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.

On April 11, 2024 Nutcracker Therapeutics, Inc., a biotechnology company dedicated to developing transformative RNA therapies through its proprietary technology platform, reported two posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego: one showcasing the latest preclinical data for the company’s mRNA drug candidate for prostate cancer, NTX-470; and the other highlighting data on the immunomodulatory cytokine, LIGHT (Press release, Nutcracker Therapeutics, APR 11, 2024, View Source [SID1234642024]).

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"Nutcracker is building a strong slate of drug candidates for oncology indications, with NTX-470 being one of the highlights of our pipeline," said Chief Executive Officer Igor Khandros, Ph.D. "Through our technology platform, Nutcracker scientists were able to engineer multiple variants of LIGHT and NTX-470 to investigate the activities of each molecule, and determine which has the most potential to be a clinical product candidate. This type of discovery process was made possible by the nature of RNA, and I look forward to sharing more progress our team has made on other drug candidates in the near future."

NTX-470

There are limited treatment options for the 10 percent to 20 percent of prostate cancer patients who develop castration resistance. Bispecific T cell engagers targeting prostate-specific membrane antigen (PSMA) and six transmembrane epithelial antigen of the prostate 1 (STEAP1) have demonstrated promising preliminary clinical activity, but have faced challenges with durability and toxicity, primarily due to erroneous on-target, off-tumor binding.

By building and iterating on RNA sequences through the proprietary CodonCrackerTM software and the Nutcracker Manufacturing Unit, Nutcracker’s scientists engineered a group of molecules with attenuated PSMA and CD3 (cluster of differentiation 3) binding to mitigate on-target, off-tumor binding and target-independent T cell activation. Of these, NTX-470 showed the strongest target cell killing activity – it was capable of engaging CD3 T cells, while displaying minimal activity in the absence of STEAP1- or PSMA-expressing target cells, retaining low bystander activity.

"The data on NTX-470, as a promising preclinical candidate, expands upon work described in a previous presentation by our partners at the University of California, San Francisco," said Chief Scientific Officer Samuel Deutsch, Ph.D. "We’re hopeful that with our continued work, NTX-470 will prove itself as a viable treatment for prostate cancer, and serve as another example of the beauty of engineering RNA to encode for complex therapeutic proteins that would be difficult to obtain in the traditional protein engineering paradigm."

LIGHT

Also at this year’s AACR (Free AACR Whitepaper) annual meeting, Nutcracker presented data on its engineered version of the immunomodulatory cytokine, LIGHT, a component of NTX-250, the company’s lead candidate for cervical intraepithelial neoplasia. LIGHT comes in two forms: membrane-bound or soluble, with the former generally having stronger activity, leading to the hypothesis that limiting membrane shedding would enhance advantageous activity. Nutcracker’s scientists engineered multiple variants of LIGHT with either flexible or rigid linkers in place of protease-sensitive sites, to explore how membrane shedding susceptibility affects immunomodulatory activity. Of the tested designs, membrane-stabilized variants of LIGHT enhanced HVEM stimulation over WT LIGHT and increased proinflammatory cytokines in the tumor microenvironment.

On April 11, 2024 Boundless Bio (Nasdaq: BOLD), a clinical-stage oncology company interrogating extrachromosomal DNA (ecDNA) biology to deliver transformative therapies to patients with previously intractable oncogene amplified cancers, reported that the first patient has been dosed with BBI-825 in a first-in-human, Phase 1/2 clinical trial for patients with locally advanced or metastatic cancer with resistance gene amplifications (NCT06299761) (Press release, Boundless Bio, APR 11, 2024, View Source [SID1234642023]). ecDNA are a key driver of high copy number amplification in cancer, and Boundless has validated multiple drug targets that are essential for ecDNA function in cancer cells. BBI-825, the Company’s second ecDNA-directed therapy (ecDTx) to enter clinical trials, is a novel, selective, oral small molecule inhibitor of ribonucleotide reductase (RNR), a rate-limiting enzyme responsible for the de novo synthesis of deoxyribonucleotides, the building blocks of DNA. Boundless has identified an essential role for RNR in ecDNA assembly and repair and in the survival of certain oncogene amplified cancer cells.

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"We are excited to announce dosing of the first patient in our first-in-human study of BBI-825, our second program to enter the clinic," said Klaus Wagner, M.D., Ph.D., Chief Medical Officer at Boundless Bio. "BBI-825 represents a new approach in the potential treatment of oncogene amplifications, particularly in resistance associated with targeted therapy treatment of MAPK pathway-activated cancers."

"Rapid resistance is a major limitation for targeted therapies, particularly in colorectal cancer, as patients with colorectal cancer often progress within about 6 months of initiating targeted treatment," said Rona Yaeger, M.D., Gastrointestinal Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center. "We have observed firsthand that tumors in patients treated with KRASG12C or BRAFV600E targeted therapies develop resistance via MAPK pathway and receptor tyrosine kinase gene amplifications, and those with pre-existing amplifications have an overall worse outcome. There remains an incredible need for therapies that can prevent amplification-driven resistance or treat patients that have already acquired such resistance."

