On May 14, 2024 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:HCM; HKEX:13) reported that it has initiated a registrational Phase III clinical trial of HMPL-306 in patients with mutated isocitrate dehydrogenase ("IDH") 1 or 2 relapsed / refractory acute myeloid leukemia ("AML") in China (Press release, Hutchison China MediTech, MAY 14, 2024, View Source [SID1234643169]). The first patient received their first dose on May 11, 2024.

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HMPL-306 is a novel dual-inhibitor of IDH1 and IDH2 enzymes. Mutations of IDH1 and IDH2 have been implicated as drivers of certain hematological malignancies, gliomas and solid tumors, particularly among AML patients. Although some IDH inhibitors have been approved in certain markets for AML, isoform switching between the cytoplasmic mutant IDH1 and mitochondrial mutant IDH2 often leads to acquired resistance to single inhibitors of IDH1 or IDH2. Targeting both IDH1 and IDH2 mutations may provide therapeutic benefits in cancer patients by overcoming this acquired resistance.

RAPHAEL is a multicenter, randomized, open-label, registrational Phase III clinical trial designed to evaluate the safety and efficacy of HMPL-306 as a monotherapy in patients with relapsed or refractory AML harboring IDH1 and/or IDH2 mutations. The primary endpoint of overall survival (OS) and the secondary endpoints, including event-free survival (EFS) and complete remission ("CR") rate, will be tested in comparison with current salvage chemotherapy regimens. The Company is looking to enroll approximately 320 patients for this registrational study, which is being led by principal investigator Prof Xiaojun Huang of Peking University People’s Hospital. Additional details may be found at clinicaltrials.gov, using identifier NCT06387069.

The study follows positive data from a two-stage, open-label Phase I study evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of HMPL-306 in this indication (NCT04272957). The first-in-human dose-escalation stage data was presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress ("EHA") in June 2023.[1] Results of the dose expansion stage of the study in over 50 patients demonstrated promising CR rates at the recommended Phase II dose are expected to be presented at the EHA (Free EHA Whitepaper) Congress in June 2024.

About IDH and Hematological Malignancies
IDHs are critical metabolic enzymes that help to break down nutrients and generate energy for cells. When mutated, IDH creates a molecule that alters the cell’s genetic programming and prevents cells from maturing. IDH1 or IDH2 mutations are common genetic alterations in various types of blood and solid tumors, including AML with approximately 14-20% of patients having mutant IDH genes, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), low-grade glioma and intrahepatic cholangiocarcinoma. Mutant IDH isoform switching, either from cytoplasmic mutant IDH1 to mitochondrial mutant IDH2, or vice versa, is a mechanism of acquired resistance to IDH inhibition in AML and cholangiocarcinoma.[2],[3],[4]

According to the National Cancer Institute (NCI), there will be approximately 20,380 new cases of AML in the U.S. in 2023 and the five-year relative survival rate is 31.7%[5]. Currently, the U.S. Food and Drug Administration (FDA) has approved two drugs for IDH1 mutation and one drug for IDH2 mutation, but no dual inhibitor targeting both IDH1 and IDH2 mutants has been approved. There were an estimated 19,700 new cases of AML in China in 2018 and is estimated to reach 24,200 in China in 2030.[6] In China one IDH1 inhibitor was approved in 2022.

On May 13, 2024 Apellis Pharmaceuticals, Inc. (the "Company") reported to have entered into a financing agreement (the "Financing Agreement") with the guarantors party thereto, the lenders party thereto (the "Lenders"), and Sixth Street Lending Partners, as the administrative agent and collateral agent for the Lenders (Filing, 8-K, Apellis Pharmaceuticals, MAY 13, 2024, View Source [SID1234643207]). The Financing Agreement provides for a senior secured term loan facility of up to $475 million (the "Credit Facility"), consisting of an initial draw of $375 million at closing and a potential additional $100 million draw at the Company’s option upon satisfaction of a $50 million minimum cash requirement and a requirement that the Company’s trailing three-month sales of SYFOVRE were at least $180 million prior to the $100 million draw. The Credit Facility matures on May 13, 2030 (the "Maturity Date") and bears interest at an annual rate equal to the 3-month Secured Overnight Financing Rate (SOFR) + 5.75% (subject to 1.00% floor). Certain additional commitment and undrawn amount fees are also payable in connection with the Credit Facility.

