Treatment Guide' for Alopecia Starman

There is not yet a strong iron bone that can withstand this four-two thousand pound torture: Do you dare to face the bald head?

According to WHO, about 1.6 billion people worldwide suffer from hair loss. By the end of 2021, the number of people with hair loss in our country was about 267 million, and by the end of 2026, this number will further increase to about 343 million.

In the face of this severe torture, how to break the situation? Don't worry, medications for hair loss treatment may be late, but they will never be absent.

Recently, Concert Pharmaceuticals, a US biopharmaceutical company, announced through its official website that its oral drug digotinib (CTP-543) has achieved positive results in phase III clinical trials for the treatment of adult patients with moderate to severe alopecia areata.

Hair loss is saved!

Drugs available for the treatment of androgenetic alopecia are available

Although hair loss treatment is constantly evolving, the treatment effect on severe alopecia areata is not ideal.

At present, the domestic treatment of alopecia areata mainly uses hormone therapy and minoxidil. Among them, hormones can be treated topically or systematically, and minoxidil is often used topically.

However, adverse reactions of hormones and minoxidil are more common, and the safety is insufficient, and the current treatment drugs often have side effects that reduce the quality of life. The table below summarizes commonly used medications and precautions.

In addition, the oral drug Dutasteride, which is also a 5α-reductase inhibitor, was approved in 2009 and 2015 in South Korea and Japan for the treatment of androgenetic alopecia, but considering the side effects of sexual dysfunction and depression, the US FDA only approved it for the treatment of benign prostatic hyperplasia in 2001.

The JAK/STAT signaling pathway and treatment of hair loss

The essence of hair loss is actually an autoimmune disease caused by the combination of genetic factors and environmental factors, and the patient's body's immune system mistakenly attacks the hair follicles, resulting in patchy or complete loss of hair on the scalp and body, and affecting the patient's physical and mental health.

In 2019, the prevalence of alopecia areata in China was 267 per 100,000 people, and nearly 4 million people were plagued by alopecia areata. The general hair growth cycle of hair loss consists of three stages: anagenic, degenerative and dormant.

Recent studies have shown that JAK inhibitors are effective in treating hair growth disorders. Activation of the JAK/STAT pathway can drive hair follicles into a quiescent state, resulting in decreased hair growth capacity. Inhibition of the JAK/STAT signaling pathway induces hair follicles to exit the resting state and enhances the ability of hair follicles to enter the hair cycle.

On November 21, Concert Pharmaceuticals, a US biopharmaceutical company, announced through its official website that its oral drug digotinib (CTP-543), a selective JAK1/2 (Janus Tyrosine Kinase) kinase inhibitor. Positive results were achieved in phase III clinical trials in the treatment of adult patients with moderate to severe alopecia areata.

Digotinib achieved the primary and critical secondary endpoint of scalp hair regrowth at both study doses of 8 mg and 12 mg, and statistically significant hair regrowth was observed at the eighth week of treatment.

"Cosmic First Pharmaceutical" Lilly also announced in May this year that the European Medicines Agency's Committee for Human Medicines (CHMP) supported the marketing of its JAK inhibitor baricitinib (English trade name Olumiant) for the treatment of adult patients with severe alopecia areata.

Subsequently, in June this year, baricitinib was officially approved by the US FDA for the treatment of alopecia areata. Barecolitinib has been approved for the treatment of autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, ulcerative enteritis and psoriasis before treatment of alopecia areata.

However, the JAK kinase inhibitors currently on sale have some serious side effects: in 2021, the US FDA required JAK inhibitors to add a "black box warning" to warn of the risk of serious cardiac events.

For example, the arthritis and ulcerative colitis drug tofacitinib (Xeljanz) increases the risk of serious heart-related events, such as heart attack or stroke, cancer, blood clots and death.

Low-dose tofacitinib also increases the risk of blood clots and death. The FDA also required a boxed warning for two other arthritis drugs of the same type as tofacitinib, JAK inhibitors, Olumiant and Rinvoq.

Of course, not all drugs that take inhibitors of JAK kinase have red flags. The drug candidate Filgotinib from Gilead and Galapagos has not been reported of deep vein thrombosis or pulmonary embolism in the data from initial clinical trials. But Filgotinib ultimately failed to reach the main endpoint.

Androgen receptor inhibitors and degradants for the treatment of hair loss

In February 2021, Suzhou Pioneer Pharmaceutical announced that the clinical trial application of GT20029, a new protein degradation chimera (PROTAC) compound independently developed targeting androgen receptor (AR), was approved by the State Food and Drug Administration for the treatment of androgenetic alopecia and acne vulgaris.

GT20029 can effectively block the miniaturization of hair follicle atrophy caused by AR signaling pathway activation by degrading AR protein, inhibit hair thinning, softening and shedding, and effectively inhibit sebaceous gland development and sebum secretion.

In July this year, GT20029 received Phase I clinical trial approval from the US Food and Drug Administration (FDA). In November, Pioneer Pharmaceuticals announced the positive results of GT20029's Phase I clinical trial in China for the treatment of alopecia areata and acne, which is safe and well tolerated in healthy subjects.

In addition, Pioneer also has a topical small molecule antagonist, the androgen receptor inhibitor Fredaen (KX-826), which is currently undergoing phase III clinical trials in China (CTR20213036) and US phase II clinical trials for the treatment of androgenetic alopecia in men, and China phase II clinical trials (CTR20212684) for androgenetic alopecia in women.

On December 1, the official website released news: the China phase II clinical trial of Fredagen for the treatment of androgenetic alopecia in women reached the primary endpoint.

The mechanism of action of Fredaen (KX-826) is to bind to androgen receptors to competitively inhibit testosterone binding to receptors without androgen effects.

However, compared with PROTAC degraders, androgen receptor inhibitors are theoretically more likely to develop resistance. In addition, according to the experimental results released by Pfizer in 21, 4362 patients, compared with patients taking TNF inhibitor Shurami or Embo, patients taking the same androgen receptor antagonist tofacitinib (Xeljanz) have a higher proportion of cardiovascular diseases (such as stroke and heart attack) and a higher incidence of cancer.

Brief summary

In fact, from the pathogenesis point of view, severe hair loss and rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc. are autoimmune diseases, which are a kind of diseases characterized by local or systemic abnormal inflammatory immune responses.

Competition for autoimmune drugs is fierce. There are also a variety of drugs in this Red Sea that target different mechanisms of action, including TNF-α inhibitors, AbbVie's global champion Adalimumab; Bristol-Myers Squibb's T-cell co-stimulation regulator abatacept injection (abatacept) and so on.

But for developers, most of the mainstream autoimmune drug treatments can only alleviate the symptoms, and there are too many side effects, which also leaves more room for latecomers.

With the in-depth elucidating of the pathological mechanism of autoimmune diseases and the discovery of new drug targets, new biological agents targeting cytokines, receptors and signaling molecules have developed rapidly.

A number of small molecule drugs targeting the JAK/STAT signaling pathway and degraders such as PROTAC targeting androgen receptors have also been developed and applied to the clinic in recent years. At the same time, they also have more and better choices for patients, cure themselves, and the future can be expected.