On March 4, 2024 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that the Company has initiated a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for mirdametinib, an investigational MEK inhibitor, in pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) (Press release, SpringWorks Therapeutics, MAR 4, 2024, View Source [SID1234640737]).

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"There is tremendous potential for mirdametinib to address the substantial needs that exist for children and adults with NF1-PN, and the initiation of our rolling NDA submission brings us one step closer toward our goal of providing these patients with a best-in-class therapy that could make a significant impact on their lives," said Saqib Islam, Chief Executive Officer of SpringWorks. "We are excited to advance the regulatory filing for our second product and look forward to working closely with the FDA on their review of our application."

The NDA submission includes data from the Phase 2b ReNeu trial, a multi-center, open-label study that opened across 50 sites in the U.S. and enrolled 114 patients across two cohorts (pediatric and adult). The primary endpoint was confirmed objective response rate (ORR), defined as ≥ 20% reduction in target tumor volume as measured by MRI and assessed by Blinded Independent Central Review (BICR). As of the data cutoff date of September 20, 2023, the BICR-confirmed objective response rate was 52% in pediatric patients and 41% in adult patients. Mirdametinib treatment showed deep and durable responses and demonstrated significant improvements in key secondary patient-reported outcome measures. Pediatric and adult patients in the ReNeu trial experienced statistically significant improvements from baseline in pain, quality of life, and physical function, as assessed across multiple patient-reported outcome tools. Mirdametinib was generally well tolerated in the trial, with the majority of adverse events (AEs) being Grade 1 or Grade 2. The most frequently reported AEs were rash, diarrhea, and vomiting in the pediatric cohort and rash, diarrhea, and nausea in the adult cohort.

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. In July 2023, the FDA granted mirdametinib Rare Pediatric Disease designation for the treatment of NF1, which provides eligibility for a priority review voucher upon FDA approval. SpringWorks expects to complete the NDA submission in the second quarter of 2024.

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 two years of age and older 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 is administered orally in a 3-week on, 1-week off dosing schedule and has a pediatric formulation (dispersible tablet) for patients who cannot swallow a pill. The primary endpoint of the ReNeu trial is confirmed objective response rate defined as ≥ 20% reduction in target tumor volume as measured by MRI and assessed by BICR. Secondary endpoints include safety and tolerability, duration of response, and changes from baseline in patient reported outcomes.

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.1,2 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.3,4 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.5 Patients with NF1 have an eight to 15-year mean reduction in their life expectancy compared to the general population.2

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.6,7 Patients with NF1-PN can also experience additional manifestations, including neurocognitive deficits and developmental delays. NF1-PNs are most often diagnosed in the first two decades of life.9 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.10,11

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.12 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.13

About Mirdametinib

Mirdametinib is a potent, oral, 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 that plays a central role in multiple oncology and rare disease indications when genetically altered.

The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity.

On March 4, 2024 Nerviano Medical Sciences S.r.l. (NMS), a part of NMS Group S.p.A. (NMS Group) and Nerviano Medical Sciences, Inc. (NMS-US), a wholly owned subsidiary of NMS Group, focused on the discovery and development of oncology drugs and the largest oncological R&D company in Italy, reported that European Commission has granted Orphan Drug Designation (ODD) for NMS-03592088 for the treatment of Acute Myeloid Leukemia (AML), just a few weeks after the US Food and Drug Administration (FDA) approval (Press release, Nerviano Medical Sciences, MAR 4, 2024, View Source [SID1234640736]).

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NMS-0359288 is a next generation FLT3 inhibitor with superior activity and selectivity with respect to approved FLT3 inhibitor drugs and higher potency on the resistance mutation F691L opening opportunities for treatment of patients who failed prior FLT3 inhibitor treatment. NMS-03592088 is being evaluated as monotherapy in a Phase I/II study in relapsed/refractory FLT3 positive AML in Europe and US. Preliminary evidence of clinical activity was observed during the dose escalation phase when administered as salvage line therapy including patients with prior FLT3 inhibitors (AACR2023). Based on these results the Committee for Orphan Medicinal Products released its positive opinion stating that "the drug showed responses in heavily pretreated patients with acute myeloid leukaemia including those who have failed treatment with the currently authorized medicinal product. The Committee considered that this constitutes a clinically relevant advantage."

After having completed Phase I in Europe, the trial is currently enrolling patients in multiple Phase II cohorts (NCT03922100).

"As we expand our focus to embrace the orphan drug destination in the EU for NMS-03592088, following the ODD approval by FDA last December, we are determined to bring new therapies to AML patients. Our dedication to innovation for patients worldwide is strong ." said Lisa Mahnke, MD, PhD, CMO of NMS | CEO and Managing Director of NMS-US.

"We are diligently implementing strategies to accelerate the development of NMS-03592088 as a promising new therapeutic option for patients battling AML with very few options. The Orphan Drug Designation is a key regulatory milestone that acknowledges the potential of NMS-03592088 for positioning as next generation FLT3 inhibitor and reinforces our commitment to expedite its development through the approval process" said Elena Ardini, MSc, Asset Leader of NMS.

