- Hepatic Transaminase Elevations: During the 52-week treatment period of Trial DM,
- Alanine transaminase (ALT) ≥ 3 x upper limit of normal (ULN) were observed in 7 (9%) placebo-treated patients and 8 (9.9%) LISRAYA-treated patients.
- Aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) were observed in 3 (3.8%) placebo-treated patients and 4 (4.9%) LISRAYA-treated patients.
- One case of probable drug-induced liver injury (mixed pattern with marked GGT elevation, normal bilirubin, and low concurrent creatine kinase [CK]) was reported in a patient who received brepocitinib 15 mg. The event resolved following discontinuation of brepocitinib.
- Lipid Elevations: During the 52-week treatment period of Trial DM, LISRAYA treatment was associated with increases in total cholesterol, HDL cholesterol, and LDL cholesterol. Elevation in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In the 52-week treatment period of Trial DM, changes from baseline in lipid parameters in LISRAYA-treated patients are summarized below:
- Mean LDL cholesterol increased by 3.8 mg/dL.
- Mean HDL cholesterol increased by 4.5 mg/dL.
- Mean LDL/HDL ratio remained stable.
Smoking
Smoking causes induction of CYP1A1 and CYP1A2 levels. The exposure of brepocitinib in current smokers is lower than in non-current smokers, and therefore, the effectiveness of LISRAYA may be reduced in smokers [see Clinical Pharmacology (12.3)].
Substrates of P-gp and BCRP
Brepocitinib is a P-gp and BCRP inhibitor. Concomitant use of LISRAYA with an orally administered P-gp or BCRP substrate may increase the systemic exposure of the P-gp or BCRP substrate [see Clinical Pharmacology (12.3)].
Substrates of OCT2 or MATEs Transporters
Brepocitinib inhibits renal uptake transporters, OCT2 and MATEs (MATE1, MATE2-K) [see Clinical Pharmacology (12.3)]. Concomitant use of LISRAYA with drugs that are substrates of OCT2 and MATEs transporters may increase plasma concentrations of the substrates. Closely monitor patients when LISRAYA is concomitantly used with drugs that are substrates of OCT2 or MATEs transporters for which minimal concentration changes in substrate plasma concentration may lead to serious adverse reactions.
Risk Summary
Based on findings in animal studies, LISRAYA may cause fetal harm when administered to a pregnant woman. Available data from LISRAYA use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
In animal reproduction studies, fetal skeletal malformations, and post-implantation loss were observed when brepocitinib was administered to pregnant rats and rabbits during the period of organogenesis at 1.6- and 3-times the exposure at the MRHD, respectively. In a pre- and postnatal study in rats, brepocitinib did not cause adverse effects in maternal animals or offspring at exposures up to 5.5 times the MRHD.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15 % to 20%, respectively.
There is a pregnancy safety study for LISRAYA. If LISRAYA is administered during pregnancy, healthcare providers or patients should report LISRAYA exposure to Priovant Therapeutics by calling 1-800-511-9141 or by emailing [email protected].
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with dermatomyositis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Data
Animal Data
In rat embryofetal developmental studies, pregnant rats were administered brepocitinib orally during the period of organogenesis. Skeletal malformations, early and late resorptions, post-implantation loss, and lower mean numbers of viable fetuses were observed with exposures 1.6 times the MRHD. No adverse effects were observed at 1.3 times the MRHD.
In a rabbit embryofetal developmental study, pregnant rabbits were administered brepocitinib orally during the period of organogenesis. Increase of late resorptions, post-implantation loss, lower mean numbers of viable fetuses, and skeletal malformations were observed at 3 times the MRHD. No developmental toxicity was observed in rabbits at 0.8 times the MRHD.
In a pre- and postnatal development study, pregnant rats were administered brepocitinib orally from gestation day 6 through day 21 of lactation. No effects on postnatal developmental, neurobehavioral, or reproductive performance of offspring were noted at 5.5 times the MRHD.
Risk Summary
There are no data on the presence of brepocitinib in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, including infections, GI perforation, and malignancy, advise patients that breastfeeding is not recommended during treatment with LISRAYA and for 3 days (approximately 5 half-lives) after the last dose.
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to starting treatment with LISRAYA [see Use in Specific Populations (8.1)].
Contraception
Females: Advise females of reproductive potential to use effective contraception during treatment with LISRAYA and for 3 days after the last dose.
Inhibition of Type I IFN and IL-6 induced STAT1 and STAT3 phosphorylation
In peripheral blood mononuclear cells isolated from dermatomyositis patients, brepocitinib resulted in concentration-dependent inhibition of Type I IFN induced and IL-6 induced phosphorylation of STAT1 and STAT3.
