Tofacitinib (Xeljanz®) is the first of a unique class of oral kinase inhibitors to be FDA approved for the treatment of rheumatoid arthritis (RA). Tofacitinib is a selective inhibitor of Janus kinase (JAK) enzymes. JAKs mediate signaling by surface receptors for several important cytokines that are fundamental to the propagation of inflammation in RA. JAK enzymes (JAK1, JAK3) are responsible for activating Signal Transducers and Activators of Transcription (STATs) which further modulate intracellular activity and gene expression. Tofacitinib prevents signaling of JAK enzymes and therefore interrupts important signal transduction of cytokines which contribute to the aberrant immune response in RA.
Based on the results of several Phase 2 and Phase 3 studies (two of which will be summarized below), the FDA has approved tofacitinib, at a dose of 5mg twice daily, for the treatment of RA in adults with moderate to severe disease, who have had an inadequate response to, or are intolerant of, methotrexate. It can be used as monotherapy or in combination with methotrexate. It is not to be used in combination with other potent immunosuppressive medications or biologic agents.
RA patients clearly demonstrated a clinical response with tofacitinib compared to placebo in these trials with improvement in the number of painful and swollen joints. However, tofacitinib did not receive a prescribing indication from the FDA for the prevention of radiographic progression, based on the available data.
Inhibition of JAK signaling is a potent pathway to interrupt, and there are some important side effects to be aware of with this drug. Notably, severe infections, including opportunistic infections, were noted in the treatment groups. However, infection rates were similar to those seen with other biologic DMARDs. All patients should be screened for latent TB prior to starting tofacitinib. Herpes zoster infections occurred at a higher rate in individuals treated with tofacitinib than placebo. This rate of herpes zoster was higher than what has been observed in other biologic DMARD studies, and while not indicated on the label, we believe that consideration should be given to vaccinating patients prior to the initiation of tofacitinib. Live vaccines (such as the herpes zoster vaccine) should not be administered to patients taking tofacitinib. Hematologic abnormalities (neutropenia, lymphopenia, and anemia) were observed with tofacitinib and need to be routinely monitored for during treatment. Monitoring of transaminases, lipids, and creatinine also should be done regularly, as abnormalities in all of these laboratory parameters were observed during the trials. Dose reduction of tofacitinib is required for patients taking CYP3A4/CYP2C19 inhibitors (i.e. ketoconazole or fluconazole) due to increased levels of the drug.
The addition of a powerful oral molecule with biologic-like efficacy on signs and symptoms of RA to the armamentarium of treatments we have to offer patients suffering with RA is an exciting prospect. However, the oral delivery of this drug should not be taken to imply increased safety or less potency than injectable or infusible biologic therapies.
Two important studies evaluating the safety and efficacy of tofacitinib for the treatment of rheumatoid arthritis were published recently in the New England Journal of Medicine. These studies are summarized below:
- Fleischmann R, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. NEJM 2012;367:495-507
Adult patients with RA and active disease (≥6 tender joints + ≥ 6 swollen joints + elevated ESR/CRP) who had failed (because of lack of efficacy or side effects) at least one other RA therapy (biologic or nonbiologic DMARD) were eligible for inclusion. The study design was a randomized, double-blind, placebo-controlled, parallel-group trial. Participants were randomized to one of four possible treatment groups for a total of 6 months. 1) Tofacitinib 5mg twice daily x 6 months; 2) tofacitinib 10mg twice daily x 6 months; 3) placebo x 3 months followed by tofacitinib 5mg twice daily x 3 months; 4) placebo x 3 months followed by tofacitinib 10mg twice daily x 3 months. Comparisons were made between placebo and tofacitinib at 3 months on three primary endpoints: ACR20 response (at least 20% reduction from baseline in the number of tender and swollen joints + 20% improvement in ≥3/5 of the following: patient pain assessment, disability, CRP, global disease activity by patient, global disease activity by physician), change in HAQ-DI (disability index), and DAS28-4(ESR) score <2.6. The DAS28-4(ESR) is a composite index of 4 weighted variables (# of tender joints from 28-joint count, # swollen joints from 28-joint count, ESR, patient’s global assessment of disease activity). Adverse events were also collected and analyzed compared to placebo.
