On September 22, 2021 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported dosing of the first patient in HERKULES-3, a Phase 1b/2 master protocol clinical trial evaluating ERAS-007 in combination with various agents in patients with gastrointestinal (GI) cancer, with initial focus on patients with advanced colorectal cancer (CRC) (Press release, Erasca, SEP 22, 2021, View Source [SID1234639382]).

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"A major barrier to durable responses with current treatment regimens for GI cancers is the emergence of resistance mechanisms, which are often associated with reactivation of the MAPK pathway," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "We have developed HERKULES-3, our GI master protocol, to evaluate ERAS-007 in rational combinations to assess the possibility of reducing susceptibility to resistance and increasing durability of treatment. Initially focused on CRC subtypes with BRAF V600E, KRAS, or NRAS mutations, HERKULES-3 has the potential to address over half of patients with CRC and could be further expanded into other GI cancers with additional combinations."

Approximately 10% of all patients with CRC have tumors that harbor a BRAF V600E mutation, with the majority developing rapid progression within four months due to resistance following initiation of the current standard of care treatment, the combination of encorafenib and cetuximab, which was approved in April 2020 for previously treated patients with BRAF V600E-mutant metastatic CRC (mCRC). Another 45-50% of CRC patients have tumors that harbor KRAS or NRAS mutations, for which there is currently no approved targeted therapeutic option.

Dr. Lim continued, "Preclinical work by Ryan Corcoran, M.D., Ph.D., at Massachusetts General Hospital Cancer Center indicates that adding an ERK inhibitor has the potential to deepen and prolong responses, as well as delay resistance, forming the scientific basis for exploring ERAS-007 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant mCRC. Additionally, Scott Kopetz, M.D., Ph.D., of MD Anderson Cancer Center presented compelling evidence at the AACR (Free AACR Whitepaper) conference this year that CDK4/6 inhibition combined with MEK inhibition had the best in vivo efficacy across KRAS mutations. We evolved this one step further based on our preclinical data demonstrating superior efficacy with an ERK inhibitor in place of a MEK inhibitor, forming the scientific rationale for evaluating the highly promising and novel combination of ERAS-007 with the CDK4/6 inhibitor palbociclib in patients with mCRC driven by KRAS and NRAS mutations. We believe both combinations offer robust therapeutic potential in patients with high unmet need."

HERKULES-3 will examine the safety, tolerability, and preliminary efficacy of ERAS-007 in combination with other cancer therapies in study participants with GI malignancies. The dose escalation portions of the first two sub-studies will assess ERAS-007 in combination with the current standard of care, encorafenib (Braftovi) and cetuximab (Erbitux), in patients with BRAF V600E-mutant mCRC, and ERAS-007 in combination with the CDK4/6 inhibitor palbociclib (Ibrance) in patients with KRAS- or NRAS-mutant mCRC. The Phase 2 dose expansion portion will further evaluate the safety and efficacy of each combination at the recommended dose identified in patients with previously treated mCRC. Future sub-studies of HERKULES-3 will explore ERAS-007 in combination with other agents in patients with different mutational subtypes of GI cancers.

About ERAS-007
ERAS-007 is a potential best-in-class ERK1/2 inhibitor being investigated alone or in combination with different inhibitors targeting upstream nodes of the MAPK pathway as part of Erasca’s MAPKlamp strategy. The extracellular signal-regulated kinases (ERK), ERK1 and ERK2, belong to a family of serine-threonine kinases that regulate cellular signaling and comprise the terminal node of the RAS/MAPK pathway. The broad therapeutic potential of ERAS-007 is being investigated initially across four HERKULES clinical trials that span multiple tumor types and include both monotherapy and combinations with approved and investigational agents, such as RTK, SHP2, RAS, RAF, and/or cell cycle inhibitors. HERKULES-1, a Phase 1b/2 clinical trial for ERAS-007 as a single agent and in combination with the SHP2 inhibitor ERAS-601 (together, Erasca’s first MAPKlamp) in advanced solid tumors, HERKULES-2, a Phase 1b/2 master protocol clinical trial for ERAS-007 in combination with various agents in patients with non-small cell lung cancer (NSCLC), and HERKULES-3, a Phase 1b/2 master protocol clinical trial for ERAS-007 in combination with various agents in patients with GI cancers, are currently enrolling patients. HERKULES-4, a Phase 1b/2 master protocol clinical trial for ERAS-007 in combination with various agents in patients with hematologic malignancies, is anticipated to begin in the first quarter of 2022.

On September 22, 2021 Endeavor BioMedicines, a clinical-stage precision medicine company targeting the core drivers of multiple terminal diseases including oncology and fibrosis, reported that the company has dosed its first patient in a Phase 2 trial of taladegib (ENV-101) to treat idiopathic pulmonary fibrosis (IPF) (Press release, Endeavor BioMedicines, SEP 22, 2021, View Source [SID1234606753]). Taladegib is a small-molecule inhibitor that uses precision therapy approaches to disrupt the Hedgehog signaling pathway, which has been implicated in chronic wound healing that plays a critical role in IPF disease pathology.

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Endeavor also announced today that Srikanth Pendyala, M.D., has been appointed as the company’s first Chief Medical Officer. Dr. Pendyala is a physician-scientist with over 20 years of experience in clinical research, translational sciences and academic medicine, and will lead the company’s clinical development and global drug development strategy.

"There are currently no approved therapies that stop the progression of fibrosis or treat the underlying causes of the disease," said John Hood, Ph.D., Co-Founder, CEO and Chairman of Endeavor BioMedicines. "This Phase 2 study now underway will help us understand how taladegib may help to stop or even reverse one of the most devastating pulmonary diseases by targeting the Hedgehog pathway. This precision therapy approach targets the underpinnings of the disease rather than solely the symptoms patients face."

Dr. Hood added, "We are also pleased to welcome Srikanth Pendyala as our chief medical officer. With his extensive background in drug development, paired with his expertise in academic medicine, we are confident that his experience will be invaluable as we advance Endeavor’s pipeline of precision medicine treatments."

Dr. Pendyala joins Endeavor from BridgeBio, where he served as vice president of clinical development, and was responsible for spearheading clinical trials at all stages of development across multiple therapeutic areas, as well as leading the strategic development of the company’s rare disease portfolio. Prior to BridgeBio, he focused on immunology-inflammation at Genentech/Roche, Merck and Theravance and led the development of a number of molecules from early/late-stage clinical trials to regulatory approval. Dr. Pendyala was also involved in multiple NDA filings with approvals and in partnered drug development programs. Dr. Pendyala has held numerous positions in academic medicine, most recently serving as assistant professor in pharmacology at the University of Illinois at Chicago. Additionally, he has published over 30 peer reviewed publications. Dr. Pendyala earned his medical degree from The Russian State Medical University. Dr. Pendyala completed his clinical fellowship at Johns Hopkins University, and post graduate coursework at Tufts University School of Medicine.

"I’m excited to be joining Endeavor at this time of growth and evolution for the company. Endeavor’s forward-thinking approach to precision therapies used to treat pulmonary disease and cancer has already exhibited immense potential since the company launched," said Srikanth Pendyala, M.D., Chief Medical Officer, Endeavor BioMedicines. "I look forward to working with the team and helping propel forward Endeavor’s pipeline of medicines for patients with significant unmet medical needs."

The Phase 2 clinical trial is a randomized, placebo controlled, multi-center study, designed to assess the efficacy and safety of taladegib as a monotherapy in subjects with mild to moderate IPF. The Phase 2 trial of taladegib is being conducted in the Asia-Pacific region, and is designed to enroll approximately 60 participants, with 30 patients per arm. It is a single dose level study with adaptive design, starting at 200mg. Patients will be randomized to receive placebo or taladegib as a daily oral dose for 12 consecutive weeks of treatment. Following treatment, patients will be observed for an additional 6 weeks. The primary endpoints of the trial include change from baseline in frequency and severity of adverse events, as well as change in key vital sign measurements. Secondary measures include Forced Vital Capacity (FVC), FEV1 and other measures of lung function. Pending the results of the current monotherapy Phase 2 study, Endeavor anticipates initiating a second Phase 2 study of taladegib in combination with standard of care by 2022. Additional information on the trial can be found at www.clinicaltrials.gov using the identifier NCT04968574.

About Taladegib (ENV-101) for the Treatment of IPF

Taladegib is an orally available small-molecule inhibitor of the Hedgehog signaling pathway, a key modulator for disease progression in IPF. Myofibroblasts – the repair cells activated by the Hedgehog pathway – become dysregulated, relentlessly remodeling lung tissue, forming fibrotic scars and contracting the lung. This tissue remodeling disorder impairs lung function in IPF patients by making the lung inelastic, smaller and with compromised tissue structure. Selectively inhibiting this pathway in lung tissue causes the myofibroblasts responsible for the disorder to become inactivated and undergo apoptosis, thereby eliminating the key cellular driver of IPF and potentially stopping or reversing the disease. Studied in 192 subjects to date, taladegib has been shown to safely and effectively inhibit the Hedgehog pathway, based on prior clinical evidence. Endeavor is also investigating precision therapy approaches for taladegib in multiple types of cancer where the hedgehog pathway is implicated in cancer cell signaling and disease progression.

On September 22, 2021 AB Science SA (Euronext – FR0010557264 – AB) reported that its clinical trial with AB8939 in adult patients with relapsed/refractory acute myeloid leukemia (AML) has been approved by Health Canada (Press release, AB Science, SEP 22, 2021, View Source [SID1234591053]). The ‘No Objection Letter’ (NOL) received from Health Canada provides an acknowledgement of AB8939’s drug candidacy and the authority to proceed with a Phase I/II study (AB18001) in patients with refractory and relapsed AML and refractory myelodysplastic syndrome (MDS) .

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AB8939 is a new generation synthetic microtubule destabilizer with the ability to overcome multidrug resistance and the potential for broad applicability as a potent anticancer drug. Microtubules play a crucial role in multiple cellular functions which makes them an important target for cancer therapy. Indeed, chemotherapies that target microtubules, such as taxanes and vinca alkaloids, are among the most successful anticancer therapeutics available. Unfortunately, the development of drug resistance (for example, via Pgp efflux pumps that transport the drugs out of the cancer cells) often restrict their clinical efficacy.

Key characteristics of AB8939 are that it circumvents difficulties associated with Pgp-dependent multidrug resistance and is not deactivated by an enzyme named myeloperoxidase, which is an advantage over existing chemotherapies. Another advantage and distinguishing characteristic of AB8939 is that it is a synthetic drug.

The therapeutic potential of AB8939 has been demonstrated through a series of preclinical experiments [1–3]. In vivo data from a highly resistant Ara-C patient derived xenograft (PDX) mouse model showed that AB8939, administered alone or in combination with Ara-C, increased survival relative to single agent Ara-C, with an accompanying significant reduction of blasts in blood and decrease in tumor growth [1]. Ara-C is considered the clinically most relevant cytotoxic drug for AML treatment. In another example, cancerous tumors from patients suffering from resistant acute megakaryoblastic leukemia (an AML subtype) were transplanted into mice. Data showed a complete response in mice treated with AB8939, as compared with rapid disease progression in control animals [2]. No apparent toxicity was observed during the time course of the treatment.

Based on these results, AB8939 was granted orphan drug designation for AML from the U.S. Food and Drug Administration (FDA) [4].

