Small Molecules Targeting JAKs in the Treatment of RA
Small Molecules Targeting JAKs in the Treatment of RA
The Phase III development programme of tofacitinib in RA has so far been successful with respect to the investigated outcome parameters, including ACR and EULAR response criteria as well as patient reported outcome (PRO) measures. In fact, all primary outcome criteria have been reached with the exception of DAS28-defined remission in ORAL Solo. In addition, importantly, evidence has been provided for the inhibition of radiological progression of disease and the primary endpoint relating to structure [mean change from baseline in modified Total Sharp Score (mTSS)] was significant for the 10 mg twice-daily dose in the ORAL Scan study.
For interpretation of the efficacy results, it is important to note that certain response rates were calculated by using the non-responder imputation method. Furthermore, an advancement penalty was defined for ACR response and DAS28 remission (<2.6) rates. In detail, in the studies of longer duration (>6 months), patients with predefined non-response at month 3 were considered as treatment failures for the remainder of the trial, even if they subsequently achieved response after month 3 when compared with placebo. These very stringent approaches provide us with statistically more conservative results avoiding overestimation of treatment effects, but making a comparison with published trials more difficult. Furthermore, a step-down analysis method with sequential assessment of the primary efficacy endpoints was employed to minimize Type 1 error. In this context in the ORAL Solo, Standard, Sync and Step studies, achievement of a significant difference in the ACR20 response rate was a precondition for evaluation of change from baseline in the HAQ-disability index (DI) score, and subsequently, a significant improvement from baseline in the HAQ-DI score was a precondition for evaluation of the percentage of patients with a DAS28-4(ESR) <2.6. In the ORAL Scan study, after evaluation of the ACR20 response rate, an additional primary endpoint defined by change from baseline in mTSS at 6 months was implemented in the statistical analyses.
The protocols of the different randomized, controlled trials have a comparison of two different dosages of tofacitinib (5 or 10 mg bd) with two placebo groups in common. In the ORAL Solo study over a period of 6 months, patients were randomized in a 4:4:1:1 ratio to two different dosages of tofacitinib (5 or 10 mg bd) as monotherapy or two placebo groups, respectively. At month 3, all placebo patients advanced blindly as specified at randomization to tofacitinib, either 5 or 10 mg monotherapy.
In the ORAL Sync trial over a period of 12 months, patients were randomized in a 4:4:1:1 ratio to tofacitinib 5 or 10 mg bd or two placebo groups, respectively. Different traditional DMARDs were allowed as stable background therapy. At month 3, patients under placebo were able to switch to a prespecified active treatment if no improvement of at least 20% of tender and swollen joint counts was reached. At month 6, all remaining patients from the placebo groups advanced in a blinded manner to active treatment with tofacitinib at one of the two different doses.
To summarize the results of the studies in non-biologic or biologic DMARD-IR patients with RA, all primary endpoints except the DAS remission rate in ORAL Solo were reached. Rapid and significant improvement of ACR20, 50 and 70 response rates as well as EULAR outcome measures (DAS low disease activity and DAS remission) was shown for both tofacitinib dosages compared with placebo except for the DAS remission in ORAL Solo. For DAS remission (<2.6), stronger effects were observed in the higher dosage group of tofacitinib 10 mg bd compared with 5 mg bd. Furthermore, PROs were also significantly improved under tofacitinib compared with placebo. Patients who advanced to active treatment with tofacitinib from placebo also showed a rapid improvement in outcome measures including disease activity and reached a comparable level of response as the patients initially treated with the study drug.
The ORAL Standard trial (duration of 12 months) was special with respect to a fifth different treatment arm. According to protocol, patients were randomized in a 4:4:4:1:1 ratio to tofacitinib 5 or 10 mg bd, adalimumab 40 mg s.c. every other week or two placebo groups, respectively. All patients were on a stable background therapy with MTX. To reduce bias, a previous therapy with adalimumab was an exclusion criteria and other previous TNF inhibitors (TNFis) were also excluded in case of treatment failure due to lack of efficacy or related adverse event (some were included if anti-TNF treatment had been stopped, for instance, for insurance reasons). At month 3, an early escape was possible for patients under placebo if no improvement of at least 20% of tender and swollen joint counts was reached. At month 6, all patients from the placebo groups advanced in a blinded manner to active treatment with tofacitinib in two different dosages. The trial was not designed for a non-inferiority or superiority comparison between tofacitinib and adalimumab. Therefore adalimumab cannot be addressed as a competitor, but rather as an active control in this setting.
In ORAL Standard, the level and onset of improvement of all outcome measures including PRO parameters was numerically similar between the tofacitinib and the adalimumab groups and for both groups superior to placebo.
The effects of tofacitinib on radiologic progression were investigated in the ORAL Scan trial. This 24-month, double-blind, Phase 3 study compared efficacy, including the reduction of structural damage progression, and safety of tofacitinib with placebo in patients with active RA with an inadequate response to MTX. Patients were randomized in a 4:4:1:1 manner to two different dosages of tofacitinib (5 or 10 mg bd) and two placebo groups in co-medication with background MTX therapy. Patients on placebo advanced to tofacitinib at 6 months, or at 3 months if non-responsive (<20% reduction from baseline in swollen/tender joint counts).
The primary outcome measure with respect to radiologic progression was the mean change from baseline in mTSS at month 6. As a result, the increase in mTSS was higher in the placebo group compared with both dosages of tofacitinib. However, the difference of radiographic changes was only statistically significant for the higher tofacitinib dosage of 10 mg bd compared with placebo. According to protocol, all placebo patients advanced in a blinded manner to treatment with tofacitinib at either month 3 or month 6, and therefore the radiology results for month 12 were extrapolated from the time of advancement (month 3 or 6) for the placebo group. The changes remained statistically significant for the higher dosage group of 10 mg tofacitinib bd. The percentage of patients with no detectable radiological progression at month 6 were 78% for placebo, 88.8% for tofacitinib 5 mg bd and 86.9% for tofacitinib 10 mg bd. Importantly, due to the predefined statistical evaluation procedures, statistical significance was not declared with 5 mg bd for HAQ-DI and DAS28-4(ESR) <2.6 responses in this trial. Due to the non-significant differences for the 5 mg bd group in the mTSS at month 6, a further step-down sequential assessment of the primary efficacy endpoints was not applicable.
Treatment of RA patients with failure to TNFi is always a challenge, and since it is likely that this cohort might represent the main target for initial tofacitinib treatment in the future, the efficacy data from the ORAL Step trial will be shown in more detail. This randomized, controlled, Phase III study of 6 months' duration recruited adult patients with moderate-to-severe RA and intolerance or inadequate response to TNFi. Patients received blindly two different dosages of tofacitinib (5 or 10 mg bd) vs placebo in a randomization ratio of 2:2:1:1 for the first 3 months. Thereafter, all patients under placebo advanced in a blinded manner to active treatment with tofacitinib in two different dosages. Altogether, 400 patients with mean disease duration of RA of 12 years were included. From these difficult-to-treat patients, 27% had already been treated with two different TNFis and 48% with three TNFis. At baseline, patients with highly active RA entered the study with a mean number of tender joints of 27 and swollen joints of 16. Furthermore, the patients were already significantly disabled due to RA with a mean HAQ-DI of 1.6.
With respect to the primary endpoint, after a treatment period of 3 months, both dosages of tofacitinib were significantly superior to placebo in achieving ACR20 response (48% for tofacitinib 10 mg bd, 42% for tofacitinib 5 mg bd compared with 24% for placebo, P < 0.0001 and P < 0.05, respectively). Significant improvement was also documented for ACR50 response (28% for tofacitinib 10 mg bd, 27% for tofacitinib 5 mg bd compared with 8% for placebo, P < 0.0001). The remission rates according to EULAR DAS28-4(ESR) (<2.6) responses were 11% and 7% for tofacitinib 5 and 10 mg, respectively, compared with 2% for placebo (P < 0.05). During the short evaluation period of 3 months, a significant improvement of disability (as measured by the mean change in HAQ-DI scores from baseline) was obvious for both tofacitinib dosages (−0.46% for tofacitinib 10 mg bd, −0.43% for tofacitinib 5 mg bd compared with −0.18% for placebo, P < 0.0001). After the switch to active treatment, patients from the placebo group reached response rates comparable to those of patients on tofacitinib (e.g. ACR20 55–52%, ACR50 37–30%, ACR70 ~16%).