Inhibition of IFNγ, IL-10, IL-12, IL-13, and IL-23 induced STAT phosphorylation
In whole blood from healthy donors, brepocitinib resulted in concentration-dependent inhibition of IFNγ, IL-10, IL-12, IL-13, and IL-23 induced STAT1, STAT3, STAT4, STAT6, and STAT3 phosphorylation, respectively.
Gene Expression
After administration of LISRAYA 30 mg once daily to patients with dermatomyositis, expression of genes associated with Type I signaling were reduced by Week 12 and sustained through Week 52 in whole blood. The clinical relevance is unclear.
Cardiac Electrophysiology
LISRAYA caused concentration-dependent QTc interval prolongation with a supratherapeutic dose of 200 mg (6.67 times the approved recommended dose). At the maximum recommended LISRAYA oral dose of 30 mg once daily, clinically significant QTc interval prolongation is not expected.
Absorption
Following oral administration of LISRAYA, the median Tmax of brepocitinib is 1 hour. The absolute oral bioavailability of LISRAYA is approximately 75%.
Effect of Food
Coadministration of LISRAYA with a high-fat meal (approximately 50% fat and 800-1000 calories) resulted in 18% decrease in AUC and 36% decrease in Cmax
[see Dosage and Administration (2.2)].
Distribution
Brepocitinib is 39% bound to plasma proteins. The blood to plasma partition ratio is 0.84.
Elimination
Metabolism
Brepocitinib is primarily cleared by metabolism, which is mediated mainly by cytochrome P450 (CYP)1A1 and CYP1A2 with minor contribution from CYP3A4. The pharmacologic activity of brepocitinib is attributed to the parent molecule. In a human radiolabeled study, unchanged brepocitinib and the major inactive metabolite M1 accounted for 48% and 37% of the total circulating radioactivity in plasma, respectively.
Excretion
Following oral administration of radiolabeled brepocitinib in healthy subjects, 88% (7.7% as unchanged and 51% as M1) and 8.7% (0.8% as unchanged and 0.7% as M1) of the total radioactivity was recovered in urine and feces, respectively. Brepocitinib mean terminal half-life ranged from 5.4 to 12 hours.
Specific Populations
Body Weight, Sex, Age, and Race
Based on population PK analysis, body weight (39-204 kg), sex, age (18-77 years) and race (White, Black, Asian, Native American, Pacific Islander, Other Race) did not have a clinically meaningful effect on brepocitinib exposure in adult patient populations.
Patients with Renal Impairment
Following a single oral administration of LISRAYA 30 mg, brepocitinib AUC was 29% lower, 48% higher, and 12% higher in subjects with mild (eGFR: 60 to 89 mL/min, based on Modification of Diet in Renal Disease formula), moderate (eGFR: 30 to 59 mL/min), and severe (eGFR: 15 to 29 mL/min) renal impairment, respectively. Cmax was 5% lower, 24% higher, and 10% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Brepocitinib metabolite M1 AUC was 45% higher, 129% higher, and 346% higher in subjects with mild, moderate, and severe renal impairment, respectively. Cmax was 33% higher, 22% higher, and 78% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function [see Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
Following a single oral administration of LISRAYA 30 mg, brepocitinib AUC and Cmax was 19% higher and 27% lower, respectively, in subjects with moderate hepatic impairment (Child-Pugh B) compared to subjects with normal hepatic function. Brepocitinib metabolite M1 AUC and Cmax was 19% higher and 19% lower, respectively, in subjects with moderate hepatic impairment compared to subjects with normal hepatic function. LISRAYA was not evaluated in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.7)].
Drug Interaction Studies
Effects of Other Drugs on Pharmacokinetics of Brepocitinib
Smoking causes induction of CYP1A1 and CYP1A2 levels. Following the administration of LISRAYA 30 mg once daily, brepocitinib AUC and Cmax at steady state was estimated to be 45% and 33% lower, respectively, in current smokers compared to non-current smokers.
There was no clinically significant effect on the pharmacokinetics of brepocitinib when co-administered with multiple doses of itraconazole 200 mg once daily (CYP3A/P-gp inhibitor).
Effects of Brepocitinib on Pharmacokinetics of Other Drugs
Multiple doses of LISRAYA 60 mg once daily (2 times the approved recommended dosage) did not have a clinically significant effect on the PK of a combined oral contraceptive containing ethinylestradiol and levonorgestrel.