The first indication AB8939 is being developed for is acute myeloid leukemia (AML), a rapid proliferating hematological cancer that originates in the bone marrow and quickly moves into the blood. Cytarabine (Ara-C) is the current standard chemotherapy for AML treatment, however, drug resistance is a major limitation to successful therapy. AB8939 therefore has strong potential as a second or third-line treatment in AML patients who are unfit to receive intensive chemotherapy.

The advantageous mechanistic characteristics of AB8939 mean that it is potentially applicable to a large number of other oncology indications currently treated by microtubule-inhibitor drugs (such as taxanes and vinca alkaloids) and in particular hematological cancers. The envisioned strategy is to position AB8939 in patients with abnormal cytogenetics that make these patients unresponsive to first-line therapy.

Professor Olivier Hermine, President of the Scientific Committee of AB Science and member of the Académie des Sciences in France said, "We believe that AB8939 could represent a major breakthrough in the development of effective microtubule-targeting agents, an extensively used class of cancer treatment. Our preclinical data show that AB8939 exhibits broad anticancer activity, with a notable advantage of it being able to overcome common mechanisms of drug resistance. AB8939 therefore has strong potential to be developed in numerous oncology indications, with our initial targets being hematological cancers. We are excited about the start of this first AB8939 study in acute myeloid leukemia (AML), which represents a significant milestone in the clinical program of AB Science. AB8939 seems particularly well-suited for the treatment of relapsed or refractory AML, for which there are very limited therapeutic options."

AB8939 was entirely discovered by the laboratories of AB Science, which retains full ownership of intellectual rights, and is an example of AB Science’s focus on innovative drug development focused on improving patients’ lives.

About Study AB18001
Study AB18001, titled ‘A Phase 1/2 Study to Assess the Safety, Pharmacokinetics, and Efficacy of Daily Intravenous of AB8939 in patients with Relapsed/Refractory Acute Myeloid Leukemia’, has a multi-stage design. The first part is a dose escalation study that aims to determine the safety and tolerability of intravenous AB8939 in patients with refractory or relapsed AML or patients with refractory MDS, and to determine the recommended dose for the second-stage dose expansion study. This dose expansion study aims to determine the schedule for a Phase 2 trial in patients with relapsed/refractory AML and to also provide an early efficacy (response rate) assessment of AB8939.

About acute myeloid leukemia (AML)
Acute myeloid leukemia (AML) is a serious, life-threating condition and the most common cause of leukemia-related mortality, with a majority of patients facing a highly unsatisfactory prognosis. As such, AML represents an unmet medical need, with limited therapeutic options for patients who are refractory or too frail to benefit from potentially curative but highly toxic treatment, or for those patients that have relapsed following a first complete response. The prevalence of AML in western countries is around 1 per 5,000 persons [5], corresponding to around 100,000 cases in Europe and 60,000 in the USA. Among AML patients, it is estimated that approximately 50% of the patients will not have stem cell transplantation and will relapse. Therefore, the estimated targeted population of AB8938 in AML is around 80,000 people in Europe and the US.

References
[1] Goubard A, Humbert M, Mansfield C, Hermine O, Dubreuil P, et al. In Vivo Assessment of the Next Generation Microtubule-Destabilizing Agent AB8939 in Patient-derived Xenograft Models of Acute Myeloid Leukemia. Blood (2019) 134 (Supplement_1): 5142. doi.org/10.1182/blood-2019-127143

[2] Goubard A, Humbert M, Mansfield C, Hermine O, Dubreuil P, et al. AB8939, a Microtubule-Destabilizing
Agent with Potential to Overcome Multidrug Resistance, is Active Across the Range (M0–M7) of Acute Myeloid Leukemia Subtypes. Blood (2019) 134 (Supplement_1): 5154. doi.org/10.1182/blood-2019-127021

[3] Humbert M, Goubard A, Mansfield C, Hermine O, Dubreuil P, et al. Anticancer Activity of a Highly Potent Small Molecule Tubulin Polymerization Inhibitor, AB8939. Blood (2019) 134 (Supplement_1): 2075. doi.org/10.1182/blood-2019-122540

[4] Press release dated November 7, 2019

[5] National Cancer Institute (View Source)

On September 22, 2021 Immunocore Holdings Plc (Nasdaq: IMCR), a late-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infection and autoimmune disease, reported that data from a phase 3 randomized trial comparing tebentafusp (IMCgp100) with investigator’s choice in first-line metastatic uveal melanoma (mUM) has been published in The New England Journal of Medicine (NEJM) (Press release, Immunocore, SEP 22, 2021, View Source [SID1234590905]).

