The late-breaking oral abstract caused a stir on the final day of EULAR 2023.
This year’s late-breaking oral abstract session at EULAR did not disappoint, with one Chinese paper in particular causing a stir.
The two presentations with the most relevance for Australian clinicians looked at dazodalibep in Sjogren’s patients and TLL-018 versus tofacitinib for difficult-to-treat rheumatoid arthritis.
JAK1/TYK2 inhibitor arouses excitement … and skepticism
Dr Chris Liang, Highlightll Pharma
Hangzhou-based pharmaceutical company founder and CEO Dr Chris Liang presented the preliminary results of a phase IIa study directly comparing TLL-018 against tofacitinib in patients with difficult-to-treat RA.
In a surprising turn of events, TLL-018 – a highly selective dual JAK1/TYK2 inhibitor – outperformed tofacitinib by a large margin, reaching an ACR50 rate greater than 66%.
At baseline, the cohort of 100 patients all had active RA with an intolerance of or inadequate response to methotrexate.
Unlike the phase I trial, which recruited both American and Chinese patients, the phase IIa trial only recruited Chinese patients.
About half had previously received bDMARDs and one in three had previously received anti-JAK medications.
Some patients had previously been exposed to tofacitinib.
There were four treatment arms of around 25 patients each – one group was on 5mg of tofacitinib and the three TLL-018 groups were on 10mg, 20mg and 30mg respectively.
After 12 weeks of treatment, if the patient achieved ACR50 then they continued the same treatment, but if they did not, they changed treatment arm.
Those in the tofacitinib group and the 10mg TLL-018 group were changed to the 20mg TLL-018 dose and those in the 20mg TLL-018 group changed to the 30mg TLL-018 dose.
“All three groups taking our compound did better,” Dr Liang told delegates.
“In particular, the middle and high dose group – which reached 65% and 72% – were statistically superior to tofacitinib.”
The secondary endpoint was DAS28 score less than or equal to 2.6, or clinical disease remission.
While just 17% of the tofacitinib group were in remission at week 12, 40% patients taking the lowest dose of TLL-018 were in clinical remission, followed by 35% of patients in the 20mg TLL-018 group and 55% of patients in the 30mg TLL-018 group.
Patients in the tofacitinib group who failed to meet the primary endpoint at 12 weeks and were subsequently switched to 20mg TLL-018 were reported to have “dramatically improved”.
There was no trade-off in terms of safety, either – Dr Liang reported that the safety profile was comparable across all four groups.
The most common treatment-emergent adverse events were hyperlipidaemia and respiratory infection across all groups.
“To summarise, our dual inhibitor demonstrated superior efficacy over tofacitinib, was well tolerated with no unexpected adverse events and has a safety profile similar to other JAK inhibitors,” Dr Liang said.
The phase III trial in patients with inadequate response to bDMARDs will go ahead in the second half of the year.
Despite – or perhaps because of – the positive results of the trial, audiences at EULAR were skeptical.
One US-based researcher seemed particularly surprised to hear that no patients in the study were on steroids.
A Canadian delegate, meanwhile, asked Dr Liang why patients who had already taken tofacitinib would enter the trial.
“One reason could be that they gain access to free drugs,” Dr Liang said.
After a long pause, the Canadian researcher said, “Maybe”.
Amazing the chatter in the room for this one. The idea that a new JAKi might genuinely outperform existing JAKi in hard-to-treat RA, without safety cost, is particularly enticing.
— David Liew (@drdavidliew) June 3, 2023
We all want to see the paper & healthy skepticism of ph2, but watch this space #EULAR2023 @RheumNow https://t.co/jEyk8zqZN8
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Dazodalibep for Sjogrens’s syndrome
Dr Chiara Baldini, University of Pisa
Speaking at the Saturday morning late breaking abstract session, University of Pisa rheumatologist and researcher Dr Chiara Baldini outlined the current clinical challenge facing a subset of Sjogren’s patients.
“Patients with an unacceptable symptomatic burden and limited extraglandular organ manifestations … have largely being excluded from recent clinical trials,” she said.
Dr Baldini presented preliminary results from a randomised phase II trial of dazodalibep in a cohort of 109 Sjogren’s patients, all of whom scored greater than or equal to five on the EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI).
Anyone who had been treated with a biologic B-cell targeting therapy within the previous year was excluded, as were people who had received any other B-cell targeting therapy in the previous three months.
At baseline, the study cohort had a mean ESSPRI score of 6.9, tending to score slightly higher in the dryness and fatigue dimensions compared to the pain component.
Dazodalibep itself is a non-antibody fusion protein which acts as a CD40L antagonist, inhibiting the costimulatory signals between immune cells.
At the stage one endpoint, roughly five-and-a-half months into the study, patients in the dazodalibep group had achieved an average ESSPRI score reduction of 1.8, while the ESSPRI scores of those in the placebo group only decreased by half a point on average.
A significantly larger proportion of dazodalibep-treated patients achieved a 15% reduction in their ESSPRI scores, relative to placebo group.
The changes in the dazodalibep group were reflected across all three dimensions of the ESSPRI.
“The study met its primary endpoint with a statistically significant improvement the ESSPRI domains,” Dr Baldini said.
“We … are now to wait for the larger clinical trials to confirm these preliminary data, in order to think about a new possible drug for this population … that has largely been neglected.”
EULAR 2023 was held at Milan’s MiCo Convention Centre between 31 May and 3 June.
