On July 1, 2024 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that the Company has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for mirdametinib, an investigational MEK inhibitor, for the treatment of pediatric and adult patients with neurofibromatosis type 1- associated plexiform neurofibromas (NF1-PN) (Press release, SpringWorks Therapeutics, JUL 1, 2024, View Source [SID1234644625]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are pleased to be one step closer towards our goal of bringing mirdametinib to patients with NF1-PN in the U.S. and believe that our ReNeu data support the potential for mirdametinib to be a differentiated and best-in-class therapy for both children and adults living with this devastating disease," said Saqib Islam, Chief Executive Officer of SpringWorks. "We look forward to working closely with the FDA throughout the review process and also plan to file for regulatory approval in the European Union later this year."

The NDA submission includes data from the pivotal Phase 2b ReNeu trial, which evaluated mirdametinib in patients ≥ 2 years of age with NF1-associated PN causing significant morbidity. Results were presented in an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and demonstrated that mirdametinib treatment resulted in significant objective response rates confirmed by blinded independent central review, deep and durable responses, improvement in pain and health-related quality of life as well as a manageable safety profile across both the adult and pediatric cohorts.1

The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1.

In the second half of 2024, SpringWorks also plans to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for mirdametinib for the treatment of children and adults with NF1-PN.

About the ReNeu Trial

ReNeu (NCT03962543) is an ongoing, multi-center, open-label Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients ≥ 2 years of age with an inoperable NF1-associated PN causing significant morbidity. The study enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or dispersible tablet. The primary endpoint is confirmed objective response rate defined as ≥ 20% reduction in target tumor volume during the 24 cycle treatment phase, as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes from baseline in patient reported outcomes to Cycle 13. The treatment phase of the trial is complete and results were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Patients who completed the treatment phase were eligible to continue receiving treatment in the optional long-term follow up portion of the study, which is ongoing.

About NF1-PN

Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.2,3 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and approximately 100,000 patients living with NF1 in the United States.4,5 The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment.6 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.3

NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.7,8 NF1-PNs are most often diagnosed in the first two decades of life.7 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.9,10

Surgical removal of these tumors is challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.11 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.12

About Mirdametinib

Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. Mirdametinib is an investigational drug for which safety and efficacy have not been established.

Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and plays a central role in multiple cancers and rare diseases when genetically altered.

The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1.

On July 01, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Orion Corporation ("Orion") reported that notice has been provided of the mutual exercise of an option to convert the companies’ ongoing co-development and co-commercialization agreement for opevesostat (MK-5684/ODM-208), an investigational CYP11A1 inhibitor, and other candidates targeting CYP11A1 into an exclusive global license for Merck (Press release, Merck & Co, JUL 1, 2024, View Source [SID1234644624]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are pleased with the progress made to date in our collaboration with Orion, including the initiation of two pivotal Phase 3 trials evaluating opevesostat in certain patients with metastatic castration-resistant prostate cancer," said Dr. Dean Y. Li, president, Merck Research Laboratories. "We will continue to advance the clinical development program for opevesostat with speed and rigor to help address the needs of patients living with prostate cancer."

"The conversion of this collaboration into a license agreement allows Orion to focus our resources to progress our other promising development candidates while both remaining well positioned to benefit from the development and potential commercialization of opevesostat and meeting our financial objectives," said Liisa Hurme, president and chief executive officer, Orion Corporation. "We believe Merck provides the best choice to maximize the potential of opevesostat, a compound discovered by Orion’s scientists, for the treatment of patients with certain types of prostate cancer."

As previously announced under the companies’ original co-development and co-commercialization agreement, each party was granted an option to convert the co-exclusive license into an exclusive global license for Merck. With the exercise of the option, Merck will gain global exclusive rights to develop and commercialize opevesostat and other candidates targeting CYP11A1 covered by the agreement.

Under the terms of the agreement, Orion is now eligible to receive development milestone payments up to $30 million, regulatory milestone payments up to $625 million and sales-based milestone payments up to $975 million as well as annually tiered royalty payments ranging from a low double-digit rate up to a rate in the low twenties on net sales for any commercialized licensed product. The development and regulatory milestones are determined by the scope of a number of treatment indications and multiple geographies. Annual sales exceeding several billion US dollars would be required to reach the total amount of the sales milestones and higher end of the royalty rate. In addition, as a result of the exercise of the option, Merck will now assume full responsibility for all past and future development and commercialization expenses associated with the candidates covered by the agreement. As a result of the option exercise and Merck’s assumption of expenses, Orion announced it will release €60 million that was reserved in July 2022 to cover Orion’s share of development cost to be accrued from the balance sheet to net sales and operating profit in Q3 2024. Orion will retain responsibility for the manufacture of clinical and commercial supply for Merck. No payment is associated with the exercise of this option.

The exclusive global license is subject to approval under the Hart-Scott-Rodino Antitrust Improvements Act and other customary conditions, and is expected to become effective in the third quarter of 2024.

About opevesostat and clinical trial program

Opevesostat is an oral, non-steroidal and selective inhibitor of CYP11A1 discovered and developed by Orion and is being investigated for the treatment of hormone-dependent cancers, such as prostate cancer. By inhibiting CYP11A1 activity, opevesostat is designed to suppress the production of all steroid hormones and their precursors that may activate the androgen receptor signaling pathway.

In 2023, Merck and Orion initiated OMAHA1 (NCT06136624) and OMAHA2a (NCT06136650), two pivotal Phase 3 clinical trials evaluating opevesostat in combination with hormone replacement therapy (HRT), for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC).

OMAHA1 is a randomized, open-label Phase 3 trial evaluating opevesostat in combination with HRT for the treatment of patients with later-line mCRPC who have failed one prior new hormonal agent (NHA) and one or two prior taxanes compared to an alternative NHA (abiraterone or enzalutamide). The trial will enroll an estimated 1,200 patients around the world. The primary endpoints are overall survival (OS) and radiographic progression-free survival (rPFS) by androgen receptor ligand-binding domain (AR LBD) mutation status. Secondary endpoints include time to first subsequent therapy (TFST), objective response rate (ORR) and duration of response (DOR).

OMAHA2a is a randomized, open-label Phase 3 trial evaluating opevesostat in combination with HRT for the treatment of patients with front-line mCRPC who have failed one prior NHA compared to physician’s choice of NHA (abiraterone or enzalutamide). The trial will enroll an estimated 1,500 patients around the world. The primary endpoints are OS and rPFS by AR LBD mutation status. Secondary endpoints include TFST, ORR and DOR.

About metastatic castration-resistant prostate cancer

Prostate cancer is the second most common cancer in male patients globally and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with metastatic castration-resistant prostate cancer (mCRPC), their prostate cancer grows and spreads to other parts of the body, despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20% of patients with prostate cancer are estimated to develop castration-resistant prostate cancer (CRPC) within five years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.

On July 1, 2024 Eisai reported that it has agreed to end its global strategic collaboration with Bristol Myers Squibb for the co-development and co-commercialization of farletuzumab ecteribulin (FZEC), formerly known as MORAb-202, a folate receptor alpha (FRα)-targeting antibody drug conjugate (ADC) due to ongoing portfolio prioritization efforts within Bristol Myers Squibb (Press release, Eisai, JUL 1, 2024, View Source [SID1234644623]). Based on the agreement, Eisai now owns all rights to FZEC and will solely conduct the global development and commercialization of the agent. Eisai will accelerate the development of the agent as a high priority with the hope to deliver it to patients as early as possible. Eisai plans to refund a part of the unused portion of the $200 million payment it received towards research and development expenses from Bristol Myers Squibb under the collaboration agreement and record the remaining as other income.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

FZEC is Eisai’s first ADC and is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the FRα, and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. Currently, three clinical studies are ongoing: Eisai’s Phase 1/2 study for solid tumors (NCT04300556), and Bristol Myers Squibb’s Phase 2 studies for ovarian, peritoneal and fallopian tube cancers (NCT05613088(New Window)) and non-small cell lung cancer (NCT05577715(New Window)).

Eisai positions oncology as a key franchise area and aims to contribute toward the cure of cancers by exploring the depths of human biology. FZEC development for refractory cancers is a testament of our dedication to addressing the unmet medical needs of patients with cancer. Eisai will make continuous efforts to increase the benefits provided to patients with cancer and their families.

[Notes to Editors]

1. Farletuzumab ecteribulin (FZEC, formerly known as MORAb-202)
FZEC is Eisai’s first antibody drug conjugate (ADC) and that is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the folate receptor alpha (FRα), and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. After FZEC enters the target FRα-positive cancer cells, it is thought that the linker is enzymatically cleaved, releasing eribulin from the antibody leading to its antitumor activity. When the anticancer agent and antibody components of an ADC are separated inside a targeted antigen-positive cancer cell, it is theorized that the released anticancer agent also has a bystander effect on neighboring antigen-negative cancer cells and the component cells of the tumor microenvironment. In pre-clinical studies, FZEC demonstrated a bystander effect*, with antitumor activity on the FRα-negative cancer cells surrounding the FRα-positive cancer cells.

The payload eribulin was the first in the halichondrin class of microtubule dynamics inhibitor. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai, and functions by inhibiting the growth phase of microtubule dynamics which prevents cell division. Eribulin has been approved in countries including Japan, the United States, China, in Europe and in Asia for use in the treatment of advanced breast cancer and liposarcoma (soft tissue sarcoma in Japan).

*Bystander effect: When the anticancer agent and antibody parts of an ADC are separated inside a targeted antigen-positive cancer cell, the released anticancer agent also affects neighboring antigen-negative cancer cells and the component cells of the cancer microenvironment.

On July 1, 2024 Circle Pharma, a leader in macrocycle drug discovery and development, reported the submission of its first Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for CID-078, a first-and-only-in-class cyclin A/B RxL inhibitor (Press release, Circle Pharma, JUL 1, 2024, View Source [SID1234644622]). This milestone marks a significant advancement in the development of novel drug candidates generated by Circle’s proprietary MXMO platform for difficult-to-drug targets in oncology and other serious illnesses.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

CID-078 is an orally bioavailable macrocycle that has shown preclinical efficacy across multiple tumor types characterized by high E2F expression, including small cell lung cancer, triple negative breast cancer, ER-low breast cancer, and HR-positive breast cancer following a CDK 4/6-inhibitor. The IND submission includes comprehensive data from preclinical studies which have demonstrated a safety, efficacy, and pharmacokinetic profile of CID-078 to support the proposed phase 1 trial.

