Heron Therapeutics' pivotal Phase 3 clinical trial, initiated in May 2006, was a multicenter, randomized, observer-blind, actively-controlled, double-dummy, parallel group study that compared the efficacy of Sustol with palonosetron. The trial stratified patients into two groups, one receiving moderately and the other receiving highly emetogenic chemotherapeutic agents in accordance with the Hesketh algorithm, which assigns emetogenic levels based on the chemotherapy agent, drug dosage and combinations employed. In each group, the patients were randomized to receive in the first chemotherapy treatment cycle either Sustol high dose (10 mg granisetron), Sustol low dose (5 mg granisetron) or the currently approved dose of palonosetron. In subsequent treatment cycles (up to three additional cycles), patients who received palonosetron were re-randomized to either of the two Sustol doses.
Pivotal Phase 3 Clinical Trial Results
During 2006 and the first half of 2007, all patient enrollments were within the U.S. Beginning in the second half of 2007, enrollments were broadened to include sites in India and Poland. Heron Therapeutics' pivotal Phase 3 study, comparing the efficacy of Sustol with palonosetron, completed patient enrollment of 1,395 patients in June 2008, and the Company announced top-line results on September 30, 2008.
The goals of the trial were to demonstrate the safety and efficacy of Sustol in the treatment of CINV following the administration of highly or moderately emetogenic chemotherapy, and to establish an effective dose for Sustol. In the trial, 5 mg and 10 mg doses of granisetron were evaluated, and based on the results, the 10 mg dose appears to provide greater efficacy with a side effect profile similar to the 5 mg dose. As such, the Sustol 10 mg dose is the proposed therapeutic dose included in the NDA. The NDA was submitted under section 505(b)(2) of the FDCA, whereby Heron Therapeutics can rely on the significant clinical data for safety and efficacy of Sustol’s active ingredient, granisetron.
The trial was structured to compare the two Sustol doses with palonosetron in four different primary efficacy endpoints, non-inferiority to palonosetron for the prevention of acute and delayed CINV in patients receiving moderately emetogenic chemotherapies, and non-inferiority and superiority to palonosetron for the prevention of acute and delayed CINV, respectively, in patients receiving highly emetogenic chemotherapies. Palonosetron is not FDA approved for the prevention of delayed-onset CINV in patients receiving highly emetogenic chemotherapies; therefore, Sustol needed to be deemed superior to palonosetron for this endpoint to obtain a corresponding label claim. The 10 mg dose of Sustol achieved complete response (CR) rates that were numerically higher than palonosetron across all four assessments. These results achieved non-inferiority to palonosetron for all four assessments, but did not achieve the superiority endpoint for the highly emetogenic delayed-onset assessment. CR was defined as the absence of emetic episodes or use of antiemetic rescue medications during a specified period of time. The time periods studied for CINV onset were acute (0 to 24 hours after chemotherapy) and delayed (24 to 120 hours after chemotherapy).
The results summarized below are the primary endpoints from the study, with such data being drawn from the first cycle of treatment:
Primary Efficacy Results: Complete Response
Patients Receiving Moderately Emetogenic Chemotherapy
Patients Receiving Highly Emetogenic Chemotherapy
Sustol was generally well tolerated, with a side effect profile consistent with previous human use of granisetron and only one serious adverse event reported as possibly attributed to Sustol.
Reported in Cycle 1
Efficacy through Multiple Chemotherapy Cycles
Additional data provided herein includes predetermined secondary efficacy endpoints and safety data that were not available at the time the top-line data were released. Review of the clinical data package demonstrates the robustness of the Sustol clinical response within and across chemotherapy cycles. In patients receiving multiple cycles of Sustol, CR rates were observed over four cycles of chemotherapy. The data summarized below supports the continued benefits of Sustol over multiple cycles:
Overall Complete Response Rates3 for Sustol 10 mg
Sustol's Efficacy with Difficult Chemo Regimens4
Post-hoc analysis of Phase 3 data by chemotherapy regimen showed good response rates for different regimens.
- The Phase 3 trial protocol predefined multiple primary and secondary endpoints, including complete response, complete control (no emesis, no rescue therapy and no-greater-than-mild nausea) and total response (no emesis, no rescue therapy and no nausea) measured over defined time intervals (acute, delayed and overall). Although there were no significant differences between the Sustol 10 mg dose vs. palonosetron, the response rates for Sustol 10 mg dose were higher than palonosetron in all nine analyses for moderately emetogenic chemotherapy and in five of nine analyses for highly emetogenic chemotherapy.
- Investigators were required to observe and record all reactions associated with the subcutaneous injection site on days one and five for each treatment cycle. Overall, greater than 90% of the recorded observations were mild in severity, the most common being redness and bruising. With each additional cycle of treatment with Sustol, the frequency of injection site reactions decreased, indicating Sustol can be administered for multiple cycles.
- During the trial, patients received more than 1,600 separate injections of Sustol 10 mg dose. Assessment of any injection site pain was made on days one and five of treatment: on day one, less than 0.1% of injections produced any reports of pain; on day five approximately 4% of injections produced reported pain. All but four of these reports of pain were recorded as mild, with the four recorded as moderate.