NEW YORK, NY, USA I January 27, 2021 I Pfizer Inc. (NYSE: PFE) announced today co-primary endpoint results from a recently completed post-marketing required safety study, ORAL Surveillance (A3921133; NCT02092467). The primary objective of this study was to evaluate the safety of tofacitinib at two doses (5 mg twice daily and 10 mg twice daily) versus a TNF inhibitor (TNFi) in subjects with rheumatoid arthritis (RA) who were 50 years of age or older and had at least one additional cardiovascular (CV) risk factor.
The co-primary endpoints of this study were non-inferiority of tofacitinib compared to TNFi in regard to major adverse cardiovascular events (MACE) and malignancies (excluding non-melanoma skin cancer (NMSC)). Results showed that for these co-primary endpoints, the prespecified non-inferiority criteria were not met for the primary comparison of the combined tofacitinib doses to TNFi. Based on the prespecified secondary comparisons, there was no evidence of a difference in the primary endpoints between the two tofacitinib treatment groups.
The study included 4,362 subjects who received study treatments. The primary analyses included 135 subjects with MACE and 164 subjects with malignancies (excluding NMSC). For tofacitinib, the most frequently reported MACE was myocardial infarction and the most frequently reported malignancy (excluding NMSC) was lung cancer. In those subjects with a higher prevalence of known risk factors for MACE and malignancy (e.g., older age, smoking), a higher occurrence of events was seen across all treatment groups.
Adjudicated MACE*
|
Tofacitinib 5 mg BID |
Tofacitinib 10 mg BID** |
Tofacitinib Doses Combined |
TNFi | |
| Total number of subjects | 1455 | 1456 | 2911 | 1451 |
| Number of subjects with first event within the risk period*** (%) | 47 (3.23) | 51 (3.50) | 98 (3.37) | 37 (2.55) |
| Person-years | 5166.32 | 4871.96 | 10038.28 | 5045.27 |
| IR (95% CI) (number of subjects with event/100 person-years) | 0.91 (0.67, 1.21) | 1.05 (0.78, 1.38) | 0.98 (0.79, 1.19) | 0.73 (0.52, 1.01) |
|
HR (95% CI) for tofacitinib vs TNFi |
1.24 (0.81, 1.91) | 1.43 (0.94, 2.18) | 1.33 (0.91, 1.94)**** |
BID=twice daily; CI=confidence interval; HR=hazard ratio; IR=incidence rate; MACE=major adverse cardiovascular event; TNFi=Tumor Necrosis Factor inhibitor.
(*) Based on Cox proportional hazard model
(**)The 10 mg BID treatment group includes patients that were switched from 10 mg BID to 5 mg BID as a result of a study modification in February 2019.
(***) The risk period was from start of therapy up to 60 days past last dose.
(****) The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8, ie, 1.94 >1.8.
Adjudicated Malignancies Excluding NMSC*
| Tofacitinib 5 mg BID |
Tofacitinib 10 mg BID** |
Tofacitinib Doses Combined |
TNFi | |
| Total number of subjects | 1455 | 1456 | 2911 | 1451 |
| Number of subjects with first event within the risk period*** (%) | 62 (4.26) | 60 (4.12) | 122 (4.19) | 42 (2.89) |
| Person-years | 5491.48 | 5311.71 | 10803.19 | 5482.30 |
| IR (95% CI) (number of subjects with event/100 person-years) | 1.13 (0.87, 1.45) | 1.13 (0.86, 1.45) | 1.13 (0.94, 1.35) | 0.77 (0.55, 1.04) |
|
HR (95% CI) for tofacitinib vs TNFi |
1.47 (1.00, 2.18) | 1.48 (1.00, 2.19) | 1.48 (1.04, 2.09)**** |
|
BID=twice daily; CI=confidence interval; HR=hazard ratio; IR=incidence rate; NMSC=non-melanoma skin cancer; TNFi=Tumor Necrosis Factor inhibitor.
(*) Based on Cox proportional hazard model
(**)The 10 mg BID treatment group includes patients that were switched from 10 mg BID to 5 mg BID as a result of a study modification in February 2019.
(***) The risk period included all available follow-up regardless of treatment exposure.
(****) The non-inferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi since the upper limit of the 95% CI exceeded the pre-specified non-inferiority criterion of 1.8, ie, 2.09 >1.8.
“Providing information on the safe and effective use of our medicines is imperative,” said Tamas Koncz, M.D., Ph.D., Chief Medical Officer, Inflammation and Immunology, Pfizer. “We believe that extensive additional analyses of these study data, and communicating them as soon as possible, will further clarify the benefit and risk profile of tofacitinib to help inform medical decision making and patient care.”
Full study results, beyond the co-primary endpoints (including, but not limited to, secondary endpoints such as pulmonary embolism and mortality as well as efficacy data), are not yet available. Pfizer is working with the U.S. Food and Drug Administration (FDA) and other regulatory agencies to review the full results and analyses as they become available.
About the Study
In contrast to previous tofacitinib studies, ORAL Surveillance was specifically designed to assess the risk of CV events and malignancies, and therefore subjects were required to be 50 years of age or older and have at least one additional CV risk factor at screening. All subjects in this study were also required to be treated with background methotrexate to be eligible for enrollment.
About XELJANZ® (tofacitinib)
XELJANZ® (tofacitinib) isapproved in the U.S. in four indications: adults with moderately to severely active rheumatoid arthritis (RA) after methotrexate failure, adults with active psoriatic arthritis (PsA) after disease modifying antirheumatic drug (DMARD) failure, adults with moderately to severely active ulcerative colitis (UC) after tumor necrosis factor inhibitor (TNFi) failure, and patients 2 years of age or older with active polyarticular course juvenile idiopathic arthritis (pcJIA). XELJANZ has been studied in more than 50 clinical trials worldwide and prescribed to over 208,000 adult patients (the majority of whom were RA patients) worldwide in the last eight years.1,2,3
As the developer of tofacitinib, Pfizer is committed to advancing the science of JAK inhibition and enhancing understanding of tofacitinib through robust clinical development programs in the treatment of immune-mediated inflammatory conditions.
INDICATIONS
Rheumatoid Arthritis
- XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate.
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Psoriatic Arthritis
- XELJANZ/XELJANZ XR (tofacitinib) is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs).
- Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ulcerative Colitis
- XELJANZ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or who are intolerant to TNF blockers.
- Limitations of Use: Use of XELJANZ in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Polyarticular Course Juvenile Idiopathic Arthritis
- XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older.
- Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
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1 Pfizer Data on File. XELJANZ Worldwide Registration Status.
2ClinicalTrials.gov
. Tofacitinib RA Studies. Accessed June 25, 2020.
3 Pfizer. Data on File. Tofa Counts. April 2019
SOURCE: Pfizer
