Can a new JAK inhibitor help with hives?

4 minute read

Dual TYK2/JAK1 inhibitor TLL-018 builds on rheum success with a foray into chronic spontaneous urticaria.

Wonder drug TLL-018 – the TYK2/JAK1 inhibitor that made a splash at last year’s EULAR meeting – has just popped up at the recent American Academy of Allergy, Asthma and Immunology annual meeting in Washington DC.

If the drug doesn’t ring any bells for you, that’s possibly because it hasn’t ventured far beyond the medical conference circuit. Yet.

At the aforementioned 2023 EULAR meeting in Milan, a late breaking oral abstract demonstrating TLL-018’s marked superiority over tofacitinib in rheumatoid arthritis caused quite a sensation.

The interim results of the phase 2a study reported that more than 65% of those taking 20mg or 30mg of TLL-018 achieved the primary endpoint of ACR50 at week 12, compared with 42% of those taking tofacitinib (48% of the 10mg TLL-018 group achieved ACR50, which was not a statistically significant difference from tofacitinib). There were no significant safety issues.

The final phase 2a data presented at ACR 2023 confirmed the good news story, arousing audience amazement and scepticism in equal measure.

“Spectacular compound. Absolutely spectacular. Unbelievably spectacular,” said Professor Roy Fleischmann after the presentation.

The drug developer, Highlightll Pharma, is forging ahead with a phase 3 trial of 450 patients and is currently recruiting at various locations within China.

“But why aren’t you doing a multinational phase 3 study, which would give us more confidence in the results?” Professor Fleischmann asked the presenter, Dr Congxin Liang.

Dr Liang explained that it came down to cost and speed – they wanted to get it registered in China as quickly as possible.

He pointed out that the drug is also being investigated in a phase 2 trial for psoriasis – and this time, it’s at multiple centres in the US. He assured the ACR 2023 audience that the results thus far are consistent with those achieved in a phase 2 psoriasis trial in China.

However, rheumatologists will want to see international multicentre trials on RA before getting too excited. Publication of detailed results in a peer-reviewed journal will also provide some reassurance.

Which brings us to the latest conference outing for TLL-018, the AAAAI annual meeting, where it  appeared in a late-breaking poster.

The indication this time was for moderate-to-severe chronic spontaneous urticaria (CSU), where TLL-018 was up against placebo in a phase 1b trial. The authors pointed out that it was the first clinical trial of a JAK inhibitor for CSU.

The trial, which was conducted in China, enrolled 41 patients with CSU and an inadequate response to antihistamine. They were allocated to one of three groups: 10mg or 30mg TLL-018, or placebo twice daily.

At the 4-week mark, those in the placebo group were switched to 20mg TLL-018 twice daily, and all patients were treated for a further eight weeks.

The main outcome measures were change from baseline in Urticaria Activity Score (UAS7) and Itch Severity Score (ISS7) and percentage achieving UAS7≤6 and UAS7=0.

TLL-018 proved successful, with statistically significant differences for UAS7 and ISS7 change from baseline when compared with placebo at week 4. There were continued improvements to week 12.

More than half the patients in all treatment groups achieved UAS7≤6. More than half the patients in the 10mg and 30mg groups achieved a zero on the UAS7, and slightly less for the 20mg group – they’d only had eight weeks of treatment. There were no concerning safety signals.

“TLL-018 was well tolerated and showed high efficacy among all dosage groups in moderate-to-severe CSU patients with inadequate response to high doses or a combination of antihistamine treatment in terms of reducing itchiness, hives and improving quality of life,” wrote the authors.

“JAK inhibitors promise new treatment option for CSU patients,” they concluded.

L36 Efficacy and Safety of TLL-018 in Moderate to Severe Chronic Spontaneous Urticaria Patients with Inadequate Response to H1 Antihistamine: Results from a Phase Ⅰb Study

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