Claims for Patent: 12,295,925

Summary for Patent: 12,295,925

Title:	Treatment of neurofibromatosis type 1 (NF1) associated plexiform neurofibromas (PN) in pediatric patients with mirdametinib
Abstract:	The present disclosure relates to methods for treating plexiform neurofibromas associated with neurofibromatosis type 1 (NF1-PN), comprising administering to a pediatric patient (e.g., 2 to 15 years of age) in need thereof mirdametinib or a pharmaceutically acceptable salt thereof.
Inventor(s):	Uchenna H. Iloeje, Abraham J. Langseth, Todd Shearer
Assignee:	SpringWorks Therapeutics Inc
Application Number:	US18/648,426
Patent Claims:	1. A method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein the patient has had no prior exposure to MEK inhibitors. 2. The method of claim 1, wherein the patient has symptomatic, inoperable plexiform neurofibromas. 3. The method of claim 1, wherein the neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) are progressing or causing significant morbidity. 4. The method of claim 1, wherein the patient has progressive PN. 5. The method of claim 1, wherein the patient has PNs that cause significant moribidity. 6. The method of claim 1, wherein the patient has head and neck lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions that are causing nerve compression and loss of function, lesions causing major deformity or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, or painful lesions. 7. The method of claim 6, wherein the lesions causing major deformity or are significantly disfiguring are tumors of the head and neck or those on other areas of the body that are unable to be concealed by standard garments. 8. The method of claim 1, wherein the patient has paraspinal lesions. 9. The method of claim 1, wherein the patient has a Lansky performance of at least 60%. 10. The method of claim 1, wherein the patient has the clinical diagnosis of NF1 using the NIH Consensus Conference and one or more of the following: (a) six or more café-au-lait macules with a diameter>5 mm in prepubertal and >15 mm in post-pubertal individuals; (b) freckling in axilla or inguinal regions; (c) optic glioma; (d) two or more Lisch nodules; (e) a distinctive bony lesion; and (f) a first degree relative with NF1. 11. The method of claim 1, wherein the patient has a constitutional NF1 mutation documented in a Clinical Laboratory Improvement Amendments/College of American Pathologists certified lab. 12. The method of claim 1, wherein the patient either (a) has a parent diagnosed with NF1 and one or more criteria of (1) through (7) or (b) does not have a parent diagnosed with NF1 but has two or more criteria of (1) through (7): (1) six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals; (2) freckling in the axillary or inguinal region; (3) two or more neurofibromas of any type or one plexiform neurofibroma; (4) optic pathway glioma; (5) two or more iris Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities; (6) a distinctive osseous lesion; and (7) a heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue. 13. The method of claim 1, wherein (a) for a patient having a body surface area no more than 0.69 m2, the patient is initially administered 1 mg mirdametinib twice daily, (b) for a patient having a body surface area of 0.7 to 1.04 m2, the patient is initially administered 2 mg mirdametinib twice daily, (c) for a patient having a body surface area of 1.05 to 1.49 m2, the patient is initially administered 3 mg mirdametinib twice daily, and (d) for a patient having a body surface area of at least 1.5 m2, the patient is initially administered 4 mg mirdametinib twice daily. 14. A method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein the patient has had no prior exposure to MEK inhibitors and wherein the maximum daily dose is 4 mg mirdametinib twice daily. 15. A method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising orally administering an effective amount of mirdametinib to the patient, wherein the patient has had no prior exposure to MEK inhibitors and wherein over each four week period, the mirdametinib is administered for the first three weeks and discontinued for the last one week. 16. The method of claim 1, wherein the patient has at least a 20% reduction in plexiform neurofibroma volume as determined by volumetric magnetic resonance imaging analysis following treatment with mirdametinib. 17. The method of claim 1, wherein the treatment results in decreased pain intensity. 18. The method of claim 1, wherein the treatment results in decreased pain interference. 19. The method of claim 1, wherein the dose administered is reduced due to an adverse event, wherein the dose is reduced as follows: (a) if the dose at the time of the event is 1 mg mirdametinib twice daily, then the reduced daily dose is 1 mg mirdametinib administered in the morning only; (b) if the dose at the time of the event is 2 mg mirdametinib twice daily, then the reduced daily dose is 2 mg mirdametinib administered in the morning and 1 mg mirdametinib administered in the afternoon or evening; (c) if the dose at the time of the event is 3 mg mirdametinib twice daily, then the reduced daily dose is 2 mg mirdametinib administered twice daily; and (d) if the dose at the time of the event is 4 mg mirdametinib twice daily, then the reduced daily dose is 3 mg mirdametinib administered twice daily. 20. The method of claim 19, wherein the adverse event resulting in the dose reduction is acneiform. 21. The method of claim 1, wherein the method further comprises prior to treatment, selecting mirdametinib as a treatment for the patient at least based on its objective response rate, where the objective response rate is defined as at least a 20% decrease in tumor size using centrally read MRI volumetric analysis. 22. The method of claim 21, wherein mirdametinib is selected based on a response rate of at least 70%. 23. A method of treating a pediatric human patient 2 to 15 years of age who has neurofibromatosis type 1 (NF1) associated inoperable plexiform neurofibromas (PN) comprising twice daily (i) disintegrating or dissolving a dispersible tablet comprising 1 mg mirdametinib in a potable liquid to form a solution, and (ii) orally administering the solution to the patient. 24. The method of claim 10, wherein the distinctive bony lesion is dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex. 25. The method of claim 12, wherein the distinctive osseous lesion is sphenoid dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone.