On April 11, 2024 Lamassu Biotech reported its pioneering effort to combat locally advanced metastatic p53 wild-type tumors has earned investigational new drug application (IND) approval from the Food and Drug Administration (FDA) to proceed in initiate Phase 1/2a clinical trials (Press release, Lamassu Pharma, APR 11, 2024, https://www.prnewswire.com/news-releases/possible-new-hope-for-metastatic-cancer-patients-food-and-drug-administration-grants-approval-for-clinical-trials-for-lamassus-groundbreaking-cancer-treatment-protocol-302114390.html [SID1234646266]).

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The trial will investigate novel therapy SA53-OS, a genetically targeted therapy that targets the MDM2 protein, a key regulator of the tumor suppressor p53 gene. By selectively activating p53, Lamassu aims to induce tumor cell death and inhibit growth, potentially providing a much-needed breakthrough in targeted cancer therapy.

Lamassu has been working in collaboration with the Cleveland Clinic on this trial, led by Peter Anderson, MD, which seeks to develop a new cancer treatment for patients with limited therapeutic options. With functional p53 present in about half of all cancers, the potential impact of this treatment could be transformative in the fight against cancer.

The IND approval by the FDA comes on the heels of Lamassu receiving one of the National Institutes of Health’s largest available SBIR grant awards to help launch the clinical trial study for its innovative approach to cancer treatment.

"This approval is the result of the vision and tenacity of our entire Lamassu team and our partners," said Dr. Gabi Hanna, CEO of Lamassu. "It is a critical step to move beyond conventional chemotherapy to targeted therapy to bring hope and healing to millions who suffer from stubborn cancers that don’t respond to conventional treatments and to reduce the toxicity of cancer treatments. With SA53-OS patented in 69 countries, successful trials could make a significant impact on the global fight against cancer."

"The initiation of this trial adds to Lamassu’s record of accelerating drug development, delivering innovative therapies that can go from the laboratory to the bedside faster and with improved outcomes," said Dr. Hanna.

On April 11, 2024, Precision BioSciences, Inc. (the "Company") reported to have received written notice from Prevail Therapeutics Inc. ("Prevail"), a wholly-owned subsidiary of Eli Lilly and Company, of Prevail’s termination of the Amended and Restated Development and License Agreement, dated June 30, 2023, between Prevail and the Company (the "Agreement") (Press release, Precision Biosciences, APR 11, 2024, View Source [SID1234642468]). Prevail’s notice informed the Company that Prevail was exercising its right pursuant to Section 15.3.2 of the Agreement to terminate the Agreement in its entirety without cause upon 90 days’ prior written notice to the Company. The termination will be effective on July 10, 2024.

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Pursuant to the terms of the Agreement, Precision and Prevail agreed to collaborate and develop the Company’s ARCUS nucleases for the research and development of potential in vivo therapies for three initial genetic disorder targets, including Duchenne muscular dystrophy ("DMD") in muscle, a liver directed target ("PBGENE-LLY2") and a central nervous system directed target ("PBGENE-LLY3" and together with DMD and PBGENE-LLY2, the "Programs"). Under the original agreement with Eli Lilly and Company signed November 19, 2020, Precision received $135 million in upfront investment consisting of $100 million upfront and $35 million from Lilly’s purchase of 125,406 shares of the Company’s common stock (on a post-reverse stock split basis). The Agreement was amended and restated in June 2023 with Prevail assuming and funding preclinical research and investigational new drug application-enabling activities, which had previously been conducted by the Company at its expense, as well as assuming responsibility for the manufacturing of initial clinical trial material for the first licensed product. Upon the achievement of various milestones, the Company would have been entitled to receive milestone payments of up to an aggregate of $390 million to $395 million per licensed product as well as nomination fees for additional targets and certain research funding. If licensed products resulting from the collaboration were approved and sold, Prevail would have also been required to pay tiered royalties ranging from the mid-single digit percentages to the low-teens percentages on world-wide net sales of the licensed products, subject to customary potential reductions. Prevail’s exercise of its termination right is contemporaneous with achievement of defined preclinical activities on the collaboration for the Programs, at which time Prevail would have taken over all remaining development activities for the Programs.

