On July 21, 2023 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported that it has entered into definitive agreements with institutional investors for the purchase and sale of 1,301,923 of the Company’s American Depositary Shares ("ADSs") (or ADS equivalents), each ADS representing four hundred (400) ordinary shares, at a purchase price of $1.35 per ADS (or ADS equivalent), in a registered direct offering (Press release, RedHill Biopharma, JUL 21, 2023, View Source [SID1234633368]).

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The Company has also entered into a definitive agreement with a certain holder of its existing Class A warrants exercisable for 1,500,000 ADSs, in the aggregate, to exercise its warrants at a reduced exercise price of $1.35 per ADS, in exchange for new warrants as described below.

H.C. Wainwright & Co. is acting as the exclusive placement agent for the transactions.

The closing of the offering and warrant exercises is expected to occur on or about July 25, 2023, subject to the satisfaction of customary closing conditions. The gross proceeds to the Company from the transactions are expected to be approximately $3.8 million, before deducting the placement agent’s fees and other offering expenses payable by the Company. The Company intends to use the net proceeds from these transactions for general working capital, acquisitions, research and development, and general corporate purposes.

The securities described above other than the new warrants are being offered by the Company, and the ADSs issuable upon exercise of the Class A warrants are registered, pursuant to a "shelf" registration statement on Form F-3 (File No. 333-258259) previously filed with the Securities and Exchange Commission (the "SEC") on July 29, 2021, and declared effective by the SEC on August 9, 2021. The offering of the securities in the registered direct offering is made only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. A final prospectus supplement and accompanying prospectus relating to the registered direct offering will be filed with the SEC. Electronic copies of the final prospectus supplement and accompanying prospectus may be obtained, when available, on the SEC’s website at View Source or by contacting H.C. Wainwright & Co., LLC at 430 Park Avenue, 3rd Floor, New York, NY 10022, by phone at (212) 865-5711 or e-mail at [email protected].

In consideration for the immediate exercise of the warrants for cash, the exercising holder (i) will receive new warrants to purchase ADSs in a private placement and (ii) have the exercise price of its existing Class B warrants exercisable for 1,500,000 ADSs, in the aggregate, reduced to $1.80 per ADS. The new warrants will be exercisable into an aggregate of up to 1,500,000 ADSs, at an exercise price of $1.80 per ADS and shall be exercisable until April 3, 2028. The new warrants described above are being offered in a private placement under Section 4(a)(2) of the Securities Act of 1933, as amended (the "Act"), and Regulation D promulgated thereunder and, along with the ADSs representing ordinary shares underlying such warrants, have not been registered under the Act, or applicable state securities laws. Accordingly, the new warrants and the ADSs underlying the warrants may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Act and such applicable state securities laws. As part of the transaction, the Company has agreed to file a resale registration statement on Form F-3 with the SEC within 15 days of the closing to register the resale of the ADSs underlying the new warrants issued in the private placement.

In connection with the registered direct offering, the Company also has agreed that (i) certain existing warrants to purchase up to an aggregate of 330,106 ADSs at an exercise price of $4.75 per ADS and (ii) certain existing warrants to purchase up to an aggregate of 971,817 ADSs at an exercise price of $4.6305 per ADS, will each be amended, effective upon the closing of the offering, so that the amended warrants will have a reduced exercise price of $1.80 per ADS.

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

On July 21, 2023 The Menarini Group ("Menarini"), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion on the approval of ORSERDU (elacestrant) monotherapy, indicated for the treatment of postmenopausal women, and men, with estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK 4/6 inhibitor (Press release, Menarini, JUL 21, 2023, View Source;locally-advanced-or-metastatic-breast-cancer-with-an-activating-esr1-mutation-301883109.html [SID1234633367]).

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The CHMP opinion will now be reviewed by the European Commission, which has the authority to grant marketing authorization for human medicines throughout the European Union (EU). If approved, Stemline and its affiliates will commercialize the product within Europe. ORSERDU would be the first and only therapy specifically indicated for the treatment of ER+, HER2- tumors that harbor ESR1 mutations. ESR1 mutations are acquired mutations that develop as a result of exposure to endocrine therapy, and they are found in up to 40% of patients with ER+, HER2- mBC. ESR1 mutations are a known driver of resistance to standard endocrine therapy, and until now, the tumors that harbor these mutations have been more difficult to treat.