In vitro studies indicate that brepocitinib does not inhibit the activity of enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, or human sulfotransferase enzymes or uridine 5'-diphospho-glucuronosyltransferases at clinically relevant concentrations.
In vitro studies indicate that brepocitinib does not induce CYP3A4, CYP2B6 or CYP1A2 at clinically relevant concentrations.
In vitro studies indicate that brepocitinib does not inhibit the transporters OATP1B1, OATP1B3, OAT1, OAT3, or BSEP. Brepocitinib inhibits OCT1, OCT2, MATE1, MATE2K, P-gp, and BCRP. The observed serum creatinine increase in clinical studies with brepocitinib is likely due to inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K. The effect of brepocitinib on P-gp and BCRP has not been studied.
Carcinogenesis
The carcinogenic potential of brepocitinib was evaluated in Wistar Han rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in mice administered brepocitinib orally up to 150 mg/kg/day. In male rats that received brepocitinib for 104 weeks at oral doses of 30 mg/kg/day (approximately 33 times the MRHD), brepocitinib caused benign Leydig cell tumors. The relevance of this finding to humans is not known. No evidence of tumorigenicity was observed in male or female rats that received brepocitinib for 104 weeks at oral doses up to 10 mg/kg/day or 30 mg/kg/day, respectively (approximately 10 or 33 times the MRHD).
Mutagenesis
Brepocitinib was negative for mutagenesis in the in vitro microbial reverse mutation assay (Ames assay). Brepocitinib was negative for mutagenesis in the in vivo micronucleus assay within rat peripheral blood cells.
Impairment of Fertility
In male rats, brepocitinib had no effect on fertility at oral doses up to 55 mg/kg/day (approximately 54 times the MRHD).
In female rats, brepocitinib reduced fertility at an oral dose of 10 mg/kg/day (approximately 10 times the MRHD) based upon higher early resorptions, higher post-implantation loss and a lower number of live embryos compared to control females. Additionally, maintenance of pregnancy was adversely affected at 55 mg/kg/day (approximately 50 times the MRHD) based upon findings of significantly lower corpora lutea and implantation sites and all pregnant females having total litter loss due to higher pre- and post-implantation loss. Brepocitinib had no effect on female fertility at 3 mg/kg/day (approximately 2 times the MRHD).
Primary Efficacy Endpoint
In Trial DM, the primary endpoint was the mean Total Improvement Score (TIS) at Week 52. The TIS is a composite myositis improvement index reflecting changes in six core set measures (CSMs): Physician Global Assessment (PhGA), Patient Global Assessment (PtGA), Manual Muscle Testing of 8 Muscles (MMT-8), Extramuscular Global Assessment (EMGA), Health Assessment Questionnaire - Disability Index (HAQ-DI), and muscle enzymes (including aldolase, creatine kinase, alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase). TIS values range from 0 to 100 with higher scores representing greater improvement.
Clinical Response
The LISRAYA group achieved a higher mean TIS at Week 52 compared to the placebo group, as shown in Table 3. Treatment with LISRAYA resulted in a higher proportion of patients who achieved a Major Improvement (TIS ≥ 60) at Week 52 compared to treatment with placebo (Table 3).
Table 3: TIS and TIS Responder Rates (% of Patients) at Week 52 in Adult Patients with Dermatomyositis in Trial DM
| Placebo
N = 79 | LISRAYA
N = 81
| Difference vs. Placebo (95% CI) |
|---|
|
|
|
LS Mean TIS (SE)
(Primary Efficacy Endpoint)
| 33.3 (3.7)
| 47.5 (3.4)
| 14.2
(5.5, 22.9)
|
| TIS ≥ 20
| 63%
| 82%
| 19%
(4.9, 33)
|
| TIS ≥ 40
| 47%
| 69%
| 20%
(5.1, 35)
|
| TIS ≥ 60
| 26%
| 48%
| 22%
(6.7, 37)
|
The results for the Core Set Measures are presented in Table 4.
Table 4: Mean Change from Baseline in Core Set Measures (LS Means) at Week 52 in the Adult Patients with Dermatomyositis in Trial DM
|
|
|
| Measure (score range) | Placebo
N=79 | LISRAYA
N=81 | Difference vs. Placebo (95% CI) |
| PhGA (0 to 10)
| -0.9
| -2.6
| -1.6 (-2.8, -0.5)
|
| PtGA (0 to 10)
| -0.6
| -2.5
| -1.9 (-2.9, -0.9)
|
| EMGA (0 to 10)
| -0.2
| -1.8
| -1.6 (-2.8, -0.4)
|
| MMT-8 (0 to 150)
| 5.9
| 12.3
| 6.4 (0.5, 12.3)
|
| HAQ-DI (0 to 3)
| 0.3
| -0.3
| -0.6 (-0.9, -0.3)
|
| Most abnormal muscle enzymea | 36.8%
| 16.9%
| -19.9% (-46.9%, 7.1%)
|
Figure 1 shows the mean TIS score through the 52-week double-blind treatment period.
