Ritlecitinib (LITFULO): Bad Choice for Severe Alopecia Areata

In June 2023 the Food and Drug Administration (FDA) approved ritlecitinib (LITFULO) — an oral drug that suppresses the immune system — for the treatment of severe alopecia areata in adults and adolescents aged 12 years and older.[1]

Alopecia areata is an autoimmune disease in which T lymphocytes — a type of blood cells — attack hair follicles, resulting in smooth patches of hair loss on the scalp, eyebrows or eyelashes.[2] The disease usually starts between 5 and 10 years of age in children and before age 40 in adults.

Ritlecitinib belongs to a potent drug class called Janus kinase (JAK) inhibitors, which are used to treat autoimmune diseases such as rheumatoid arthritis. In 2021, based on evidence from a post-marketing safety clinical trial, the FDA concluded that certain JAK inhibitors can increase the risk of serious cardiovascular events (such as blood clots in the legs, lungs or heart; heart attack; or stroke), cancer and death.[3],[4] Therefore, the FDA mandated adding this risk to the boxed warnings — the most prominent safety warnings required by the agency — in the labeling of these drugs. The FDA also limited the approved uses of JAK inhibitors in rheumatoid arthritis to patients who have not responded to (or cannot tolerate) one or more drugs that belong to another drug class known as tumor necrosis factor (TNF) blockers, such as adalimumab (HUMIRA and biosimilars), etanercept (ENBREL and biosimilars) and infliximab (REMICADE, ZYMFENTRA and biosimilars).

Although a small, short-term efficacy clinical trial showed that ritlecitinib may trigger hair regrowth in some patients, Public Citizen’s Health Research Group has designated this drug as Do Not Use because its possible limited benefits do not outweigh its serious harms. Despite a hefty price tag (approximately $49,000 annually),[5] ritlecitinib does not cure alopecia areata, and its effects on hair regrowth, if any, do not last after the drug is stopped.[6]

In general, we advise against the use of new prescription drugs until at least seven years after their approval — except in the case of apparently safe, “truly” breakthrough ones — because the drug approval process is heavily tilted toward establishing evidence of benefit but is underpowered to detect the full risks of drugs.[7]

Limited short-term evidence

Pfizer, the maker of ritlecitinib, sponsored a single randomized, placebo-controlled trial to support the efficacy of the drug.[8] The FDA reviewed data for 261 subjects (average age 34 years) from these trials who had severe alopecia areata (at least 50% scalp hair loss). Of those subjects, 130 received the approved dose of ritlecitinib (50 milligrams) once daily and 131 received a matching placebo. After 24 weeks of follow-up, 23% of ritlecitinib subjects had 20% or less scalp hair loss, compared with 2% of placebo users. Additionally, 13% of ritlecitinib subjects had 10% or less scalp hair loss, compared with 2% of placebo users.

Pfizer reported safety data for 130 subjects with severe alopecia areata who had received the approved dose of ritlecitinib for 24 weeks and 213 subjects who had received a placebo. Among these 343 subjects, higher percentages of diarrhea, headache, fever and skin reactions (including acne, rash or urticaria) were reported among ritlecitinib subjects. In addition, 2% of ritlecitinib subjects (and none of the subjects in the placebo group) had any of the following adverse effects: decreased red blood cell counts, increased blood levels of creatine phosphokinase (an enzyme that suggests problems in the brain tissue or heart or skeletal muscles), shingles and tongue inflammation.

Similar to other JAK inhibitors, the boxed warnings on ritlecitinib’s drug label highlight the risk of serious infections, death, malignancy, major adverse cardiovascular events and blood clots (see the Text Box on page 4 for details). Moreover, in placebo-controlled trials, for up to 24 weeks, three ritlecitinib subjects developed serious infections (including appendicitis, COVID-19 infection [and related pneumonia] and sepsis), one subject had breast cancer and another subject had a decreased platelet count. Importantly, several events of increased liver enzymes (at least three times the upper normal limit) were observed in ritlecitinib subjects. Additionally, three ritlecitinib subjects either developed blood clots in the heart or lung or had an occlusion in the retinal artery.

Post-marketing safety evidence, required by the FDA, from an ongoing open-label ritlecitinib study will not be available until August 2026.[9] Additional evidence required by the European Medicines Agency (which also has approved the drug) to assess ritlecitinib’s neurotoxicity and long-term effects on growth and bone development as well as maturation and development in adolescent patients will not be available until March 2037.[10]

To protect patients, it would have been better for the FDA and other regulatory agencies to have required larger and longer studies of ritlecitinib before approving this potent immunosuppressive drug with limited evidence of benefit and major safety concerns.

Boxed Warnings for Ritlecitinib

SERIOUS INFECTIONS, DEATH, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS and BLOOD CLOTS[11]

• Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis:
  • If serious infection occurs, interrupt treatment with ritlecitinib until the infection is controlled.
  • The drug should not be given to patients with active tuberculosis. Test for latent tuberculosis before and during therapy, and treat latent tuberculosis prior to use.
  • Monitor all patients for active tuberculosis during treatment with ritlecitinib, even patients with an initial negative latent tuberculosis test.
• Higher rate of all-cause mortality, including sudden cardiovascular death, occurred with another JAK inhibitor than with TNF blockers.*
• Malignancies have occurred in patients treated with ritlecitinib. Higher rates of lymphomas and lung cancers occurred with another JAK inhibitor than with TNF blockers.*
• Higher rate of major adverse cardiovascular events (defined as cardiovascular death, myocardial infarction and stroke) occurred with another JAK inhibitor than with TNF blockers.*
• Thrombosis (blood clots) has occurred in patients treated with ritlecitinib. Increased rates of pulmonary embolism and venous or arterial thrombosis occurred with another JAK inhibitor compared with TNF blockers.*

* These risks occurred in rheumatoid arthritis patients. Ritlecitinib has not been approved for use in these patients. “Another JAK inhibitor” refers to tofacitinib (XELJANZ and generics), which belongs to the same drug class as ritlecitinib.

What You Can Do

If you have alopecia areata or any other type of hair loss, do not assume that ritlecitinib or baricitinib (OLUMIANT)[12] — the only other JAK inhibitor that has been approved to treat alopecia areata — is your silver bullet for safe, lasting hair regrowth. If you are already taking these or similar drugs, do not stop taking them before talking to your clinician, because doing so may seriously worsen your condition. Likewise, be aware that there is no “super supplement” that can stop hair loss due to autoimmune diseases.

If you are struggling with psychological aspects of hair loss, such as body image issues or depression, seek support from family, friends, community groups or a therapist.

Report all adverse events related to ritlecitinib and other drugs to the FDA’s MedWatch adverse event reporting program by visiting www.fda.gov/MedWatch or by calling 800-FDA-1088.

References

[1] Pfizer Inc. Label: ritlecitinib (LITFULO). June 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215830s000lbl.pdf. Accessed July 9, 2024.

[2] Food and Drug Administration. Multidisciplinary review of ritlecitinib (application # 215830Orig1s000). October 12, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/215830Orig1s000MultidisciplineR.pdf. Accessed July 9, 2024.

[3] Food and Drug Administration. FDA drug safety communication: FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. September 1, 2021. https://www.fda.gov/safety/medical-product-safety-information/janus-kinase-jak-inhibitors-drug-safety-communication-fda-requires-warnings-about-increased-risk. Accessed July 9, 2024.

[4] FDA limits approved uses of tofacitinib (XELJANZ, XELJANZ XR) because of serious adverse effects January 2022. Worst Pills, Best Pills News. https://www.worstpills.org/newsletters/view/1444. Accessed July 9, 2024.

[5] Kansteiner F. Pfizer's Litfulo enters the scene in alopecia with adolescent nod to rival Lilly's Olumiant. June 26, 2023. https://www.fiercepharma.com/pharma/pfizers-litfulo-enters-scene-alopecia-adolescent-nod-rival-lillys-olumiant. Accessed July 9, 2024.

[6] Sardana K, Bathula S, Khurana A. Which is the ideal JAK inhibitor for alopecia areata - baricitinib, tofacitinib, ritlecitinib or ifidancitinib - revisiting the immunomechanisms of the JAK pathway. Indian Dermatol Online J. 2023;14(4):465-474.

[7] Editorial: The seven-year rule for safer prescribing. Worst Pills, Best Pills News. October 2012. https://www.worstpills.org/newsletters/view/816. Accessed July 11, 2024.

[8] Pfizer Inc. Label: ritlecitinib (LITFULO). June 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215830s000lbl.pdf. Accessed July 9, 2024.

[9] Food and Drug Administration. Approval letter to Pfizer, ritlecitinib (Litfulo), NDA 215830. June 23, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/215830Orig1s000ltr.pdf. Accessed July 9, 2024.

[10] European Medicines Agency. Assessment report: ritlecitinib (Litfulo). July 20, 2023.

[11] Pfizer Inc. Label: ritlecitinib (LITFULO). June 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215830s000lbl.pdf. Accessed July 9, 2024.

[12] Eli Lilly and Company. Label: Baricitinib (OLUMIANT). June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207924s007lbl.pdf. Accessed July 9, 2024.