On June 8, 2022 CNS Pharmaceuticals, Inc. (NASDAQ: CNSP) ("CNS" or the "Company"), a biopharmaceutical company specializing in the development of novel treatments for primary and metastatic cancers in the brain and central nervous system, reported that Sigmund Hsu, MD, member of the Company’s Scientific Advisory Board, presented an overview of its ongoing clinical trial evaluating Berubicin for the treatment of recurrent glioblastoma multiforme (GBM), at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting (Press release, CNS Pharmaceuticals, JUN 8, 2022, View Source [SID1234615789]).

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The abstract titled "Design and initiation of an adaptive, randomized, controlled study of berubicin, a topoisomerase 2 poison that crosses the blood brain barrier (BBB), for the treatment of recurrent glioblastoma multiforme (GBM) after first-line therapy," was presented in the Central Nervous System Tumors poster session by Dr. Hsu.

Berubicin is a novel anthracycline and the first that appears to cross the blood-brain barrier (BBB) with central nervous system (CNS) uptake. The induction of apoptosis and DNA damage by Berubicin was significantly higher than that of doxorubicin (Dox) in all tested cancer cells, demonstrating Berubicin’s greater potential potency and consistently higher cytotoxicity in GBM cell lines than Dox. In models of intracranial orthotopic gliomas, Berubicin prolongs survival when compared to temozolomide (TMZ), currently the standard of care in GBM for first line therapy in combination with radiation. Further evaluation of the orthotopic glioma models demonstrated that Berubicin had greater infiltration into intracranial glioblastoma cells compared to normal tissue, supporting the potential for improved efficacy. TMZ has been shown to be less effective in approximately 50% of patients due to changes (methylation) to a DNA repair enzyme, MGMT, that when unmethylated proves to be a prognostic indicator of a poorer prognosis. These differences have been proven to not be a factor in the activity of Berubicin.

Based on this data, a Phase 1 dose escalation study was conducted by a prior developer in patients with recurrent primary brain tumors. Berubicin was well tolerated, with myelosuppression (neutropenia and thrombocytopenia) as dose-limiting toxicities. Of 25 patients evaluable for efficacy, there was 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease over 6 weeks for a clinical benefit rate of 44%.

"We are fully dedicated to advancing the development of Berubicin toward potentially providing an innovative and much-needed option for treatment in GBM, an area of significant unmet medical need. With this goal in mind, we consider that our global study, which has been thoughtfully designed based on prior data as well as input from key opinion leaders and feedback from the FDA, could potentially be pivotal. We also believe that valuable interactions with our investigators on this study, as well as our heartfelt consideration of the needs of patients has positioned us for a successful outcome," added Dr. Sandra L. Silberman, M.D., Ph.D., Chief Medical Officer of CNS Pharmaceuticals. "Moreover, the positive feedback we’ve received from the regulatory authorities across Europe for this trial bolsters confidence in our state-of-the-art trial design and will significantly expand our ability to reach these patients."

The Company’s ongoing global study is an adaptive, multicenter, open-label, randomized, controlled study in adult patients with recurrent glioblastoma multiforme (WHO Grade IV) after failure of standard first-line therapy evaluating efficacy and safety of Berubicin. The primary endpoint of this study, being conducted in the United States and Europe, is overall survival (OS), with a projected 243 patients enrolled in a 2:1 randomization design (Berubicin:Lomustine). This study has pharmacokinetic (PK) evaluations of all patients enrolled, with 15 patients undergoing complete PK assessments throughout the dosing period. Patients will be stratified on the basis of MGMT methylation, documentation of IDH mutational status that now defines Grade IV GBM. No prior administration of bevacizumab will be allowed. An interim analysis will evaluate the comparative effectiveness of these treatments, an adaptive design intended to demonstrate that Berubicin’s efficacy is at least equal to that of Lomustine such that continuation of the study is in patients’ best interests (futility analysis). The overall survival endpoint and sample size have been calculated to be able to show a statistical difference between the two therapies as second line treatment for GBM. Additional studies in malignant diseases of the CNS (e.g., pediatric brain tumors, primary CNS lymphoma, metastatic tumors) are also being explored based on the potential for anthracycline activity in these indications.