Orphan drug designation in the European Union (EU) is granted by the European Commission based on a positive opinion issued by the European Medical Association (EMA) Committee for Orphan Medicinal Products. The EMA grants orphan designation for the treatment, diagnosis or prevention of life-threatening or chronically debilitating diseases or conditions that affect fewer than five in 10,000 persons in the EU. Drugs that meet the EMA’s orphan designation criteria qualify for financial and regulatory incentives that include a 10-year period of marketing exclusivity in the EU after product approval, reduced regulatory fees, access to protocol assistance from the EMA during development and access to centralized marketing authorization.

On March 4, 2024, Nektar Therapeutics (the "Company") reported to have entered into a securities purchase agreement (the "Purchase Agreement") with TCG Crossover Fund II, L.P. (the "Purchaser"), for the private placement (the "Private Placement") of a pre-funded warrant (the "Pre-Funded Warrant") to purchase 25,000,000 shares of the Company’s common stock (the "Common Stock"), par value $0.0001 per share (the "Warrant Shares" and together with the Pre-Funded Warrant, the "Securities"), at a total purchase price of $30.0 million (or a purchase price of $1.20 per Warrant Share that can be issued upon exercise of the Pre-Funded Warrant) (Filing, 8-K, Nektar Therapeutics, MAR 4, 2024, View Source [SID1234640735]). The Pre-Funded Warrant will have an exercise price of $0.0001 per share of Common Stock. The holder of the Pre-Funded Warrant may not exercise the Pre-Funded Warrant if the holder, together with its affiliates, would beneficially own more than 9.99% of the number of shares of Common Stock outstanding immediately after giving effect to such exercise. The holder of the Pre-Funded Warrant may increase or decrease such percentages not in excess of 19.99% by providing at least 61 days’ prior notice to the Company. The aggregate gross proceeds for the Private Placement will be $30 million, before deducting expenses payable by the Company.

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The closing of the Private Placement is anticipated to occur on or before March 6, 2024 (the "Closing Date"), subject to the satisfaction of customary closing conditions. Pursuant to the Purchase Agreement, the Company also agreed to file a registration statement with the Securities and Exchange Commission (the "SEC") on or before the date that is ninety (90) days after the Closing Date for purposes of registering the resale of the Warrant Shares and to use its reasonable best efforts to have such registration statement to be declared effective within the time period set forth in the Purchase Agreement. The Company also agreed, among other things, to indemnify the Purchaser and the Purchaser’s affiliates against certain liabilities in connection with such registration statement and pay all fees and expenses (excluding any fees and expenses of counsel or other advisers to the Purchaser, and any underwriting discounts, brokerage fees and selling commissions incurred by the Purchaser) in connection with the filing of such registration statement and the registration of the Warrant Shares pursuant to such registration statement.

The Private Placement is exempt from registration pursuant to Section 4(a)(2) of the Securities Act of 1933, as amended (the "Securities Act") and Rule 506(b) of Regulation D promulgated by the SEC thereunder, as a transaction by an issuer not involving a public offering. The Purchaser has acquired the Securities for investment only and not with a view to or for sale in connection with any distribution thereof, and appropriate legends have been affixed to the Securities issued in this transaction.

The foregoing summaries of the Private Placement, the Purchase Agreement and the form of Pre-Funded Warrant do not purport to be complete and are qualified in their entirety by reference to the Purchase Agreement and the form of Pre-Funded Warrant, which are filed as Exhibits 10.1 and 4.1, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.

On March 4, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, is scheduled to participate in a fireside chat at the Leerink Partners Global Biopharma Conference 2024 on Monday, March 11, 2024, at 12:40 p.m. ET (Press release, Merck & Co, MAR 4, 2024, View Source [SID1234640733]).

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Investors, analysts, members of the media and the general public are invited to listen to a live audio webcast of the presentation at this weblink.

On March 4, 2024 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a commercial biotechnology company focused on innovating, developing, and delivering novel polyclonal tumor infiltrating lymphocyte (TIL) therapies for patients with cancer, reported that the U.S. Food and Drug Administration (FDA) lifted a partial clinical hold placed on the registrational IOV-LUN-202 trial investigating LN-145 TIL cell therapy in non-small cell lung cancer (NSCLC) (Press release, Iovance Biotherapeutics, MAR 4, 2024, View Source [SID1234640731]). In collaboration with the FDA and an independent data monitoring committee, Iovance developed additional safety and monitoring measures. Upon reviewing this proposal, the FDA has cleared Iovance to resume patient enrollment in IOV-LUN-202.

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The IOV-LUN-202 trial is investigating LN-145 in patients with advanced (unresectable or metastatic) NSCLC without EGFR, ROS or ALK genomic mutations who were previously treated with chemotherapy and anti-PD-1 therapy and at least one line of an approved targeted therapy if indicated by other actionable tumor mutations. Iovance expects to complete enrollment of approximately 120 patients in the IOV-LUN-202 registrational cohorts in 2025.

Preliminary data from the IOV-LUN-202 trial support the potential benefit of one-time TIL therapy, including the opportunity for more durable responses than available second line chemotherapies. Initial preliminary data were reported in July of 2023. An updated analysis in November of 2023 showed additional ongoing responses and duration of response greater than six months for 71% of the confirmed responders in the trial.

For more information about the IOV-LUN-202 trial please visit www.lungcelltherapy.com.