APF530 Phase 3 Clinical Trial

In December 2005, A.P. Pharma held its end-of-Phase-2 meeting with the FDA, at which the Company discussed its regulatory approval strategy and proposed design for the pivotal Phase 3 trial. Following this meeting, the Company finalized plans for its pivotal Phase 3 trial in accordance with FDA input. The trial’s primary objectives were to demonstrate:

• non-inferiority, or comparability, of APF530 to palonosetron (Aloxi®) for the prevention of acute onset CINV following the administration of either moderately emetogenic or highly emetogenic chemotherapy;
• non-inferiority of APF530 in comparison to palonosetron for the prevention of delayed onset CINV following administration of moderately emetogenic chemotherapy; and
• superiority of APF530 in comparison to palonosetron for the prevention of delayed onset CINV following administration of highly emetogenic chemotherapy.

A.P. Pharma’s 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 APF530 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 APF530 high dose (10 mg), APF530 low dose (5 mg) or the currently approved dose of palonosetron. In subsequent treatment cycles (up to three additional cycles), the patients were re-randomized to either of the two APF530 doses. The diagram below provides further graphical representation of the patient stratification design for patient randomization in our clinical trial.

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. A.P. Pharma’s pivotal Phase 3 study, comparing the efficacy of APF530 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 APF530 in the treatment of CINV following the administration of highly or moderately emetogenic chemotherapy, and to establish an effective dose for APF530. 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 APF530 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 A.P. Pharma can rely on the significant clinical data for safety and efficacy of APF530’s active ingredient, granisetron.

The trial was structured to compare the two APF530 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, APF530 needed to be deemed superior to palonosetron for this endpoint to obtain a corresponding label claim. The 10 mg dose of APF530 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:

 (NI) Non-inferior efficacy was established using a modified Bonferroni step down procedure. APF530 non-inferior to palonosetron (i.e. lower bound of adjusted 95% CI for APF530), palonosetron difference excludes less than or equal to negative 15%. The Confidence Intervals shown for the moderately emetogenic and highly emetogenic levels are 97.5% and 98.3%, respectively. (NS) No significant difference. (I) Inferior efficacy.

APF530 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 APF530. In Cycle 1, the data showed a low incidence of patients discontinuing therapy due to any adverse events (related or unrelated to study drugs): 0.5%, 0.9% and 0.9% in the moderately emetogenic patient group, and 2.0%, 3.5% and 1.2% in the highly emetogenic patient group for APF530 5 mg, APF530 10 mg and palonosetron, respectively. Further, of the patients completing the first cycle, 1,043 went on to receive a total of 2,374 additional doses of APF530 in Cycles 2 to 4. Of these patients, only 2 (or 0.2%) discontinued therapy due to treatment related adverse events.

Additional data from the pivotal Phase 3 trial comparing APF530 with palonosetron was released on November 5, 2008, and is reported below. The 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 APF530 clinical response within and across chemotherapy cycles. Some of the additional key findings follow:

• Collectively, the Phase 3 efficacy and safety data support the conclusion that the APF530 10 mg dose is the most effective dose and therefore will be the selected dose for the NDA.
• In patients receiving multiple cycles of APF530, CR rates were observed to generally increase over four cycles of chemotherapy. The data summarized below supports the continued benefits of APF530 over multiple cycles:

Complete Response of APF530 10 mg Dose Over Four Chemotherapy Cycles

• The evaluation of “time to first treatment failure,” defined as either time to first emetic episode or use of rescue medication, showed that a greater proportion of patients treated with APF530 10 mg dose (vs. palonosetron) remained “failure free” on days one through five following either moderate or highly emetogenic chemotherapy.
• 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 APF530 10 mg dose vs. palonosetron, the response rates for APF530 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.
• The safety profile for APF530 was very similar to that for palonosetron; the most notable adverse event was constipation, observed in 15.4% and 13.4% of patients receiving APF530 10 mg and palonosetron, respectively. Headache was observed in 10.0% and 9.7% of patients receiving APF530 10 mg dose and palonosetron, respectively.
• 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 APF530, the frequency of injection site reactions decreased, indicating APF530 can safely be administered for multiple cycles.
• During the trial, patients received more than 1,600 separate injections of APF530 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.

Regulatory

Based on A.P. Pharma’s discussions with the FDA, the Company filed its NDA in May 2009 under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act (FDCA). A.P. Pharma received a Complete Response Letter on the APF530 NDA in March 2010 and is in the process of preparing a resubmission responsive to the deficiencies listed in the Complete Response Letter.

Section 505(b)(2) of the FDCA permits the FDA, in its review of a NDA, to rely on previous FDA findings of safety and efficacy of the active ingredient in APF530, granisetron. The 505(b)(2) approval pathway is distinguished from the Abbreviated New Drug Application, or generics route, by the requirement that drug products approved under this section must have significant difference relative to the reference approved product. The additional information in the 505(b)(2) applications can be provided by literature or reference to past FDA findings of safety and efficacy for approved drugs, or it can be based upon studies conducted by or for the applicant to which it has obtained a right of reference. The majority of 505(b)(2) applications are filed for new formulations of currently approved drugs, so there is an existing understanding—on the part of the FDA, as well as the medical community—of their safety and efficacy.