For more information about this Berubicin trial, visit clinicaltrials.gov and reference identifier NCT04762069.

About Berubicin
Berubicin is an anthracycline, a class of anticancer agents that are among the most powerful chemotherapy drugs and effective against more types of cancer than any other class of chemotherapeutic agents. Anthracyclines are designed to utilize natural processes to induce deoxyribonucleic acid (DNA) damage in targeted cancer cells by interfering with the action of topoisomerase II, a critical enzyme enabling cell proliferation. Berubicin treatment of brain cancer patients appeared to demonstrate positive responses that include one durable complete response in a Phase 1 human clinical trial conducted by Reata Pharmaceuticals, Inc. Berubicin, was developed by Dr. Waldemar Priebe, Professor of Medicinal Chemistry at The University of Texas MD Anderson Cancer Center.

On June 8, 2022 Alpha Tau Medical Ltd. (Nasdaq: DRTS and DRTSW), ("Alpha Tau" or the "Company"), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported that the U.S. Food and Drug Administration (FDA) has conditionally approved the Company’s Investigational Device Exemption (IDE) application to initiate its multi-center pivotal study for the treatment of recurrent cutaneous Squamous Cell Carcinoma (SCC) using the Alpha DaRT (Press release, Alpha Tau Medical, JUN 8, 2022, View Source [SID1234615788]).

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The clinical study, entitled "A Prospective Multicenter, Pivotal, Single Arm, Open Label Clinical Study to Assess the Efficacy and Safety of Intratumoral Alpha DaRT for the Treatment of Patients with Recurrent Cutaneous Squamous Cell Carcinoma" has been approved to enroll up to 86 U.S. patients at up to 20 institutions in the U.S., in addition to any sites that may be added outside the U.S., and will focus on patients with recurrent cutaneous SCC who have failed at least first line standard of care therapy and are not indicated for another curative standard of care therapy.

"We are very excited about the upcoming commencement of our U.S. pivotal study, undoubtedly our most significant clinical trial to date," commented Alpha Tau CEO Uzi Sofer. "Our receipt of FDA conditional approval of our IDE submission is a critical milestone on our journey to bringing this exciting new therapy to patients in the U.S. and around the world"

Dr. Robert B. Den, Alpha Tau Chief Medical Officer, added, "We are thrilled to have received FDA conditional approval of our IDE, after tremendous focus on the U.S. over the past year, including successful completion of our pilot study and the upcoming initiation of this pivotal study under the FDA’s Breakthrough Device Designation Program. We have seen tremendous engagement and excitement from dozens of leading institutions in the U.S. and around the world, keen to be part of this study, and look forward to working with them on this clinical study."

Yaniv Sagie, Alpha Tau VP Quality and Regulatory Affairs, noted, "This amazing milestone represents the culmination of Alpha Tau’s rigorous teamwork and unwavering commitment to quality and regulatory excellence."

On June 8, 2022 Promontory Therapeutics Inc., a clinical stage pharmaceutical company focused on oncology therapeutics, reported the peer-reviewed publication of its first-in-human Phase 1 study of lead therapeutic candidate, PT-112 in the July 2022 issue of eClinicalMedicine, part of The Lancet’s Discovery Science (Press release, Promontory Therapeutics, JUN 8, 2022, View Source [SID1234615787]). The study, entitled "Phase I Study of PT-112, a novel Pyrophosphate-Platinum Immunogenic Cell Death Inducer, in Advanced Solid Tumours," showed that PT-112 was safe and well-tolerated in heavily pre-treated patients with advanced cancers, and demonstrated prolonged responses against thymoma and lung cancers, along with radiographic and serum marker improvement in prostate cancer.

