8 years since launch, oral JAK inhibitors topping the market

[Meta Focus] Five follow-on drugs joined the competition with first-in-class oral targeted therapy

“Blood clot issue in high-dose medication still needs to be resolved”

Starting from rheumatoid arthritis to psoriatic arthritis, ulcerative colitis, atopic dermatitis and alopecia areata, oral Janus kinase (JAK) inhibitors expanding indications are heating up the prescription competition among themselves.

 

For decades, autoimmune disease area was covered by biological medicines (injection) like tumor necrosis factor alpha (TNF alpha) and interleukin (IL).

 

But lately, the prescription competition has been intensified as oral JAK inhibitors were introduced to the market and tendency of prescription is shifting from injection to oral medication.

 

An oral option of JAK inhibitor with benefit of convenience, was first introduced to the Korean market with Pfizer’s first-in-class Xeljanz (tofacitinib).

 

Later, Lily’s Olumiant (baricitinib) and Astellas Pharma’s Smyraf (peficitinib) have received reimbursement, recently.

 

Other new follow-on medications, such as AbbVie’s Rinvoq (upadacitinib), Gilead’s filgotinib and Pfizer’s atopic dermatitis-specific JAK inhibitor 'PF-04965842 (local administration)' are waiting for the authority’s green light.

 

In fact, oral JAK inhibitor is continuing to grow in prescription volume as its market’s competition has gotten saturated.

 

By expanding indication from treating rheumatoid arthritis to psoriatic arthritis and ulcerative colitis, the medication has globally generated USD 1.77 billion (approximately 2.15 trillion won).

 

The first-in-class medication, Pfizer’s Xeljanz has almost doubled the revenue in the global market as it steadily expanded indication and pushed up the treatment line.

 

Initially limited to treat early stage patients, the expanded indication of JAK inhibitors could have been a significant influence to the growth.

 

Likewise in the Korean market, Xeljanz has attracted new patients, who felt burdened of injection, by expanding indication and enabling prescription on the same treatment level as other biological medicine.

 

This meant the trend in prescription has shifted.

 

And the oral JAK inhibitor’s indication expansion has been notable.

 

First approved as rheumatoid arthritis treatment in Korea in 2014, Xeljanz was green lit to treat ulcerative colitis and psoriatic arthritis with 5 mg tablet in September of 2018.

 

It was first time a JAK inhibitor in 5 mg dose was indicated to treat those diseases.

 

American College of Gastroenterology’s (ACG) ulcerative colitis clinical treatment guideline that has been showing major changes from 2010, also favored oral JAK inhibitor as recommendation.

 

The updated list of recommended biological medicines included TNF inhibitors Remicade (infliximab) and Humira (adalimumab), both used for over a decade, but also the list highlighted anti-integrin medication vedolizumab (trade name: Kynteles) and JAK inhibitor Xeljanz for patients showing no response with TNF alpha inhibiting therapy.

 

The fact that ACG guideline ‘strongly recommends’ JAK inhibitor Xeljanz for treating patients with severe and active ulcerative colitis as first-line treatment and for patients who have failed from TNF inhibitor therapy, means the Xeljanz has more prescription market to grow into.

 

Professor Choi Chang Hwan of Chung-ang University College of Medicine evaluated, “Although biological medicine induce great initial response, injection could be inconvenient and protein drug could develop an antibody and tolerance, and lose treatment response.” The professor added, “Orally administered Xeljanz is convenient and theoretically the treatment response would be maintained.” Expanding indication from ulcerative colitis to atopic dermatitis and psoriatic arthritis Lily’s Olumiant, considered as Xeljanz’ competitor, is also worth a look.

 

Following after Xeljanz, Olumiant has received reimbursement and is now speeding up on expanding other various indications.

 

Differentiating from Xeljanz, the follow-on drug chose atopic dermatitis treatment market with vast amount of patients.

 

Olumiant is considered second to win the indication to treat rheumatoid arthritis after the first-in-class, Xeljanz.

 

But that is why its indication expansion calls for attention.

 

Most of JAK inhibitors in same class have ongoing clinical trial on atopic dermatitis like Olumiant has, so prescription competition in the market would be unavoidable.

