# US 11,433,059 B2 · BYL719 (alpelisib) for use in the treatment of PIK3CA-related overgrowth spectrum (pros-CLOVES syndrome)

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- Number: US 11,433,059 B2
- Document ID: US11433059B2
- Status: Granted
- Kind: B2
- Application number: 15/998,950
- Filed: 2017-02-17
- Published: 2020-07-09
- Granted: 2022-09-06
- Earliest claimed: 2016-02-19
- Assignees: Inserm (Institut National De La Sante Et De La Recherche Medicale); Centre National de la Recherche Scientifique (CNRS); Université Paris Cité; Assistance Publique-HôPitaux De Paris (Aphp)
- Applicants: Inserm (Institut National De La Santé Et De La Recherche MéDicale); Centre National De La Recherche Scientifique (Cnrs); Université Paris Cité; Assistance Publique-HôPitaux De Paris (Aphp)
- Inventors: Guillaume Canaud
- Web page: https://patentgrep.com/patent/US11433059B2

## CPC

- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 19/00: Drugs for skeletal disorders
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a method of treating PIK3CA-Related Overgrowth Spectrum (PROS) more particularly, Congenital, Lipomatous, Overgrowth, Vascular Malformations, Epidermal Nevi and Spinal/Skeletal Anomalies and/or Scoliosis (CLOVES) 10 syndrome. To date, there are no specific treatments for patients and no animal models of PROS to better understand the physiopathology of the disorder. Inventors developed a genetic mouse model of PROS that recapitulates the human disease and demonstrated the efficacy of BYL719. Based on these results they treated two patients, one adult and one child, with severe CLOVES syndrome using BYL719. The drug had a robust efficiency on disease in the 15 two patients inducing quick recovery of all affected organs. Thus, the invention relates to a method of treating PROS in a subject in need thereof comprising the step of administrating the subject with a therapeutically effective amount of BYL719.

## Claims

### Claim 1

A method of treating a subject having a PIK3CA-related overgrowth spectrum (PROS) disorder, comprising the steps of
identifying the subject as suffering from the PROS disorder and having an overgrowth of multiple organs or tissues caused by a somatic mosaic mutation;
administering orally to the subject a therapeutically effective amount of BYL719, wherein the therapeutically effective amount of BYL719 is sufficient to treat said PROS disorder; and reverses said overgrowth of multiple organs or tissues, wherein said PROS disorder is not responsive to treatment with rapamycin.

### Claim 2 (depends on 1)

The method of claim 1, wherein the PROS disorder is Congenital Lipomatous Overgrowth, Vascular Malformation, Epidermal Nevi and Spinal/Skeletal Anomalies and/or Scoliosis (CLOVES) syndrome.

### Claim 3 (depends on 1)

The method of claim 1, wherein the PROS disorder is Klippel-Trenaunay syndrome.

### Claim 4 (depends on 1)

The method of claim 1, wherein BYL719 is administered daily and the dose is in the range of 25 to 250 mg or in the range of 0.5 to 6 mg/kg.

### Claim 5 (depends on 1)

The method of claim 1, wherein the subject is an adult, and the therapeutically effective amount is a starting dose of at least 250 mg per day.

### Claim 6 (depends on 1)

The method of claim 1, wherein the subject is a child, and the therapeutically effective amount is a starting dose of at least 50 mg per day.

### Claim 7 (depends on 1)

The method of claim 1, wherein the subject is an infant, and the therapeutically effective amount is a starting dose of at least 25 mg per day.

### Claim 8

A method of treating a plurality of symptoms of a PIK3CA-related overgrowth spectrum (PROS) disorder in an adult, child or infant suffering from a PROS disorder, comprising the steps of
identifying an adult, child or infant suffering from a PROS disorder causing the plurality of symptoms due to overgrowth of multiple organs or tissues,
administering orally to the subject with a therapeutically effective amount of BYL719 in the range of 15 to 500 mg or in the range of 0.3 to 12 mg/kg, and
reversing the plurality of symptoms due to overgrowth of multiple organs or tissues, wherein the plurality of symptoms are selected from the group consisting of paraplegia, loss of bladder control, edema, enlarged circumference of thorax and abdomen, venous dilation, vascular tumors, elevated brain natriuretic peptide blood level, proteinuria, kidney dysfunction, cardiac enlargement, cardiac dysfunction, overgrown tissue, limb hypertrophy, dysregulated adipose tissue, scoliosis, enlarged bony structures without progressive bony overgrowth, benign tumors, megalencephaly-capillary malformation, lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, epidermal nevi, lymphatic malformation, muscle hypertrophy, kidney dysfunction, liver steatosis and spleen disorganization, and wherein the PROS disorder is selected from the group consisting of
fibroadipose overgrowth;
megalencephaly-capillary malformation syndrome;
congenital lipomatous asymmetric overgrowth, lymphatic capillary, venous and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies and/or scoliosis (CLOVES) syndrome;
hemihyperplasia multiple lipomatosis; and
Klippel-Trenaunay syndrome, and
wherein said PROS disorder is not responsive to treatment with rapamycin.

### Claim 9 (depends on 4)

The method of claim 4, wherein the subject is an adult, and the therapeutically effective amount is a starting dose of at least 250 mg per day.

### Claim 10 (depends on 4)

The method of claim 4, wherein the subject is a child, and the therapeutically effective amount is a starting dose of at least 50 mg per day.

### Claim 11 (depends on 4)

The method of claim 4, wherein the subject is an infant and the therapeutically effective amount is a starting dose of at least 25 mg per day.

### Claim 12 (depends on 8)

The method of claim 8, wherein the PROS disorder is CLOVES syndrome.

### Claim 13 (depends on 8)

The method of claim 8, wherein the PROS disorder is Klippel-Trenaunay syndrome.

### Claim 14

A method of treating a patient who is an adult having a PIK3CA-related overgrowth spectrum (PROS) disorder caused by a somatic mosaic mutation, comprising the steps of
identifying the subject as suffering from the PROS disorder of an overgrowth of multiple organs or tissues;
administering orally to the subject a therapeutically effective amount of BYL719, wherein the therapeutically effective amount of BYL719 is a starting dose of 250 mg daily; and
reversing the overgrowth of multiple organs or tissues;
wherein said PROS disorder is not responsive to treatment with rapamycin.

### Claim 15

A method of treating a patient who is a child having a PIK3CA-related overgrowth spectrum (PROS) disorder caused by a somatic mosaic mutation, comprising the steps of
identifying the subject as suffering from the PROS disorder of an overgrowth of multiple organs or tissues;
administering orally to the subject a therapeutically effective amount of BYL719, wherein the therapeutically effective amount of BYL719 is a starting dose of 50 mg daily; and
reversing the overgrowth of multiple organs or tissues;
wherein said PROS disorder is not responsive to treatment with rapamycin.

### Claim 16 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of BYL719 is in the range of 15 to 500 mg or the range of 0.3 to 12 mg/kg.