Deuruxolitinib

Based on the findings from animal reproduction studies, deuruxolitinib may cause fetal harm during pregnancy. Available data from pregnancies reported in clinical trials with deuruxolitinib are not sufficient to evaluate for a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of deuruxolitinib to pregnant rats during the period of organogenesis at a dose 4.8 times the maximum recommended human dose (MRHD) resulted in reduced fetal weight and increased skeletal malformation. Oral administration of deuruxolitinib to pregnant rabbits during the period of organogenesis at a dose 0.3 times the MRHD resulted in maternal toxicity, reduced fetal weight, and increased post-implantation loss. Oral administration of deuruxolitinib to pregnant rats during pregnancy and lactation periods at a dose 5 times the MRHD resulted in maternal toxicity, decreased pup survival, and adverse effects on postnatal development. Advise pregnant women of the potential risk to a fetus.

The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2 to 4% of the general population and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

There are no data on the presence of deuruxolitinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Deuruxolitinib was present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment with deuruxolitinib and for one day after the last dose (approximately 5 to 6 elimination half-lives).

Deuruxolitinib was not carcinogenic when administered orally in a 6-month transgenic rasH2 mouse study at doses up to 100 mg/kg/day. In a 2-year rat carcinogenicity study, no drug-related tumors were observed at oral doses of deuruxolitinib up to 30 mg/kg/day (0.6 times the MRHD based on AUC comparison).

Deuruxolitinib was positive in an in vitro micronucleus assay, but negative in a bacterial mutation assay (the Ames test), an in vitro chromosome aberration assay and an in vivo rat micronucleus assay.

In fertility and early embryonic development studies in rats, deuruxolitinib was administered to male rats prior to mating to conception, or to female rats prior to mating, through conception, to gestation day 7. Deuruxolitinib had no adverse effects on male or female fertility at oral doses up to 100 mg/kg/day (2.2 times MRHD in males and 14 times MRHD in females based on AUC comparison). However, adverse effects on early embryonic development were noted, including decreased viable embryos and increased pre-implantation loss observed at doses ≥30 mg/kg/day (0.9 times MRHD based on AUC comparison), and increased post-implantation loss and resorption at 100 mg/kg/day (14 times MRHD based on AUC comparison). No adverse effects on early embryonic development were observed at 10 mg/kg/day (0.2 times MRHD based on AUC comparison).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of deuruxolitinib was evaluated in three randomized, placebo-controlled clinical trials (including a dose-ranging trial), two open-label trials, and two long-term extension trials in adult subjects with severe alopecia areata. These subjects had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool (SALT) for more than six months. A total of 1,730 subjects with alopecia areata were treated across all trials, representing 1,962.9 patient-years of exposure. There were 974 subjects who were exposed to either deuruxolitinib 8 mg or deuruxolitinib 12 mg for at least 1 year and 104 subjects who were exposed for at least 3 years.

Deuruxolitinib 12 mg is not approved.

Among 1,020 subjects enrolled in the placebo-controlled clinical trials, 640 subjects received deuruxolitinib 8 mg twice daily, 380 subjects received deuruxolitinib 12 mg twice daily and 299 subjects received placebo twice daily for up to 24 weeks.

Adverse Reactions occurring at ≥1% in the deuruxolitinib 8 mg or deuruxolitinib 12 mg twice daily group and at a higher rate than in the placebo group are presented in the table below. A total of 20 (3.1%) of subjects treated with deuruxolitinib 8 mg were discontinued from the trials due to adverse reactions.

Adverse Reactions Reported in ≥1% of Subjects with Alopecia Areata Treated with deuruxolitinib 8 mg Twice Daily or Deuruxolitinib 12 mg Twice Daily (and More Frequently than Placebo) in Placebo-Controlled Trials Over 24-Weeks:

^a %-study size adjusted percentages.
^b Acne includes: acne, dermatitis acneiform, and acne pustular.
^c Hyperlipidemia includes: blood cholesterol increased, low density lipoprotein increased, blood triglycerides increased, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, and dyslipidaemia.
^d Fatigue includes: fatigue, asthenia, hypersomnia, somnolence, and lethargy.
^e Skin and soft issue infections includes: folliculitis, impetigo, skin infection, subcutaneous abscess, furuncle, paronychia, and pustule.
^f Anemia includes: anemia, hematocrit decreased, hemoglobin decreased, iron deficiency anemia, and red blood cell count decreased.
^g Neutropenia includes: neutropenia and neutrophil count decreased.
^h Thrombocytosis includes: thrombocytosis and platelet count increased.
ⁱ Herpes includes: oral herpes, herpes simplex, genital herpes simplex, and nasal herpes.

Additional adverse drug reactions occurring in fewer than 1% of subjects: herpes zoster, lipase increased, and candidiasis.

A total of 868 subjects in the long-term extension trials received treatment with deuruxolitinib 8 mg twice daily and 991 subjects received treatment with deuruxolitinib 12 mg twice daily for 52 weeks. In two open-label extension trials up to 3 years, 829 subjects received treatment with deuruxolitinib 8 mg twice daily, and 1066 subjects received treatment with deuruxolitinib 12 mg twice daily.

Specific Adverse Reactions (0-52 weeks)

All Infections

During the 24-week treatment period, infections were reported in 97 subjects (88.0 per 100 patient-years) treated with placebo, 222 subjects (101.5 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 153 subjects (117.0 per 100 patient years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, infections were reported in 435 subjects (95.5 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 408 subjects (74.1 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Serious Infections

During the 24-week treatment period, serious infections were reported in 1 subject (0.8 per 100 patient-years) treated with placebo, 5 subjects (1.8 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 2 subjects (1.2 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, serious infections were reported in 5 subjects (0.7 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 4 subjects (0.5 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Herpes Zoster

During the 24-week treatment period, opportunistic infections (herpes zoster) were reported in 0 subjects treated with placebo, 3 subjects (1.1 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 3 subjects (1.8 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, herpes zoster was reported in 10 subjects (1.5 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 15 subjects (1.9 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Malignancies

During the 0-52 week period, malignancy excluding NMSC was reported in 3 subjects (0.4 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 4 subjects (0.5 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Thrombosis

During the 0-52 week period, thrombosis was reported in 0 subjects treated with deuruxolitinib 8 mg twice daily and 1 subject (0.1 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily who developed bilateral pulmonary embolism.

Laboratory Abnormalities

Anemia:

During the 24-week treatment period, anemia was reported in 3 subjects (2.3 per 100 patient-years) treated with placebo, 19 subjects (6.9 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 16 subjects (9.6 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, anemia was reported in 17 subjects (2.6 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 38 subjects (5.0 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Neutropenia:

During the 24-week treatment period, neutropenia was reported in 3 subjects (2.3 per 100 patient-years) treated with placebo, 10 subjects (3.6 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 10 subjects (6.0 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, neutropenia was reported in 11 subjects (1.6 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 15 subjects (1.9 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Lymphopenia:

During the 24-week treatment period, lymphopenia was reported in 2 subjects (1.5 per 100 patient-years) treated with placebo, 2 subjects (0.7 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 7 subjects (4.2 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, lymphopenia was reported in 4 subjects (0.6 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 10 subjects (1.3 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Lipid Elevations:

During the 24-week treatment period, lipid elevations were reported in 10 subjects (7.7 per 100 patient-years) treated with placebo, 30 subjects (11.0 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 18 subjects (10.9 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, lipid elevations were reported in 47 subjects (7.2 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 66 subjects (8.7 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Creatine Phosphokinase (CPK) Elevations:

During the 24-week treatment period, CPK elevations were reported in 7 subjects (5.4 per 100 patient-years) treated with placebo, 35 subjects (12.9 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 27 subjects (16.6 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily. During the 0-52 week period, CPK elevations were reported in 49 subjects (7.6 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 46 subjects (6.1 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Thrombocytosis:

During the 24-week treatment period, an increase in platelet count was reported in 0 subjects treated with placebo, 18 subjects (6.6 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 6 subjects (3.6 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

During the 0-52 week period, an increase in platelet count was reported in 20 subjects (3.0 per 100 patient-years) treated with deuruxolitinib 8 mg twice daily and 26 subjects (3.4 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Adverse Reactions Observed after 52 weeks

Thrombosis

Venous thromboembolic events were reported in 4 subjects treated with deuruxolitinib 12 mg twice daily between Week 52 and Week 98. These 4 subjects experienced 7 thrombotic events (0.2 per 100 patient-years), including deep vein thrombosis (DVT), bilateral pulmonary embolism (PE), pulmonary embolism, and cerebral venous sinus thrombosis (CVT).