In connection with the termination, the Company has exercised its reversion option (the "Reversion Option") under the Agreement to regain control over development of the Programs and plans to explore opportunities to further develop the Programs. As a result, Prevail is required upon Precision’s request and to the extent permitted by law or terms of third party agreements, to assign and transfer to the Company all right, title and interest in and to all materials, preclinical and clinical data, safety data and all other supporting data in Prevail’s control related to the terminated products for the continued development and commercialization of such products.

The foregoing description of the Agreement does not purport to be complete and is qualified in its entirety by the full text of the Agreement, a copy of which was filed as Exhibit 10.1 to the Company’s Current Report on Form 8-K filed on July 6, 2023, and is incorporated herein by reference.

On April 11, 2024 REGiMMUNE Limited, a clinical-stage biopharmaceutical company focused on creating innovative immunotherapies for immune disorders and cancer, reported the poster presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, REGimmune, APR 11, 2024, View Source [SID1234642233]). The poster presentation is to highlight RGI-2001 phase 2b result, including the latest correlative analyses of changes in regulatory T (Treg) and natural killer T (NKT) cell populations to assess the cellular kinetics of RGI-2001 in the prevention of acute Graft versus host disease.

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Based on literature, higher numbers of NKT cells are associated with a reduced risk of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (alloHCT) (Rubio et al. 2017; Rubio et al. 2012). Patients with rapid NKT cell expansion exhibit a lower risk of GVHD and improved survival (Chaidos et al. 2012; Malard et al. 2016).

Flow cytometry studies indicate peripheral NKT expansion at Day 28 in patients receiving clinical benefit from RGI- 2001.The mean levels of absolute Tregs at Day 42, 1 week following the last dose of RGI-2001, were higher in subjects who were alive and had not developed Grade II-IV aGVHD by Day 180 compared with those who had died and/or did develop aGVHD. A large percentage of activated Tregs were proliferating, with activated Tregs proliferating to a greater extent compared with nonactivated Tregs. The proliferation was greater in after- treatment compared to baseline samples. This effect was also observed in the single-dose study (Phase 1/2a RGI-2001-002). The results from exploratory correlative analyses are consistent with the proposed mechanism of action of RGI-2001. RGI-2001 may induce activation and proliferation of NKT cells, leading to a reduction in aGVHD through increasing the proliferation of activated Tregs.

"Our data suggest that RGI-2001 prevents acute GVHD through NKT and Treg cells without compromising general immune function and has the potential to become a best-in-class drug for preventing acute GVHD," said Kenzo Kosuda, CEO of REGiMMUNE. Based on these results, a phase 3 randomized controlled study is being planned to confirm the efficacy and safety of RGI-2001 in alloHCT.

Dr Jack Bui,MD,Ph.D. from University of California, San Diego, is the presenter for this important poster for RGI-2001. Details of presentation, please see RGI-2001 AACR (Free AACR Whitepaper) Poster Presentation.

Title: Phase 2b study of alloHSCT patients receiving RGI-2001, an NKT cell activator, demonstrates safety and protection from acute GVHD, correlating with increased NKT cell number in patient blood.
Authors: J. D. Bui1, C. Lee1, C. Caron1, D. Lee2, Z. DeFilipp3, Y.-B. Chen3;
Session Title: PO.CT02.02 – Phase II Clinical Trials 2
Session Date and Time: April 8th 2024, 1:30 PM – 5:00 PM

On April 11, 2024, Rigel Pharmaceuticals, Inc. ("Rigel") reported to have entered into Amendment No. 4 (the "Amendment") to that certain Credit and Security Agreement, dated as of September 27, 2019 (as further amended, supplemented or otherwise modified from time to time prior to the Amendment, the "Existing Credit Agreement," and as amended by the Amendment, the "Amended Credit Agreement") with Midcap Financial Trust ("MidCap"), as administrative agent, and the lenders party thereto ("Lenders"), pursuant to which MidCap and the Lenders agreed to amend the Existing Credit Agreement to, among other things, (i) extend the maturity date for the term loans to September 1, 2027 (the "Maturity Date"), (ii) extend the interest only period for the term loans to October 1, 2025, (iii) reset the prepayment fee applicable to the term loans, (iv) increase the exit fee payable on the term loans, (v) revise the interest rate payable on the term loans, and (vi) update certain financial covenants in connection with the new maturity date (Filing, 8-K, Rigel, APR 11, 2024, View Source [SID1234642036]).

