Benefit Equivocal for RA Triple Therapy
Adding the anti-B cell agent rituximab (Rituxan) to conventional therapy for rheumatoid arthritis boosted both response rates and adverse effects modestly, said researchers conducting a small trial.
Response rates by ACR20 criteria were 30% in those receiving rituximab along with a tumor necrosis factor (TNF) inhibitor and methotrexate, compared with 17% in patients on the latter two drugs plus placebo in the 24-week study, according to Maria Greenwald, MD, of Desert Medical Advances in Palm Desert, Calif., and colleagues.
But the 51-patient trial was designed primarily to assess safety, with a primary endpoint of serious infections through week 24. Only one patient — in the rituximab group — developed such an infection (pneumonia) during the study, Greenwald and colleagues reported in the March issue of Arthritis Rheumatism.
“The preliminary safety profile of rituximab in combination with a TNF inhibitor and methotrexate was consistent with the safety profile of rituximab in combination with methotrexate in other rheumatoid arthritis trials without a TNF inhibitor, with no new safety signals observed,” they wrote.
However, the small number of patients in the trial, and a disparity between groups at baseline in the use of corticosteroids, prevented definitive conclusions.
“A larger, open-label study evaluating the safety profile of rituximab in combination with TNF inhibitors is currently in progress and may provide additional information with regard to the treatment of rheumatoid arthritis using multiple concomitant biologic DMARDs (disease-modifying anti-rheumatic drugs),” Greenwald and colleagues wrote.
Rituximab is currently approved to treat rheumatoid arthritis in combination with methotrexate. Its safety and efficacy when also combined with TNF inhibitors remains uncertain, particularly because the double hit to patients’ immune systems might leave them more prone to infections.
In the current study, patients with at least five swollen and five tender joints while receiving stable doses of methotrexate and either etanercept (Enbrel) or adalimumab (Humira) were recruited.
Participants remained on the same doses of these drugs and were assigned in a 2:1 ratio to receive two IV doses of either 500 mg of rituximab or placebo.
Five patients in the rituximab group experienced grade 3 adverse events versus none in the control group. But the only serious infection was the lone case of pneumonia.
One other adverse event rated as serious was a case of coronary artery occlusion, also occurring in a patient assigned to rituximab.
Overall, with less-severe incidents included, the rituximab group had a slightly higher rate (94% versus 83%, P not reported).
The difference appeared largely attributable to infusion-related reactions, which were seen in 33% of the rituximab group compared with 11% of the control patients.
There was no difference in the rate of infections at all levels of severity, nor were there any grade 4 infections in either treatment group.
In addition to the case of pneumonia, two other grade 3 infections were seen with rituximab: one influenza case and one postoperative infection. No one in the control group had grade 3 infections.
Greenwald and colleagues noted that the study was not powered to evaluate efficacy, but nevertheless they collected data on ACR20 and ACR50 response rates (improvements of 20% and 50%, respectively, according to American College of Rheumatology criteria).
The addition of rituximab to conventional treatment did not show dramatic effects, the researchers acknowledged.
ACR20 responses were achieved in 30% of patients receiving the three drugs versus 17% of the control group. ACR50 responses were even scarcer — seen in 12% of rituximab-treated patients and 6% of the control group.
An important limitation of the study was that nearly twice as many patients in the rituximab group were taking corticosteroids at baseline (36% versus 17%, P not reported). Steroid use at stable doses during the study was permitted as part of its design.
Another limitation cited by Greenwald and colleagues was the rituximab dose, which, at two 500-mg infusions, was half the approved level of two 1,000-mg doses. They also noted that 24 weeks of follow-up is not enough to fully evaluate the regimens’ safety.
The study was funded by Biogen Idec, Genentech, and Roche.
Greenwald reported research grants from Biogen Idec and Genentech. One other author received speaking fees from Biogen Idec (less than $10,000) and three authors reported owning stock or options in the firm.
Article source: http://www.medpagetoday.com/Rheumatology/Arthritis/25323
Encouraging Data on Pfizer Drug
Pfizer Inc. (PFE – Analyst Report) recently presented encouraging data on its rheumatoid arthritis candidate tofacitinib (formerly known as tasocitinib). Tofacitinib met its primary endpoint in the ORAL Sync phase III study (A3921046), which was conducted on patients suffering from moderate-to-severe rheumatoid arthritis. Results showed that compared to placebo, tofacitinib achieved a statistically significant reduction in signs and symptoms of rheumatoid arthritis.
The safety profile of the candidate was found to be consistent with previous results with no new safety signals being detected. Pfizer intends to present full safety and efficacy data at a scientific meeting.
Earlier, in November 2010, Pfizer had reported results from a late-stage trial (ORAL Solo – 1045) on tofacitinib in patients with signs and symptoms of moderate to severely active rheumatoid arthritis. The study met two primary endpoints after three months of treatment with tofacitinib.
The candidate demonstrated a statistically significant reduction in the signs and symptoms of moderate to severely active rheumatoid arthritis and an improvement in physical function of the patients as compared with placebo.
Although patients in the tofacitinib arm experienced a higher rate of disease remission compared with placebo, the results were not statistically significant.
Pfizer had also reported data from an ongoing phase II/III trial (ORAL Sequel – 1024) on tofacitinib. The study demonstrated results consistent with an earlier trial and showed sustained efficacy over 24 months of treatment with tofacitinib when administered as monotherapy or in combination with methotrexate.
Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor which, once approved, will compete with products like Abbott’s (ABT – Analyst Report) Humira, Johnson Johnson’s (JNJ – Analyst Report) Remicade and Simponi. Being an oral treatment, tofacitinib could have an edge over existing injectable therapies.
In addition to evaluating tofacitinib for the treatment of rheumatoid arthritis, Pfizer is studying the candidate for other indications including psoriasis, Crohn’s disease, ulcerative colitis and renal transplant. Moreover, a topical version of tofacitinib is being evaluated for psoriasis and dry eye disease.
In October 2010, Pfizer had presented positive phase II data on tofacitinib for the psoriasis indication. Results showed that tofacitinib met its primary endpoint in the phase II efficacy and safety study. Tofacitinib is currently being evaluated in a phase III program (OPT – Oral Psoriasis Treatment) for the treatment of chronic moderate to severe plaque psoriasis.
We currently have a Neutral recommendation on Pfizer, which is supported by a Zacks #3 Rank (short-term Hold” rating). The successful development and commercialization of tofacitinib would be a major boost for Pfizer.
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