Alopecia areata is a chronic autoimmune disease characterized by rapid hair loss without scarring. Hair loss usually occurs on the head and beard area, but can occur on any part of the body.
The most common type of alopecia areata is patchy (localized) alopecia areata: round bald spots with complete hair loss. The most severe types of alopecia areata result in complete hair loss on the head (alopecia totalis) or the entire body (alopecia universalis).
Alopecia areata occurs more frequently in persons under the age of 40 (up to 80% of patients), equally in men and women, and in half of the cases it develops before the age of 20.
Alopecia areata occurs in 0.1%–0.2% of the general population.
The cause of alopecia areata is unknown. It is probably due to a multifactorial genetic predisposition triggered by environmental factors. An autoimmune inflammatory process leads to destruction of the immune privilege of the hair follicle and subsequent attacks on previously healthy hair follicles. Since in alopecia areata, which is not a scarring disease, the hair follicle retains the ability to regenerate and continue its development cycle and its stem cells are usually not destroyed, hair loss followed by alopecia areata is positioned as a reversible condition in principle.
The existing pharmacological armamentarium to combat baldness due to alopecia areata is represented by the following drugs: topical corticosteroids (triamcinolone, betamethasone, clobetasol, mometasone, fluocinolone), topical minoxidil, topical tretinoin, topical anthralin (dithranol), topical immunotherapy (diphenylcyclopropenone [DPCP], squaric acid dibutylester [SADBE], systemic immunosuppressants (azathioprine, cyclosporine, methotrexate).
Despite the relatively wide variety of proposed pharmacological interventions for the treatment of alopecia areata, current approaches cannot be called unequivocally effective. This is why pharmaceutical companies continue to develop new medications against alopecia areata.
The pathogenesis of alopecia areata involves genetic  and immune factors.   The proliferation and activation of autoreactive CD8+ T cells attacking hair follicles is driven by cytokines including interferon gamma (IFN-γ) and interleukin-15 (IL-15).  Since the latter are dependent on the JAK–STAT signaling pathway, inhibition of Janus kinases (JAKs) can be an effective treatment for alopecia areata.  JAK inhibitors have previously been shown to reverse hair loss in patients with alopecia areata.   
In general, JAK inhibitors have long and repeatedly proven their worth in the treatment of alopecia areata. This is evidenced by the positive results of a number of clinical trials and numerous individual cases of off-label use of this class of drugs.
It should be understood that the beneficial effect of JAK-inhibition, manifested by the recovery of hair growth, persists until the treatment is discontinued: after withdrawal of the drug, alopecia areata recurs in most cases. At the same time, its course may worsen, when the disease progresses more severely, resulting in more significant alopecia areata than before the start of treatment. It is unknown whether the rebound effect is true one (secondary to an increase in disease activity), a consequence of telogen effluvium (JAK inhibitors drive hair follicles into the anagen phase), or a consequence of quorum sensing effect at the organ level.
The question with the balance of efficacy and safety in case of long-term multi-year use of JAK inhibitors remains open to the end: their direct interference with the body’s immune system carries certain risks of developing serious adverse events, including infectious diseases (upper respiratory tract infections, urinary tract infections, tuberculosis, herpes zoster, herpes simplex), malignancies (lymphoma), major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke), thrombosis, gastrointestinal perforation.
- These risks of serious adverse events remain, however, very low, based on the results of the long-term use of JAK inhibitors in the treatment of other diseases, such as rheumatoid arthritis, psoriatic arthritis, polycythemia vera, ulcerative colitis.      
In mid-June 2022, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved Olumiant (baricitinib) for the treatment of severe alopecia areata in adults.
Baricitinib (LY3009104, INCB28050) is an oral small-molecule selective reversible inhibitor of Janus kinase 1 and 2 (JAK1/JAK2).
Baricinitib was developed by Incyte, which licensed it to Eli Lilly in December 2009. It was paid $90 million up front and promised up to $665 million as the project developed, plus royalties from sales of the finished drug.
Olumiant debuted in February 2017 to treat moderate-to-severe rheumatoid arthritis, then expanded its indications to include treatment for atopic dermatitis (eczema). A combination of Olumiant and Veklury (remdesivir) is used to treat COVID-19 infection in hospitalized adults and children requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
The BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) phase 2/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trials, identical in design, enrolled adult patients (n=1200) with severe or very severe alopecia areata (SALT score ≥ 50).
