AMP945 Combined with FOLFIRINOX Enhances Treatment Effects in model of Pancreatic Cancer

On May 29, 2023 Amplia Therapeutics Limited (ASX: ATX) ("Amplia" or the "Company") reported new data showing the efficacy of its investigational FAK inhibitor, AMP945, in a preclinical model of pancreatic cancer, when used in combination with FOLFIRINOX treatment (Press release, Amplia Therapeutics, MAY 29, 2023, View Source [SID1234632170]). FOLFIRINOX, a combination of four chemotherapies used in the treatment of pancreatic cancer patients, is currently a widely-used treatment in many major markets around the world including the US.

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New data from preclinical studies conducted in the laboratory of Prof. Paul Timpson at the Garvan Institute of Medical Research in Sydney, demonstrate that mice treated with AMP945 in addition to FOLFIRINOX show improved overall survival compared to those treated with FOLFIRINOX alone. The data, available in the Meeting Abstracts for the forthcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting in Chicago, USA, (here) 1 describe studies in mice bearing pancreatic cancer tumours derived from a human patient. AMP945 was given in the days preceding FOLFIRINOX treatment (given on a 12-day cycle) resulting in a statistically significant increase in survival (up to 35% approx.) compared to FOLFIRINOX-only treated mice.

Dr Chris Burns, Amplia’s CEO and Managing Director commented: "The exciting results from this mouse study further indicate the potential of AMP945 in pancreatic cancer treatment when used in combination with standard-of-care therapies. In light of this data, we have filed a patent to cover the use of FAK inhibitors, and particularly AMP945, in combination with FOLFIRINOX and related treatment regimes."

With this data, and the Company’s previously reported preclinical data demonstrating the benefit of combining AMP945 with gemcitabine and nab-paclitaxel, AMP945 has shown promising activity in models of pancreatic cancer with the two most common first-line chemotherapy regimens for treatment of the disease.

Prof. Nick Pavlakis, a medical oncologist at the Royal North Shore Hospital in Sydney, and an investigator in the current ACCENT trial, commented: "FOLFIRINOX is employed under certain conditions in Australia and more broadly in the USA and Europe, and the data from this study, coupled with the developing safety and tolerability data from Amplia’s current ACCENT trial, provide strong support to undertake a future clinical study of AMP945 with FOLFIRINOX."

Immutep Selects Charles River Laboratories for IMP761’s GLP Toxicology Study

On May 29, 2023 – Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a clinical-stage biotechnology company developing novel LAG-3 immunotherapies for cancer and autoimmune disease, reported that it has entered into an agreement with Charles River under which Charles River will conduct a GLP toxicology study for IMP761, Immutep’s proprietary preclinical candidate for autoimmune diseases (Press release, Immutep, MAY 29, 2023, View Source [SID1234632168]). IMP761 is a first-in-class LAG-3 agonist antibody that aims to address the underlying cause of many autoimmune diseases, namely the overactivation of self-antigen-specific memory T cells expressing LAG-3.

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Preclinical toxicology studies are an essential part of drug development as they help to evaluate the potential safety and toxicity of a drug candidate before it is tested in humans. With its well-established expertise assisting companies in early-stage drug development, Charles River is the partner of choice to help progress our IMP761 program through this key stage of IND-enabling studies.

"Immutep is continuing its pioneering work in the LAG-3 immunotherapy landscape, as we advance IMP761, the world’s first LAG-3 agonist antibody, towards the clinic in the first half of next year. With its novel ability to enhance the signalling of the LAG-3 inhibitory receptor and down-regulate auto-reactive memory T cells at the centre of many autoimmune diseases, we believe IMP761 has the potential to change how immune disorders are treated. We are pleased to be working with an established global company like Charles River for this next important step of our pre-clinical development," stated Immutep’s Chief Scientific Officer, Frédéric Triebel, M.D., Ph.D.

IMP761’s agonistic activation of LAG-3 is relevant for many diseases, including the Th1-driven autoimmune disease setting. In a pre-clinical oligoarticular juvenile idiopathic arthritis model IMP761 decreased secretion of nearly all measured cytokines, and several key cytokines (IL-10, IL-12, IL-1β, IL-4, and IL-6) reached the level of statistical-significance (p < 0.01). These results were published in Pediatric Research in May 2021. The GLP (Good Laboratory Practice) toxicology results and other preclinical studies will be an essential part of the Company’s clinical trial application for IMP761.