"Patients living with metastatic breast cancer are in need of efficacious and tolerable treatment options. ORSERDU may become the first product, if approved by the European Commission, indicated in ER+, HER2- advanced breast cancer with ESR1 mutations, which are a strong driver of resistance to treatment in up to 40% of patients in second line mBC. ORSERDU, if approved, will also provide a convenient daily oral treatment," said Elcin Barker Ergun, CEO of the Menarini Group. "We are proud of today’s positive CHMP opinion as it reflects our commitment to developing innovative solutions that address the greatest unmet needs in cancer treatment, and brings us one step closer to providing an important new option to the patients and families impacted by ESR1-mutated, ER+, HER2- metastatic breast cancer."

The positive CHMP opinion for ORSERDU is supported by data from the Phase 3 EMERALD trial, which demonstrated statistically significant progression-free survival (PFS) with elacestrant versus standard-of-care (SOC), defined as investigator’s choice of an approved endocrine monotherapy. The primary endpoints of the study were PFS in the overall patient population and in patients with ESR1 mutations. In the group of patients whose tumors had ESR1 mutations, elacestrant achieved a median PFS of 3.8 months vs 1.9 months on the SOC, and reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC.

A post hoc subgroup analysis of the EMERALD PFS results, which were presented at the San Antonio Breast Cancer Symposium (SABCS) 2022, demonstrated that the duration of prior CDK4/6i treatment was positively associated with longer PFS on elacestrant but not with SOC. For patients with ESR1 mutations who were treated with CDK4/6i for ≥12 months prior to randomization on EMERALD, elacestrant achieved a median PFS of 8.6 months versus 1.9 months on SOC, with a 59% reduction in the risk of progression or death (HR=0.41 95% CI: 0.26-0.63).³

"As an oncologist, it is remarkable that we are on the cusp of having the first treatment option for patients with advanced or metastatic ER+, HER2- breast cancer harboring ESR1 mutations, which occur in up to 40% of patients in the metastatic setting," said Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milano and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy. "Elacestrant has demonstrated efficacy and a manageable safety profile, underscoring the potential benefit this therapy may soon bring to the patients we care for, and to the broader oncology community."

Safety data were consistent with previously reported results. Serious adverse reactions reported in ≥ 1% of patients included nausea, dyspnoea, and thromboembolism (venous). The most common (≥ 10%) adverse reactions with ORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia, potassium decreased, and alanine aminotransferase increased. The most common Grade ≥3 (≥2%) adverse reactions of elacestrant were nausea (2.7%), AST increased (2.7%), ALT increased (2.3%), anaemia (2%), back pain (2%), and bone pain (2%).

About the EMERALD Phase 3 Study (NCT03778931)

The EMERALD Phase 3 trial is a randomized, open label, active-controlled study evaluating elacestrant as second- or third-line monotherapy in ER+, HER2- advanced/metastatic breast cancer patients. The study enrolled 478 patients who had received prior treatment with one or two lines of endocrine therapy, including a CDK4/6 inhibitor. Patients in the study were randomized to receive either elacestrant or the investigator’s choice of an approved hormonal agent. The primary endpoints of the study were progression-free survival (PFS) in the overall patient population and in patients with estrogen receptor 1 gene (ESR1) mutations. In the group of patients whose tumors had ESR1 mutations, elacestrant achieved a median PFS of 3.8 months vs 1.9 months on the SOC, and reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC.

Elacestrant is also being investigated in several clinical trials in metastatic breast cancer disease, alone or in combination with other therapies: ELEVATE (NCT05563220); ELECTRA (NCT05386108); and ELCIN (NCT05596409). Elacestrant is also planned to be evaluated in early breast cancer disease.

The Menarini Group obtained global licensing rights for elacestrant in July 2020 from Radius Health, Inc. The Menarini Group is now fully responsible for global registration, commercialization, and further development activities for elacestrant.