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Apellis used the majority of the proceeds of the $375 million draw at closing to buy out its remaining obligations owed to SFJ Pharmaceuticals ("SFJ"), in the amount of approximately $326 million. The buyout of the SFJ development liability will eliminate $366 million in payments owed to SFJ, including approximately $200 million owed through 2025.

The Credit Facility does not provide for scheduled amortization payments during the term. All principal will be due on the Maturity Date. The Company will have the right to prepay loans under the Credit Facility at any time. The Company is required to repay loans under the Credit Facility with proceeds from certain asset sales, condemnation events and extraordinary receipts, subject, in some cases, to reinvestment rights. Repayments are subject to a prepayment premium.

All obligations under the Financing Agreement will be secured on a first-priority basis, subject to certain exceptions, by security interests in substantially all assets of the Company and material subsidiaries of the Company, including its intellectual property, and will be guaranteed by material subsidiaries of the Company, including foreign subsidiaries, subject to certain exceptions.

The Financing Agreement contains customary covenants, including, without limitation, a financial covenant to maintain liquidity of at least $50 million if the Company’s market capitalization is below $3 billion, and negative covenants that, subject to certain exceptions, restrict indebtedness, liens, investments (including acquisitions), fundamental changes, asset sales and licensing transactions, dividends, modifications to material agreements, payment of subordinated indebtedness, and other matters customarily restricted in such agreements. Among other permissions, the Company is permitted, on terms and conditions set forth on the Financing Agreement, to enter into a separate asset-based financing arrangement with a third party in an amount of up to $100 million, which amount is increased to $200 million upon certain sales or market capitalization thresholds, and to have outstanding convertible unsecured notes in an amount equal to the greater of $400 million and 10% of the Company’s market capitalization, but not to exceed $600 million. The Company is subject to restrictions on sales and licensing transactions with respect to its core intellectual property, defined to include SYFOVRE, EMPAVELI, and other pegcetacoplan product assets, subject to certain exceptions, including certain transactions related to areas outside the United States and Europe.

The Financing Agreement also contains certain events of default after which loans under the Credit Facility may be due and payable immediately, including payment defaults, material inaccuracy of representations and warranties, covenant defaults, bankruptcy and insolvency proceedings, cross-defaults to certain other agreements, judgments against the Company and its subsidiaries, and change of control.

The above description of the Financing Agreement and Credit Facility is a summary only and is qualified in its entirety by reference to the Financing Agreement, which will be filed as an exhibit to the Company’s Quarterly Report on Form 10-Q for the quarter ending June 30, 2024.

On May 13, 2024 Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), reported the closing of an oversubscribed $95 million Series C financing (Press release, Ajax Therapeutics, MAY 13, 2024, View Source [SID1234643180]). Proceeds from the financing will be used to support the clinical development of Ajax’s first-in-class Type II JAK2 inhibitor, AJ1‑11095, for the treatment of myelofibrosis, as well as advancing the company’s pipeline of treatments for MPNs.

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The financing was led by Goldman Sachs Alternatives with participation by Eli Lilly and Company, Vivo Capital, RA Capital Management, Point72 and existing investors EcoR1 Capital, Boxer Capital, Schrödinger, Inc. and Inning One Ventures. Concurrent with the financing, Amit Sinha, Head of Life Sciences Investing and Ming Cheah, PhD, Vice President, within Life Sciences Investing at Goldman Sachs Alternatives, joined Ajax’s board of directors.

