The clinical trial was a multicenter, randomized, double-blind, placebo-controlled, ascending dose study involving 189 patients in three approximately equal size cohorts receiving 50, 100, or 150 mg po bid. Within each cohort, patients were assigned on a 3:1 basis to R788 or placebo. The clinical trial was conducted over a 12-week treatment period in patients who had RA for at least 12 months. These patients had active disease despite receiving adequate stable doses of methotrexate over the preceding 6 months. All patients continued to receive their same stable dose of methotrexate throughout the clinical trial period and extension. The primary efficacy endpoint for the study was the percent of patients who were ACR20 responders at the end of week 12; secondary efficacy endpoints were ACR-50 and -70 scores as well as DAS at the end of week 12.
The results at 12 weeks presented below are based on an intention to treat analysis that includes all randomized patients, regardless of how long treatment lasted. Any patient who dropped out of the study for any reason, or for whom week 12 data was unavailable, was considered a treatment failure (ACR nonresponder). DAS scores are based on a 28 joint count and C-reactive protein (CRP) at week 12.
| Treatment po bid |
Number (N) |
ACR20 %(N) |
ACR50 % (N) |
ACR 70 % (N) |
DAS28-CRP<2.6 %(N) |
| Placebo | 47 | 38 (18) | 19 (9) | 4 (2) | 17 (8) |
| 50 mg | 46 | 32 (15) | 17 (8) | 2 (1) | 20 (9) |
| 100 mg | 49 | 65 (32) (P =.008) |
49 (24) (P =.002) |
33 (16) (P <.001) |
35 (17) (P =.005) |
| 150 mg | 47 | 72 (34) (P <.001) |
57 (27) (P <.001) |
40 (19) (P <.001) |
47 (22) (P <.001) |
The most common clinically meaningful adverse events noted in the clinical trial were dose-related neutropenia, mild elevations of liver function tests, and gastrointestinal side effects. Dose reduction (to one half the assigned dose, by taking the drug once per day) was prespecified in the protocol, contingent on neutrophil counts and/or liver function tests. Notably, 19 out of 21 patients who had their dose reduced, successfully completed the clinical trial with minimal safety issues.
R788 has a novel mechanism of action, blocking Fc receptor signaling in macrophages and B-cells that promote swelling and inflammatory response.
Initiated in January 2007, Rigel announced results of its phase II clinical study of R788 in patients with Immune Thrombocytopenic Purpura (ITP). The single-center, open-label, dose-escalating study (with most patients receiving between 100 to 175 mg/day po bid) showed that R788 can improve platelet counts in this autoimmune disorder. The study evaluated the safety and efficacy of R788 in adult, chronic refractory ITP. Nine of the first 14 patients (64%) studied responded favorably to R788 treatment with higher stable platelet counts; six patients had peak platelet counts of >100,000 platelets/µL of blood. Two study patients who had previously failed a wide range of other treatments and were receiving weekly intravenous gammaglobulin, maintained platelet counts while on only R788 for 20 weeks. For those two patients, this marked the first time in 10 years that each achieved prolonged avoidance of intravenous immunoglobulin injections. Overall, these patients were highly refractory with most having failed several other therapies, 10 patients had failed splenectomy, and 5 were over 70 years old.