On July 21, 2023 Mabwell (688062.SH), an innovative biopharmaceutical company with entire industry chain, reported that its clinical trial application of 7MW3711 for advanced malignant solid tumor was approved by the National Medical Products Administration (NMPA) (Press release, Mabwell Biotech, JUL 21, 2023, View Source [SID1234633366]). 7MW3711 is developed by Mabwell’s next-generation antibody-drug conjugate platform IDDC.

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B7-H3 is a member of the B7 ligand family and is overexpressed in most cancer types but expressed at a low level in normal tissues. In malignant tissues, B7-H3 inhibits tumor antigen-specific immune responses, resulting in a protumorigenic effect. Additionally, B7-H3 promotes migration and invasion, angiogenesis, chemotherapy resistance, endothelial-to-mesenchymal transition, and affects tumor cell metabolism.

The next generation antibody-drug conjugate molecule 7MW3711 with proprietary intellectual property right, developed by Mabwell’s next-generation antibody-drug conjugate platform IDDC, is composed of innovative antibody molecule, novel linker, and novel payload (topoisomerase I inhibitor). When 7MW3711 enters human body, it specifically binds to antigens on the tumor cell membrane surface, be internalized and transferred to the lysosome, release cytotoxic drug, and induce the apoptosis of tumor cells.

7MW3711 is pharmaceutical characterized as stable structure, homogeneous composition, high purity, and it is suitable for industrial scale-up. Compared with drugs in the same class at home and abroad, 7MW3711 has shown better tumor killing effects in multiple animal tumor models. In the safety evaluation model of animals including cynomolgus monkeys, the on-target and off-target toxicities of 7MW3711 are effectively controlled, showing its good safety profile and pharmacokinetic properties. The above research results indicate that 7MW3711 has clinical differentiation characteristics and a promising future of clinical development.

Next generation antibody-drug conjugate platform IDDC

Mabwell has developed multiple ADC technology platforms, and its Nectin-4-targeting ADC (R&D code: 9MW2821) is currently in the phase II clinical study.

IDDC is a next generation ADC site-specific conjugate technology platform independently developed by Mabwell. It is composed of multiple systematized core patent technologies including site-specific conjugate process DARfinity, special designed linker IDconnect, novel payload Mtoxin, and conditional release structure LysOnly, which improves structural homogeneity, quality stability, pharmacodynamics and tolerability of the ADC products.

Currently, the advantage of the IDDC platform has been validated in several products under development. Trop-2-targeting ADC (R&D code: 9MW2921) has been approved for clinical study in advanced solid tumor. It is expected multiple ADC products will enter clinical development in 2023 and 2024.

On July 21, 2023 Gilead Sciences, Inc. (Nasdaq: GILD) reported that the Phase 3 ENHANCE study in higher-risk myelodysplastic syndromes (MDS) has been discontinued due to futility based on a planned analysis (Press release, Gilead Sciences, JUL 21, 2023, View Source [SID1234633365]). The safety data seen in this study is consistent with the known magrolimab profile and adverse events that are typical in this patient population. Gilead recommends discontinuing treatment with magrolimab in patients with MDS. Magrolimab is a potential first-in-class, anti-CD47 immunotherapy with a clinical development program spanning ten potential indications including ongoing trials in solid tumors and two pivotal trials: ENHANCE-2 study in acute myeloid leukemia (AML) with TP53 mutations and ENHANCE-3 in first-line, unfit AML.

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"The health and well-being of patients are our top priorities and while this is disappointing news it confirms the challenges of treating HR-MDS, where no new class of treatments have been approved in nearly 20 years," said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. "Gilead is deeply grateful to the patients, families, investigators, and the advocacy community who contributed to this research as we learn more about magrolimab and explore its potential in treating other cancers."

Gilead is working with study investigators on appropriate next steps for patients enrolled in the ENHANCE study. Data will be submitted for presentation at an upcoming medical meeting.

About ENHANCE

The Phase 3 randomized, double-blind study evaluated the combination of magrolimab plus azacitidine as first-line treatments for higher-risk myelodysplastic syndromes (HR-MDS), a disease without a new class of treatments approved in almost 20 years. The study enrolled more than 500 patients who were randomized to receive magrolimab in combination with azacitidine or azacitidine monotherapy. Primary endpoints were complete response and overall survival. Secondary endpoints included duration of response, transfusion independence, progression free survival, and time to transformation to acute myeloid leukemia, among others. Additional information can be found at www.clinicaltrials.gov (NCT04313881).

