Vomiting is a protective reflex against ingestion of what the body perceives to be potentially harmful substances, including some chemotherapeutic agents. These chemotherapeutic agents activate or destroy cells in the lining of the gut, releasing a neurotransmitter called serotonin. When serotonin binds to the 5-hydroxytryptamine type 3 (5-HT3) receptors, the patient experiences nausea and vomiting. By blocking the 5-HT3 receptors, granisetron and the other 5-HT3 antagonists prevent serotonin from binding to the
5-HT3 receptors, thereby inhibiting the vomiting reflex. Physicians may combine these 5-HT3 antagonists with other agents, such as corticosteroids or neurokinin-1 (NK1) antagonists, to better prevent CINV.
Current treatment options for CINV include 5-HT3 antagonists such as palonosetron (Aloxi®), ondansetron (Zofran®), dolasetron (Anzemet®) and granisetron (Kytril®), as well as aprepitant (Emend®), an NK1 antagonist, which is always used in combination with a 5-HT3 antagonist. As shown in the table below, all of the 5-HT3 antagonists are approved for the prevention of acute onset CINV in patients receiving either moderately or highly emetogenic chemotherapy. Only palonosetron is approved for the prevention of delayed onset CINV in patients receiving moderately emetogenic chemotherapy. No 5-HT3 antagonist is approved for the prevention of delayed onset CINV in patients receiving highly emetogenic chemotherapy.
Chemotherapy Regimen 5-HT3 Antagonists for Acute Onset CINV
5-HT3 Antagonists for Delayed Onset CINV
Moderately Emetogenic APF530
Granisetron (Kytril)
Ondansetron (Zofran)
Dolasetron (Anzemet)
Palonosetron (Aloxi)
APF530
Palonosetron (Aloxi)
Highly Emetogenic APF530
Granisetron (Kytril)
Ondansetron (Zofran)
Dolasetron (Anzemet)
Palonosetron (Aloxi)
NONE
Despite evidence that delayed onset CINV affects as many as 50–70% of patients, and that more patients experience delayed onset CINV than acute onset CINV, oncology nurses and physicians are likely to underestimate the magnitude of these problems in the patients for whom they care. This may occur in part since patients often do not report side effects they experience at home following chemotherapy treatments. Even though high percentages of chemotherapy patients experience such delayed nausea and emesis, presently palonosetron is the only 5-HT3 antagonist approved for dealing with this delayed onset CINV. We believe that our APF530, if approved, could become the second long-acting product given in a single administration that is capable of dealing with this important medical need.
Our Solution - APF530
The Company’s lead product, APF530, is being developed for the prevention of CINV in patients receiving either moderately or highly emetogenic chemotherapy. APF530 is delivered by a single subcutaneous injection and contains the 5-HT3 antagonist, granisetron. Granisetron, for infusion and oral tablets, is approved for the prevention of acute onset CINV, but not delayed onset CINV. We selected granisetron because it is a potent drug and the applicable granisetron patent expired in the United States on December 29, 2007.
Granisetron and other 5-HT3 antagonists, as a class, have become the most common antiemetic agents used in chemotherapy. However, no 5-HT3 antagonist formulation is currently approved for the prevention of both acute and delayed onset CINV for both moderately and highly emetogenic chemotherapy. A.P. Pharma's APF530 Phase 3 clinical trial demonstrated that it can deliver therapeutic levels of granisetron to prevent acute onset CINV for both moderately and highly emetogenic chemotherapy, and to prevent delayed onset CINV in moderately emetogenic chemotherapy. The sector efficacy data involving delayed onset CINV in highly emetogenic chemotherapy showed results for the higher dose of APF530 that were numerically better than palonosetron and statistically non-inferior, but did not achieve the statistically significant level of superiority necessary to support a claim in this sector. If A.P. Pharma obtains product approval for all uses except the delayed onset highly emetogenic one, the Company should have a product comparable to palonosetron, which despite the limitation of its claim for prevention of delayed onset CINV to only moderately emetogenic treatments, has achieved considerable commercial success.
In May 2009, A.P. Pharma submitted an NDA for APF530 under section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, whereby the Company can rely upon the FDA's prior safety and efficacy findings for APF530's active ingredient, granisetron. The FDA has accepted for review the NDA and, based on the Prescription Drug User Fee Act (PDUFA), has issued an action date of March 18, 2010.
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