- The severity of the disease was assessed by the Severity of Alopecia Tool (SALT), with a final score ranging from 0 to 100, where 0 means no hair loss and 100 means complete hair loss.
Daily 36-week administration of baricitinib at a dose of 2 mg or 4 mg resulted in a statistically significant difference with the placebo group in the proportion of patients demonstrating hair growth on at least 80% of the scalp (SALT score ≤ 20).
6%, 23%, and 39% of patients in the placebo, 2-mg baricitinib, and 4-mg baricitinib groups, respectively, reached the indicated score in BRAVE-AA1. In BRAVE-AA2, this rate was recorded for 3%, 19%, and 36% of patients.
At least 90% hair regrowth (SALT ≤ 10) was reported in 4%, 13%, 28%, and 1%, 12%, 26% of subjects, respectively.
Oral Xeljanz (tofacitinib), a Pfizer-developed Janus kinase 1, 2, and 3 (JAK1/JAK2/JAK3) inhibitor, is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, polyarticular course juvenile idiopathic arthritis.
Tofacitinib has long been successfully used off-label in the treatment of alopecia areata. However, Pfizer is not specifically evaluating tofacitinib in alopecia areata, believing that it is more appropriate to develop other drug compounds that may be more effective and safer against this condition.
Oral Jakafi/Jakavi (ruxolitinib), a Janus kinase 1 and 2 (JAK1/JAK2) inhibitor developed by Incyte and Novartis, is approved for the treatment of myelofibrosis (primary and secondary due to polycythemia vera or essential thrombocythemia), polycythemia vera, graft-versus-host disease.
Ruxolitinib has long been successfully used off-label in the treatment of alopecia areata. However, neither Incyte nor Novartis are conducting a specific clinical trial of ruxolitinib for alopecia areata because the former already has baricitinib approved for this indication, while the focus of the latter is shifted to more profitable areas.
In the first half of 2023, Concert Pharmaceuticals plans to submit to regulators the New Drug Application (NDA) for oral deuruxolitinib (CTP-543), which is ruxolitinib whose chemistry is altered by deuterium.
The suggested brand name for deuruxolitinib is Leqselvi or Tidasviq.
- Selective inclusion of deuterium instead of hydrogen in the chemical structure of the drug leads to changes in its therapeutic properties, including increased half-life, improved oral bioavailability, optimized metabolic profile, and improved safety.
In the THRIVE-AA1 (NCT04518995) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial among adult patients (n=706) with moderate-to-severe alopecia areata, administration of deuruxolitinib twice daily in a dose of 8 mg or 12 mg for 24 weeks resulted in a SALT score ≤ 20 for 30% and 42% of subjects, respectively — versus 0.8% in the placebo group (p<0,0001).
In the THRIVE-AA2 (NCT04797650) phase 3 clinical trial, similar in design, which enrolled adult patients (n=517) with moderate-to-severe alopecia areata, deuruxolitinib administered twice daily at a dose of 8 or 12 mg for 24 weeks yielded a SALT score ≤ 20 among 33% and 38% of patients — versus 0.8% in controls (p<0.0001).
China’s Jiangsu Hengrui Pharmaceuticals is testing ivarmacitinib (SHR0302), an oral Janus kinase 1 (JAK1) inhibitor, for the treatment of several autoimmune diseases including alopecia areata.
China’s Reistone Biopharma, which has licensed ivarmacitinib from Hengrui, has successfully completed the CRYSTAL2 (NCT04346316) phase 2 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial among adult patients (n=94) with moderate-to-severe alopecia areata.
China’s Suzhou Zelgen Biopharmaceuticals is rolling out jaktinib, an oral Janus kinase 1, 2, and 3 (JAK1/JAK2/JAK3) inhibitor, to treat a variety of autoimmune diseases including alopecia areata.
Pfizer is developing oral ritlecitinib (PF-06651600), which, in addition to inhibiting Janus kinase 3 (JAK3), inhibits the family of non-receptor protein-tyrosine kinases (TEC), leading to suppression of cytolytic function of CD8+ T cells and natural killer (NK) cells.
The ALLEGRO (NCT03732807) phase 2b/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial enrolled patients (n=718) aged 12 years and older with moderate-to-severe alopecia areata. Daily administration of ritlecitinib at 30 mg or 50 mg resulted in a statistically significant difference with the placebo group in achieving a SALT score ≤ 20 after 24 weeks of treatment. Thus, 23% and 14% of patients reached the specified primary efficacy endpoint — versus 2% in the placebo group.