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The term loans under the Amended Credit Agreement may be prepaid in full or in part through September 30, 2025 with payment of a 1.5% prepayment premium, and thereafter they may be prepaid in full or in part through the date immediately prior to the Maturity Date with payment of a 1.0% prepayment premium.

The interest rate applicable to the term loans under the Amended Credit Agreement is the secured overnight financing rate ("SOFR") (as defined in the Existing Credit Agreement) plus 6.50%, subject to a SOFR floor of 4.00%. The amortization payments on the term loans under the Amended Credit Agreement start on October 1, 2025. All unpaid principal and accrued interest is due and payable in full no later than the Maturity Date.

The Amended Credit Agreement requires that (i) Rigel maintains Borrower Unrestricted Cash of at least $10.0 million at all times, and (ii) upon Borrower Unrestricted Cash falling below 1.25x of the term loans outstanding, Rigel maintains TAVALISSE Net Revenue in the U.S. (with capitalized terms as defined in the Amended Credit Agreement).

The foregoing description of the Amendment in this Current Report on Form 8-K does not purport to be complete and is qualified in its entirety by reference to the Amendment, a copy of which will be included as an exhibit to Rigel’s Quarterly Report on Form 10-Q for the fiscal period ending March 31, 2024, to be filed with the U.S. Securities and Exchange Commission.

On April 11, 2024 MEI Pharma, Inc. (Nasdaq: MEIP), a clinical-stage pharmaceutical company evaluating novel drug candidates to address known resistance mechanisms to standard-of-care cancer therapies, reported that 25% of evaluable patients with relapsed metastatic colorectal cancer ("mCRC") in Cohort 1 of the ongoing Phase 1b study evaluating ME-344, an investigational inhibitor of mitochondrial oxidative phosphorylation ("OXPHOS"), in combination with bevacizumab (Avastin) had no disease progression at Week 16 (Press release, MEI Pharma, APR 11, 2024, View Source [SID1234642025]). This landmark analysis exceeded the 20% threshold set in the Clinical Study Protocol to add an additional 20 patients to the study via the initiation of Cohort 2. The combination was also observed to be generally well-tolerated to date. While the threshold was met to proceed to Cohort 2, it was separately reported today that following a strategic review, the Company decided to continue to advance ME-344 development via its ongoing development of a new formulation rather than through the addition of a new cohort. The Company believes this represents the optimal approach to leveraging the potential of the program. The Company has already initiated research and development activity of the new formulation with encouraging results, with the goal of increasing biological activity, improving convenience of administration and increasing commercial opportunity.

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"The data reported today, including progression-free survival, overall survival, and safety results of the combination, represent an important development supporting the potential of ME-344 in combination with Avastin to induce synthetic lethality in tumors using a completely novel therapeutic strategy," said Richard Ghalie, chief medical officer of MEI Pharma. "The development of a new formulation with enhanced biologic activity is aimed at further improving patient outcomes and treatment convenience in a well-tolerated manner."

"At MEI we are committed to our mission of developing novel drug candidates to address known resistance mechanisms to standard-of-care cancer therapies, and ME-344 holds significant potential as a novel therapeutic strategy to advance this mission," said David Urso, president and chief executive officer of MEI Pharma. "We believe that the best approach to optimize the potential of ME-344 for patients, prioritize resource utilization, and build value for shareholders, is to continue advancing the program via development of a new formulation of ME-344. In the short term, this plan will reduce expenditures on the ME-344 program and ultimately, if successful, create an improved formulation for continued clinical development."

Phase 1 Study Details

The ongoing Phase 1b study is evaluating ME-344 in combination with bevacizumab in patients with relapsed metastatic colorectal cancer ("mCRC") after failure of standard therapies. The combination of ME-344 and bevacizumab is intended to create metabolic synthetic lethality by leveraging the ability of antiangiogenics like bevacizumab to reduce glycolysis, forcing tumors to switch to mitochondrial respiration via OXPHOS, which is inhibited by ME-344.

The study was designed to evaluate ME-344 plus bevacizumab in up to two cohorts of approximately 20 patients each. The option to enroll the second cohort was conditioned upon Cohort 1 reaching a predetermined non-progression threshold of at least 20% at four months. Patients in the study are treated until disease progression or intolerability. The primary endpoint of the study is 16-week progression free survival ("PFS"), and secondary endpoints include overall PFS, duration of response, overall survival and safety.