Efficacy Data for Tofacitinib in Patients With RA With Failure to DMARDs Including TNF Inhibitors
The Phase III development programme of tofacitinib in RA has so far been successful with respect to the investigated outcome parameters, including ACR and EULAR response criteria as well as patient reported outcome (PRO) measures. In fact, all primary outcome criteria have been reached with the exception of DAS28-defined remission in ORAL Solo. In addition, importantly, evidence has been provided for the inhibition of radiological progression of disease and the primary endpoint relating to structure [mean change from baseline in modified Total Sharp Score (mTSS)] was significant for the 10 mg twice-daily dose in the ORAL Scan study.
For interpretation of the efficacy results, it is important to note that certain response rates were calculated by using the non-responder imputation method. Furthermore, an advancement penalty was defined for ACR response and DAS28 remission (<2.6) rates. In detail, in the studies of longer duration (>6 months), patients with predefined non-response at month 3 were considered as treatment failures for the remainder of the trial, even if they subsequently achieved response after month 3 when compared with placebo. These very stringent approaches provide us with statistically more conservative results avoiding overestimation of treatment effects, but making a comparison with published trials more difficult. Furthermore, a step-down analysis method with sequential assessment of the primary efficacy endpoints was employed to minimize Type 1 error. In this context in the ORAL Solo, Standard, Sync and Step studies, achievement of a significant difference in the ACR20 response rate was a precondition for evaluation of change from baseline in the HAQ-disability index (DI) score, and subsequently, a significant improvement from baseline in the HAQ-DI score was a precondition for evaluation of the percentage of patients with a DAS28-4(ESR) <2.6. In the ORAL Scan study, after evaluation of the ACR20 response rate, an additional primary endpoint defined by change from baseline in mTSS at 6 months was implemented in the statistical analyses.
Tofacitinib in Non-biologic or Biologic DMARD-IR Patients (ORAL Solo and Sync)
The protocols of the different randomized, controlled trials have a comparison of two different dosages of tofacitinib (5 or 10 mg bd) with two placebo groups in common. In the ORAL Solo study over a period of 6 months, patients were randomized in a 4:4:1:1 ratio to two different dosages of tofacitinib (5 or 10 mg bd) as monotherapy or two placebo groups, respectively. At month 3, all placebo patients advanced blindly as specified at randomization to tofacitinib, either 5 or 10 mg monotherapy.
In the ORAL Sync trial over a period of 12 months, patients were randomized in a 4:4:1:1 ratio to tofacitinib 5 or 10 mg bd or two placebo groups, respectively. Different traditional DMARDs were allowed as stable background therapy. At month 3, patients under placebo were able to switch to a prespecified active treatment if no improvement of at least 20% of tender and swollen joint counts was reached. At month 6, all remaining patients from the placebo groups advanced in a blinded manner to active treatment with tofacitinib at one of the two different doses.
To summarize the results of the studies in non-biologic or biologic DMARD-IR patients with RA, all primary endpoints except the DAS remission rate in ORAL Solo were reached. Rapid and significant improvement of ACR20, 50 and 70 response rates as well as EULAR outcome measures (DAS low disease activity and DAS remission) was shown for both tofacitinib dosages compared with placebo except for the DAS remission in ORAL Solo. For DAS remission (<2.6), stronger effects were observed in the higher dosage group of tofacitinib 10 mg bd compared with 5 mg bd. Furthermore, PROs were also significantly improved under tofacitinib compared with placebo. Patients who advanced to active treatment with tofacitinib from placebo also showed a rapid improvement in outcome measures including disease activity and reached a comparable level of response as the patients initially treated with the study drug.
Tofacitinib in MTX-IR Patients (ORAL Standard and ORAL Scan)
The ORAL Standard trial (duration of 12 months) was special with respect to a fifth different treatment arm. According to protocol, patients were randomized in a 4:4:4:1:1 ratio to tofacitinib 5 or 10 mg bd, adalimumab 40 mg s.c. every other week or two placebo groups, respectively. All patients were on a stable background therapy with MTX. To reduce bias, a previous therapy with adalimumab was an exclusion criteria and other previous TNF inhibitors (TNFis) were also excluded in case of treatment failure due to lack of efficacy or related adverse event (some were included if anti-TNF treatment had been stopped, for instance, for insurance reasons). At month 3, an early escape was possible for patients under placebo if no improvement of at least 20% of tender and swollen joint counts was reached. At month 6, all patients from the placebo groups advanced in a blinded manner to active treatment with tofacitinib in two different dosages. The trial was not designed for a non-inferiority or superiority comparison between tofacitinib and adalimumab. Therefore adalimumab cannot be addressed as a competitor, but rather as an active control in this setting.
