R935788: A Phase II, Single Center, Open Label, Efficacy and Safety, Ascending Dose, Pilot Study for the Treatment of Adult Immune Thrombocytopenic Purpura (ITP).

Syk kinase is central to FcR and B-cell signaling in inflammatory cells. By inhibiting syk, and thereby IgG signaling, R788 (a small molecule prodrug for biologically active R406), inhibits the downstream activation of mast cells, macrophages and B-cells. (Braselmann S. Pharm Exp Ther. 2006). Preclinical study showed that R788 minimized thrombocytopenia in mice treated with anti-platelet antibodies (Crow, A.R. Blood 2005). In this study, adult, refractory ITP patients (pts) were treated with escalating doses of R788 in cohorts of ≥3 pts to evaluate safety and efficacy. After a cohort completed four weeks, the next cohort could be initiated. Pts completed 2 weeks of dosing before the dose could be increased (by 25 mg twice daily). Dosing was initiated at 75mg PO BID to 150 mg PO BID. Pts who responded and then had their platelet (plt) counts (cts) decline, could have their dose increased to a maximum of 175mg bid.

Safety: 14 pts entered the study, 10 after failed splenectomy and 5 who were >70 yo. Six pts withdrew due to failure to respond (4) or gastrointestinal (GI) symptoms (2). GI symptoms (vomiting & diarrhea) were seen in 5 of 14 pts with mild elevations in ALT in 2 pts (2 >2XULN, one of whom had pre-existing hepatitis). Two pts were hospitalized for GI side effects (dehydration) and one developed an unrelated UTI with subsequent diagnosis of DVT. R788 also elevated blood pressure in some pts but appeared to not have a significant effect on neutrophil counts.

Efficacy: By protocol standards, 9/14 pts are considered responders with stable platelet counts > 30,000/ul (30k). Six pts had peak counts > 100k. The mean change from pre treatment to the peak count in the 8 on study pts was 125k. Two pts, who previously had failed a wide range of other treatments, have maintained counts generally above 20k completing > 20 weeks of study with 0 and 1 IVIG treatments respectively, in each for the first time in > 10 years that they achieved prolonged avoidance of IVIG. Five had not responded to a thrombopoietic agent, 2 of whom responded to R788. Two responders discontinued the study because of nausea and vomiting at the dose that provided a response.

Conclusions: The effects of R788 treatment are preliminary but, despite GI toxicity in certain patients, nonetheless impressive in this very refractory ITP population. Certain pts have had important clinical although numerically unimpressive benefit. Further studies are ongoing including studies of FcR expression before and after treatment.