ME-344 is administered at 10 mg/kg once weekly for 3 weeks in combination with bevacizumab every two weeks in 28-day cycles. Cohort 1 enrolled a total of 23 patients with relapsed mCRC, with a median age 58 years (range 42-83). Patients were generally heavily pretreated; the median number of prior lines of therapy was 4 (range 1-8), 18 (78%) patients had ≥3 prior lines, and all patients had previously received bevacizumab and standard chemotherapy.

In the first cohort, 5 of 20 (25%) evaluable patients completed 16 weeks of therapy without evidence of disease progression, exceeding the 20% predetermined threshold as set forth in the Clinical Study Protocol to proceed to Cohort 2. Although Cohort 1 exceeded the predetermined PFS threshold, the Company decided not to initiate enrollment in a second cohort in favor of continuing to advance ME-344 development via a new formulation. Two patients are currently enrolled in Cohort 1.

The Phase 1b study is being conducted at member centers of the Academic GI Cancer Consortium (AGICC), an oncology consortium dedicated to identifying new drugs to treat gastrointestinal cancers.

ME-344 Plus Bevacizumab Combination: Initial Safety and Tolerability Data

ME-344 in combination with bevacizumab at the dose and schedule evaluated was generally well tolerated with no overlapping toxicities observed. Two patients (9%) discontinued therapy due to an adverse event: fatigue considered related to study drugs and sepsis considered unrelated. The most common (≥10% of patients) drug-related adverse events (all grades/grade ≥3) were fatigue in 8 (35%) / 3 (13%) patients and abdominal pain in 3 (13%) / 2 (9%) patients.

ME-344 Plus Bevacizumab Combination: Initial Efficacy Data

Of the 23 patients enrolled in Cohort 1, three patients were not evaluable for 16-weeks disease progression analysis due to early discontinuation prior to first disease assessment on therapy. Of the 20 patients that were evaluable, 5 (25%) completed at least 16 weeks of therapy without disease progression, exceeding the predetermined threshold of 4 (20%) patients defined by the protocol as the condition to initiate enrollment in a second cohort. The median PFS was 1.9 months, the 4-month PFS rate was 31.2%, and the median overall survival was 6.7 months with 15 patients censored at the time of analysis. Nine (45%) of the 20 evaluable patients had stable disease.

About ME-344

ME-344, an investigational drug candidate, is a novel inhibitor of mitochondrial oxidative phosphorylation (OXPHOS), a fundamental metabolic pathway involved in the production of adenosine triphosphate (ATP) in the mitochondria. ATP provides energy to drive many metabolic cell processes, including division, proliferation, and growth. By disrupting the production of ATP, ME-344 has been shown to induce cancer cell death in nonclinical models and was associated with antitumor activity in clinical studies.

The two main sources of ATP production in cells are OXPHOS and glycolysis; the latter is highly active in most tumors. Anti-angiogenics, like the vascular endothelial growth factor ("VEGF") inhibitor bevacizumab (Avastin), have the potential to normalize vasculature and decrease reliance on glycolysis. The resulting reduction in glycolysis may trigger an increased dependence on mitochondrial ATP production for energy to support continued tumor proliferation. In such cases of tumor plasticity, the combination of ME-344 and bevacizumab may induce metabolic synthetic lethality, providing a novel therapeutic strategy. Specifically, leveraging the ability of antiangiogenics like bevacizumab to reduce glycolysis and force tumor cells to switch to mitochondrial respiration via OXPHOS, which is inhibited by ME-344, may reduce access to ATP needed for cell division and growth in tumors.

This approach was first clinically evaluated in a multicenter, investigator-initiated, randomized, open-label, window of opportunity clinical study, evaluating ME-344 (3 doses) plus bevacizumab (1 dose) in 42 women with early HER2-negative breast cancer. Study results demonstrated significant biological antitumor activity as measured by a reduction in the proliferative biomarker Ki-67 compared to placebo. The combination appeared to be generally well tolerated. The data from this study were consistent with preclinical data suggesting that combining ME-344 can augment anti-angiogenic therapy and provided support for continued evaluation of the combination of ME-344 with bevacizumab and other VEGF inhibitors. An earlier Phase 1 clinical study evaluating ME-344 as a single-agent in patients with refractory solid tumors also demonstrated anti-tumor activity, further supporting the potential of inhibition of OXHPOS by ME-344 as a promising therapeutic modality.