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PT-112 has been validated as an immunogenic cell death inducer in pre-clinical models, and is under active Phase 2 clinical development. In the first-in-human dose escalation study PT-112 was given as monotherapy to eligible patients with progressing, advanced solid tumors via intravenous infusion on days 1, 8, 15 of a 28-day cycle in a 3+3 dose-escalation trial. The primary endpoint was to assess safety and pharmacokinetics, and to identify a recommended Phase 2 dose. The secondary objective was exploratory assessment of anti-tumor activity.

Study findings from 66 heavily pre-treated patients treated across 11 dose levels of PT-112 (12-420 mg/m2) include:

The recommended phase 2 dose was determined to be 360 mg/m2
The most common treatment-related adverse events included fatigue (35%), nausea (24%), and peripheral neuropathy (21%)
Treatment-related Grade 3 adverse events were experienced by 27% of patients, with no grade 4-5 events observed.
Durable, confirmed RECIST partial responses were induced in non-small cell lung cancer, small cell lung cancer, and thymoma, some of which persisted for prolonged periods even after treatment discontinuation. Two additional unconfirmed RECIST responses were observed.
Radiographic and serum marker reductions were observed among ten patients with metastatic castration resistant prostate cancer, four of whom survived two years or longer
"We are pleased to publish the results of our first Phase 1 study of PT-112 in The Lancet’s eClinicalMedicine," said Matthew Price, Executive VP & COO of Promontory Therapeutics. "The evidence supports our belief that PT-112’s immunogenic cell death induction makes it a promising future treatment option in several possible cancer indications, and that its foundational safety allows us to consider numerous ways to deploy it. The experience we gained in this study underlies the direction taken by the company in our current Phase 2 studies of PT-112."

The study is registered under NCT02266745 and the full dose-escalation results are available in eClinicalMedicine and online here.

About PT-112
PT-112 is the first small-molecule conjugate of pyrophosphate in oncology, and possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD) through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) Annual Congress. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. A Phase 1 study in patients with relapsed or refractory multiple myeloma was presented at ASH (Free ASH Whitepaper) 2020. Monotherapy Phase 2 development is ongoing in mCRPC, and in a Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal collaboration with the National Cancer Institute (NCI).

On June 8, 2022 Integral Molecular and Optimeos Life Sciences reported a partnership to develop next-generation mRNA and DNA therapeutics that will use antibody-based molecular targeting to direct vaccines and gene therapies to relevant tissues in a patient’s body (Press release, Integral Molecular, JUN 8, 2022, View Source [SID1234615786]). This partnership combines Integral Molecular’s experience in antibody discovery and mRNA immunization with Optimeos’ technology for nanoparticle-based drug delivery systems.

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DNA and mRNA therapeutics harness a patient’s own molecular machinery to encode proteins. Integral Molecular and Optimeos plan to encapsulate these therapeutic molecules within nanoparticle spheres that are decorated with antibodies on the outer surface. The antibodies can then target the particles to specific tissues. Currently, gene therapies and mRNA vaccines are delivered into the body via infusion or injection, but only a fraction of the molecules arrive at their intended site. The proposed molecular targeting strategy has the potential to transform the delivery of vaccines and therapeutics by dramatically reducing dosages, decreasing toxicity, and enabling scalable administration.

Integral Molecular will apply its industry-leading antibody discovery expertise against complex cell-surface proteins to provide targeting moieties for the therapies. Its specialized MPS Antibody Discovery platform is tailored to work with challenging membrane protein targets and routinely uses mRNA-based immunization strategies. "Precision targeting of an isolated cell type with gene therapy holds great promise for genetic diseases and may provide brand-new directions in cancer immunotherapy including in vivo CAR-T cell therapeutics," said Joseph Rucker, Co-founder and VP of R&D at Integral Molecular.

Optimeos’ technology allows the robust and scalable incorporation of mRNA and DNA therapeutics and other biologics into customizable nanoparticles. "We are excited to work with Integral Molecular towards the next generation of gene-therapy that no longer relies on viral-based delivery systems," said Robert Prud’homme, Co-founder and Chief Technical Officer of Optimeos.