CID-078 is designed to selectively inhibit key protein-to-protein interactions involving cyclins A and B, which are implicated in the proliferation and survival of cancer cells. Cyclins are a family of proteins that function as master regulators of the cell cycle. Early work in the laboratory of Nobel Laureate and Circle Pharma’s Scientific Advisory Board Chair William G. Kaelin Jr., MD, showed that disrupting the function of cyclins in certain types of cancer cells that had dysregulated cell cycle control was synthetic lethal – meaning that these cancer cells were selectively killed while the viability of normal cells was unaffected.1 The mechanism of action of CID-078 offers a novel therapeutic approach to potentially address unmet medical needs in patients with advanced solid tumors who currently have limited therapeutic choices.

"I am proud that we have reached this critical milestone in the development of CID-078," said David J. Earp, CEO of Circle Pharma. "Our team has worked diligently to advance this promising candidate from discovery through preclinical development. The IND filing represents a major step forward in our mission to harness the power of macrocycle therapies to create effective treatments for cancer and other serious illnesses."

"We believe, based on our preclinical data package, that CID-078 has the potential to provide a transformative therapeutic option for patients with cancer," said Michael Cox, PharmD, MHSc, BCOP, head of Early Development and senior vice president. "We are excited to advance CID-078 into clinical studies. This step underscores our commitment to develop innovative therapeutics that target challenging and previously undruggable proteins."

Pending regulatory approval, Circle Pharma plans to initiate a phase 1 clinical trial of CID-078 in patients with advanced solid tumor malignancies. The dose escalation and dose expansion portions of the trial will evaluate safety, tolerability, and pharmacokinetics, as well as anti-tumor activity as assessed by objective response rate and duration of response.

About CID-078, Circle Pharma’s Cyclin A/B RxL Inhibitor Program

CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple xenograft models.

On July 1, 2024 Can-Fite BioPharma Ltd., a biotechnology company with a pipeline of proprietary small molecule drugs that address oncological and inflammatory diseases, reported that a patient with liver decompensated cirrhosis who was treated with Namodenoson at the Soroka Medical Center in Israel under compassionate use showed an improvement in liver indices (Press release, Can-Fite BioPharma, JUL 1, 2024, View Source [SID1234644621]). This drug candidate is currently used in a pivotal Phase III study for patients with advanced liver cancer and a Phase IIb study for MASH (metabolic dysfunction-associated steatohepatitis).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Decompensated cirrhosis is defined as an acute deterioration in liver function in a patient with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage. While some drugs can treat symptoms, there is no therapeutic approach that has shown efficacy in slowing disease progression.

In the past year Can-Fite has initiated a compassionate use program at the Soroka Medical Center, Beersheva, Israel, for the treatment of decompensated patients with Namodenoson. The first patient, a 63-year-old female with a history of decompensated primary biliary cirrhosis is now treated for one year with Namodenoson. Prior to the treatment with Namodenoson and despite best medical care for her underlying disease, she developed ascites and was admitted to the hospital with acute variceal bleeding. Currently, the patient shows improvement in liver function tests hematological parameters and FibroScan values and has not experienced any event of decompensation since starting treatment with Namodenoson. Namodenoson is known to induce liver protective effects in other liver pathologies, and Phase IIa data in patients suffering from MASH (metabolic dysfunction-associated steatohepatitis), responded positively to the drug, showing anti-inflammatory, anti-steatotic, and antifibrotic effects with a very favorable safety profile.

Ohad Etzion, MD, Director, Department of Gastroenterology and Liver Diseases at the Soroka Medical Center, Beer Sheva, Israel, the Investigator and Initiator of this study commented, "We were very much encouraged by the response of the first patient with decompensated liver cirrhosis who showed a rapid and sustained response to the drug with an improvement with liver indices. We plan to treat more patients and hopefully see an improvement of liver function in this devastating disease.

Decompensated cirrhosis is defined as an acute deterioration in liver function, with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage. While some drugs can treat symptoms, there is no therapeutic approach that has shown efficacy in slowing disease progression. An estimated 10.6 million people globally had decompensated cirrhosis in 2017, with few treatment options available aside from liver transplants if the decompensated cirrhosis has reached an advanced stage. Underscoring the need for an effective treatment, the American Liver Foundation states there are more people who need a liver than supply available, and some people can be on the wait list for a liver transplant for more than 5 years. The treatment of liver cirrhosis globally is estimated to become an approximately $29.2 billion market by 2031.

About Namodenoson

Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). Namodenoson was evaluated in Phase II trials for two indications, as a second line treatment for hepatocellular carcinoma, and as a treatment for Metabolic Dysfunction-Associated Steatohepatitis (MASH). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug.