combination of two therapies with distinct mechanisms of action often enables patients to achieve deeper, more durable responses. As such, we are excited to begin evaluating EO-3021 together with ramucirumab, a VEGFR2 inhibitor, and with dostarlimab, a PD-1 inhibitor, in the second- and first-line settings, respectively. In parallel, we continue to advance our Phase 1 trial of EO-3021 monotherapy toward initial safety and efficacy data by mid-third quarter."

Clinical Development Plans for EO-3021 in Combination

EO-3021 is a differentiated, potential best-in-class antibody drug conjugate (ADC) targeting Claudin 18.2. EO-3021 was designed with site-specific conjugation at glutamine (Q295), with the goal of increasing the stability of the linker-payload and minimizing the potential for free monomethyl auristatin E (MMAE) compared to traditional cysteine-based conjugation. In preclinical studies and the Phase 1 clinical trial conducted by Elevation Oncology’s partner, data showed a favorable tolerability profile, with limited MMAE-related toxicities.

Initial development of EO-3021 in combination will explore two regimens for the treatment of gastric or gastroesophageal junction cancer:

EO-3021 in combination with ramucirumab in second-line patients: Ramucirumab is a monoclonal antibody that targets VEGFR2 and is approved for use in combination with paclitaxel for the treatment of second-line gastric or gastroesophageal junction cancer with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. With EO-3021, Elevation Oncology aims to introduce a combination agent that, when paired with ramucirumab, can potentially deliver improved safety and efficacy as compared to the approved combination of ramucirumab and paclitaxel.
EO-3021 in combination with dostarlimab in front-line patients: Dostarlimab is approved alone and in combination with chemotherapy for certain types of dMMR and MSI-H endometrial cancer in the US; it also has an accelerated approval in certain dMMR solid tumors. By combining EO-3021 and an immune checkpoint inhibitor, Elevation Oncology aims to deliver synergistic benefit, potentially offering patients improved outcomes beyond those seen with existing immunotherapy regimens for gastric or gastroesophageal junction cancer in the front-line setting.
Each combination cohort will include a dose escalation and expansion portion, evaluating the combination of EO-3021 and ramucirumab or EO-3021 and dostarlimab. The primary endpoints will include safety and anti-tumor activity. Elevation Oncology plans to initiate dosing in the combination portion of the Phase 1 trial by year-end 2024.

In June 2024, Elevation Oncology entered into clinical supply agreements with Lilly and GSK to supply their respective compounds for these combination cohorts. Elevation Oncology will sponsor and conduct all clinical development of both combinations and will assume all costs associated with the study. All companies will retain commercial rights to their respective compounds.

Elevation Oncology continues to enroll patients in the monotherapy cohort of its ongoing Phase 1 clinical trial (NCT05980416) and remains on track to share initial safety and efficacy data by mid-third quarter 2024, with additional data in the first half of 2025.

About EO-3021

EO-3021 (also known as SYSA1801) is a differentiated, clinical-stage antibody drug conjugate (ADC) with best-in-class potential comprised of an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets Claudin 18.2. EO-3021 is site-specifically conjugated to the monomethyl auristatin E (MMAE) payload via a cleavable linker with a drug-to-antibody ratio (DAR) of 2. Claudin 18.2 is a specific isoform of Claudin 18 that is normally expressed in gastric epithelial cells. During malignant transformation, the tight junctions may become disrupted, exposing Claudin 18.2 and allowing them to be accessible by Claudin 18.2 targeting agents. Elevation Oncology is evaluating EO-3021 in a Phase 1 study (NCT05980416) in patients with advanced, unresectable or metastatic solid tumors likely to express Claudin 18.2 including gastric, gastroesophageal junction, pancreatic or esophageal cancers.

Elevation Oncology has the exclusive rights to develop and commercialize EO-3021 in all global territories outside Greater China.

On June 27, 2024 Oncopeptides, a biotech company focused on difficult-to-treat cancers, reported that the first candidate drug based on the company´s unique platform for Small Polypeptide based innate Killer Engagers (SPiKE) has been selected (Press release, Oncopeptides, JUN 27, 2024, View Source [SID1234646776]).

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The SPiKE platform uses multi-specific constructs, able to bind to multiple targets simultaneously. The first drug candidate, OPSP1, is a bi-specific construct designed to both engage natural killer cells, a type of immune cell, and target cancer cells. The goal of OPSP1 is to prove the ability of the SPiKE platform to activate these natural killer cells. To do this, OPSP1 targets a specific protein called BCMA that is expressed in some cancers including multiple myeloma. By targeting this protein, Oncopeptides will be able to assess how well the SPiKE platform can activate natural killer cells to fight cancer, a crucial step before continued clinical development of the SPiKE platform.

"There is significant potential in NK cell-mediated therapy for difficult-to-treat cancers," says Dr. Karl-Johan Malmberg, professor at Oslo University and Karolinska Institutet. "Despite the substantial advancements in current treatments, the reality is that resistance to these therapies often develops. This underscores the urgent need for new and innovative treatment options to address this unmet medical need."

NK cell-mediated therapy represents a promising avenue in cancer immunotherapy, with ongoing research aimed at overcoming existing challenges and enhancing its therapeutic potential. As a next step for Oncopeptides, a first-in-human clinical trial will be designed to evaluate the safety, efficacy, and overall therapeutic potential of OPSP1.

"The ability to show a promising product pipeline behind its flagship product is important for a growing biotech company. Following the accomplishments we have seen with our first technology platform PDC, where we have an approved product, we are excited to also announce progress with SPiKE, our second technology platform," says Sofia Heigis, CEO of Oncopeptides. "This milestone is a major step forward in our ambition to ensure that Oncopeptides can continue to provide hope for patients suffering from difficult-to-treat cancers, and value to shareholders investing in our science."

A pre-clinical project for the SPiKE platform has received a financial grant from the Eurostars 3-program, co-financed by the European Union research and innovation program "Horizon Europe" and is driven by an international research consortium that includes world-leading expertise from the department of Cancer Immunology at Oslo University Hospital, Pharmatest Services Ltd in Turku, Finland and the Royal Institute of Technology in Stockholm (KTH), from where the technology originally stems. With this grant, Sweden’s Innovation Agency, Vinnova, has provided Oncopeptides resources to develop pre-clinical proof of concept for a novel synthetic small polypeptide for the treatment of multiple myeloma.

On June 27, 2024 Kazia Therapeutics Limited (NASDAQ: KZIA), a biotechnology company specialising in oncology, reported that the presentation of new data from its lead program, paxalisib, at the upcoming 21st International Symposium on Pediatric Neuro-Oncology (ISPNO 2024) June 29 – July 2, 2024, in Philadelphia, PA (Press release, Kazia Therapeutics, JUN 27, 2024, View Source [SID1234644585]). Kazia concurrently announces publication of an article in European Journal of Cancer highlighting the need for evaluating mutation-specific, CNS penetrant, inhibitors to treat pediatric patients with Diffuse Midline Glioma (DMG).

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There will be three paxalisib-related presentations in total at ISPNO, including data from the Phase 2 PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) study evaluating the efficacy and safety of paxalisib in combination with ONC201. As a follow up to data presented last year at the Society for NeuroOncology, 28th Annual Meeting, lead researchers will discuss survival, pharmacokinetics, and tumor biomarkers from 132 diffuse midline glioma (DMG) patients enrolled in the Phase 2 study. Highlights of the abstract include median overall survival of 13.2 months in Cohort 1 (newly diagnosed, enrolled pre-radiation n=33), 15.8 months in Cohort 2 (newly diagnosed, enrolled post-radiation n=69) and 8.8 months in Cohort 3 (relapsed patients, enrolled after progression n=30).

The second presentation is based on novel preclinical data utilizing the addition of a novel HDAC inhibitor to the backbone therapy of paxalisib in DMG models. The third presentation will highlight preclinical data results of the combination therapy of paxalisib and gemcitabine for patients with relapsed/recurrent atypical teratoid/rhabdoid tumors AT/RT by Johns Hopkins University researchers. Based on these findings, the Pacific Pediatric Neuro-Oncology Consortium is planning to include this combination therapy in its next AT/RT international clinical trial.

Summary of Abstracts (View Source;date=%222024-6-30%22)
Clinical Trials; July 2, 2024; 8:15am
TRLS-14: PNOC022 report: a combination therapy trial using an adaptive platform design for patients with diffuse midline glioma at initial diagnosis, post-radiation therapy, or progression
Cassie Kline, Andrea Franson, Anuradha Banerjee, Alyssa T Reddy, et al

Poster Session I; June 30, 2024; 5pm
ATRT-15 Combining the PI3K inhibitor paxalisib with nucleoside analog gemcitabine to improve survival of atypical teratoid/rhabdoid tumors
Tyler Findlay, Kristen Malebranche, Anupa Geethadevi, Charles Eberhart, Jeffrey Rubens, Eric Raabe

DIPG-21 Preclinical assessment of a multimodal treatment approach with Givinostat, Paxalisib, and radiotherapy for Diffuse Midline Glioma (DMG)
Aimée du Chatinier, Michaël H Meel, Piotr Waranecki, Dennis S Metselaar, Esther

The European Journal of Cancer publication titled Paediatric Strategy Forum for Medicinal Product Development of PI3-K, mTOR, AKT and GSK3β Inhibitors in Children and Adolescents with Cancer is the output from a two-day forum in April 2023 at Dana Farber Cancer Institute. Consisting of patient advocates, regulators, researchers and pediatric clinicians, the publication concludes "Evaluation of mutation-specific, CNS-penetrant PI3-K inhibitors in children with DMG should be prioritised and innovative regulatory approaches are needed in view of the rarity of the population." The paper can be accessed at the following website: View Source(24)00801-3/fulltext

On June 27, 2024 Bicara Therapeutics, a clinical-stage biotechnology company developing transformative bifunctional therapies for patients with solid tumors, reported the presentation of updated interim data from its ongoing, open-label Phase 1/1b dose expansion study of ficerafusp alfa (BCA101) at the 3rd Hawaii Global Summit on Thoracic Malignancies, taking place from June 25-29, 2024 (Press release, Bicara Therapeutics, JUN 27, 2024, View Source [SID1234644561]). Ficerafusp alfa is a bifunctional antibody that combines two clinically validated targets: an epidermal growth factor receptor (EGFR) directed monoclonal antibody with a domain that binds to human transforming growth factor beta (TGF-β).