"We’re pleased to have attracted this level of support from such distinguished life sciences investors and biopharmaceutical companies in addition to our existing investor syndicate," said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. "We are now well positioned to bring much needed innovation to the field of JAK inhibitors for the treatment of MPNs and look forward to advancing AJ1‑11095 into the clinic for myelofibrosis later this year."

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, using structure-based drug design and computational methods at scale, to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

"Despite significant advances brought by the introduction of JAK inhibitors, patients with MPNs continue to have major unmet needs as current therapies, including Type I JAK2 inhibitors, often fail to provide adequate symptomatic relief and have little effect on the underlying disease," said Amit Sinha, Head of Life Sciences Investing at Goldman Sachs Alternatives. "We look forward to working with Ajax’s management team to bring novel therapies, such as AJ1-11095, to patients with myelofibrosis."

"JAK2 overactivation is central to the pathogenesis of MPNs and a Type II JAK2 inhibitor has the potential to address MPNs beyond myelofibrosis, including patients with polycythemia vera and essential thrombocythemia" said Ming Cheah, a Vice President in Life Sciences Investing at Goldman Sachs Alternatives. "We are proud to support the Company in delivering a new generation of transformational treatments for MPN patients."

"This financing reinforces the value of Ajax’s approach to inhibiting JAK2 with its Type II inhibitor, AJ1-11095," said Dr. Ross Levine, Ajax co-founder and Chair of Ajax’s Scientific Advisory Board, Senior Vice President for MH Translational Research and Member of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. "My lab has been studying Type II inhibition of JAK2 for over 10 years and we believe AJ1-11095 possesses the unique therapeutic properties and disease modifying effects of a highly selective and potent Type II JAK2 inhibitor and we’re excited to bring it to patients with MF."

On May 13, 2024 Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), reported that it has received clearance for its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 1clinical study of AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis (Press release, Ajax Therapeutics, MAY 13, 2024, View Source [SID1234643179]).

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"We are thrilled to obtain clearance to advance AJ1-11095 into the clinic and excited to bring this innovative new medicine to patients with myelofibrosis," said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. "This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients."

"We look forward to the clinical development of AJ1-11095 in myelofibrosis and to initiating our Phase 1 dose escalation study, AJX-101, later this year," said David Steensma, MD, FACP, Chief Medical Officer at Ajax. "As a first-in-class therapy with a unique mechanism as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myelofibrosis by offering the potential for improved efficacy with disease modifying effects compared to existing therapies."

About AJ1-11095

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, to be a next generation JAK2 inhibitor by using structure-based drug design and computational methods at scale to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

About Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer that affects approximately 20,000 patients in the United States. The disease is characterized by spleen enlargement, scarring (fibrosis) in the bone marrow, progressive anemia, and debilitating symptoms, such as fatigue, night sweats, itching, and abdominal discomfort, which can impair a patient’s’ quality of life. The most widely used treatment for MF patients are Type I JAK2 inhibitors which can reduce spleen size and provide symptomatic improvement but have little effect on the underlying cause of disease. Over time, most MF patients stop Type I JAK2 inhibitor therapy. The most common causes for treatment discontinuation include a lack of benefit or loss of response, adverse events, and disease progression, leaving significant unmet treatment needs for these patients.

On May 13, 2024 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global leader in cell therapy, reported its first quarter 2024 unaudited financial results and key corporate highlights (Press release, Legend Biotech, MAY 13, 2024, View Source [SID1234643178]).

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"Legend made great progress in the first quarter, culminating in our exciting announcements in recent weeks. We received label expansions for CARVYKTI in the U.S., Europe, and Brazil that have changed the treatment paradigm for multiple myeloma and will enable more patients to receive our transformative therapy earlier in the course of their disease," said Ying Huang, Ph.D., Chief Executive Officer of Legend Biotech. "With more patients needing access to CARVYKTI, we have increased our manufacturing capacity and have scaled up our operations to reach our goal of 10,000 annual doses by the end of 2025. The expansion of our partnership with Novartis demonstrates our commitment to ensuring every patient who needs CARVYKTI can access it."

