FDA Approves Extended-Release CINV Drug

Sustol, an extended-release formulation of granisetron, was just approved by the U.S. Food and Drug Administration (FDA) to treat chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic therapies, according to Heron Therapeutics, the manufacturer of the drug.

The novel formulation of the 5-HT3 receptor antagonist can maintain therapeutic levels of Sustol for five or more days. The approved indication is specifically for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” Ralph V. Boccia, medical director, Center for Cancer and Blood Disorders, said in a statement. “In our experience, other 5-HT3 receptor antagonists, including Aloxi (palonosetron), are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full five days.”

The efficacy data supporting the approval of Sustol came from a multicenter double-blind trial that included 733 patients who received MEC or AC combination chemotherapy. Patients were randomized to 10 mg of subcutaneous Sustol (371 patients) or a single 0.25 mg intravenous dose of Aloxi hydrochloride (362 patients).

The mean patient age was 57 years (range, 22-91). Seventy-nine percent of the patients were female and 63 percent were white. MEC was administered to 55 percent of patients and 45 percent received AC combination chemotherapy. The most frequently used MEC regimen was carboplatin/paclitaxel (31 percent).

Both treatments were administered 30 minutes before chemotherapy on day one. Intravenous dexamethasone was also administered at 8 or 20 mg on day one, depending on the chemotherapy regimen. Those individuals who received 20 mg of intravenous dexamethasone were also given an 8 mg oral dose of the drug twice daily on days two, three and four.

The primary endpoint of the study was complete response (CR), which the trial defined as no emetic episodes or rescue medication during the acute phase (0-24 hours) and the delayed phase (over 24 to 120 hours) after chemotherapy administration in cycle one.

The design of the trial also allowed for the evaluation of noninferiority of Sustol to Aloxi hydrochloride in the acute and delayed phases.

The results demonstrated that the Sustol formulation was noninferior to Aloxi. Among patients receiving MEC (406 patients) the CR in the acute phase was 83 percent (166/200) in the Sustol arm compared with 89 percent (183/206) in the Aloxi group. The CR rates in the delayed phase were 69 percent (137/200) and 70 percent (144/206), respectively.

Among patients who received AC combination chemotherapy (327 patients), the CR rate in the acute phase for the Sustol group was 70 percent (120/171) compared with 64 percent (99/156) with Aloxi. The CR rates in the delayed phase were 50 percent (85/171) versus 47 percent (74/156), respectively.

“The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, CEO and director of clinical research, North Shore Hematology Oncology Associates and vice president, Community Oncology Alliance. “Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

The safety of the FDA-recommended 10-mg subcutaneous dose of Sustol was evaluated in 924 patients across two double-blind, randomized active-controlled studies.

In the first study, 468 patients received 10 mg of subcutaneous Sustol and 463 patients received 0.25 mg of intravenous Aloxi hydrochloride. The most common all-grade adverse events (AEs) included injection site reactions (37 percent with Sustol vs 15 percent with Aloxi), constipation (14 percent vs 11 percent), fatigue (11 percent vs 10 percent), headache (9 percent each), diarrhea (8 percent vs 7 percent), abdominal pain (7 percent each), insomnia (4 percent vs 2 percent), dyspepsia (3 percent each), dizziness (3 percent vs 2 percent), asthenia (4 percent vs 6 percent) and gastroesophageal reflux (1 percent each).

The second study included 456 patients who received 10 mg of subcutaneous Sustol and 459 patients who received 0.15 mg/kg of intravenous ondansetron. Sixty-percent of patients receiving Sustol had injection site reactions. The remaining AEs that were most commonly reported matched those reported for the first trial: constipation (22 percent with Sustol vs 15 percent with Aloxi), fatigue (21 percent vs 24 percent), headache (13 percent vs 19 percent), diarrhea (9 percent vs 8 percent), abdominal pain (7 percent vs 4 percent), insomnia (5 percent vs 6 percent), dyspepsia (6 percent vs 7 percent), dizziness (5 percent each), asthenia (2 percent each) and gastroesophageal reflux (5 percent vs 4 percent each).

"The approval of Sustol is a major step in Heron’s evolution into a fully-integrated biopharmaceutical company with both development and commercial capabilities," Robert H. Rosen, president of Heron Therapeutics, said in a statement. “Our focus now turns to ensuring patients have access to this important therapy. We look forward to collaborating with the oncology community to make Sustol available in the fourth quarter of this year.”