Alopecia Treatment Update on JAK Inhibitors Ruxolitinib and Tofacitinib

Further to our initial reports on clinical trials involving the study of JAK inhibitor drugs as potential treatments for Alopecia Areata, new information has now become available. Columbia University has just released the findings of this latest study, which have been published in the Science Advances journal.

These latest updates bring with them renewed hope for people with Alopecia Areata (AA), as well as indicating that, with further research, both ruxolitinib and tofacitinib may also prove useful in treating other forms of hair loss.

Research into JAK inhibitors and hair loss

Columbia University's Latest JAK Inhibitor Hair Loss Treatment Study has Shown Promising Regrowth in Recent Mice Trials Where Half of Each Mouse was Treated Over a 5 Day Period

Janus kinase inhibitors, more commonly known as JAK inhibitors, are a type of drug which suppresses the functionality of JAK enzymes within the body.

As certain JAK enzymes are involved in the hair growth cycle, recent research into whether JAK inhibitor drugs, such as ruxolitinib and tofacitinib, could be plausible hair loss treatments revolves around this aspect.

Initially these drugs were trialled in relation to Alopecia Areata, an autoimmune condition which can cause patchy hair loss through to total baldness. This is because, whilst other forms of hair loss tend to be due to genetics or lifestyle factors, hair fall from AA comes when something triggers the normal hair growth cycle to get stuck in its resting (telogen) phase. What precisely this trigger is is still unknown although stress or sudden shock is thought to be a contributing factor in many cases. Whilst in most cases the hair will generally recover and regrow on its own, when - or indeed, if - this will happen is currently impossible to predict.

JAK inhibitor treatment specifically targets the enzymes inside hair follicles which are responsible for maintaining their dormant state in cases of AA. In doing so, they stir the follicles out of the telogen phase and back into active growth.

Columbia's latest trials studied the impact of JAK inhibitors ruxolitinib and tofacitinib on AA using mice, human hair follicles grown in culture, and human skin grafted onto mice. The latter option was believed to be more effective than using human test subjects as, according to the researchers, transitions from telogen to anagen phases of the hair growth cycle are 'extremely difficult to assess' in humans. This is because, unlike mice, humans' hair growth is not synchronised and 90 per cent of the follicles will be in the growth phase at any time.

In the trials, seven week old, shaved, wild mice were treated daily for five days with either 3 per cent ruxolitinib or tofacitinib regrew new hair within ten days. The control mouse who was given something called a 'a sonic hedgehog (Shh) agonist' - a substance which had been 'previously shown to promote anagen initiation' showed no hair growth, with its hair continuing to remain in the telogen phase throughout the trial.

The mice, aged 8.5 weeks, were then treated for a further five days to assess the appearance of skin pigmentation which signals the start of the hair's anagen growth phase. As you can see from the graph pictured, ruxolitinib excelled here with tofacitinib not far behind, whilst the control languished behind, showing no signs at all.

Based on applying the JAK inhibitors topically (directly to the skin) to interfere with the hair growth mechanism, or 'pathway', researchers report that this 'treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth.'

In what is believed to be a new discovery, the team further states that their research paper shows 'that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae.'

Ruxolitinib (Jakafi)

In October 2014 we brought you details of a promising small-scale trial involving ruxolitinib (brand name: Jakafi) which was taking place at Columbia University.

This clinical study involved investigating the myelofibrosis drug as a potential treatment for Alopecia Areata and produced significant results. Each of the three participants treated with ruxolitinib - all male with a minimum of 30 per cent hair loss of the scalp due to AA - experienced full regrowth within four to five months.

In the recent trials, also carried out by the the same team at Columbia, ruxolitinib was shown to regrow hair in mice in just three weeks. During the initial trial the drug was administered orally, however, this time it was found to be more effective to apply it topically.

Tofacitinib (Xeljanz)

The initial, 'accidental' discovery of this JAK inhibitor's potential for promoting hair regrowth came about when Yale University was investigating tofacitinib (brand name: Xeljanz) as a treatment for plaque psoriasis. The patient they were treating also happened to have Alopecia Universalis and had not grown any hair in seven years, yet at the end of the seven month trial, his hair had fully regrown.

Tofacitinib is already FDA-approved for the treatment of rheumatoid arthritis (another autoimmune condition), however, there were concerns about the drug's safety in relation to other potential applications. Earlier this month the drug's manufacturer, Pfizer, had its supplemental New Drug Application (sNDA) request blocked by the FDA. This application sought to further clear Xeljanz for the treatment of moderate-to-severe plaque psoriasis. A statement posted to the company's website confirmed that it plans to work with the FDA on this to address all issues, including providing further safety anaylses.

Despite this setback, research into tofacitinib as a potential hair loss treatment, particularly in cases of severe AA - such as Alopecia Totalis and Alopecia Universalis - are continuing. There are currently at least two additional clinical trials underway, both of which are believed to be going well although results will not be available until 2016 at the earliest.

When the Columbia team investigated tofacitinib alongside ruxolitinib, they applied the drug topically whereas in the first trial at Yale it was administered orally in varying doses. As can be seen from the mice pictured above, it promoted significant regrowth.

What next?

Professor Angela Christiano

Although the results of the Columbia trial are incredibly encouraging, further and broader studies are still required in order to ensure the long-term efficacy and wider safety implications of using JAK inhibitors to treat Alopecia Areata.

Additional trials can also concentrate on using the team's discoveries to investigate its potential relevance for the genetic conditions, Male Pattern Baldness and Female Pattern Hair Loss, which are the most common causes of hair loss in the world, beating Alopecia Areata into second place.

These exciting developments 'open new avenues' for JAK-STAT inhibition research as well as highlighting the role of this pathway in 'regulating the activation of hair follicle stem cells'.

Columbia's Professor Angela Christiano, who has herself experienced AA, explained the significance of using topical JAK inhibitors to promote strong hair growth.

"There aren’t many compounds that can push hair follicles into their growth cycle so quickly,’ she told Metro. "Some topical agents induce tufts of hair here and there after a few weeks, but very few compounds have this potent an effect so quickly." We are assuming that Dr Christiano is referring to minoxidil here, as in cases of mild-to-moderate Alopecia Areata, we have seen encouraging regrowth in many Belgravia clients who follow treatment courses including topically-applied high strength minoxidil.

Talking to the Daily Mail she concluded, "What we've found is promising, though we haven't yet shown it's a cure for pattern baldness... More work needs to be done to test if JAK inhibitors can induce hair growth in humans using formulations specially made for the scalp."