611 RA patients were randomized for this study. 122 received placebo for the first 3 months. 243 received 5mg tofacitinib twice daily, and 245 received 10mg tofacitinib twice daily. The patients had a mean age of 50-52 years, and a mean RA disease duration of 7.7-8.6 years. After 3 months, 59.8% in the 5mg tofacitinib group, 65.7% in the 10mg tofacitinib group, and 26.7% in the placebo group met ACR 20 response criteria (p<0.001). There was a significantly greater decrease in HAQ-DI scores among the treatment groups compared to placebo at 3 months (p<0.001). After 3 months, there was not a significant difference between the groups by the outcome DAS28-4(ESR), however there was by 6 months. There were more adverse events in the tofacitinib groups compared to placebo. 6 patients had serious infections. 54% had adverse events with the most common being upper respiratory tract infections, headaches, and diarrhea. Lab abnormalities that occurred more frequently among the tofacitinib groups were neutropenia, elevated transaminases, elevated LDL cholesterol, and serum creatinine.
Tofacitinib as monotherapy, compared with placebo, reduced signs and symptoms of RA and improved function among adults who had failed a previous DMARD. However, the endpoint for remission (DAS28-4(ESR)<2.6) was not met. There were more adverse events in the tofacitinib groups compared to placebo with infections, including serious infections, topping the list.
- Van Vollenhoven R, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. NEJM 2012;367:508-519 The ORAL Standard trial
Adult patients with RA and active disease (≥6 tender joints + ≥ 6 swollen joints + elevated ESR/CRP) despite receiving treatment with 7.5-25mg of methotrexate weekly were eligible for inclusion. Important exclusion criteria were current treatment with other anti-rheumatic agents (including biolgoics), prior treatment with adalimumab, lack of response to previous anti-TNFα agent, or current infection. The study design was a randomized, phase 3 clinical trial. Participants were randomized to one of 5 possible treatment. 1) Tofacitinib 5mg twice daily; 2) tofacitinib 10mg twice daily; 3) 40mg adalimumab every other week; 4) placebo for 3 or 6 months followed by tofacitinib 5mg twice daily; 4) placebo for 3 or 6 months followed by tofacitinib 10mg twice daily. If patients who received placebo did not have a 20% reduction in swollen and tender joints after 3 months they were randomly assigned to 5 or 10mg of tofacitinib. After 6 months, all patinets on placebo were switched to tofacitinib.
The primary endpoints were: ACR20 response , HAQ-DI, and DAS28-4(ESR) score <2.6. Adverse events were also collected and analyzed compared to placebo. The study lasted 12 months.
717 RA patients were randomized for this study. 56 received placebo and 5mg tofacitinib. 52 received placebo and 10mg tofacitinib. 204 received 5mg tofacitinib twice daily. 201 received 10mg tofacitinib twice daily. 204 received 40 mg adalimumab every other week. The patients had a mean age of 52-55 years, and a mean RA disease duration of 6.9-9.0 years. After 6 months, 51.5% in the 5mg tofacitinib group, 52.6% in the 10mg tofacitinib group, 47.2% in the adalimumab group, and 28.3% in the placebo group met ACR 20 response criteria (p<0.001). There was a significantly greater decrease in HAQ-DI scores among the treatment groups compared to placebo at 3 months (p<0.001). After 3 months, there was also significantly more patients in the treatment groups compared to placebo who reached the DAS28-4(ESR) outcome.
Adverse events in the treatment groups included neutropenia, elevated transaminases, elevated LDL cholesterol, elevated serum creatinine, and low hemoglobin. Other adverse events included primarily infections. The rates of serious adverse event in the first three months were higher in tofacitinib groups than placebo or adalimumab. This included 2 cases of pulmonary tuberculosis.
Tofacitinib in combination with methotrexate was superior to placebo to treat the signs and symptoms of RA. In this study, the efficacy of tofacitinib at 12 months was numerically similar between all treatment groups, including adalimumab.