Combining a Tyk2 inhibitor with a JAKi in RA? Save

There have been several observational studies of treatment in rheumatoid arthritis (RA) using another JAKi after an initial one fails (1,2). 

The JAK Pot study combined several registries and it appeared that in RA patients, there was a treatment response switching from one JAKi to another (1). 

At EULAR 2023 there was a late breaking abstract that compared difficult to treat patients with RA who had received treatment (including TNFi and JAKi in some patients) previously and still had active disease (3). They were treated in a RCT of monotherapy with a Tyk2/JAK1 inhibitor (TLL-018) vs Tofacitinib 5 mg bid. Interestingly, the Tky2/JAKi at 20 and 30 mg a day treatment arms (but not 10 mg daily) outperformed the ACR50 compared to Tofacitinib. Some patients in this trial had received Tofacitinib and other JAKis so we don’t know how many had already failed Tofacitinib. However, it may be that other drugs that inhibit the JAK-STAT pathway and/or Tyk2 may be feasible to use after failure (often secondary loss of effect) of a JAKi in RA. The surprising finding of this abstract was that the ACR50 exceeded that of Tofacitinib which is unusual to see a Tyk2 type drug be effective in RA. In past the Tyk2 pathway has been successful in psoriasis and psoriatic arthritis but was not thought to be effective in RA.

More trials are needed to determine if it is better after a JAKi treatment to try a different mechanism of action or to use another drug in the JAKi class. We also need to wait and see if the strikingly positive results where the new molecule exceeded the performance of an established JAK inhibitor are reproduced in the phase III study. 

References

1. Pombo-Suarez M, et al. After JAK inhibitor failure: to cycle or to switch, that is the question - data from the JAK-pot collaboration of registries. Ann Rheum Dis. 2023 Feb;82(2):175-181.

2. Ciciriello S, Smith T, Osullivan C, et al. POS0223 Patterns of Janus Kinase Inhibitor Cycling for the Management of Rheumatoid Arthritis in Real-World Clinical Practice: An Analysis of the Opal Dataset.  Annals of the Rheumatic Diseases 2021;80:330-331.

3.Xeng Y, el al. Head to head comparison of TL-018 and tofacitinib in patients with active rheumatoid arthritis: interim results from a phase IIa study. LB0001, EULAR 2023