Integral Molecular and Optimeos will be attending the BIO International Convention in San Diego later this month.

On June 8, 2022 Medison Pharma ("Medison"), a global pharma company focused on providing access to highly innovative therapies to patients in international markets, reported the approval of KIMMTRAK (tebentafusp) by Health Canada and Therapeutics Goods Administration (TGA) for the treatment of unresectable or metastatic uveal melanoma (mUM), a rare and aggressive form of melanoma that affects the eye (Press release, Medison Pharma, JUN 8, 2022, View Source [SID1234615785]).

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KIMMTRAK was developed by Immunocore Holdings plc ("Immunocore"), a commercial-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.

The approval will enable Medison to commercialize KIMMTRAK (tebentafusp) in Canada and Australia, as part of a multi-territorial agreement between Medison and Immunocore, covering a total of 24 markets in Canada, Israel, 20 markets across Central Eastern Europe, as well as Australia and New Zealand.

"We are pleased to provide patients in Canada and Australia with access to this breakthrough therapy, as part of our multi-territorial partnership with Immunocore", said Meir Jakobsohn, Founder and CEO of Medison. "We look forward to continuing the momentum and reaching more patients around the globe".

"The approvals of KIMMTRAK by Health Canada and TGA are a milestone for uveal melanoma patients in Canada and Australia," said Victor Papamoniodis VP International Markets at Medison. "We are proud to make this breakthrough treatment available to Canadian and Australian patients and we are working diligently to secure additional approvals in the rest of our countries."

"The approval of KIMMTRAK by Health Canada and TGA represent another positive step forward for uveal melanoma patients. As a team, we are extremely proud that this groundbreaking treatment can now be made available to patients in over 30 countries around the world," said Mark Moyer, Head of Regulatory Affairs at Immunocore. "To have achieved this in such a short period of time demonstrates the impact that international initiatives such as Project Orbis, which enabled these rapid approvals, can have in providing faster patient access to innovative cancer treatments in countries outside of the US and EU."

"For years, metastatic uveal melanoma patients have had to make do with therapeutic options not ideally suited for their condition," said. Dr. Marcus Butler, Medical Oncologist, Tumor Immunotherapy Program, Melanoma/Skin Medical Oncology Site Lead at Princess Margaret Cancer Centre in Toronto, Canada. "Today’s approval of tebentafusp represents a paradigm shift in the treatment of unresectable or metastatic uveal melanoma and offers patients with new hope and a chance at longer survival."

About Uveal Melanoma

Uveal melanoma is a rare and aggressive form of melanoma, which affects the eye. Although it is the most common primary intraocular malignancy in adults, the diagnosis is rare. Up to 50% of people with uveal melanoma will eventually develop metastatic disease. Unresectable or metastatic uveal melanoma typically has a poor prognosis and had no approved treatment until KIMMTRAK.

About KIMMTRAK

KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognise and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom.

KIMMTRAK Clinical Review

Health Canada’s approval is based on the results of Immunocore’s Phase 3 IMCgp100-202 clinical trial, a randomized pivotal trial that evaluated overall survival (OS) of KIMMTRAK compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with previously untreated mUM. KIMMTRAK demonstrated an unprecedented OS benefit with a Hazard Ratio (HR) in the intent-to-treat population favoring KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).

IMPORTANT SAFETY INFORMATION

Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.

In the randomised Phase 3 trial of KIMMTRAK, treatment-related adverse reactions were generally manageable and consistent with the proposed mechanism of action. Among the patients treated with KIMMTRAK, the most common Grade 3 or higher adverse events were rash (18%), pyrexia (4%), and pruritus (5%). In the 245 patients treated with KIMMTRAK, Grade 3 cytokine release syndrome (CRS) occurred in <1% of patients and were generally well-managed. There were no Grade 4 or higher CRS events observed in the Phase 3 clinical trial.

Skin Reactions

Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.

Elevated Liver Enzymes

Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.

Embryo-Fetal Toxicity

KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose.

The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.

For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS).