OPKO Health Inc. announced that its licensee TESARO has introduced Varubi (rolapitant), an NK-1 receptor antagonist, in the United States. The US Food and Drug Administration (FDA) approved Varubi on September 1, 2015, for use in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
Varubi is a selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, with a plasma half-life of approximately seven days. Results from all three phase 3 trials of Varubi demonstrated that patients receiving highly and moderately emetogenic chemotherapy agents, including platinum and anthracycline/cyclophosphamide-containing regimens, experienced a significant reduction in episodes of vomiting or use of rescue medication during the 25 to 120 hour period following chemotherapy administration. In addition, patients who received Varubi reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, when administering Varubi. A single dose (two 90 milligram tablets) of Varubi is to be administered approximately one to two hours prior to chemotherapy administration, in combination with a 5-HT3 receptor antagonist and dexamethasone.
Just three weeks after the approval of Varubi by the US FDA, the National Comprehensive Cancer Network (NCCN) added Varubi to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Antiemesis Version 2.2015 as a recommended option, in combination with other antiemetic agents, for patients receiving both high emetic risk intravenous chemotherapy (HEC) and moderate emetic risk intravenous chemotherapy (MEC). Category 1, the highest level category of evidence and consensus, was granted to Varubi for both HEC and MEC chemotherapy.
Chemotherapy-induced nausea and vomiting is a debilitating, yet often preventable, side effect of chemotherapy.
Up to 50 per cent of patients undergoing highly or moderately emetogenic chemotherapy experience delayed CINV (25 to 120 hours post chemotherapy)—even when prescribed a 5-HT3 receptor antagonist and corticosteroid.
Blocking both 5-HT3 and NK-1 receptors has been shown to offer better control of nausea and vomiting than inhibiting 5-HT3 receptors alone. Adding a single dose of Varubi to an antiemetic regimen, including a 5-HT3 receptor antagonist and corticosteroid, further improves prevention of CINV in the delayed phase following chemotherapy.
Varubi is a substance P/neurokinin-1 (NK-1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. A Positron Emission Tomography (PET) study with rolapitant in normal, healthy volunteers demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK-1 receptors at high levels for up to 120 hours. Varubi has a half-life of approximately seven days, which may contribute to the ability of a single dose of Varubi to cover the entire delayed CINV phase (25-120 hours).
An intravenous formulation of rolapitant is also being developed. TESARO licensed exclusive rights for the development, manufacture, commercialization, and distribution of Varubi (rolapitant) from OPKO Health, Inc.
The superior efficacy of Varubi was established in multiple global, randomized, well-controlled, blinded clinical trials that enrolled more than 2,500 patients. Varubi, when administered in combination with a 5-HT3 receptor antagonist and dexamethasone, was significantly superior to a 5-HT3 receptor antagonist and dexamethasone in preventing delayed CINV in patients receiving either moderately or highly emetogenic chemotherapy.
The clinical profile of Varubi in cisplatin-based, highly emetogenic chemotherapy (HEC) was confirmed in two identical phase 3 studies: HEC1 and HEC2. Both trials met their primary endpoint of complete response (CR) in the delayed phase (25-120 hours) of CINV and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone). In HEC1, 264 patients received rolapitant 180 mg, and 262 received control. The proportion of patients achieving a CR was 72.7 per cent vs. 58.4 per cent (p= < 0.001). In HEC2, 271 patients received rolapitant, and 273 received control. The proportion of patients achieving a CR was 70.1 per centvs. 61.9 per cent (p=0.043). The most common adverse reactions (=3 per cent) among patients receiving cisplatin-based chemotherapy were neutropenia (9 per cent Varubi vs. 8 per centcontrol), hiccups (5 per cent vs. 4 per cent), and abdominal pain (3 per cent vs. 2 per cent).
A phase 3 trial was also conducted to evaluate rolapitant 180 mg compared to active control in 1,332 patients receiving anthracycline/cyclophosphamide combinations or moderately emetogenic chemotherapy regimens, including carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. This trial met its primary endpoint of CR in the delayed phase of CINV and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone). The proportion of patients achieving a CR was 71.3 per centvs 61.6 per cent (p= < 0.001). The most common adverse reactions (=3 per cent) among patients receiving these chemotherapies were decreased appetite (9 per cent Varubi vs. 7 per cent control), neutropenia (7 per cent vs. 6 per cent), dizziness (6 per cent vs. 4 per cent), dyspepsia (4 per cent vs. 2 per cent), urinary tract infection (4 per cent vs. 3 per cent), stomatitis (4 per centvs. 2 per cent), and anemia (3 per centvs. 2 per cent).
Primary data from the three phase 3 studies have been published in Lancet Oncology. The analysis of the non-AC MEC population was presented at the 2015 annual meeting for the Multinational Association for Supportive Care in Cancer, and commentary has been provided in Nature Reviews Clinical Oncology.