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In the Phase 1/1b clinical trial, ficerafusp alfa in combination with pembrolizumab has demonstrated clinically meaningful anti-tumor activity, with a 64% overall response rate (ORR), 18% complete response (CR) rate and median progression free survival (mPFS) of 9.8 months in frontline human papillomavirus (HPV)-negative, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), along with a favorable tolerability profile.

"Data from our ongoing Phase 1/1b clinical trial reflected a substantial increase over the historical 19% ORR observed in a Phase 3 trial with pembrolizumab monotherapy, the current standard of care in R/M HNSCC," said David Raben, M.D., chief medical officer of Bicara Therapeutics. "Now with at least a year of follow-up on this cohort, it is encouraging to see a number of patients experience durable responses with the CR and mPFS data that have emerged. We believe these data indicate that ficerafusp alfa in combination with pembrolizumab may become a new chemotherapy-free standard of care treatment for HPV-negative first-line R/M HNSCC."

"Ficerafusp alfa has the potential to exert potent anti-tumor activity by simultaneously blocking both cancer cell intrinsic EGFR survival and proliferation, as well as immunosuppressive TGF-β signaling within the tumor microenvironment to lead to durable responses and improved survival," said Claire Mazumdar, Ph.D., MBA, chief executive officer of Bicara Therapeutics. "Given these data, we intend to initiate a pivotal Phase 2/3 trial of ficerafusp alfa in combination with pembrolizumab in frontline R/M HNSCC excluding HPV-positive patients. We also remain excited about the potential of ficerafusp alfa to expand into other populations of HNSCC patients and across other squamous cell tumor types where there is a strong biologic rationale for the dual inhibition of both EGFR and TGF-β."

Presentation Highlights:

Updated interim data (April 2024 cut-off date) from the Phase 1/1b dose expansion cohort of BCA101 in combination with pembrolizumab include 39 evaluable frontline R/M HNSCC patients with a PD-L1 combined positive score (CPS) of ≥1. 28 patients were HPV-negative and 11 patients were HPV-positive, as determined by p16 testing.
o 54% ORR in total evaluable study population (21/39 patients), including 3 unconfirmed responses1.
o 15% complete response (CR) rate (6/39 patients). 26% (10/39) of patients with 100% reductions in target lesions.
o Favorable tolerability profile with the most common treatment-related adverse events (TRAEs) including acneiform rash (76%, with majority being Grade 1/2 in severity), fatigue (43%), and hypophosphatemia (38%).
In HPV-negative population (n=28):
o 64% ORR (18/28 patients) with responses observed across different levels of PD-L1 expression, including 3 unconfirmed responses1.
o 18% complete response (CR) rate (5/28 patients). 29% (8/28) of patients with 100% reductions in target lesions.
o Median progression free survival (mPFS) of 9.8 months.
o With at least 12 months of follow-up, median duration of response (DOR) and median overall survival (OS) have not yet been reached.
Presentation Details:
Title: Altering the HNSCC landscape: Breaking through the Tumor Defense with EGFR-TGF-β blockade
Presentation Date and Time: Thursday, June 27, 2:50 p.m. HST
Presenter: Dr. David Raben

About Head and Neck Squamous Cell Carcinoma
Head and neck squamous cell carcinomas (HNSCCs) develop from the mucosal epithelium in the oral cavity, pharynx and larynx and are the most common malignancies that arise in the head and neck. HNSCC is one of the most common cancers in the United States and globally with a rising incidence anticipated to reach one million new global cases annually by 20302. Ten percent of HNSCC patients are diagnosed with metastatic disease and up to 30% develop a recurrence or metastases over time after initial treatment for advanced HNSCC.

Most cases of HNSCC are believed to arise from mutations that accumulate due to carcinogenic exposure, such as tobacco smoke, or by HPV. Approximately 80% of patients with R/M HNSCC are HPV-negative. HPV-negative HNSCC tumors typically recur locally and are associated with an increased risk of fatal tumor bleeding, excruciating pain and difficulty swallowing. Thus, there remains a significant unmet need for therapies with a durable anti-tumor response in this population.

About Ficerafusp Alfa (BCA101)
Ficerafusp alfa is a bifunctional antibody designed to inhibit the epidermal growth factor receptor (EGFR) and disable transforming growth factor beta (TGF-β) directly at the tumor site. This approach is designed with the intent to allow ficerafusp alfa to inhibit tumor proliferation, while restoring the cytolytic activity of the local immune cells.

Ficerafusp alfa is currently being evaluated in a dose expansion phase of an open-label Phase 1/1b study in combination with pembrolizumab in HPV-negative patients with R/M HNSCC, advanced squamous non-small cell lung cancer (SqNSCLC), or squamous cancer of the anal canal (SCAC) and as a monotherapy for cutaneous squamous cell carcinoma (cSCC).