In ORAL Standard, the level and onset of improvement of all outcome measures including PRO parameters was numerically similar between the tofacitinib and the adalimumab groups and for both groups superior to placebo.
The effects of tofacitinib on radiologic progression were investigated in the ORAL Scan trial. This 24-month, double-blind, Phase 3 study compared efficacy, including the reduction of structural damage progression, and safety of tofacitinib with placebo in patients with active RA with an inadequate response to MTX. Patients were randomized in a 4:4:1:1 manner to two different dosages of tofacitinib (5 or 10 mg bd) and two placebo groups in co-medication with background MTX therapy. Patients on placebo advanced to tofacitinib at 6 months, or at 3 months if non-responsive (<20% reduction from baseline in swollen/tender joint counts).
The primary outcome measure with respect to radiologic progression was the mean change from baseline in mTSS at month 6. As a result, the increase in mTSS was higher in the placebo group compared with both dosages of tofacitinib. However, the difference of radiographic changes was only statistically significant for the higher tofacitinib dosage of 10 mg bd compared with placebo. According to protocol, all placebo patients advanced in a blinded manner to treatment with tofacitinib at either month 3 or month 6, and therefore the radiology results for month 12 were extrapolated from the time of advancement (month 3 or 6) for the placebo group. The changes remained statistically significant for the higher dosage group of 10 mg tofacitinib bd. The percentage of patients with no detectable radiological progression at month 6 were 78% for placebo, 88.8% for tofacitinib 5 mg bd and 86.9% for tofacitinib 10 mg bd. Importantly, due to the predefined statistical evaluation procedures, statistical significance was not declared with 5 mg bd for HAQ-DI and DAS28-4(ESR) <2.6 responses in this trial. Due to the non-significant differences for the 5 mg bd group in the mTSS at month 6, a further step-down sequential assessment of the primary efficacy endpoints was not applicable.
Tofacitinib in TNFi Inadequate Responders (ORAL Step Study)
Treatment of RA patients with failure to TNFi is always a challenge, and since it is likely that this cohort might represent the main target for initial tofacitinib treatment in the future, the efficacy data from the ORAL Step trial will be shown in more detail. This randomized, controlled, Phase III study of 6 months' duration recruited adult patients with moderate-to-severe RA and intolerance or inadequate response to TNFi. Patients received blindly two different dosages of tofacitinib (5 or 10 mg bd) vs placebo in a randomization ratio of 2:2:1:1 for the first 3 months. Thereafter, all patients under placebo advanced in a blinded manner to active treatment with tofacitinib in two different dosages. Altogether, 400 patients with mean disease duration of RA of 12 years were included. From these difficult-to-treat patients, 27% had already been treated with two different TNFis and 48% with three TNFis. At baseline, patients with highly active RA entered the study with a mean number of tender joints of 27 and swollen joints of 16. Furthermore, the patients were already significantly disabled due to RA with a mean HAQ-DI of 1.6.
With respect to the primary endpoint, after a treatment period of 3 months, both dosages of tofacitinib were significantly superior to placebo in achieving ACR20 response (48% for tofacitinib 10 mg bd, 42% for tofacitinib 5 mg bd compared with 24% for placebo, P < 0.0001 and P < 0.05, respectively). Significant improvement was also documented for ACR50 response (28% for tofacitinib 10 mg bd, 27% for tofacitinib 5 mg bd compared with 8% for placebo, P < 0.0001). The remission rates according to EULAR DAS28-4(ESR) (<2.6) responses were 11% and 7% for tofacitinib 5 and 10 mg, respectively, compared with 2% for placebo (P < 0.05). During the short evaluation period of 3 months, a significant improvement of disability (as measured by the mean change in HAQ-DI scores from baseline) was obvious for both tofacitinib dosages (−0.46% for tofacitinib 10 mg bd, −0.43% for tofacitinib 5 mg bd compared with −0.18% for placebo, P < 0.0001). After the switch to active treatment, patients from the placebo group reached response rates comparable to those of patients on tofacitinib (e.g. ACR20 55–52%, ACR50 37–30%, ACR70 ~16%).
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