On January 3, 2023, Applied Therapeutics, Inc., a Delaware corporation (the "Company"), entered into an Exclusive License and Supply Agreement (the "Agreement") with Mercury Pharma Group Limited (trading as Advanz Pharma Holdings), a company organized and existing under the laws of England and Wales ("ADVANZ PHARMA"), a UK headquartered global pharmaceutical company with a strategic focus on specialty, hospital, and rare disease medicines in Europe (Filing, 8-K, Applied Therapeutics, JAN 4, 2023, View Source [SID1234625864]). Pursuant to the Agreement, the Company granted ADVANZ PHARMA the exclusive right and license to commercialize drug products containing AT-007 (also known as govorestat), the Company’s proprietary Aldose Reductase Inhibitor (ARI) (the "Licensed Product"), for use in treatment of sorbitol dehydrogenase deficiency ("SORD") and galactosemia in humans (each, a "Licensed Indication") in the European Economic Area, Switzerland and the United Kingdom (the "Territory"). The Company also grants ADVANZ PHARMA a right of negotiation and "most-favored nation" rights with respect to acquiring the European commercialization rights for any additional indications for which the Licensed Product may be developed in the future (or any other products the Company may develop solely to the extent used for the Licensed Indications).

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ADVANZ PHARMA is required to use commercially reasonable efforts to launch and commercialize the Licensed Products in the major markets in the Territory in each Licensed Indication following, and subject to, receipt of marketing authorization therein. Under the Agreement, ADVANZ PHARMA agrees to pay the Company (i) an upfront payment of EUR 10 million (approx. USD $10.6 million), and certain development milestone payments upon clinical trial completions and receipt of marketing authorization in the Territory, as well as certain commercial milestone payments, totaling EUR 134 million (approx. USD $142.2 million) in the aggregate, and (ii) royalties of 20% of net sales of the Licensed Product. Such royalty rate will be payable on a country-by-country basis until the later of (i) the expiration of the licensed patents covering the composition of matter of AT-007, or (ii) 10 years after the European Medicines Agency’s grant of marketing authorization for the Licensed Product. The royalties are subject to certain deductions, including certain secondary finishing costs, certain step-in establishment costs and a portion of fees for any potential third party patent licenses if applicable in the future. Following the initial term of the license, as described above, the royalty rate shall be reduced to 10% and shall continue in perpetuity unless the Agreement is terminated in various circumstances in accordance with its terms.

Certain of the patents licensed to ADVANZ PHARMA under the Agreement are sub-licensed from the University of Miami and Columbia University, and thus remain subject to certain obligations of the Company (including royalty obligations) to such institutions.

Under the Agreement, the Company remains responsible for development of the Licensed Product, and must conduct such development through grant of marketing authorizations in the Licensed Indications in the Territory and as otherwise required under such marketing authorization, in accordance with any timeframe required by regulatory authorities. The Company retains sole responsibility for the conduct of all clinical trials (subject in some circumstances to cost-sharing with ADVANZ PHARMA), unless the Company provides ADVANZ PHARMA prior consent to conduct certain studies following marketing authorization, or ADVANZ PHARMA exercises certain step-in rights (as described below). The Company also agrees to manufacture and supply the Licensed Product in bulk form to ADVANZ PHARMA. ADVANZ PHARMA is responsible for secondary packaging and release for the Territory.

The Agreement includes indemnification obligations on the part of both parties for third-party claims arising out of, among other things, a breach of the Agreement; an election by the other party not to initiate a recall; gross negligence or willful misconduct; and violation of applicable laws. In addition, both parties have agreed to indemnification obligations for third party liability product liability claims and certain exclusions from liability disclaimers, such as for breaches of confidentiality, death or personal injury caused by negligence or willful default.

In certain circumstances, including in the event of specified supply shortages, bankruptcy and certain other financial events, a force majeure event lasting more than three months, or termination as a result of the Company’s gross negligence or willful misconduct, ADVANZ PHARMA may exercise certain step-in rights. Such step-in rights include the ability for ADVANZ PHARMA to perform its own supply arrangements, and in some cases, specified development rights in the Licensed Indications in the Territory and assignment of certain contract rights. In all such circumstances, ADVANZ PHARMA must continue to pay royalties and milestone payments. ADVANZ PHARMA may recoup certain of its manufacturing and development establishment costs, and deduct such costs from royalties.