The long-term ALLEGRO-LT (NCT04006457) phase 3 clinical trial is ongoing, including participants of NCT02974868 and NCT03732807, which evaluates the efficacy and safety of daily use of ritlecitinib in a 50 mg dose to treat alopecia areata for 3 years.
Korea’s D.Nature offers Anacell, also known as CMX and DN-001, an over-the-counter topical cosmeceutical that contains the plant-derived sesquiterpene lactone brevilin A derived from Centipeda minima. Brevilin A is a Janus kinase 3 (JAK3) inhibitor and activator of Wnt/beta-catenin signaling pathway responsible, among others, for neogenesis of hair follicles and anagen phase initiation.    
D.Nature is working on an improved version of Anacell.
Pfizer is studying etrasimod (APD334), an oral agonist of sphingosine-1-phosphate receptors 1, 4, and 5 (S1PR1/S1PR4/S1PR5).
The immunomodulatory mechanism of action of etrasimod is due to internalization of sphingosine-1-phosphate receptors (S1PRs) with their subsequent degradation (functional antagonism) in the ubiquitin–proteasome metabolic pathway. This leads to inhibition of migration of a certain subtype of activated lymphocytes (T helpers CD4+ CCR7+ and T killers CD8+ CCR7+) from the lymphoid tissue to the sites of inflammation. The integrity of immunological surveillance for infections and tumors is preserved because S1P signaling does not affect a subset of lymphocytes that do not migrate through the lymphoid tissue.
Etrasimod-like S1PRs agonists such as Gilenya (fingolimod), Mayzent (siponimod), Zeposia (ozanimod), and Ponvory (ponesimod), are used in the treatment of relapsing forms of multiple sclerosis and inflammatory bowel disease (ulcerative colitis).
Etrasimod, obtained from Arena Pharmaceuticals, purchased in March 2022 for nearly $6.7 billion, is in a 24-week NCT04556734 phase 2 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial among adult patients (n=78) with moderate-to-severe alopecia areata who receive daily etrasimod at a dose of 2 mg or 3 mg.
- Mayzent: New Drug for Treatment of Secondary Progressive Multiple Sclerosis
Siponimod released by Novartis is an improved version of Gilenya.
- Zeposia: New Drug to Treat Relapsing Multiple Sclerosis
Bristol-Myers Squibb has come up with ozanimod, a direct competitor to Novartis’ fingolimod and siponimod, for the treatment of multiple sclerosis.
- Zeposia: New Drug for Ulcerative Colitis
Oral ozanimod will provide clinical remission of ulcerative colitis for a third of patients.
- Ponvory: Another Drug for Multiple Sclerosis
Ponesimod is a new drug that changes the course of multiple sclerosis and is a direct competitor to Gilenya (fingolimod), Mayzent (siponimod), and Zeposia (ozanimod).
Switzerland’s Legacy Healthcare came up with Coacillium (LH-8), also known as Cellium, CG210 and CG428, a proprietary blend of water-alcoholic extracts from onion bulb (Allium cepa), lemon fruit (Citrus limon), cocoa seed (Theobroma cacao), and guarana seed (Paullinia cupana).
In autoimmune diseases, this cosmeceutical combination of flavonoids and polyphenols has a pleiotropic effect on the skin when applied topically. This has been confirmed by a number of clinical trials treating androgenic alopecia in men and women.    A clinical trial of treatment of chemotherapy-induced alopecia has been successfully completed. 
Coacillium is believed to normalize cellular resistance to apoptosis by restoring the number of cells expressing the antiapoptotic protein Bcl-2, which acts during the catagen phase (resting stage in the hair development cycle), thereby prolonging the anagen phase (growth stage) and cell survival. Coacillium has an anti-inflammatory effect due to a significant increase in the number of Langerhans cells and mast cells in the perifollicular area, which prevents miniaturization of follicles and fibrosis. Coacillium promotes collagen content and remodeling around the hair follicle.  
Coacillium, which is an over-the-counter hair care product, is freely available for purchase. The lotion is marketed under different brands with partner support from Galderma, Abbott Laboratories, Sanofi, DKSH, and other pharmaceutical manufacturers.
