StemCell Therapy

The toll-like receptor 4 (TLR4) pathway is not likely arelevant target in treating patients with rheumatoid arthritis (RA) whodemonstrate an inadequate response to methotrexate therapy, according toresearch published in the Annals of the Rheumatic Diseases.

Researchers conducted a phase 2, proof-of-concept, randomized, placebo-controlled, double-blind, international, multicenter study of patients with moderate to severe anticitrullinated protein antibody-positive RA who previously demonstrated an inadequate response to methotrexate therapy. The study included adults with active RA 6 months who fulfilled the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria.

In total, 250 patients were screened for eligibility and 90were randomly assigned to receive either placebo (n=29) or 5 mg/kg NI-0101 afirst-in-class humanized monoclonal antibody-blocking TLR4 every 2 weeks for12 weeks (n=61). All participants also continued methotrexate therapy. Fromeach group, 57 and 29 patients (from treatment and control group, respectively)completed both the 12-week visit and the follow-up phase through week 24.

Overall, no major differences were noted between groups interms of individual disease parameters, although patients in the NI-0101 grouphad a longer RA duration (8.5 vs 5.4 years) and were younger at the time ofdiagnosis (45.7 vs 51.2 years). The mean C-reactive protein (CRP) level wasalso higher in this group at baseline (18.3 mg/L vs 13.4 mg/L).

Both treatment groups demonstrated similar decreases frombaseline to week 12 disease activity scores in 28 joints with CRP, with nosignificant between-group differences noted. Both Clinical Disease ActivityIndex and Simplified Disease Activity Index scores decreased approximately 40%from baseline to 12 weeks, and the proportion of patients who achieved good ormoderate EULAR responses increased with treatment.

By week 12, 27.6% and 26% of patients in both groups(placebo and NI-0101, respectively) achieved good EULAR responses whereas 55.2%and 53.6%, respectively, achieved EULAR moderate responses. Similarly, nosignificant between-group differences were noted in ACR responses at week 12,with 55.2% in the placebo group and 58.9% in the treatment group achieving improvement of 20% in ACRcriteria responses, 20.7% and 14.3% achieving improvement of 50% in ACR criteria (ACR50)responses, and 10.3% and 10.7% achieving improvement of 70% in ACR criteria responses. Asubgroup analysis found no significant effects on stratification by either CRPor FcRIIa genotype for either disease activity score in 28 joints with CRP orACR50 response.

A pharmacokinetics profile of NI-0101 showed expectedconcentrations and elimination consistent with simulations. NI-0101concentrations were maintained above the targeted threshold of 10,000 ng/mL ina majority of patients. In terms of pharmacodynamics, no significantdifferences between treatment groups were noted for all evaluated biomarkers.

NI-0101 infusions every 2 weeks demonstrated an acceptablesafety and tolerability profile in patients with RA, with similar proportionsof treatment-emergent adverse events occurring in both the placebo andtreatment groups (51.7% and 52.5%, respectively). The most frequently reportedadverse events were infections (13.8% in the placebo group and 11.5% in theNI-0101 group).

The lack of significant effect of NI-0101 in thiswell-controlled prospective clinical trial indicates that blocking the TLR4pathway alone is unlikely to benefit patients with established RA, theresearchers concluded. The good NI-0101 safety and [pharmacokinetic]profiles support further exploration in other diseases.

Disclosure: Thisclinical trial was supported by Novimmune SA. Please see the original referencefor a full list of authors disclosures.

Reference

Monnet E, Choy EH, McInnes I, et al. Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: aphase II study [published online December 31, 2019]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2019-216487

Read more here:
TLR4 Blockade May Not Treat RA With Inadequate Response to MTX - Rheumatology Advisor

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