The Company may terminate the Agreement upon certain specified events, including ADVANZ PHARMA’s failure to launch or achieve certain sales threshold for the Licensed Product in major markets within a certain timeframe, or if ADVANZ PHARMA challenges a licensed patent, and either party may terminate the Agreement upon the other party’s material breach or insolvency, certain material safety issues or a force majeure event of the other party lasting longer than six months. ADVANZ PHARMA may also terminate the agreement if the Licensed Product does not receive marketing authorization for use in a Licensed Indication in any country in the Territory by a specified date, or in the event of the Company’s gross negligence or willful misconduct (subject to a cure period).

On January 4, 2023 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported that Pascal Touchon, President and Chief Executive Officer, will present at the 41st Annual J.P. Morgan Healthcare Conference on Wednesday, January 11, 2023 at 3:45 PM PST / 6:45 PM EST at the Westin St. Francis Hotel in San Francisco (Press release, Atara Biotherapeutics, JAN 4, 2023, View Source [SID1234625857]).

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A live audio webcast of the presentation will be available by visiting the Investor Events and Presentations section of atarabio.com. An archived replay of the webcast will be available on the Company’s website for 30 days following the live presentation

On January 4, 2023 Daiichi Sankyo (TSE: 4568) reported that the European Medicines Agency (EMA) has validated the Type II Variation application for ENHERTU (trastuzumab deruxtecan) as a monotherapy for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations and who have received a prior systemic therapy (Press release, Daiichi Sankyo, JAN 4, 2023, View Source [SID1234625853]).

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ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

Validation confirms that the application is complete and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use. This application is based on data from the DESTINY-Lung02 phase 2 trial presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2022 Congress and the DESTINY-Lung01 phase 2 trial published in The New England Journal of Medicine with updated data also presented at ESMO (Free ESMO Whitepaper) 2022.

"ENHERTU is the first HER2 directed medicine shown to have a clinically meaningful tumor response in patients with previously treated HER2 mutant metastatic non-small cell lung cancer based on the results of the DESTINY-Lung02 and DESTINY-Lung01 trials," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "As there are no approved therapies targeting HER2 mutant non-small cell lung cancer in Europe, we look forward to working closely with the European Medicines Agency to potentially bring a new treatment option to these patients."

About DESTINY-Lung02

DESTINY-Lung02 is a global, randomized phase 2 trial evaluating the safety and efficacy of ENHERTU in patients with HER2 mutant metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomized 2:1 to receive ENHERTU 5.4 mg/kg (Cohort 1; n=102) or ENHERTU 6.4 mg/kg (Cohort 2; n=50).

The primary endpoint of the trial is confirmed objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary endpoints include confirmed disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) assessed by investigator and BICR, investigator-assessed overall survival (OS) and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe, Oceania and North America. For more information about the trial, visit ClinicalTrials.gov.

About DESTINY-Lung01

DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg or 6.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (cohort 1 and 1a, n=90) (defined as immunohistochemistry (IHC) 3+ or IHC 2+) unresectable or metastatic non-squamous NSCLC relapsed from or refractory to standard treatment or for which no standard treatment is available.

The primary endpoint of the trial is confirmed ORR by independent central review (ICR). Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant NSCLC

Lung cancer is the second most common form of cancer globally, with more than two million cases diagnosed in 2020.1 In Europe, lung cancer is the third most commonly diagnosed cancer with more than 477,000 cases diagnosed in 2020.2 Lung cancer is also the leading cause of cancer-related deaths in Europe, with nearly 400,000 deaths reported in 2020.2 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 8% will live beyond five years after diagnosis.3

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2% to 4% of patients with this type of lung cancer.4,5 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.8,9

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2 directed therapies in NSCLC prior to the accelerated U.S. Food and Drug Administration (FDA) approval of ENHERTU in unresectable or metastatic HER2 mutant NSCLC.10,11

On January 4, 2023 Orano Med, a clinical stage radiopharmaceutical company, reported that the first patient has been dosed in a Phase 1 trial of the alpha radioligand therapy with lead-212, 212Pb-GRPR, in patients with advanced solid tumors that express gastrin-releasing peptide receptor (GRPR) (Press release, Orano Med, JAN 4, 2023, View Source [SID1234625852]). 212Pb-GRPR is the first targeted alpha therapy (TAT) targeting GRPR, a protein located on the surface of cells that is highly expressed in prostate cancer, lung cancer, breast cancer and other solid tumors.

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"Dosing the first patient in our Phase I 212Pb-GRPR clinical trial is a key development milestone for Orano Med in our strategy to develop a pipeline of alpha radiopharmaceuticals targeting difficult to treat cancers," said Julien Dodet, Chief Executive Officer. "The short-range cancer cell killing capabilities of alpha-emitting radioisotopes could mean there is limited toxicity to surrounding healthy cells. Based on promising preclinical results with 212Pb-GRPR, we believe that this first alpha therapy targeting GRPR could significantly improve outcomes for cancer patients who have exhausted other therapies."

