Summary Basis of Decision for Litfulo

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Litfulo is located below.

Recent Activity for Litfulo

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Litfulo, a product which contains the medicinal ingredient ritlecitinib (supplied as ritlecitinib tosylate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: SBD Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Updated: 2024-07-18

Drug Identification Number (DIN):

DIN 02543532 - 50 mg ritlecitinib, capsule, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

Drug product (DIN 02543532) market notification

Not applicable

Date of first sale: 2024-02-13

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 268723

2022-10-14

Issued NOC 2023-11-29

NOC issued for the New Drug Submission.

Summary Basis of Decision (SBD) for Litfulo

Date SBD issued: 2024-07-18

The following information relates to the New Drug Submission for Litfulo.

Ritlecitinib (supplied as ritlecitinib tosylate)

Drug Identification Number (DIN): DIN 02543532 - 50 mg ritlecitinib, capsule, oral administration

Pfizer Canada ULC

New Drug Submission Control Number: 268723

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): L04 Immunosuppressants

Date Filed: 2022-10-14

Authorization Date: 2023-11-29

On November 29, 2023, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Litfulo.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Litfulo is favourable for the treatment of adults and adolescents 12 years and older with severe alopecia areata.

1 What was approved?

Litfulo, a selective Janus-associated kinase (JAK) 3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family inhibitor, was authorized for the treatment of adults and adolescents 12 years and older with severe alopecia areata.

Litfulo is not recommended for use in combination with JAK inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants.

Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Litfulo in pediatric patients 12 to 17 years of age have been established for severe alopecia areata. Health Canada has not authorized an indication for pediatric use in patients under 12 years of age.

There are limited data in patients 65 years of age and older. As there is a higher incidence of infections in the geriatric population in general, caution should be used when treating geriatric patients.

Litfulo (50 mg ritlecitinib, supplied as ritlecitinib tosylate) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains crospovidone, FD&C Blue no. 1, ferric oxide yellow, glyceryl dibehenate, hypromellose, lactose monohydrate, microcrystalline cellulose, and titanium dioxide.

The use of Litfulo is contraindicated in:

  • patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non‑medicinal ingredient or component of the container,

  • pregnant and lactating/breastfeeding women, and

  • severe hepatic impairment.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Litfulo Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Litfulo approved?

Health Canada considers that the benefit-harm-uncertainty profile of Litfulo is favourable for the treatment of adults and adolescents 12 years and older with severe alopecia areata.

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

Alopecia areata is an autoimmune disorder characterized by non-scarring hair loss on the scalp or any hair-bearing surface. The clinical manifestations of alopecia areata vary from small, well-defined patches of hair loss to the diffuse involvement of the scalp or the entire body. The majority of patients with alopecia areata experience unpredictable episodes of relapse and remission. In a number of patients, it can be persistent, especially when the hair loss is extensive.

Hair follicles typically exist in an immune-privileged environment, which is protected against autoimmune responses. This is achieved by modified expression of immunosuppressant and inflammatory molecules. Inflammation in the absence of this immune-privileged environment for the hair follicles is said to induce a dystrophic anagen phase, then a premature catagen phase, and finally, alopecia areata. The cytolytic activities of the CD8+ and natural killer (NK) cells are thought to be critical signalling processes in the development of alopecia areata.

Ritlecitinib (the medicinal ingredient in Litfulo) is a covalent irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family, and blocks the adenosine triphosphate (ATP) binding site. It inhibits cytokine-induced signal transducer and activator of transcription (STAT) phosphorylation mediated by JAK3-dependent receptors. Ritlecitinib also inhibits signalling of immune receptors dependent on TEC family kinase members. Through its inhibition of JAK3 and TEC family members, ritlecitinib has been shown to inhibit the cytolytic activities of CD8+ and NK cells in vitro, which provides a rationale for pursuing it for the treatment of alopecia areata. Ritlecitinib differs from other approved JAK inhibitors in that it lacks activity against JAK1, JAK2, and tyrosine kinase 2 (TYK2) leading to a narrower spectrum of cytokine inhibition.