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The paper concluded that tebentafusp is the first systemic treatment to show a survival benefit in mUM and should become a new treatment option for this poor prognosis disease.

"The publication of these phase 3 data in a leading peer-reviewed scientific publication like NEJM demonstrates the significance of Immunocore’s work in the field of TCR therapy," said Bahija Jallal, Chief Executive Officer of Immunocore. "This further validates the potential of tebentafusp to provide a much needed treatment option for patients with metastatic uveal melanoma, making a meaningful difference to patients’ lives. In addition, we believe these data show the broader potential of Immunocore’s TCR technology for the treatment of other solid tumors."

Results from the randomized, open-label, phase 3 trial of tebentafusp vs. investigator’s choice in previously untreated HLA-A*02:01-positive patients with mUM demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) as a first-line treatment in mUM. The OS Hazard Ratio (HR) in the intent-to-treat population favored tebentafusp, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 12% ipilimumab; 6% dacarbazine). Treatment-related adverse events were manageable and consistent with the proposed mechanism.

Tebentafusp has been granted Breakthrough Therapy Designation, Fast Track designation and orphan drug designation by the U.S. Food and Drug Administration (FDA) and Promising Innovative Medicine (PIM) designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma. Immunocore’s biologics license application for approval of tebentafusp for the treatment of HLA-A*02:01-positive adult patients with metastatic uveal melanoma was recently accepted by the FDA. In addition, the European Medicine Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) accepted Immunocore’s Marketing Authorisation Application (MAA).

On September 22, 2021 Cannabics Pharmaceuticals Inc. (OTCQB: CNBX), a global leader in the development of cancer related cannabinoid-based medicine, reported that the Company will present at the 4th Annual International Cannabinoid-Derived Pharmaceuticals Summit in Boston (Press release, Cannabics Pharmaceuticals, SEP 22, 2021, View Source [SID1234590540]). Our team will be participating along with others from across the cannabinoid research and drug development space, including industry and academic experts from major pharmaceutical companies, biotech firms, and world leading universities.

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Gabriel Yariv, company President and COO said: "The Cannabinoid Derived Pharmaceuticals Summit in Boston is the world largest conference exclusively devoted to CDP for medical conditions using FDA/EMA approval regularly pathways and with focus on clinical trials across the world and we are honored and proud to have been invited to participate at this 2021 4th Edition in Boston."

Eyal Barad, Cannabics Pharmaceuticals’ Co-founder and CEO commented: "The remarkable success of cannabinoids being approved today is just the beginning and we are excited to participate at the Cannabinoid Derived Pharmaceuticals Summit."

Read more:

Recent expansion of Cannabics Pharmaceuticals’ Board of Advisors to include: Prof. Caroline Robert (MD, Ph.D.), a Melanoma expert, and, Dr. Sigal Tavor (MD), a Hematology expert, along with Prof. Amos Toren (MD), Prof. Zamir Halpern (MD), Prof. Noam Shomron (Ph.D.), Dr. Erez Scapa (MD), Dr. Dana Ben-Ami Shor (MD), Dr. Sigalit Arieli-Portnoy (Ph.D.) and Dr. Tal Mofkadi (Ph.D.).

Recent expansion of Cannabics Pharmaceuticals’ Board of Directors to include: Dr. Inbar Maymon-Pomeranchik (Ph.D.), and Dr. Gil Feiler (Ph.D.) as Independent Directors.