Regulatory Updates

The U.S. Food and Drug Administration (FDA) approved CARVYKTI for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and are refractory to lenalidomide following the Oncologic Drug Advisory Committee’s (ODAC) unanimous (11 to 0) vote recommending the approval of CARVYKTI.
The European Commission (EC) granted approval for the label expansion of CARVYKTI for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide.
The Brazilian Health Regulatory Agency, ANVISA (Agência Nacional de Vigilância Sanitária), approved CARVYKTI for the treatment of adult patients with multiple myeloma, who previously received a proteasome inhibitor and are refractory to lenalidomide, as well as adult patients with relapsed or refractory multiple myeloma, who previously received a proteasome inhibitor, an immunomodulatory agent and anti-CD38 antibody.
Key Business Developments

Legend and Johnson & Johnson* entered into a Master Manufacturing and Supply Services Agreement with Novartis Pharmaceuticals Corporation to supplement our existing manufacturing capabilities and increase commercial supply of CARVYKTI
Published inaugural Environmental, Social & Governance (ESG) report which aligns with the Sustainable Accounting Standards Board (SASB) Biotechnology and Pharmaceutical sector standards, shares ESG data collection and disclosure roadmap, and future growth strategy for good corporate citizenship
* In December 2017, Legend Biotech entered into an exclusive worldwide collaboration and license agreement with Janssen Biotech, Inc., a Johnson & Johnson company, to develop and commercialize cilta-cel (the Janssen Agreement).

First Quarter 2024 Financial Results

License Revenue: License revenue was $12.2 million for the first quarter of 2024 and consisted of the recognition of deferred revenue in connection with the global license agreement with Novartis Pharma AG to develop, manufacture, and commercialize LB2102 and other potential CAR-T therapies selectively targeting DLL3. Legend did not recognize any license revenue for the first quarter of 2023.
Collaboration Revenue: Collaboration revenue was $78.5 million for the first quarter of 2024 compared to $36.3 million for the first quarter of 2023. The increase was primarily due to an increase in revenue generated from sales of CARVYKTI in connection with the Janssen Agreement.
Collaboration Cost of Revenue: Collaboration cost of revenue was $49.1 million for the first quarter of 2024 compared to $35.6 million for the first quarter of 2023. The increase was primarily due to Legend Biotech’s share of the cost of sales in connection with CARVYKTI sales under the Janssen Agreement.
Cost of License and Other Revenue: Cost of license and other revenue for the three months ended March 31, 2024 was $5.6 million and consisted of costs in connection with the global license agreement with Novartis Pharma AG to develop, manufacture, and commercialize LB2102 and other potential CAR-T therapies selectively targeting DLL3. The Company did not incur any cost of license and other revenue for the three months ended March 31, 2023.
Research and Development Expenses: Research and development expenses were $101.0 million for the first quarter of 2024 compared to $84.9 million for the first quarter of 2023. The increase was primarily driven by continuous research and development activities in cilta-cel, including start up costs for clinical production in Belgium and continued investment in Legend’s solid tumor programs.
Administrative Expenses: Administrative expenses were $31.9 million for the first quarter of 2024 compared to $22.2 million for the first quarter of 2023. The increase was primarily due to the expansion of administrative functions and infrastructure to increase manufacturing capacity.
Selling and Distribution Expenses: Selling and distribution expenses were $24.2 million for the first quarter of 2024 compared to $18.0 million for the first quarter of 2023. The increase was primarily driven by costs associated with commercial activities for cilta-cel, including the expansion of the sales force and second line indication launch preparation.
Net Loss: Net loss was $59.8 million for the first quarter of 2024, compared to a net loss of $112.1 million for the first quarter of 2023.
Cash Position: Cash and cash equivalents, time deposits, and short-term investments were $1.3 billion as of March 31, 2024.
Webcast/Conference Call Details:
Legend Biotech will host its quarterly earnings call and webcast today at 8:00 am ET. To access the webcast, please visit this weblink.

A replay of the webcast will be available on Legend Biotech’s website at View Source