 

Besides, Olumiant has initiated a transnational clinical trial 'BRAVE-AA1’ since last March to confirm its efficacy in treating severe case of alopecia areata.

 

The Phase 2/3 transnational clinical trial is ongoing, targeting to treat 725 participants from 11 major university hospitals including Seoul National University Hospital, Gangdong Kyung Hee University Hospital, and Catholic University of Korea St.

 

Paul’s Hospital.

 

Moreover, AbbVie’s Rinvoq and Astellas Pharma’s JAK inhibitor Smyraf are also busy applying for approval.

 

Rinvoq was indicated to treat severe rheumatoid arthritis by the U.S.

 

Food and Drug Administration (FDA) in last August, and it started seeking for approval around the world, whereas Smyraf has been launched in Korea in last January.

 

On last Jan 23, Smyraf jumped into the once-daily oral administration market.

 

The company aims to treat patients not responding to disease-modifying antirheumatic drugs (DMARDs).

 

Although oral JAK inhibitors are late in the game, their companies are assertively expanding indication to treat other immune disease.

 

Pfizer is also in process of conducting a clinical trial on atopic dermatitis.

 

The global company was fast to start Phase 3 trial for another JAK inhibitor 'PF-0496584' that received Breakthrough Therapy designation by the U.S.

 

FDA.

 

Also, Gilead’s filgotinib and AbbVie’s Rinvoq, not yet commercialized, have already started clinical studies simultaneously to expand indication later.

 

Rinvoq has even unveiled Phase 3 clinical study treating atopic dermatitis, and received Breakthrough Therapy designation from FDA.

 

First targeting Crohn’s disease and ulcerative colitis, Gilead is in process of running a clinical program.

 

After receiving FDA’s approval in last August, Rinvoq has presented second Phase 3 study on treating psoriatic arthritis, 'SELECT-PsA 1 and 2’ in the beginning of the year, and demonstrated efficacy in treating patients with severely active psoriatic arthritis.

 

The key finding in the study was that the patient group had not been treated with biological medicine before.

 

Based on the result, Rinvoq could compete against Xeljanz, Olumiant, and even psoriatic arthritis-treating IL-17A inhibitor Cosentyx (secukinumab) and Taltz (ixekizumab) Endless adverse reaction issues, what should be done?

 

Regardless of settling into the market, many of the oral JAK inhibitors are also faced with challenges.

 

The issue constantly raised since the beginning of the marketing is risk in blood clots in lung when treated with high dose.

 

The U.S.

 

and European health regulators have issued a warning in last July about increased risk of developing pulmonary embolism (PE) when using high-dose of 10 mg formulation.

 

Based on the post-marketing surveillance result, the health regulator has decided to insert Black Box Warning on Xeljanz and Xeljanz XR items’ label explaining the medication’s risk of PE and death.

 

The warning is applicable for XR formulation for patients taking 10 mg high-dose tablets twice-daily to treat ulcerative colitis, not rheumatoid arthritis.

 

Similar risk was also found in Olumiant as well.

 

As high dose of the medication has raised blood clot issue, only the low dose of Olumiant has been approved partially to market.

 

While preparing for launch, Gilead’s filgotinib and AbbVie’s Rinvoq have noticed the issue.

 

Filgotinib has attracted the industry’s attention as it received approval in shortest time last year, but its approval application procedure has been hindered as its safety confirmation data submission has been delayed.

 

The long-term analysis result unveiled last year did not find abnormal signs of severe infectious disease or blood clot.

 

The medication’s safety profile has been confirmed by outcomes of 24 week-long Phase 3 FINCH 1, 2 and 3 and DARWIN 3 (Phase 2b), and now it is expected to expedite the global market approval review process.

 

In this month, AbbVie’s Rinvoq has disclosed the outcomes of late-stage clinical study on efficacy in treating psoriatic arthritis.

 

The researchers analyzed ongoing Stage 3 Select-PsA 2 trial’s data and found the Rinvoq patient group had improved joint pain and edema more than the placebo group.

 

Also, the patients have experienced improved daily-life body function, such as putting clothes on or having a meal.

 

Treated for 16 weeks, patients did not report any adverse reaction like PE.

 

The company announced its plan to request for approval based on psoriatic arthritis indication.