The ongoing 24-week RAAINBOW (NCT03240627) phase 2/3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trial enrolled patients (n=106) aged 2–18 years with moderate-to-severe pedatric alopecia areata lasting up to 3 years. Subjects were administered a topical 21% Coacillium solution twice daily.
AnaptysBio believes it can do well with the treatment of alopecia areata by targeting a key regulator of the immune response that suppresses T cell inflammatory activity. We are talking about programmed cell death protein 1 (PD-1).
There are many PD-1 and its ligand, PD-L1, blockers on the market, such as Keytruda (pembrolizumab), Opdivo (nivolumab), and Tecentriq (atezolizumab), which by binding to PD-(L)1 and inhibiting its activity, effectively remove the brakes from the immune system allowing it to actively counteract cancer.
AnaptysBio has taken a different, opposite path. The humanized monoclonal antibody rosnilimab (ANB030) binds to PD-1, but instead of acting antagonistically on this receptor expressed on immune cells, has an agonist effect, thereby suppressing T cell inflammatory activity, which is desirable in alopecia areata as a T cell–mediated autoimmune disease. Genetic mutations in the PD-(L)1 signaling pathway that result in a lack of its functional expression are thought to be associated with increased susceptibility to inflammatory diseases, and therefore it makes sense to enhance PD-1 function.     
The ongoing 24-week AZURE (NCT05205070) phase 2 (randomized, double-blind, placebo-controlled, multicenter) clinical trial enrolling adult patients (n=45) with moderate-to-severe alopecia areata is testing monthly subcutaneous injections of rosnilimab.
Equillium is trying its hand with EQ101 (BNZ-1) from Bioniz Therapeutics, which was acquired in February 2022.
EQ101 is a pegylated peptide inhibitor of interleukin 2 (IL-2), interleukin 9 (IL-9), and interleukin 15 (IL-15), cytokines that control basic immune responses. EQ101 targets the common gamma chain signal receptor subunit for these cytokines. Administration of EQ101 results in pharmacodynamic effects associated with decreased levels of regulatory T cells (Treg), natural killer (NK) cells, and CD8+ central memory T cells (Tcm). Such action may be more effective and safer than Janus kinase (JAK) inhibition, which is not particularly selective due to partial inhibition of signaling of all six cytokines with the gamma chain.
A 12-week NCT03532958 phase 2 (randomized, double-blind, placebo-controlled) clinical trial is planned in adult patients (n=125) with moderate-to-severe alopecia areata who will receive weekly intravenous infusions of EQ101.
At one time, the University Hospital of Nice (France) tested exactly the opposite idea. They claimed that administration of low-dose recombinant interleukin 2 (IL-2) had a beneficial therapeutic effect on the course of alopecia areata. The theory was that a key role in the pathogenesis of the disease is played by impaired inhibitory function of Treg CD4+ CD25+, leading to a loss of immune privilege of hair follicles, and IL-2 administration can restore it by expanding the population of these immune cells.      
In the NCT01840046 phase 1/2 (nonrandomized, open-label) clinical trial, adult patients (n=5) with severe alopecia alopecia resistant to prior systemic therapy received subcutaneous IL-2: 5 consecutive days of 1.5 million IU/day, followed by three 5-day courses of 3 million IU/day at weeks 3, 6 and 9. After 6 months, the median SALT score changed from 82 to 69.
In a subsequent phase 2 (randomized, open-label, placebo-controlled, multicenter) clinical trial among adult patients (n=43) with severe alopecia areata, administration of subcutaneous IL-2 in four cycles did not result in the desired treatment effect. After 12 months of follow-up, a 50% reduction in SALT score was observed for 14.3% of patients — versus 9.1% in the placebo group (p=0.66).
Serpin Pharma’s focus is on serpins, a family of proteins that are primarily serine protease inhibitors.
Serpin’s main and so far only medicinal asset is the drug candidate SP16, which is a short amino acid sequence derived from alpha-1 antitrypsin (AAT), a well-known serpin that plays a critical role in the inflammation cascade. The mechanism of action of SP16 is seen in the agonism of the low density lipoprotein receptor-related protein (LRP1), which, ubiquitously expressed in multiple tissues, plays a key role in intracellular signaling and endocytosis. LRP1 agonism is reflected by its potent anti-inflammatory and immunomodulatory actions. SP16, which is positioned as a first-in-class peptide master switch for inflammation, is being studied in the treatment of a wide range of inflammatory and autoimmune diseases including alopecia areata.