US Appl. No.: N218213 Applicant Holder: Bristol Myer Squibb Co.
Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1G2032R, CD74-ROS1, CD74-ROS1G2032R, CD74 ROS1D2033N, and CD74-ROS1L2026M.
Pfizer’s Xalkori and Roche’s Rozlytrek are currently approved to target it. Bristol Myers believes Augtyro has an opportunity to roughly double the size of the ROS1 market, which the company has estimated to be around $500 million to $600 million, based on annual revenue from Xalkori and Rozyltrek. (Jonathan Gardner, FDA approves new Bristol Myers drug for lung cancer, www.biopharmadive.com, Nov. 16, 2023)
As of April 14, 2024, there is no ANDA approved for AUGTYRO.
INDICATIONS AND USAGE
AUGTYRO is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).
API
Repotrectinib is a kinase inhibitor. The molecular formula for repotrectinib is C18H18FN5O2 and the molecular weight is 355.37 Daltons. Repotrectinib is a white to off-white powder, slightly or insoluble in water.
EXCIPIENTS
AUGTYRO (repotrectinib) capsules for oral use are supplied as printed hard shell capsules containing 40 mg of repotrectinib. Inactive ingredients are microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, and colloidal silicon dioxide. The white opaque capsule shell contains gelatin and titanium dioxide. The printing ink contains shellac and FDC blue #2 aluminum lake.
DOSAGE AND ADMINISTRATION
Select patients for the treatment of locally advanced or metastatic NSCLC with AUGTYRO based on the presence of ROS1 rearrangement(s) in tumor specimens. An FDA-approved test to detect ROS1 rearrangements for selecting patients for treatment with AUGTYRO is not currently available.
Prior to initiating AUGTYRO, discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor.
Prior to initiation of AUGTYRO, evaluate liver function tests including bilirubin and uric acid level.
The recommended dosage of AUGTYRO is 160 mg taken orally once daily with or without food for 14 days, then increase to 160 mg twice daily and continue until disease progression or unacceptable toxicity.
Administration
Take AUGTYRO at approximately the same time each day with or without food
PK
Repotrectinib Cmax and AUC0-inf increases approximately dose proportional over the single dose range of 40 mg to 240 mg. Steady state PK was time-dependent with an autoinduction of CYP3A4. Steady state is achieved within 14 days of daily administration of 160 mg.
Absorption
The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%).
Tmax: 2 to 3 hours post a single oral dose of 40 mg to 240 mg under fasted conditions
Food Effect: No clinically significant
Plasma protein blinding: 95.4% in vitro
Repotrectinib elimination: time-dependent due to autoinduction of CYP3A4.
Mean terminal half-life: 50.6 h for patients with cancer following a single dose.
Steady state terminal half-life: 35.4 h for patients with cancer.
Metabolism: Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation.
Excretion: Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces.
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
Central Nervous System Adverse Reactions
Interstitial Lung Disease (ILD)/Pneumonitis
Hepatotoxicity
Myalgia with Creatine Phosphokinase Elevation
Hyperuricemia
Skeletal Fractures
Embryo-Fetal Toxicity
ORANGE BOOK PATENTS (AS OF 04/15/2024)
9714258 (Exp 01/23/2035): Chemical
10294242(Exp 07/05/2036): A crystalline polymorph form
11452725(Exp 07/24/2036): A method of treating a cancer
The Independent Claim of 10294242: 1. A crystalline polymorph form of (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin-4(5H)-one, wherein the crystalline polymorph form has a powder X-ray diffraction pattern comprising a peak at diffraction angle (2θ) of 27.4±0.1.
Claim 1 of 11452725: A method of
treating a cancer in a patient in need thereof, comprising administering
to the patient a therapeutically effective amount of Compound 1:
or a pharmaceutically acceptable salt thereof,
wherein the
cancer is mediated by a kinase selected from the group consisting of
ALK, ROS1, TRKA, TRKB, TRKC, JAK1, JAK2, JAK3, SRC, FYN, LYN, YES, FGR,
FAK, and ARK5.
Claim 13 of 11452725: A method of treating a cancer in a patient, comprising:
(i) identifying a
genetically altered kinase selected from the group consisting of ALK,
ROS1, TRKA, TRKB, TRKC, JAK1, JAK2, JAK3, SRC, FYN, LYN, YES, FGR, FAK,
and ARK5, in the patient, and
(ii) administering to the patient a therapeutically effective amount of Compound 1:
or a pharmaceutically acceptable salt thereof.