Evidence of the clinical efficacy of Litfulo was obtained predominantly from Study AA‑I (B7981015), a Phase IIb/III pivotal and dose-ranging study conducted in adults and adolescents 12 years of age and older with alopecia areata. The primary objective of the study was to evaluate the efficacy of Litfulo compared to placebo in adult and adolescent participants with 50% or greater scalp hair loss, including alopecia totalis (AT) and alopecia universalis (AU). The mean baseline Severity of Alopecia Tool (SALT) score, which describes the percentage of scalp hair loss (range: 0 to 100), ranged from 88.3 to 93.0 across treatment groups. The majority of participants (85.4%) were 18 years of age or older, with 105 participants (14.6%) 12 to 17 years of age and 20 participants (2.8%) 65 years of age or older.

The treatment period consisted of a placebo‑controlled 24‑week period and a 24‑week extension period. Study AA‑I evaluated 718 patients who were randomized in a 2:2:2:2:1:1:1 ratio to blinded Litfulo and matching placebo to one of the following treatment regimens for 48 weeks:

  1. 200 mg once daily for 4 weeks, followed by 50 mg once daily for 44 weeks;

  2. 200 mg once daily for 4 weeks, followed by 30 mg once daily for 44 weeks;

  3. 50 mg once daily for 48 weeks;

  4. 30 mg once daily for 48 weeks;

  5. 10 mg once daily for 48 weeks;

  6. placebo for 24 weeks, followed by 200 mg once daily for 4 weeks and 50 mg once daily for 20 weeks; or

  7. placebo for 24 weeks followed by 50 mg for 24 weeks.

The primary efficacy endpoint of this study was the proportion of patients who achieved a SALT score of ≤20 (SALT ≤20) at Week 24. At baseline, the mean SALT score ranged from 88.3 to 93.0 across treatment groups, and in patients without AT/AU, the mean SALT score ranged from 78.3 to 87.0. At Week 24, 23% of participants had a SALT ≤20 response with Litfulo 50 mg once daily compared to 1.6% of participants who received placebo (difference of 21.4%; 95% confidence interval [CI]: 13.4, 29.5). The SALT ≤20 response rate for patients treated with Litfulo increased further after Week 24 through Week 48. Statistical separation from placebo in the SALT ≤20 response first occurred at Week 18.

Secondary efficacy endpoints included a SALT score of ≤10 (90% or more scalp hair coverage) at Week 24, a change from baseline in SALT scores over time, improvements in the regrowth of eyebrows and/or eyelashes at Week 24, and the Patient’s Global Impression of Change (PGI‑C) response (a patient-reported outcome). Improvements were observed in participants who received Litfulo 50 mg compared to those who received placebo with respect to these secondary outcomes.

The clinical safety evaluation was based on data from three randomized studies, including the pivotal Study AA‑I, and one long‑term study conducted in patients with alopecia areata. In total, 1,011 patients had at least one year of exposure to a 50 mg dose of Litfulo once daily, including 133 adolescents. In the placebo‑controlled period of clinical trials conducted in patients with alopecia areata, 668 patients were exposed to ritlecitinib, with 130 patients receiving 50 mg once daily for up to 24 weeks. The majority of participants had prior exposure to pharmacologic treatment for alopecia areata.

In the placebo-controlled period of pooled clinical trials in alopecia areata (PCPAA), the most frequent adverse events overall (≥2% in any treatment group) that occurred more commonly in patients treated with Litfulo than in patients that received placebo were headache (9.2% versus [vs.] 8.0%), diarrhea (9.2% vs. 3.8%), abdominal pain upper (3.1% vs. 0.9%), acne (6.2% vs. 4.7%), pyrexia (3.1% vs. 0%), folliculitis (3.1% vs. 1.9%), urticaria (4.6% vs. 1.4%), rash (3.8% vs. 0.9%), dermatitis atopic (2.3% vs. 0.5%), dizziness (2.3% vs. 1.4%), blood creatine phosphokinase increased (1.5% vs. 0%), and red blood cell count decreased (1.5% vs. 0%). Additionally, herpes zoster appeared to have a dose response and occurred more commonly in the Litfulo groups compared to placebo (1.5% vs. 0%).

The adjudicated treatment-emergent adverse events (TEAEs) of interest were opportunistic infections including tuberculosis and herpes zoster, malignancy, major cardiovascular events (MACE), thromboembolic events, audiological events, and neurological events. In patients exposed to 50 mg ritlecitinib, there were 2 cases of adjudicated opportunistic infections with 21 cases of herpes zoster, 3 cases of MACE, 1 case of thromboembolic events, 7 malignancies excluding non‑melanoma skin cancer, 4 cases of peripheral neuropathies, and 15 cases of sensorineural hearing loss which were discovered through protocol-specified audiological assessments and did not meet the criteria for central hearing disorder. In the clinical development program, the number of serious infections was low and appendicitis was the most frequently reported serious infection in patients exposed to 50 mg ritlecitinib.

The number of participants ≥65 years of age enrolled in the pivotal study (Study AA‑I) was low. There were higher proportions of elderly participants than other adult participants (18 to 64 years of age) experiencing severe adverse events, serious adverse events, and adverse events leading to permanent discontinuations. In patients exposed to a 50 mg dose of Litfulo once daily, TEAEs reported in ≥10% of elderly participants and at a higher frequency in elderly participants than in adult participants included urinary tract infections (16.7% vs. 5.3%), lymphocyte count decreased (10.0% vs. 1.3%), and arthralgia (13.3% vs. 3.4%). There was also a higher proportion of elderly participants than other adult participants experiencing serious infection and herpes zoster. Serious infection was reported in one elderly participant (3.3%; incidence rate per 100 patient-years 2.11, 95% CI: 0.10, 11.52) and 10 adult participants (0.7%; 0.64 [0.32, 1.16]), and herpes zoster was reported in 3 elderly participants (10.0%, 8.23 [2.09, 22.41]) and 21 (1.6%, 1.34 (0.85, 2.03]) adult participants. Herpes simplex was not reported in any elderly participants. Treatment‑emergent adverse events of decreased lymphocyte count were reported in 3 elderly participants (10.0%, 7.94 [2.20, 21.66]) and 17 adult participants (1.3%, 1.06 [0.64, 1.68]).

The safety profile of Litfulo in adolescent patients was generally similar to the safety profile in adults. The frequency of acne and upper respiratory tract infections was higher in adolescent patients than in adults.

There are limited long-term data to support the chronic use of Litfulo. The long-term safety studies are ongoing.

Consistent with the mechanism of action of ritlecitinib as a JAK3 inhibitor, decreased lymphocyte count and decreased platelet count were observed in clinical studies. Information about these risks, along with guidance on stopping treatment if necessary, are included in the Litfulo Product Monograph. Consistent with the labelling for all products classified as JAK inhibitors, the risks of serious infections and malignancies are in a Serious Warnings and Precautions Box and in the Warnings and Precautions section of the Litfulo Product Monograph.

Litfulo is contraindicated in pregnant and breastfeeding women due to the potential serious risk to the fetus. Litfulo is also contraindicated in patients with severe hepatic insufficiency and because it has not been studied in this patient population.

A Risk Management Plan (RMP) for Litfulo was submitted by Pfizer Canada ULC to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Litfulo Product Monograph met the necessary regulatory labelling, plain language, and design element requirements.

Litfulo has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Litfulo Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Litfulo?

The review of the quality, non-clinical, and clinical, components of the New Drug Submission (NDS) for Litfulo was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references, as described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. Multiple methods were used during the clinical and quality reviews, and Method 3 was used during the review of the non-clinical data. The Canadian regulatory decision on the Litfulo NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Litfulo

Submission Milestone

Date

Pre-submission meeting

2022-03-22

New Drug Submission filed

2022-10-14

Screening

Screening Deficiency Notice issued

2022-12-05

Response to Screening Deficiency Notice filed

2022-12-16

Screening Acceptance Letter issued

2023-02-02

Review

Review of Risk Management Plan completed

2023-11-16

Clinical/medical evaluation completed

2023-11-20

Quality evaluation completed

2023-11-23

Non-clinical evaluation completed

2023-11-23

Labelling review completed

2023-11-27

Notice of Compliance issued by Director General, Pharmaceutical Products Directorate

2023-11-29

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations.

5 What post-authorization activity has taken place for Litfulo?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Litfulo is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

As outlined in the What steps led to the approval of Litfulo? section, the clinical review of the New Drug Submission for Litfulo was conducted using multiple methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Ritlecitinib, the medicinal ingredient in Litfulo, irreversibly and selectively inhibits Janus‑associated kinase (JAK) 3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family by blocking the adenosine triphosphate (ATP) binding site. In cellular settings, ritlecitinib specifically inhibits the signalling of γ-common cytokines (interleukin [IL]-2, IL-4, IL-7, IL-15 and IL-21) through JAK3-dependent common-γ chain receptors. Additionally, ritlecitinib inhibits the TEC family of kinases, resulting in reduced cytolytic activity of natural killer (NK) cells and CD8+ T cells. The JAK3‑ and TEC family‑mediated signalling pathways are both involved in the pathogenesis of alopecia areata, although the complete pathophysiology is still not understood.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Litfulo have been characterized. Ritlecitinib is well absorbed. The fraction of a dose absorbed (fa) was approximately 89% after oral administration, with an absolute oral bioavailability of approximately 64%. Peak plasma concentrations are reached within one hour, and steady state is reached approximately by Day 4. In clinical studies, Litfulo was administered without regard to meals and may be taken without regard to food. After intravenous administration, the volume of distribution of ritlecitinib is about 74 L. Approximately 14% of circulating ritlecitinib is bound to plasma proteins. The blood/plasma distribution ratio of ritlecitinib is 1.62. The metabolism of ritlecitinib is mediated by multiple isoforms of glutathione S-transferase (GST) and cytochrome P450 (CYP) enzymes, with no clearance route contributing more than 25%. Therefore, drugs inhibiting a selective metabolic pathway are unlikely to impact the systemic exposures of ritlecitinib. Specific inhibitors of transporters are unlikely to result in clinically relevant changes in the bioavailability of ritlecitinib. Four important drug-drug interactions have been identified (with rifampin, caffeine, midazolam, and sumatriptan), and are addressed in the Litfulo Product Monograph. In a radiolabelled study in humans, ritlecitinib was the most prevalent circulating species after intravenous administration, accounting for 30.4% of circulating radioactivity. A major cysteine conjugate metabolite, M2, accounted for 16.5% of the circulating radioactivity and was pharmacologically inactive.

Ritlecitinib is eliminated primarily by metabolic clearance mechanisms, with approximately 4% of the dose excreted as unchanged drug in urine. The metabolites of ritlecitinib are excreted in urine (66% of recovered radioactivity) and feces (20%). Following multiple oral doses, steady state was reached approximately by Day 4 due to non-stationary pharmacokinetics. The steady state pharmacokinetic parameters, exposure as measured by the area under the concentration-time curve (AUCtau) and the peak plasma concentration (Cmax), increased in an approximately dose-proportional manner, with the mean terminal half-life ranging from 1.3 to 2.3 hours.

In patients with moderate hepatic impairment (Child Pugh B), an 18.5% increase was observed in ritlecitinib exposure (as measured by the AUC for 0-24 hours [AUC24]) compared to participants with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic impairment based on this consideration. Ritlecitinib has not been studied in patients with severe hepatic impairment (Child Pugh C) and is contraindicated for use in this patient population.

The AUC24 observed in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min) was 55.2% higher than in matched participants with normal renal function. Ritlecitinib has not been studied in patients with mild (eGFR 60 to <90 mL/min) or moderate (eGFR 30 to <60 mL/min) renal impairment, as a clinically relevant increase in ritlecitinib exposure is not expected in these patients. Ritlecitinib has not been studied in patients with end-stage kidney disease (ESRD) or in renal transplant recipients.

For further details, please refer to the Litfulo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence of the clinical efficacy of Litfulo was obtained predominantly from Study AA‑I (B7981015), a Phase IIb/III pivotal and dose-ranging study conducted in adults and adolescents 12 years of age and older with alopecia areata. The primary objective of the study was to evaluate the efficacy of Litfulo compared to placebo in adult and adolescent participants with 50% or greater scalp hair loss, including alopecia totalis (AT) and alopecia universalis (AU).

The treatment period consisted of a placebo‑controlled 24‑week period and a 24‑week extension period. Study AA‑I evaluated 718 patients who were randomized in a 2:2:2:2:1:1:1 ratio to blinded Litfulo and matching placebo in one of the following treatment regimens for 48 weeks:

  1. 200 mg once daily for 4 weeks, followed by 50 mg once daily for 44 weeks;

  2. 200 mg once daily for 4 weeks, followed by 30 mg once daily for 44 weeks;

  3. 50 mg once daily for 48 weeks;

  4. 30 mg once daily for 48 weeks;

  5. 10 mg once daily for 48 weeks;

  6. placebo for 24 weeks, followed by 200 mg once daily for 4 weeks and 50 mg once daily for 20 weeks; or

  7. placebo for 24 weeks followed by 50 mg for 24 weeks.

The majority of participants (85.4%) were 18 years of age or older, with 105 participants (14.6%) 12 to 17 years of age and 20 participants (2.8%) 65 years of age or older. The mean age of all participants was 33.7 years. There were more female participants (62.1%) than male participants (37.9%). Most participants were White (68.0%), 25.9% were Asian, and 3.8% were Black or African American.

The mean baseline Severity of Alopecia Tool (SALT) score, which describes the percentage of scalp hair loss (range: 0 to 100), ranged from 88.3 to 93.0 across treatment groups. Among patients without AT/AU at baseline, the mean SALT score ranged from 78.3 to 87.0. Across treatment groups, the majority of participants had abnormal eyebrows (83.0%) and eyelashes (74.7%) at baseline. The median duration since alopecia areata diagnosis was 6.9 years, and the median duration of the current alopecia areata episode was 2.5 years. Randomization was stratified by the AT/AU status, with 46% of participants classified as AT/AU based on a baseline SALT score of 100.

The primary efficacy endpoint of this study was the proportion of patients who achieved a SALT score of ≤20 (SALT ≤20) at Week 24. At this time point, 23% of participants had a SALT ≤20 response with Litfulo 50 mg once daily compared to 1.6% of participants who received placebo (difference of 21.4%; 95% confidence interval [CI]: 13.4, 29.5). The SALT ≤20 response rate for patients treated with Litfulo increased further after Week 24 through Week 48. Statistical separation from placebo in the SALT ≤20 response first occurred at Week 18.

Secondary efficacy endpoints included a SALT score of ≤10% at Week 24, a change from baseline in SALT scores over time, and improvements in the regrowth of eyebrows and/or eyelashes at Week 24. At this time point, 13.4% of participants had a SALT ≤10 response with Litfulo 50 mg once daily compared to 1.5% of participants who received placebo (difference of 11.9%; 95% CI: 5.4, 18.3). The SALT ≤10 response rate increased further at Week 48. Patients receiving Litfulo 50 mg experienced greater improvement in SALT scores over time compared to patients who received placebo at Week 24, and with further increases observed through Week 48. Improvements in regrowth of eyebrows and/or eyelashes were observed at Week 24 in patients treated with Litfulo 50 mg, with further improvements seen at Week 48.

The Patient’s Global Impression of Change (PGI‑C) response is a patient‑reported outcome measure. Patients are asked whether there has been a global improvement or worsening in their disease status compared to the start of the study. The PGI‑C response (defined as a score of “moderately improved” or “greatly improved” based on a 7‑point Likert scale ranging from “greatly improved” to “greatly worsened”) was assessed at Week 24 to evaluate the treatment benefit from the patient’s perspective. Significant improvement in the PGI‑C response was reported between Litfulo 50 mg and placebo at Week 24, with response rates continuing to increase through Week 48.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Litfulo (ritlecitinib) is indicated for the treatment of adults and adolescents 12 years and older with all types of alopecia areata (including alopecia totalis and alopecia universalis) for hair regrowth, including scalp, eyebrow and eyelash, in patients who are candidates for systemic therapy.

Litfulo (ritlecitinib) is indicated for the treatment of adults and adolescents 12 years and older with severe alopecia areata.

For more information, refer to the Litfulo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety evaluation was based on data from three randomized studies, including the pivotal study AA‑I, and one long‑term study conducted in patients with alopecia areata. In total, 1,011 patients had at least one year of exposure to a 50 mg dose of Litfulo once daily, including 133 adolescents. There were 585 patients with at least 18 months of exposure to all 50 mg ritlecitinib, including 90 adolescents, and 279 patients with at least 24 months of exposure to all 50 mg ritlecitinib, including 44 adolescents.

In the placebo‑controlled period of clinical trials in alopecia areata, 668 patients were exposed to ritlecitinib, with 130 patients receiving 50 mg once daily for up to 24 weeks. Patients that received a 50 mg dose once daily for any duration included 38 adolescent, 307 adult, and 8 elderly patients. The median duration of alopecia areata disease for patients in this group was 6.9 years, and 44.4% of patients had AT/AU while 55.6% of patients did not have AT/AU. The majority of participants had prior exposure to pharmacologic treatment considered to be a therapy for alopecia areata.

In the placebo-controlled period of pooled clinical trials in alopecia areata (PCPAA), the most frequent adverse events overall (≥2% in any treatment group) that occurred more commonly in patients treated with Litfulo than in patients that received placebo were headache (9.2% versus [vs.] 8.0%), diarrhea (9.2% vs. 3.8%), abdominal pain upper (3.1% vs. 0.9%), acne (6.2% vs. 4.7%), pyrexia (3.1% vs. 0%), folliculitis (3.1% vs. 1.9%), urticaria (4.6% vs. 1.4%), rash (3.8% vs. 0.9%), dermatitis atopic (2.3% vs. 0.5%), dizziness (2.3% vs. 1.4%), increased blood creatine phosphokinase (1.5% vs. 0%), and decreased red blood cell count (1.5% vs. 0%). Additionally, herpes zoster appeared to have a dose response and occurred more commonly in the Litfulo groups compared to placebo (1.5% vs. 0%).

The adjudicated treatment-emergent adverse events (TEAEs) of interest were opportunistic infections including tuberculosis and herpes zoster, malignancy, major cardiovascular events (MACE), thromboembolic events, audiological events, and neurological events. In patients exposed to 50 mg ritlecitinib, there were 2 cases of adjudicated opportunistic infections with 21 cases of herpes zoster, 3 cases of MACE, 1 case of thromboembolic events, 7 malignancies excluding non‑melanoma skin cancer, 4 cases of peripheral neuropathies, and 15 cases of sensorineural hearing loss which were discovered through protocol-specified audiological assessments and did not meet the criteria for central hearing disorder. In the clinical development program, the number of serious infections was low and appendicitis was the most frequently reported serious infection in patients exposed to 50 mg ritlecitinib.

No effects were observed on the growth or development of adolescent patients. No cases of herpes simplex, herpes zoster, malignancies, MACE, thromboembolic events, or sensorineural hearing loss were reported in adolescent patients in the all exposure pool (all participants taking ritlecitinib regardless of the dose).

The frequency of hepatic enzyme elevation and creatine kinase elevation (without evidence of rhabdomyolysis) was higher in patients treated with Litfulo compared to patients who received placebo.

The number of participants ≥65 years of age enrolled in the pivotal study was low. There were higher proportions of elderly participants than other adult participants (18 to 64 years of age) who experienced severe adverse events, serious adverse events, and adverse events leading to permanent discontinuations. In patients exposed to a 50 mg dose of ritlecitinib once daily, the TEAEs reported in ≥10% of elderly participants and at a higher frequency than in adult participants included urinary tract infections (16.7% vs. 5.3%), decreased lymphocyte count (10.0% vs. 1.3%), and arthralgia (13.3% vs. 3.4%). There was also a higher proportion of elderly participants than other adult participants experiencing serious infection and herpes zoster. Serious infection was reported in one elderly participant (3.3%; incidence rate per 100 patient-years 2.11, 95% CI: 0.10, 11.52) and 10 adult participants (0.7%; 0.64 [0.32, 1.16]). Herpes zoster was reported in 3 elderly participants (10.0%, 8.23 [2.09, 22.41]) and 21 (1.6%, 1.34 (0.85, 2.03] adult participants. Herpes simplex was not reported in any elderly participants. Treatment‑emergent adverse events of decreased lymphocyte count were reported in 3 elderly participants (10.0%, 7.94 [2.20, 21.66]) and 17 adult participants (1.3%, 1.06 [0.64, 1.68]).

The safety profile of Litfulo in adolescent patients was generally similar to the safety profile in adults. The frequency of acne and upper respiratory tract infections was higher in adolescent patients than in adults.

There are limited long-term data to support the chronic use of Litfulo. The long-term safety trial B7981032 and the clinical mechanistic safety study B7981037 (Phase IIa study to provide additional data regarding the clinical relevance of an axonal dystrophy finding in the 9‑month dog toxicity study) are ongoing.

Ritlecitinib (the medicinal ingredient in Litfulo) is a covalent irreversible inhibitor of JAK3 and the TEC family of kinases. Consistent with the mechanism of action of ritlecitinib as a JAK3 inhibitor, decreased lymphocyte count and decreased platelet count were observed in clinical studies. Information about these risks, along with guidance on stopping treatment if necessary, are included in the Litfulo Product Monograph. Consistent with the labelling for all products classified as JAK inhibitors, the risks of serious infections and malignancies are in a Serious Warnings and Precautions Box and in the Warnings and Precautions section of the Litfulo Product Monograph.

Litfulo is contraindicated in pregnant and breastfeeding women due to the potential serious risk to the fetus. Litfulo is also contraindicated in patients with severe hepatic insufficiency because it has not been studied in this patient population.

Overall, the safety of Litfulo for the proposed indication is supported by the data reviewed. The inherent and potential risks associated with Litfulo are described in the Product Monograph, along with risk mitigation measures. Evaluation of the long‑term safety of Litfulo is ongoing.

For more information, refer to the Litfulo Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

As outlined in the What steps led to the approval of Litfulo? section, the review of the non-clinical component of the New Drug Submission for Litfulo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non-clinical pharmacology program for ritlecitinib (the medicinal ingredient in Litfulo) was designed to evaluate its pharmacodynamic properties, pharmacokinetic profile, and pharmacological safety. The results of these studies demonstrated that ritlecitinib is a selective, covalent, and irreversible inhibitor of Janus-associated kinase (JAK) 3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family. Ritlecitinib was also found to have a low probability of interaction with non‑intended targets.

In small animal models with alopecia areata, animals that were dosed with ritlecitinib showed decreased inflammation and presented hair regrowth. The administration of ritlecitinib to small animals did not reveal any risks to vital organ systems (i.e., nervous, respiratory, or cardiovascular systems).

Orally administered ritlecitinib was potently absorbed. Ritlecitinib distributed quickly to every tissue examined, and was detected at significant levels in the uveal tract, and in gastrointestinal, metabolic, and excretory organs. Ritlecitinib and its metabolites were still detected in the adrenal gland, aorta, blood, eye, heart, lens, liver, lung, kidney, spleen, and uveal tract 28 days after dosing. The cytochrome P450 (CYP) enzymes CYP3A4/5 and CYP2C9 contributed to most of the oxidative metabolism of ritlecitinib. The glutathione S‑transferase (GST) enzymes GST A3, GST P1, GST T2, GST Z1, and microsomal GST 1, GST 2, and GST 3 contributed to the glutathione conjugation metabolism of ritlecitinib.

Ritlecitinib administered to nursing female animals was excreted in milk, and was detected at a greater concentration in milk than in plasma (2.2-fold greater when comparing exposure as measured by the area under the concentration-time curve through 8 hours [AUC8]; 3.36-fold when comparing the maximum concentration [Cmax]). Litfulo is contraindicated in pregnant and breastfeeding women based on these findings.

Repeat‑dose toxicity studies were conducted up to 9 months, which indicated that Litfulo has reasonable margins of safety relative to the recommended human dose (RHD). Dogs appeared to be the most sensitive species. In a 9‑month dog toxicity study, the no‑observed-adverse‑effect level (NOAEL) was 10 mg/kg body weight per day, which corresponds to 7.4 times the RHD. In a 6‑month rat toxicity study, the NOAEL was 200 mg/kg body weight per day, which corresponds to 50 times the RHD. Non‑adverse observations consistent with JAK3 and TEC kinase inhibition (lower leukocyte counts, lymphocyte counts and decreased cellularity in the spleen, thymus, lymph nodes, gut‑associated lymphoid tissue, and bone marrow) were consistent across species at or below the NOAELs. Treatment‑related but non‑adverse effects were observed on hematology parameters consistent with oxidative damage to red blood cells, along with a subsequent erythroid regenerative response. Notable adverse effects in dogs included systemic infections, axonal dystrophy and auditory deficits (higher auditory thresholds and loss of clarity of auditory waves 4 and 5). The auditory deficits were fully reversible, and the axonal dystrophy was partially reversible.

Litfulo is not expected to pose a significant genotoxic risk to humans. Although some evidence indicates that Litfulo is aneugenic in vitro, Litfulo is not aneugenic or clastogenic in rats at doses up to 400 mg/kg body weight per day. Based on the results of a bacterial mutagenicity assay (Ames assay), Litfulo is not mutagenic.

Some findings from studies in rats indicate that Litfulo is carcinogenic. Combined benign and malignant thymomas were observed in female rats, and thyroid follicular cell adenomas and combined thyroid follicular adenomas and carcinomas were observed in male rats in the 2‑year rat study at doses corresponding to 29 times the RHD.

Adverse reproductive and developmental effects were observed in rats and rabbits. Adverse effects on fertility, pre‑ and postnatal development were observed in rats. Adverse effects on embryo‑fetal development were observed in rats and rabbits. A higher incidence of pre‑implantation loss was observed in treatment-naïve female rats when paired with male rats dosed with 200 mg/kg body weight per day (55 times the RHD). No treatment-related effects were observed on spermatogenesis or female rat fertility.

Skeletal malformations and variations were observed in the rat and rabbit embryo-fetal development studies. Malpositioned left or right kidney (visceral malformation), post-implantation loss, higher incidence of total (late and early) resorptions, and lower fetal body weights were observed in the rabbit embryo-fetal development study. External malformations or variations were not observed in rats or rabbits. A delay in vaginal patency in females, lower postnatal survival during postnatal days (PND) 0-4, lower number of implantation sites, corpora lutea, and viable embryos were observed in the rat pre‑ and postnatal development study.

There was no evidence of cutaneous or ocular phototoxicity in rats based on a 3-day oral gavage phototoxicity study. There was no evidence of hypersensitivity in the mouse based on a subcutaneous mouse allergy model study.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Litfulo Product Monograph. Considering the intended use of Litfulo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Litfulo Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

As outlined in the What steps led to the approval of Litfulo? section, the review of the quality component of the New Drug Submission for Litfulo was conducted using multiple methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Litfulo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.