About IMP761

IMP761, a first-in-class immunosuppressive LAG-3 agonist antibody, has the potential to address the root cause of many autoimmune diseases by specifically silencing autoimmune memory T cells that accumulate at disease sites. These T cells express LAG-3 as an "exhaustion marker" after being repeatedly stimulated with dominant self-peptides. As published in the Journal of Immunology in January 2020, encouraging pre-clinical results were achieved with IMP761 leading to significant inhibition of inflammatory T cell infiltration. Additional pre-clinical findings published in Pediatric Research in May 2021 show IMP761 led to large decreases in effector T cell cytokine secretion in a juvenile arthritis model.

Abbisko to present the updated clinical phase Ib data of Pimicotinib (ABSK021) at the 2023 ASCO Annual Meeting

On May 28, 2023 Abbisko Therapeutics Co., Ltd. ("Abbisko Therapeutics" hereafter) reported that the updated results of Phase Ib study of its CSF-1R inhibitor Pimicotinib (ABSK021) in treating patients with advanced tenosynovial giant cell tumor ("TGCT"), will be released at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") annual meeting to be held in Chicago, USA from June 2 to June 6, 2023 (Press release, Abbisko Therapeutics, MAY 28, 2023, View Source [SID1234632169]).

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The data demonstrates the excellent antitumor efficacy and the safety profile of Pimicotinib in the treatment of patients with advanced TGCT and will be presented with the title of "EFFICACY AND SAFETY PROFILE OF PIMICOTINIB (ABSK021) IN TENOSYNOVIAL GIANT CELL TUMOR (TGCT): PHASE 1B UPDATE" in a poster presentation with the poster Bd# of "493".

Among the data released by Abbisko, the most remarkable result is the objective response rate (ORR) of the 50 mg QD dose group of Pimicotinib (ABSK021), which reached 77.4% (24/31), including two complete responses (CR) and 22 partial responses (PR). Additionally, 87.5% (21/24) of patients with objective response were observed within the first 25 weeks.

In addition, Pimicotinib (ABSK021) also presented apparent advantages in terms of safety profile.

Currently Pexidartinib developed by Daiichi Sankyo is the only drug approved for the treatment of TGCT (tenosynovial giant cell tumor) in the global market. However, it has been given a "black box warning" by the FDA due to the potential risk of fatal liver damage, and its objective response (ORR) is only 38%. Nevertheless, Daiichi Sankyo achieved sales of approximately US$40 million in the global market with Pexidartinib. CICC predicts that the global market of TGCT could amount to around 1 billion US dollars. Compared with Pexidartinib of Daiichi Sankyo, Abbisko’s Pimicotinib shows better efficacy and safety in the treatment of TGCT. Thus, it is expected to become a best-in-class drug. Assuming that Pimicotinib could be approved for the indication of TGCT in the United States in 2025 with a market penetration rate of 20%, its peak sales is expected to reach 3.14 billion yuan (after risk adjustment) with listing price reference to Pexidartinib of $250,000 per year.

About Pimicotinib

Pimicotinib is a novel, orally available, highly selective, and highly potent small molecule inhibitor of CSF-1R independently discovered and developed by Abbisko Therapeutics. A number of studies have shown that blocking the CSF-1R signaling pathway could effectively modulate and change macrophage functions, and potentially treat many macrophage-dependent human diseases. Pimicotinib has been granted the breakthrough therapy designation from both CDE on July 20, 2022 and FDA on January 30, 2023 for the treatment of tenosynovial giant cell tumor (TGCT) patients who are not amenable to surgery.

Pimicotinib is the first highly selective CSF-1R inhibitor discovered by a Chinese company that entered into a global phase III clinical trial. April 27, 2023, the first patient dosing of "A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study of ABSK021 to Assess the Efficacy and Safety in Patients with Tenosynovial Giant Cell Tumor" was completed in Beijing Jishuitan Hospital. This study is the first global Phase III study of TGCT to be conducted simultaneously in China and the US. Approximately 100 participants are scheduled to be enrolled in approximately 50 centers worldwide, including 30 centers in China.

About TGCT

TGCT is a locally aggressive neoplasm which usually affects synovial joints, mucous sacs, and tendon membranes, resulting in swelling, pain, stiffness, and decreased activity of the affected joints which seriously affect the patient’s quality of life. According to the 2013 World Health Organization classification, TGCTs were classified as localized TGCT and diffuse TGCT. Diffuse TGCT encompasses formerly known nodular tenosynovitis and pigmented villonodular synovitis (PVNS). Overexpression of CSF-1 occurs in most TGCTs. Surgical resection is the standard treatment for TGCT. However, not all patients are suitable for surgical treatment. It is difficult to remove tumors of diffuse TGCT patients by surgery, which may possibly lead to severe joint damage, total synovectomy, joint replacement, or even amputation, and the risk of surgical complications can be high. It has been reported that more than 50% of patients with diffuse TGCT will undergo recurrence after surgical resection. For TGCT patients not amenable to surgery, there is currently no approved drug available in China.