212Pb-GRPR is being evaluated in an ongoing, multi-center, single arm, non-randomized, open-label basket trial that will enroll approximately 30 patients with advanced solid tumors. It includes a dose escalation phase followed by an expansion phase. The primary endpoint is to evaluate the safety and tolerability of 212Pb-GRPR. Exploratory efficacy endpoints include objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using RECIST v1.1 criteria. Additional information about the trial, which is recruiting patients, can be found on clinicaltrials.gov: NCT 05283330.

"We are convinced that targeted alpha therapies, such as 212Pb-GRPR, are the future of radiopharmaceutical therapies, providing an increased cytotoxic potential against cancer cells and the ability to improve treatments in areas of high unmet needs. We were excited about the success of recent beta emitters but believe that alpha radiopharmaceutical therapies will be the next more effective game changer, which will advance the field significantly," said Michael Morris, MD, Founder & Medical Director of Advanced Molecular Imaging and Therapy, the specialist center where the first patient was dosed.

About Targeted Alpha Therapy

Targeted alpha therapy (TAT) relies on a simple concept: combining the ability of biological molecules to target cancer cells with the short-range cell-killing capabilities of alpha-emitting radioisotopes. Alpha decay consists of the emission of a helium nucleus (alpha particle) together with very high linear energy transfer and a range emission of only few cell layers, resulting in irreparable double strand DNA breaks in cells adjacent only to area of alpha emission. This approach results in an increased cytotoxic potential toward cancer cells while limiting toxicity to nearby healthy cells. As a result, alpha emitters are considered as the most powerful payloads to be found for targeted therapies.

About GRPR

Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor of the family of bombesin receptors. Its ligand, gastrin-releasing peptide (GRP), is a peptide that regulates numerous physiologic functions of the gastrointestinal and central nervous systems, and is overexpressed in a number of cancers, such as prostate, breast, and lung. Oncology research has made tremendous progress in recent years in treatment of these cancers. However, in the 2020’s, around 25,000 patients are expected to be diagnosed with metastatic prostate cancer in the United States, with an average 5-year survival rate of 30%. In breast cancer, around 50,000 patients are expected to have metastatic tumors, with an average 5-year survival rate of 27%.

On January 4, 2023 -SURGE Therapeutics (SURGE) reported that the U.S. Food & Drug Administration (FDA) has accepted its Investigational New Drug (IND) application to proceed with a Phase 1/2a study of its intraoperative immunotherapy, SURGERx with resiquimod (STM-416), for prevention of recurrence and/or progression after transurethral resection of bladder tumor (TURBT) in patients with non-muscle invasive bladder cancer (NMIBC) who were previously diagnosed with high-grade disease and experience recurrence (Press release, SURGE Therapeutics, JAN 4, 2023, View Source [SID1234625851]).

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"Receiving IND clearance to advance our intraoperative immunotherapy platform into a Phase 1/2a trial in our first indication represents an important milestone as we continue to advance our pipeline," said Michael Goldberg, Ph.D., CEO & Founder of SURGE. "Surgery is presently a physical intervention only, and we believe that it should be a biochemically therapeutic intervention as well. We are excited about the prospects of our novel approach and how it can potentially improve the standard of care for cancer patients in this critical context."

"SURGE’s injectable biodegradable hydrogel enables extended, localized release of various cancer immunotherapies at the site of surgical tumor resection. We look forward to working with Michael and his team at SURGE on this initial Phase 1/2a study to advance their lead intraoperative immunotherapy candidate, STM-416, in patients with recurrent bladder cancer to improve post-resection outcomes," said Seth P. Lerner, M.D., Professor of Urology and holds the Beth and Dave Swalm Chair in Urologic Oncology, in the Scott Department of Urology, Baylor College of Medicine.

SURGE’s proprietary hydrogel has been shown in preclinical studies to reduce post-surgical recurrence and metastasis, which account for 90 percent of cancer-related deaths and have been linked to the immune suppression caused by surgery. Reprogramming the body’s response to surgery from immunosuppressive to immunostimulatory can trigger the patient’s immune system to destroy both local and distal residual cancer cells, reducing recurrence and improving survival.

The SURGERx platform is designed to improve the efficacy and safety of immunotherapy treatment, concentrating the effective dose where and when it can yield tremendous impact. It also potentially increases the number of addressable patients for highly potent molecules that are currently limited to treatment of accessible lesions via intratumoral injection.