Figure 1: TIS by Visit Through Week 52 in Adult Patients with Dermatomyositis in Trial DM
Abbreviations: LS: least squares; CI: confidence interval
Effect on Cutaneous Disease
In Trial DM, treatment with LISRAYA resulted in an improvement in skin disease activity, driven primarily by reductions in erythema.
Effect on Concomitant Corticosteroid Treatment
At baseline, 76% of patients received oral corticosteroids, with a mean dose of 11.4 mg/day of prednisone or equivalent in Trial DM. The proportion of patients who achieved TIS ≥ 40 with minimal-to-no corticosteroids (≤ 2.5 mg/day) at Week 52 in the LISRAYA and placebo groups was 55% and 30%, respectively, with a difference of 23.3% (95% CI: 8.3%, 38.2%).
Among patients who received ≥ 7.5 mg/day of corticosteroids at baseline, the proportion of patients who used a corticosteroid dose ≤ 2.5 mg/day at both Week 48 and Week 52 was 62% in the LISRAYA group and 38% in the placebo group, while the proportion of patients with no corticosteroid use (0 mg/day) at both Week 48 and Week 52 was 45% in the LISRAYA group and 29% in the placebo group.
Physical Function Response
In Trial DM, the LISRAYA group showed a higher observed improvement in physical function compared to the placebo group as assessed by HAQ-DI at Week 52.
Serious Infections
Inform patients that they may be more likely to develop infections when taking LISRAYA. Instruct patients to contact their healthcare provider immediately during treatment if they develop any signs or symptoms of an infection [see Warnings and Precautions (5.1)].
Advise patients that the risk of herpes zoster infection is increased in patients taking LISRAYA and some cases can be serious [see Warnings and Precautions (5.1)].
Malignancies
Inform patients that LISRAYA may increase their risk of certain cancers and that periodic skin examinations should be performed while using LISRAYA. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.3)].
Advise patients to limit exposure to ultraviolet light (natural or artificial) by wearing protective clothing and using a broad-spectrum sunscreen.
Major Adverse Cardiovascular Events
Inform patients that LISRAYA may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.4)].
Thrombosis
Advise patients that LISRAYA may increase the risk of thromboembolic events. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions (5.5)].
Hypersensitivity Reactions
Advise patients to discontinue LISRAYA and seek immediate medical attention if they develop any signs and symptoms of an allergic reaction [see Warnings and Precautions (5.6)].
Gastrointestinal Perforations
Inform patients that gastrointestinal perforation has been reported in clinical trials with LISRAYA and that risk factors include the use of NSAIDs, corticosteroids, and history of diverticulitis. Instruct patients to seek medical care immediately if they experience new onset of abdominal pain, fever, chills, nausea, or vomiting [see Warnings and Precautions (5.7)].
Hypoglycemia in Patients with Diabetes
Inform patients with diabetes that LISRAYA can cause hypoglycemia. Consider advising patients with diabetes to increase monitoring of blood glucose. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia [see Warnings and Precautions (5.8)].
Laboratory Abnormalities
Inform patients that LISRAYA may affect certain lab tests, and that blood tests are required before and during LISRAYA treatment [see Warnings and Precautions (5.9)].
Immunizations
Advise patients to avoid use of live vaccines with LISRAYA. Instruct patients to inform their healthcare provider that they are taking LISRAYA prior to a potential vaccination [see Warnings and Precautions (5.10)].
Embryofetal Toxicity
Advise pregnant women and females of reproductive potential that exposure to LISRAYA during pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].
Advise females of reproductive potential that effective contraception should be used during treatment and for 3 days following the final dose of LISRAYA [see Use in Specific Populations (8.1, 8.3)].
Inform patients to report their pregnancy to Priovant Therapeutics by calling 1-800-511-9141 or emailing [email protected] [see Use in Specific Populations (8.1)].
Lactation
Advise women not to breastfeed during treatment with LISRAYA and for 3 days after the last dose [see Use in Specific Populations (8.2)].
Manufactured for:
Priovant Therapeutics, Inc.
1007 Slater Road, Suite 250
Durham NC, 27703
LISRAYA™ is a trademark of Priovant Therapeutics, Inc.
U.S. Patent No. 9,663,526 and 11,197,867