About Magrolimab

Magrolimab is a potential, first-in-class investigational monoclonal antibody that binds to CD47. The primary mechanism of action of magrolimab is to block the inhibitory CD47-signal regulatory protein (SIRPα) interaction, enhancing the ability of macrophages and other phagocytes to identify and destroy foreign and malignant cells, with the goal of blocking the "don’t eat me" signal used by cancer cells. Magrolimab is a novel immunotherapy being developed in several hematologic cancers and solid tumor malignancies. More information about clinical trials with magrolimab is available at www.clinicaltrials.gov.

On July 21, 2023 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a commercial stage biotechnology company, reported the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a negative opinion on the Conditional Marketing Authorisation Application (MAA) for KRAZATI (adagrasib) for treatment of patients with KRASG12C -mutated advanced non-small cell lung cancer (NSCLC) (Press release, Mirati, JUL 21, 2023, View Source [SID1234633363]) .

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Mirati disagrees with the opinion and intends to request a formal re-examination.

CHMP states that KRAZATI has a positive risk-benefit profile, however, does not fulfill certain requirements for a Conditional Marketing Authorisation. Mirati believes KRAZATI addresses the Conditional Marketing Authorisation requirements despite there being a currently conditionally approved KRASG12C inhibitor and that KRAZATI possesses a differentiated clinical profile. Key differentiators include KRAZATI’s efficacy profile, potential central nervous system activity and combinability with other agents, including concurrent with or following treatment with an immune checkpoint inhibitor.

"We remain steadfast in our belief in the potential of adagrasib to provide hope for patients in the European Union," said David Meek, chief executive officer, Mirati Therapeutics, Inc. "We will continue to work closely with the EMA and the CHMP to bring adagrasib to eligible patients. We are committed to delivering therapeutic options for patients living with KRASG12C-mutated NSCLC in the EU, as we have in the United States following the Accelerated Approval of KRAZATI in December 2022."

The MAA for KRAZATI was based on the Phase 2 registration-enabling cohort of the KRYSTAL-1 study, evaluating KRAZATI 600 mg administered orally twice daily in 116 patients with KRASG12C-mutated advanced NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor.

Mirati is supplying KRAZATI to eligible European patients with a KRASG12C mutation based on individual requests from healthcare professionals. Mirati intends to continue supplying KRAZATI under early access in EU Member States in alignment with applicable laws and regulations.

This decision will have no impact on any of Mirati’s clinical trials. Study enrollment for KRYSTAL-12, the confirmatory Phase 3 trial evaluating adagrasib versus docetaxel in patients who have been previously treated for metastatic NSCLC with a KRASG12C mutation, is progressing as expected. Progression-free survival and interim overall survival results are anticipated in the first half of 2024.

About KRAZATI (adagrasib)

Mirati has risen to meet one of the most challenging mutations in cancer research by developing KRAZATI, a highly selective and potent oral small-molecule inhibitor of KRASG12C.

Intentionally designed to meet the challenge of KRASG12C, adagrasib is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C-mutated cancers, as the KRASG12C protein regenerates every 24-48 hours.1 Adagrasib has shown clinically to be a CNS penetrant, which may be important given that CNS metastases frequently occur in NSCLC and lead to poor prognosis.2,3,4

The FDA provided KRAZATI Accelerated Approval (Subpart H), allowing for the approval of drugs that treat serious conditions, and that fill an unmet medical need based on surrogate endpoints. Adagrasib continues to be evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science.

About the KRYSTAL-1 Study

KRYSTAL-1 is an open-label Phase 1/2 multiple-expansion cohort trial evaluating adagrasib as monotherapy and in combination with other anti-cancer therapies in patients with advanced solid tumors harboring the KRASG12C mutation.

About KRASG12C in NSCLC

Lung cancer is one of the most common cancers worldwide, accounting for 2.21 million new cases and 1.8 million deaths worldwide in 2020.5 Lung cancer consists of NSCLC in approximately 85% of cases and small cell lung cancer (SCLC) in approximately 15% of cases.6 KRASG12C is the most common KRAS mutation in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker mutation of poor prognosis.