Leqselvi 8 mg film-coated tablets

Leqselvi is indicated for the treatment of adult patients with severe alopecia areata.

Posology

The recommended dosage of Leqselvi for the treatment of severe alopecia areata is 8 mg orally twice daily, with or without food.

If a dose is missed, skip the missed dose and resume dosing at the next scheduled dose.

Serious or opportunistic infections

If a patient develops a serious or opportunistic infection, interrupt Leqselvi treatment until the infection is controlled.

Haematologic abnormalities

Recommendations for Leqselvi treatment interruption for haematologic abnormalities are described in Table 1.

Table 1: Recommendations for Leqselvi Treatment Interruption for Haematologic Abnormalities and Resumption

Renal impairment

Leqselvi is not recommended for use in patients with severe renal impairment or end-stage renal disease (eGFR <30 mL/min). No adjustment of dosage is required in patients with mild or moderate renal impairment.

The effect of severe renal impairment on deuruxolitinib pharmacokinetics is unknown.

Hepatic Impairment

Leqselvi is not recommended for use in patients with severe hepatic impairment (Child Pugh C). No adjustment of dosage is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.

The effect of severe hepatic impairment on deuruxolitinib pharmacokinetics is unknown.

CYP2C9 Poor Metabolizers

Based on PBPK modelling, higher exposure of deuruxolitinib in patients who are CYP2C9 poor metabolizers is expected with concomitant use of Leqselvi, which may increase the risk of Leqselvi -associated serious adverse reactions. Before initiation of treatment with Leqselvi, test patients to determine CYP2C9 genotype.

Elderly

There are limited data in patients ≥ 65 years of age.

Paediatric population

The safety and efficacy of Leqselvi in children less than 18 years of age has not been established.

No data are available.

Method of administration

Oral use

Leqselvi should be swallowed with water, with or without food.

Precautions to be taken before handling or administering the medicinal product.

Perform the following prior to treatment with Leqselvi:

  • CYP2C9 genotype determination: Test patients for CYP2C9 variants to determine CYP2C9 genotype. Leqselvi is contraindicated in patients who are CYP2C9 poor metabolizers (patients with decreased cytochrome P450 (CYP) 2C9 function).

  • Evaluation for use of concomitant CYP2C9 inhibitors: Leqselvi is contraindicated in patients taking moderate or strong CYP2C9 inhibitors (see Section 4.5).

  • Active and latent tuberculosis (TB) evaluation: Leqselvi treatment is not recommended in patients with active TB. For patients with latent TB or those with a negative latent TB test who are at high risk of TB, start preventive therapy for TB prior to Leqselvi treatment.

  • Viral hepatitis screening in accordance with clinical guidelines: Leqselvi treatment is not recommended in patients with active hepatitis B or hepatitis C.

  • Hepatitis B infection screening: If hepatitis B infection is discovered, follow hepatitis B clinical guidelines, or refer to a liver specialist. Monitor patients for reactivation in accordance with clinical guidelines during treatment.

  • Complete blood count (CBC): Leqselvi treatment is not recommended in patients with an absolute lymphocyte count (ALC) <500 cells/mm³ absolute neutrophil count (ANC) <1000 cells/mm³, or haemoglobin level <8 g/dL. Monitor complete blood counts periodically during treatment and modify dosage as recommended.

  • Complete any necessary immunizations, including herpes zoster vaccinations, according to current immunization guidelines prior to Leqselvi treatment.

Pharmacogenomics

Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%). CYP2C9 activity is reduced in patients with genetic variants in CYP2C9, such as the CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of deuruxolitinib has not been directly evaluated. Based on drug-drug interaction modelling data, CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have up to 2-fold higher concentrations of deuruxolitinib, when compared to normal metabolizers.

The pharmacokinetics of deuruxolitinib were not evaluated in individuals who are intermediate metabolizers (e.g., individuals with *1/*3 genotype).

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in Black or African American populations. Other decreased or nonfunctional CYP2C9 alleles (e.g., *5, *6, *8, *11) are more prevalent in Black or African American populations.

Leqselvi is contraindicated in patients who:

  • Are CYP2C9 poor metabolizers (See Section 4.4).

  • Are on concomitant moderate or strong CYP2C9 inhibitors (See Section 4.4).

  • Are pregnant or breast-feeding (See Section 4.6)

  • Hypersensitive to the active substance or to any of the excipients listed in section 6.1

Limitations of Use

Leqselvi is not recommended for use in combination with other Janus-associated kinase (JAK) inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants.

Deuruxolitinib should only be used if no suitable treatment alternatives are available in patients:

  • 65 years of age and older;

  • patients with history of atherosclerotic cardiovascular disease or other

  • cardiovascular risk factors (such as current or past long-time smokers);

  • patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Serious Infections

Serious infections have been reported in subjects with alopecia areata receiving Leqselvi (see section 4.8).

Avoid use of Leqselvi in patients with an active, serious infection including localized infections.

Prior to Leqselvi treatment, consider the risks and benefits in patients:

  • with chronic or recurrent infection

  • who have been exposed to tuberculosis

  • with a history of a serious or opportunistic infection

  • who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or

  • with underlying conditions that may predispose them to infection

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Leqselvi. If the patient develops a serious infection, interrupt treatment with Leqselvi until the infection resolves or is adequately treated.

If a patient develops a new infection during treatment with Leqselvi, initiate complete diagnostic testing appropriate for an immunocompromised patient and appropriate antimicrobial therapy.

Tuberculosis

Evaluate patients for latent and active tuberculosis (TB) infection prior to Leqselvi treatment. Leqselvi is not recommended for use in patients with active TB.

Treat patients with latent TB before Leqselvi treatment. Consider anti-TB therapy prior to Leqselvi treatment in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

Monitor patients receiving Leqselvi for signs and symptoms of active TB during treatment, including patients who tested negative for latent TB infection prior to treatment.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were reported in clinical trials with Leqselvi. If a patient develops herpes zoster, consider interrupting Leqselvi treatment until the episode resolves.

The impact of Leqselvi on chronic viral hepatitis reactivation is unknown. Subjects with positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), or hepatitis C virus (HCV) with detectable HCV RNA at screening were excluded from Leqselvi clinical trials. Perform screening for viral hepatitis before treatment with Leqselvi. Leqselvi is not recommended for use in patients with active hepatitis B or hepatitis C (HCV RNA detected).

If non-active hepatitis B infection is discovered, monitoring for reactivation or prophylactic treatment is recommended. Follow hepatitis B clinical guidelines or refer to a liver specialist. Hepatitis B viral load (HBV-DNA titer) increase, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, has been reported in subjects with chronic HBV infections receiving JAK inhibitors used to treat inflammatory conditions. The effect of Leqselvi on viral replication in patients with chronic HBV infection is unknown.

Mortality

In a large, randomized, post-marketing safety trial of another JAK inhibitor in rheumatoid arthritis (RA) subjects 50 years and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in subjects treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to and during treatment with Leqselvi.

Malignancy and Lymphoproliferative Disorders

Malignancies were observed in clinical trials of Leqselvi.

In a large, randomized, post-marketing safety trial of another JAK inhibitor in subjects with RA, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this trial, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to and during treatment with Leqselvi, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Non-melanoma skin cancers

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with Leqselvi. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Major Adverse Cardiovascular Events (MACE)

In a large, randomized, post-marketing safety trial of another JAK inhibitor in subjects with RA 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to and during treatment with Leqselvi, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue Leqselvi in patients that have experienced a myocardial infarction or stroke.

Thrombosis

Thrombosis, including pulmonary embolism (PE), deep vein thrombosis (DVT) and cerebral venous sinus thrombosis (CVT) have been reported in clinical trials of deuruxolitinib. There was no clear relationship between platelet count elevations and thrombotic events.

Thrombosis, including DVT, PE, and arterial thrombosis have been reported in subjects receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death.

In a large, randomized, post-marketing safety trial of another JAK inhibitor in subjects with RA 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

Avoid Leqselvi in patients who may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue Leqselvi and evaluate and treat patients appropriately.

Increased risk of Leqselvi-associated serious adverse reactions in CYP2C9 poor metabolizers or with concomitant use of moderate or strong CYP2C9 inhibitors

Higher plasma concentrations of deuruxolitinib, which may increase the risk of Leqselvi- associated serious adverse reactions such as thrombosis, may occur when Leqselvi is used in patients who:

  • Are CYP2C9 poor metabolizers.

  • Are on a concomitant moderate or strong CYP2C9 inhibitor.

Prior to Leqselvi treatment, test patients for CYP2C9 variants to determine if they are poor metabolizers (see section 4.2). A test for the detection of CYP2C9 variants to direct the use of Leqselvi is not currently available.

Leqselvi is contraindicated in patients who are CYP2C9 poor metabolizers or patients who are on concomitant moderate or strong CYP2C9 inhibitors. See section 4.3.

Gastrointestinal Perforations

Gastrointestinal perforations have been reported in clinical trials with Leqselvi.

Monitor patients treated with Leqselvi who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Evaluate promptly patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

Lipid Elevations, Anaemia, Neutropoenia, and Lymphopenia

Perform a CBC prior to and periodically during treatment with Leqselvi.

Lipid elevations

Treatment with Leqselvi was associated with increases in triglycerides and total cholesterol, including HDL-C and LDL-C. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Perform assessment of lipid parameters at baseline and periodically during treatment with Leqselvi. Manage patients according to clinical guidelines for hyperlipidaemia.

Anaemia

Treatment with Leqselvi was associated with an increased incidence of anaemia (haemoglobin less than 8 g/dL) compared to placebo. Avoid or interrupt Leqselvi treatment in patients with haemoglobin less than 8 g/dL.

Neutropenia

Treatment with Leqselvi was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo. Avoid or interrupt Leqselvi treatment in patients with an ANC less than 1000 cells/mm³.

Lymphopenia

Treatment with Leqselvi was associated with an increased incidence of lymphopenia (ALC less than 500 cells/mm³) compared to placebo. Avoid or interrupt Leqselvi treatment in patients with an ALC less than 500 cells/mm³.

Immunizations

Prior to Leqselvi treatment, complete all necessary immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in accordance with current immunization guidelines. Avoid use of live vaccines during or immediately prior to Leqselvi treatment.

Elderly

There are limited data in patients ≥ 65 years of age. Considering the increased risk of MACE, malignancies, serious infections, and all-cause mortality in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another JAK inhibitor), deuruxolitinib should only be used in these patients if no suitable treatment alternatives are available.

Paediatric population

The safety and effectiveness of Leqselvi have not been established in paediatric patients.

Excipients with known effect

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effect of other drugs on Leqselvi

Strong CYP3A and moderate or strong CYP2C9 inducers:

Avoid concomitant use of Leqselvi with strong CYP3A (e.g. barbiturates, carbamazepine, efavirenz, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort, troglitazone) and moderate or strong CYP2C9 inducers (e.g. enzalutamide, rifampin).

Deuruxolitinib is a CYP2C9 and CYP3A substrate. Concomitant use with a strong CYP3A and moderate or strong CYP2C9 inducer decreases deuruxolitinib exposure (Cmax and AUC), which may reduce Leqselvi efficacy. See section 5.2.

Moderate or strong CYP2C9 inhibitors:

Leqselvi is contraindicated in patients taking moderate or strong CYP2C9 inhibitors (e.g. amiodarone, fluconazole, miconazole, sulphaphenazole, piperine). See section 4.3.

Deuruxolitinib is a CYP2C9 substrate. Concomitant use with a moderate or strong CYP2C9 inhibitor is estimated to increase deuruxolitinib exposure (Cmax and AUC), which may increase the risk of Leqselvi serious adverse reactions such as thrombosis. See section 5.2.

Paediatric population

Interaction studies have only been performed in adults.

Women of childbearing potential

Deuruxolitinib is not recommended in women of childbearing potential not using contraception. Women of childbearing potential have to use effective contraception during treatment.

Pregnancy

There are no or limited data from the use of deuruxolitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Leqselvi is contraindicated during pregnancy (see section 4.3).

Based on animal studies, deuruxolitinib may cause foetal harm when administered during pregnancy. Consider pregnancy planning and prevention for females of reproductive potential.

Breast-feeding

Available toxicological data in animals have shown excretion of deuruxolitinib in milk (see section 5.3). A risk to newborns/infants cannot be excluded.

Leqselvi is contraindicated during breast-feeding (see section 4.3).

Fertility

The effect of deuruxolitinib on human fertility has not been evaluated. There were no effects on fertility in rats at clinically relevant exposures (see section 5.3).

No data are available on the ability to drive and use machines during Leqselvi treatment.

Summary of the safety profile

The safety of Leqselvi 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.

The most frequently (>1%) reported adverse reactions are headache, nasopharyngitis, acne, nasopharyngitis, blood creatine phosphokinase increased, hyperlipidemia, fatigue, weight increased, lymphopenia, thrombocytosis, anemia, skin and soft tissue infections, neutropenia, and herpes.

Tabulated list of adverse reactions

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 Leqselvi 8 mg (326 subjects) or deuruxolitinib 12 mg (454 subjects) for at least 1 year and 104 subjects who were exposed for at least 3 years.

Table 2 lists all adverse reactions observed in alopecia areata placebo-controlled studies presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse Reactions

1. Skin and soft issue infections includes: folliculitis, impetigo, skin infection, subcutaneous abscess, furuncle, paronychia, and pustule.

2. Herpes includes: oral herpes, herpes simplex, genital herpes simplex, and nasal herpes.

3. Anemia includes: anemia, hematocrit decreased, hemoglobin decreased, iron deficiency anemia, and red blood cell count decreased.

4. Neutropenia includes: neutropenia and neutrophil count decreased.

5. Thrombocytosis includes: thrombocytosis and platelet count increased.

6. Hyperlipidemia includes: blood cholesterol increased, low density lipoprotein increased, blood triglycerides increased, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, and dyslipidaemia.

7. Acne includes: acne, dermatitis acneiform, and acne pustular.

8. Fatigue includes: fatigue, asthenia, hypersomnia, somnolence, and lethargy.

Description of selected 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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.

Anaemia

During the 24-week treatment period, anaemia was reported in 3 subjects (2.3 per 100 patient- years) treated with placebo, 19 subjects (6.9 per 100 patient-years) treated with Leqselvi 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, anaemia was reported in 17 subjects (2.6 per 100 patient- years) treated with Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 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 Leqselvi 8 mg twice daily and 26 subjects (3.4 per 100 patient-years) treated with deuruxolitinib 12 mg twice daily.

Description of selected 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).

Paediatric population

The safety of Leqselvi has not been established in paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no experience regarding human overdose with Leqselvi.

There is no specific antidote for overdose with Leqselvi. Treatment should be symptomatic and supportive and monitor patients for signs and symptoms of adverse reactions.

Pharmacotherapeutic group: Immunosuppressants, Janus-associated kinase (JAK) inhibitors, ATC code: L04AF09.

Mechanism of action

Deuruxolitinib is a Janus-associated kinase (JAK) inhibitor. JAKs mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. JAK signalling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

In an in vitro kinase activity assay, deuruxolitinib had greater inhibitory potency for JAK1, JAK2 and TYK2 relative to JAK3. The relevance of inhibition of JAK enzymes to therapeutic effectiveness is not currently known.

Pharmacodynamic effects

Deuruxolitinib Inhibition of IL-6 Induced STAT3 Phosphorylation

Deuruxolitinib inhibited whole blood IL-6 stimulated pSTAT3 in healthy subjects 2 hours post-dose. The relevance of this finding in patients is unknown.

Cardiac Electrophysiology

At concentrations approximately 4-fold higher than the Cmax associated with the highest dose evaluated clinically, 12 mg twice-daily, deuruxolitinib does not prolong the QT interval to any clinically relevant extent.

Clinical efficacy and safety

Two multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trials (AA-1 [NCT04518995] and AA-2 [NCT04797650]), evaluated a total of 1,209 adult subjects with alopecia areata (AA), who had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool (SALT) for more than six months. In both trials, subjects received Leqselvi 8 mg twice daily, deuruxolitinib 12 mg twice daily, or placebo twice daily for 24 weeks.

Deuruxolitinib 12 mg is not approved.

The trial population ranged from 18 to 65 years of age. Among the subjects enrolled, 64% were female, 74% were White, 9% were Black or African American, and 6% were Asian; 8% identified as Hispanic or Latino. At baseline, subjects had average current episode of hair loss of approximately 4 years, with 59% of subjects having complete or near complete scalp hair loss (defined as ≥ 95% scalp hair loss). The mean pooled baseline SALT scores across treatment groups ranged from 85.9 to 88.6 with a mean duration of current episode of hair loss of ranging 3.7 to 3.9 years. Approximately 73% of subjects had eyebrow hair involvement and 70% of subjects had eyelash hair involvement.

The primary endpoint for both trials assessed the proportion of subjects who achieved at least 80% scalp hair coverage (SALT score of ≤ 20) at Week 24. Key secondary outcomes included the percentage of responders (defined as “satisfied” or “very satisfied”) at Week 24 on the Satisfaction of Hair Patient- Reported Outcome (SPRO) and the percentage of subjects achieving an absolute SALT score of ≤ 20 at Week 20, 16, 12, and 8.

Upon completion of the 24-week trials, subjects were eligible to enrol in a long-term extension trial.

Clinical response

Assessment of scalp hair loss was based on the SALT score. At Week 24, a greater proportion of subjects had a SALT ≤ 20 response (80% or more scalp hair) and SALT ≤ 10 response (90% or more scalp hair) with Leqselvi 8 mg twice daily compared to placebo (Table 3).

Table 3: Clinical Response at Week 24 in Adult Subjects with Severe AA in Trials AA-1 and AA-2

^a Not adjusted for multiplicity.

Table 4: Evaluation of Patient Satisfaction with Scalp Hair Coverage at Weeks 24 in Adult Subjects with Severe AA in Trials AA-1 and AA-2

^a In Trial AA-1, the proportion of responders (defined as subjects who were “satisfied” or “very satisfied”) on Leqselvi was 42% compared to 5% on placebo. In trial AA-2, the proportion of responders on Leqselvi was 46% compared to 2% on placebo.

^b In Trial AA-2, the proportion of non-responders (defined as subjects who were “dissatisfied” or “very dissatisfied”) on Leqselvi was 38% compared to 80% on placebo. In Trial AA-2, the proportion of non-responders on Leqselvi was 39% compared to 85% on placebo.

Figure 1: Clinical Response over Time in Adult Subjects with Severe AA in Trials AA-1 and AA-2

The efficacy of Leqselvi was generally comparable across multiple subgroups including age, gender, and body weight among these subgroups. The results for SALT score ≤ 20 at Week 24 by baseline scalp hair loss severity are presented in Table 5.

Table 5: Adult Subjects with Severe AA with Absolute SALT Scores ≤ 20 at Week 24 by Baseline Scalp Hair Loss Severity in Trials AA-1 and AA-2

BID = twice daily

Clinical efficacy in alopecia areata (SALT ≤ 20)

In two pivotal Phase III studies (CP543.3001 and CP543.3002), efficacy was assessed by the proportion of patients achieving a Severity of Alopecia Tool (SALT) score of ≤ 20. The time to onset of clinically meaningful hair regrowth is summarized in Table 6.

Table 6: Proportion of patients achieving a Severity of Alopecia Tool (SALT) score of ≤ 20

Together, these studies suggest that:

  • Some patients may begin to respond by Week 8, with modest effect size.

  • The majority of clinically meaningful regrowth appears after Week 8, typically emerging between Weeks 12 and 16.

  • Peak or stabilized responses are observed through Week 20.

These findings highlight a latency in onset of action, which should be considered in clinical decision-making and patient counseling

Elderly

Of the 600 subjects treated with Leqselvi 8 mg in phase 3 clinical trials, 2 (0.3%) were 65 years of age or older. Clinical trials of Leqselvi did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Paediatric population

The Licensing Authority has deferred the obligation to submit the results of studies with deuruxolitinib in one or more subsets of the paediatric population in alopecia areata.

Following oral administration of deuruxolitinib, C_max and AUCs increased dose proportionally over a dose range from 8 mg to 48 mg (6 times the approved recommended dosage) in healthy subjects. Steady-state plasma concentrations were achieved within 1 to 2 days, with minimal accumulation, after twice daily administration.

Absorption

Deuruxolitinib bioavailability is 90%, with peak plasma concentrations reached within 1.5 hrs.

Effect of Food

No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed following administration of a high fat, high calorie meal (approximately 50% fat and 800-1000 calories).

Distribution

The deuruxolitinib steady state volume of distribution is approximately 50 L. Deuruxolitinib plasma protein binding is 91.5% and blood to plasma concentration ratio is approximately 1.3.

Elimination

An apparent systemic clearance (CL/F) of 8.96 L/h was estimated in treated patients. The deuruxolitinib mean elimination half-life is approximately 4 hrs. After a single dose of radiolabelled deuruxolitinib, deuruxolitnib and its metabolites are primarily excreted by urine (~70%) and faeces (~20%). There was no deuruxolitnib recovered in either urine or faeces.

Metabolism

Deuruxolitinib is primarily metabolized by CYP2C9 (76%) and CYP3A4 (21%) and to a lesser extent by CYP1A2 (3%). The two most abundant human metabolites C-21714 and C-21717, each of which accounted for approximately 5% of total drugrelated AUC and both are approximately 10-fold less pharmacologically active than deuruxolitinib.

Excretion

After a single dose of radiolabeled deuruxolitinib, there was no unchanged dose recovered in either urine or feces.

Special populations

No clinically significant differences in the pharmacokinetics of deuruxolitinib were observed based on race [White (75%), African American (17%) and Asian (6%)], ethnicity [Hispanic or Latino (12%)], age (18-65 years), body weight (40.4-173 kg), mild to moderate renal impairment (eGFR 30-89 mL/min, MDRD), or mild to moderate hepatic impairment (Child Pugh A or B).

The effect of severe renal impairment (eGFR < 30 mL/min, MDRD) or severe hepatic impairment (Child Pugh C) on deuruxolitinib pharmacokinetics is unknown.

Elderly

There are limited data in patients ≥ 65 years of age.

Drug Interaction Studies

Strong CYP3A4 and Moderate or strong CYP2C9 Inducers: Deuruxolitinib AUC decreased by 78% and C_max by 41% following concomitant use of multiple doses of 600 mg rifampin (strong CYP3A4 and moderate CYP2C9 inducer) with a single dose of 12 mg deuruxolitinib (1.5 times the approved 8 mg dose).

Strong CYP2C9 Inhibitors: Based on PBPK modelling, deuruxolitinib AUC is predicted to be increased by 200% and C_max by 25% following concomitant use of multiple dosages of a strong CYP2C9 inhibitor with a single dose of 12 mg deuruxolitinib (1.5 times the 8 mg dose).

Moderate CYP2C9 Inhibitors: Deuruxolitinib AUC increased by 140% and C_max by 21% following concomitant use of multiple dosages of 200 mg fluconazole (dual moderate CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5 times the 8 mg dose).

Other Drugs: No clinically significant differences in deuruxolitinib pharmacokinetics were observed when used concomitantly with itraconazole (strong CYP3A4 inhibitor) or are expected with efavirenz (moderate CYP3A4 inducer).

Effect of Leqselvi on Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when co-administered with deuruxolitinib: midazolam (a sensitive CYP3A4 substrate), oral contraceptives (ethinyl oestradiol and levonorgestrel).

Cytochrome P450 (CYP) Enzymes: Deuruxolitinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4. Deuruxolitinib is not an inducer of CYP1A2 or CYP2B6, CYP2C8 or CYP2C19.

Transporter Systems: Deuruxolitinib is a substrate of BCRP and MDR1 but not a substrate of the uptake transporters OATP1B1 and OATP1B3. Deuruxolitinib is not an inhibitor of OATP1B1, OATP1B3 and OCT1 but is an inhibitor of BCRP, BSEP, OAT3 and MATE2-K.

General Toxicity

Oral administration of deuruxolitinib to rats was generally well tolerated with NOAELs at doses up to 100 mg/kg/day for 28 days and 37.5 mg/kg/day (0.8 and 4.6 times the maximum recommended human dose (MRHD) of 16 mg per day for male and female, respectively, based on AUC comparison), for 13 and 26 weeks. Typical findings in these studies included changes consistent with the known pharmacology of JAK1/JAK2 inhibition (decreases in white blood cell count, decreased lymphoid organ weights, and lymphocyte depletion in primary and secondary lymphoid organs). These changes were partially or completely reversible when dosing was discontinued, and the rats were allowed to recover. Doses of deuruxolitinib above these NOAEL values were associated with adverse body weight gain suppression, reduced body weights, death/moribundity, and more severe alterations in haematology parameters and the lymphoid depletion in immune organs.

In dogs, repeated dose toxicology studies were performed for up to 52 weeks. In the 28-day study, 10 mg/kg/day (NOAEL) was well tolerated with minor effects on lymphoid organs and red blood cell mass. After 13- or 52-weeks of oral dosing, the NOAEL was 3 mg/kg/day (2.0 and 1.4 times the MRHD for male and female, respectively, based on AUC comparison). Deuruxolitinib-related findings at these doses included non-adverse decreases in peripheral blood haematology parameters and reduced cellularity in the haematopoietic and lymphoid organs. These changes were reversible and consistent with JAK pharmacology and the findings reported in the rat. Higher doses for longer durations resulted in mortality/moribundity (believed due to deuruxolitinib-mediated immune suppression resulting in infection by opportunistic organisms), more severe suppression of haematology parameters, and increased severity of microscopic lymphoid depletion. Even at the higher doses (considered adverse), there was reversibility of the haematologic and lymphoid changes.

Carcinogenesis

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 tumours were observed at oral doses of deuruxolitinib up to 30 mg/kg/day (0.6 times the MRHD based on AUC comparison).

Mutagenesis

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.

Reproductive and Developmental Toxicity

Impairment of Fertility

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).

Pregnancy

In an embryo-foetal development study, deuruxolitinib was administered to pregnant rats during the period of organogenesis at oral doses of 15, 30, and 60 mg/kg/day. Reduced foetal weight and increased foetal skeletal malformation were noted at 60 mg/kg/day (4.8 times the MRHD based on AUC comparison) with no maternal toxicity. No embryo-foetal toxicity was observed at doses up to 30 mg/kg/day (equivalent to MRHD based on AUC comparison). In another embryo-foetal development study, deuruxolitinib was administered to pregnant rabbits during the period of organogenesis at oral doses of 6, 30, and 60 mg/kg/day. Reduced foetal weight and increased post- implantation loss were noted at 60 mg/kg/day (0.3 times the MRHD based on AUC comparison), at which maternal toxicity was observed. No embryo-foetal toxicity was noted at doses up to 30 mg/kg/day (0.05 times the MRHD based on AUC comparison).

In a pre- and postnatal development study in rats, deuruxolitinib was administered to pregnant rats during pregnancy and lactation periods at oral doses of 15, 30, and 75 mg/kg/day. Decreases in liveborn pups and pup survival, decreased pup activity and lower pup body weights, and adverse effects on reproductive outcome in the second generation females (decreased corpora lutea, implantation, and number of live embryos, and increased resorption and post-implantation loss) were noted at 75 mg/kg/day (5 times the MRHD based on AUC comparison), at which maternal toxicity was also observed. No adverse effects on pre- and postnatal development were noted at doses up to 30 mg/kg/day (0.8 times the MRHD based on AUC comparison).

Lactation

Following a single oral dose of 10 mg/kg administered to lactating rats on Lactation Day 14, deuruxolitinib concentrations were up to 20 times higher in milk than in plasma.

Tablet core content

Microcrystalline cellulose

Lactose monohydrate

Povidone K30 (E1201)

Low-substituted hydroxypropyl cellulose

Colloidal silicon dioxide

Magnesium stearate

Purified water

Film coating content

Polyvinyl alcohol

Talc

Titanium dioxide

Glyceryl mono and dicaprylocaprate

Sodium lauryl sulfate

Fd&c blue #2 aluminum lake

Carmine

Purified water

Not applicable.

4 years.

This medicinal product does not require any special temperature storage condition.

Store in the original package in order to protect from moisture.

Multidose high density polyethylene (HDPE) bottle with a silica gel desiccant, and closed with 24 mm white child-resistant cap with foil liner.

Each bottle contains 60 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

This medicinal product must not be mixed with other JAK inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants (see section 4.3).