Nascent Biotech Regains Worldwide Rights for Pritumumab

On May 26, 2023 Nascent Biotech, Inc. (OTCQB:NBIO) ("Nascent Biotech", "Nascent", or the "Company"), a clinical-stage biotechnology Company whose business is focused in therapeutic monoclonal antibody space, reported that the Company and China based BioRay Pharmaceutical Co have mutually agreed to terminate the license agreement entered into on March 31, 2021 (Press release, Nascent Biotech, MAY 27, 2023, View Source [SID1234632167]). Nascent gains back worldwide marketing and distribution rights previously licensed to BioRay. Management concludes with gaining back the worldwide rights, the company is in a stronger position going forward.

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FORE Biotherapeutics to Present Promising New Data from Phase 1/2a Trial Evaluating Plixorafenib (FORE8394) in Patients With BRAF-Altered Advanced Solid and Central Nervous System Tumors at ASCO 2023

On May 26, 2023 FORE Biotherapeutics reported new clinical data from the Phase 1/2a clinical trial for plixorafenib (FORE8394), a novel, investigational, small-molecule, next-generation, orally available selective inhibitor of BRAF alterations (Press release, Fore Biotherapeutics, MAY 26, 2023, View Source [SID1234632166]). The results demonstrate promising single-agent activity against BRAF-altered tumors, including primary central nervous system (CNS) tumors, and will be featured in presentations at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held June 2-6, 2023, in Chicago, IL.

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"The updated data from our Phase 1/2a study further reinforces plixorafenib’s differentiated clinical profile," said Stacie Shepherd, MD, PhD, and Chief Medical Officer of FORE. "Plixorafenib has demonstrated both promising antitumor activity with durable responses and favorable tolerability as a single agent in patients with advanced BRAF-altered tumors. Notably, plixorafenib has a striking safety profile as compared to the currently approved BRAF/MEK and investigational pan-raf inhibitors."

"In addition, our results demonstrate that targeted efficacious exposures are achieved at the recommended Phase 2 dose of 900mg a day with cobicistat in patients greater than 10 years of age, and that this dose provides the most favorable efficacy and safety profile," continued Shepherd. "We look forward to advancing plixorafenib in our ongoing, global FORTE Phase 2 clinical basket study in patients with V600E-mutated primary recurrent CNS malignancies and in patients with advanced solid and CNS tumors with non-V600 alterations."

Updated safety and efficacy data from the Phase 1/2a study will be highlighted during an oral presentation, with dose optimization results presented in a poster session. As of the data cutoff date of March 31, 2023, 113 adults and children have received ≥1 dose of plixorafenib under continuous dosing and fasting conditions on 28-day cycles until disease progression and are included in the safety population. Forty-two adults (≥18 years) met the criteria for the V600+ efficacy analysis with an ORR of 28.6%, based upon confirmed responses, and a mDOR of 17.8 months. An additional analysis was conducted in the MAPKi-naïve subset (N=24). Both analyses excluded patients with colorectal cancer, due to known intrinsic resistance pathways. A wide range of doses (900–3600 mg/d) and schedules with and without cobicistat, a novel CYP3A inhibitor, were explored.

Key Findings from the Ongoing Phase 1/2a Study

Efficacy Highlights:

MAPKi-naïve adult V600+ population (N=24, excluding CRC):
Confirmed and durable responses and disease control were seen across multiple tumor types.
Clinical activity observed in this population includes nine confirmed partial responses (PR) for a 37.5% ORR, mDOR was 32.2 months and mPFS was 28.6 months.
In primary CNS tumors, six of ten efficacy-evaluable patients experienced a PR, with durable responses in both high grade and low grade glioma
Patients experienced long term benefit and tolerability:
Three V600+ patients with papillary thyroid cancer are ongoing after more than six years of treatment
Four of the ten with primary CNS tumor have remained on treatment for over a year, including a patient with glioblastoma on treatment for 34 months
MAPKi pre-treated adult V600+ population (N=18, excluding CRC):
Clinical activity observed in this population includes three confirmed PRs for a 16.7% ORR, mDOR was 12.9 months
Responses were observed in two of two patients with V600+ ovarian cancer, both of whom had prior MAPKi treatment and one with multiple regimens and documented progression of disease (PD)
BRAF fusion population (N=14):
Clinical activity continued to be observed in patients with tumors harboring BRAF non-V600 alterations, including a patient with metastatic melanoma with complete response who continues on plixorafenib after five years of treatment with a DOR of 55+ months
Eight patients experienced stable disease (up to 9.2+ months)
Four patients are ongoing with plixorafenib treatment
Safety and Tolerability Highlights