"Advancing our second ecDTx into clinical development is an important milestone for Boundless Bio and underscores the power of our Spyglass platform to identify synthetic lethal targets essential to ecDNA formation and function in oncogene amplified cancers," said Zachary Hornby, President and Chief Executive Officer at Boundless Bio. "We are excited to enroll patients in this first-in-human Phase 1/2 study, focused initially on patients with KRASG12C and BRAFV600E mutated colorectal cancer with resistance gene amplifications. If data are supportive, we may have the opportunity to expand into broader patient populations, including pan-tumor, pan-RAS, and pan-RAF indications, potentially addressing these populations of cancer patients with very high unmet need."

About the STARMAP Trial

STARMAP ("Study Treating Acquired Resistance: MAPK Amplifications") is an open-label, non-randomized, three-part Phase 1/2 clinical trial to evaluate the safety, pharmacokinetics, pharmacodynamic biomarkers, preliminary antitumor activity, and identify the maximum tolerated dose and recommended Phase 2 dose (RP2D) of BBI 825 administered as a single agent or in combination with select targeted therapies (NCT06299761). Part 1 is a dose escalation of BBI-825 as a monotherapy in patients with solid tumors. Part 2 is a combination dose escalation of BBI-825 and targeted therapies, encorafenib and cetuximab, or adagrasib and cetuximab, in patients with advanced or metastatic colorectal cancer with BRAFV600E or KRASG12C mutations, respectively, and co-occurring resistance gene amplifications. Part 3 is a combination dose expansion to evaluate preliminary anti-tumor activity at the RP2D of BBI-825 and each targeted therapy combination from Part 2.

On April 11, 2024 ARTMS Inc. (ARTMS) reported that the acquisition by Telix Pharmaceuticals Limited (Telix) has been completed (Press release, Telix Pharmaceuticals, APR 11, 2024, View Source [SID1234642022]). This acquisition further enhances the vertical integration of Telix’s supply chain and manufacturing by providing a greater level of supply chain and regulatory control over the production of key isotopes.

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ARTMS will support the high efficiency, large-scale and cost-effective production of commercially important medical isotopes for Telix’s portfolio of products, such as zirconium-89 (89Zr), gallium-68 (68Ga), technetium‐99m (99mTc) and copper-64 (64Cu), and will continue to partner with additional radiopharmaceutical companies to ensure that these critical isotopes are available on demand for patients. In addition, ARTMS’ portfolio of advanced cyclotron technologies has immediate application and differentiation for Telix in the production of future commercially important alpha-emitting, therapeutic isotopes, including actinium-225 (225Ac) and astatine-211 (211At).

The history of ARTMS is rooted in a Canadian government funded project focused on solid target production of 99mTc. After that project was successfully completed, the innovation continued and resulted in a full suite of PET products. In 2017, ARTMS Inc. was formed with support and seed funding from Quark Venture, through their Global Health Sciences Fund (GHS) and founding institutions TRIUMF, BC Cancer, Lawson Health Research Institute and the Center for Probe Development. In May of 2020, ARTMS completed a $20M USD Series A fundraising that included GHS and welcomed Deerfield Management to the ARTMS family. In the subsequent years ARTMS has played a critical role in alternative production of medical isotopes with a focus on accelerating the production capabilities of the world’s most commonly installed cyclotrons. The collaboration between ARTMS’ unparalleled team, its investors and founding members has resulted in a truly differentiated organization.

Solomon Partners Securities LLC acted as financial advisor and Norton Rose Fulbright Canada LLP acted as legal advisor to ARTMS during the negotiations and due diligence process related to the acquisition by Telix.

On April 11, 2024 VBI Vaccines Inc. (Nasdaq: VBIV) (VBI), a biopharmaceutical company driven by immunology in the pursuit of powerful prevention and treatment of disease, reported the closing of its previously announced registered direct offering priced at-the-market under Nasdaq rules of 2,272,728 of its common shares and warrants to purchase up to 2,272,728 common shares, at an offering price of $0.88 per common share and associated warrant (Press release, VBI Vaccines, APR 11, 2024, View Source [SID1234642021]). The warrants have an exercise price of $0.76 per share, are exercisable on the date of issuance, and will expire five years following the date of issuance.

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H.C. Wainwright & Co. acted as the exclusive placement agent for the offering.

The gross proceeds to VBI from this offering were approximately $2 million, before deducting the placement agent’s fees and other offering expenses. VBI intends to use the net proceeds from this offering for working capital and general corporate purposes.

A "shelf" registration statement (File Number 333-267109) relating to the securities described above was filed with the Securities and Exchange Commission ("SEC") on August 26, 2022 and was declared effective on September 6, 2022. The offering of the securities in the registered direct offering was made only by means of a prospectus, including a prospectus supplement, forming a part of an effective registration statement. A prospectus supplement and accompanying prospectus relating to the registered direct offering have been filed with the SEC. Electronic copies of the prospectus supplement and accompanying prospectus may be obtained on the SEC’s website at www.sec.gov or by contacting H.C. Wainwright & Co., LLC at 430 Park Avenue, 3rd Floor, New York, NY 10022, by phone at (212) 856-5711 or e-mail at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.