Plixorafenib demonstrated a favorable safety profile with a low frequency and grade of treatment-emergent adverse events (TEAEs) that are frequently seen with MAPKi therapies, including approved BRAF/MEK inhibitor combinations
Only one participant discontinued treatment due to treatment-related adverse event
Symptomatic adverse events (AEs) were predominantly low grade (Grade 1 or 2) and included fatigue, nausea, diarrhea & vomiting

No secondary cutaneous skin malignancies occurred, in contrast to the early single agent data with the approved BRAF inhibitors

"These results demonstrate that plixorafenib has promising activity against V600 & non-V600 BRAF mutant tumors, and in particular, primary CNS tumors," shared Macarena de la Fuente, MD, Associate Professor and Chief of Neuro-oncology at the University of Miami Sylvester Comprehensive Cancer Center. "With no signs of paradoxical activation of the MAPK pathway and plixorafenib’s long term tolerability, this investigational agent is ideally suited for continued investigation in recurrent primary CNS tumors harboring BRAF V600E mutations and unresectable, locally advanced/metastatic solid tumors/primary CNS tumors harboring BRAF fusions."

Dose Optimization Results

Twelve patients (10.6%) are still on treatment as of the data cutoff; overall experience with plixorafenib represents 80 patient-years of exposure, including patients with over seven years of treatment.
The most common reasons for discontinuation are progressive disease (n=65 [57.5%]) and clinical progression (n=18 [15.9%]); one discontinuation due to plixorafenib treatment-related AE occurred with 3600 mg/day + cobicistat.
Measurable clinical responses were observed across all doses, with a wide therapeutic window
ORR was greatest with total daily doses of plixorafenib 900 mg + cobicistat, with three of four V600+ MAPKi-naïve patients having confirmed PR at this dose once daily; no increase in efficacy was observed at higher doses or exposures
This dose provided favorable tolerability, maximizing dose intensity, with pharmacodynamically active exposures. As such plixorafenib 900 mg QD + cobicistat was declared the optimal dose and RP2D for further development
"The plixorafenib Phase 1/2a trial results demonstrate that the 900mg QD with cobicistat is the optimal monotherapy dose and schedule for this novel inhibitor of mutated BRAF," added Eric Sherman, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center. "With responses observed in both MAP-kinase naïve treated and previously treated patients and its depth of durable remissions, plixorafenib has shown both promising tolerability as a single agent and has achieved durable responses and long-term benefit across a variety of patients harboring both V600 and nonV600 alterations. I look forward to the further study of plixorafenib to address patients where high unmet needs remain."

Plixorafenib was granted Orphan Drug Designation by the U.S. Food and Drug Administration in March 2023 for the treatment of primary CNS malignancies. In September 2022, the Agency granted plixorafenib Fast Track Designation for the treatment of patients with cancers harboring BRAF Class 1 (V600) and Class 2 alterations (including fusions) who have exhausted prior therapies.

Details for the ASCO (Free ASCO Whitepaper) 2023 presentations are as follows:

Oral Presentation
Title: Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study
Presenter: Macarena de la Fuente, MD, University of Miami Sylvester Comprehensive Cancer Center
Session Title: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology
Presentation Date and Time: Monday, June 5, 2023, 8:00a.m. – 11:00 a.m. CDT
Abstract Number: 3006

Poster Presentation
Title: Dose optimization of novel BRAF inhibitor FORE8394 based on PK and efficacy results
Presenter: Eric Sherman, MD, Memorial Sloan-Kettering Cancer Center
Session Title: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology
Presentation Date and Time: Saturday, June 3, 2023, from 8:00a.m. – 11:00 a.m. CDT
Abstract Number: 3106

About Plixorafenib (FORE8394)

Plixorafenib is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF mutations while sparing wild-type forms of RAF. Preclinical studies and clinical trials have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants and others. Unlike first-generation RAF inhibitors, plixorafenib does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a "paradox breaker," plixorafenib could therefore treat acquired resistance to current RAF inhibitors and, more generally, yield improved safety and more durable efficacy than first-generation RAF inhibitors.