Building on the base of its anti-emetic Zofran , GlaxoSmithKline is poised to broaden its leadership in the market for oncology supportive care with near-term offerings for thrombocytopenia and chemotherapy-induced nausea and vomiting.

Growing oncology supportive care is part of GSK's overall strategy of establishing the company as an oncology powerhouse (see ¹ [A#00690260011]). At its June 18 post-ASCO oncology pipeline review, the firm's thrombocytopenia drug Promacta (eltrombopag) and anti-emetic Rezonic (casopitant) were among the pipeline highlights.

GSK is counting on its expertise with Zofran(ondansetron) as a strong basis for the introduction of its next round of products.

"We hope that GSK's experience in emesis and [the] oncology market with our relationships with the oncologists and nurses and the portfolio that you see today, as well as a dedicated oncology sales force, will allow us to make this molecule a success and meet that unmet medical need," Debasish Roychowdhury, VP of Global Clinical Development for GSK's Oncology Medicine Development Center, said during his presentation on Rezonic.

The exec explained that CINV remains a significant medical need despite the availability of numerous treatment options. While nearly 95 percent of patients with CINV, and 60 percent of post-operative nausea and vomiting patients, receive prophylactic anti-emetics, 40 to 50 percent still experience nausea and vomiting, and it is still reported to be "the single most important concern for patients," Roychowdhury said.

"Despite this unmet medical need, and the fact that there is [Merck's] antiemetic Emend (aprepitant), there is not much use of aprepitant in this situation," he said, citing a 4.5 percent rate of prophylactic use with Emend. "We feel that the package that we are creating for Rezonic ... will fulfill this unmet medical need that Emend has not been able to fill."

Like Emend, Rezonic is an NK-1 receptor antagonist, a novel mechanism for GSK; Zofran is a 5-HT3 receptor blocker. Zofran was "the first solution" for CINV, Roychowdhury said, "and completely changed the face of chemotherapy."

Generics of Zofran hit the market at the end of 2006, the first generic entry for a 5-HT3 antagonist. Brand products in the class include MGI's Aloxi (palonosetron), Roche's Kytril (granisetron) and Sanofi-Aventis' Anzemet (dolasetron). Other competitors include Valeant's cannabinoid Cesamet (nabilone) and Merck's Emend.

Merck is facing a delay for its line-extension fosaprepitant. The firm received an "approvable" letter for Emend IV for the prevention of CINV on May 3 and will respond in the "next few months."

With all of the competition in the anti-emetic space, GSK is "creat[ing] a package that is very comprehensive and will really be a good package for us to take to the marketplace," the exec said.

"It has to be a total CINV solution, both for [highly emetogenic chemotherapy] and [moderately emetogenic chemotherapy], both an I.V. and oral formulation at the time of launch ... and a flexible and convenient dosing - a one day as well as a three-day dosing."

Rezonic is still in Phase III for CINV. The HEC trial completed enrollment in May and the MEC trial was fully enrolled in early June; results of both studies, which use Zofran and dexamethasone backbones, are expected by year-end.

In a Phase II HEC trial, casopitant yielded complete response rates (0-120 hours) of 76 percent for 50 mg, 86 percent for 100 mg and 77 percent for 150 mg (all given for three days) - and 75 percent for a single day one dose of 150 mg - versus 60 percent for the control arm and 72 percent for Emend.

Casopitant has completed two Phase III studies for PONV, added to a Zofran backbone. Both oral (50 mg) and I.V. (30 mg) achieved a 69 percent complete response rate within 24 hours, a statistically significant benefit over placebo.

GSK intends to submit the Rezonic application, with the full range of indications and formulations, in both the U.S. and Europe in the first half of 2008.

The company's next oncology drug submission will be the small molecule thrombopoietin receptor agonist Promacta. The first filing - for short-term treatment of idiopathic thrombocytopenic purpura - is expected by the end of 2007 or early 2008.

"Our strategic vision for Promacta is to first get an approval for Promacta in ITP for short duration of treatment," Roychowdhury said. "Then we intend to get into the market with further indications in the chronic treatment of ITP, in hepatitis C virus-associated thrombocytopenia as well as chemotherapy-induced thrombocytopenia."

The first oral, non-peptide platelet growth factor, eltrombopag is the first drug to show an improvement in bleeding in ITP patients and the first drug to be tested in randomized controlled studies, according to GSK. The firm has played up eltrombopag's mechanism of action, emphasizing that it "stimulates platelet production rather than preventing platelet destruction."

In the Phase III study, 59 percent of patients treated with Promacta 50 mg once-daily, compared to 16 percent of placebo patients, achieved a platelet count of more than 50,000 µL after 42 days of dosing, the primary endpoint of the trial.

"Importantly, there was a significantly lower incidence of bleeding events during treatment with Promacta compared to placebo," Roychowdhury said, with clinically significant bleeding in 16 percent of Promacta patients and 36 percent of placebo patients. He called the adverse event profile "excellent," though noting the incidence of nausea and vomiting was slightly higher with Promacta than in the placebo arm.

"Based on those results, we went to the FDA and asked them whether we could use that data of the Phase II and Phase III studies to have a submission for the short-term use of Promacta. The FDA [was] impressed by the efficacy results and wanted us to actually test repeated exposure to Promacta because that's what they expected that the patients might be getting" in the real-world setting, he explained.

"So we designed a study called REPEAT where we are giving patients with ITP who have a platelet count between 20,000 and 50,000 three repeated cycles of Promacta, each cycle lasting for a maximum of six weeks with a gap between cycles [of] a maximum of four weeks." Enrollment should be completed soon. Interim data will be provided to FDA in the early fourth quarter as the trial is ongoing, "and with that interim data and the Phase II and III studies we hope to submit for short-term ITP," Roychowdhury said.

At the same time, GSK is enrolling patients into its RAISE study of long-term Promacta use. So far 125 of the 180 patients are enrolled in the study, which will have a six-month treatment period.

"The other chronic study that we are doing, which is to be able to gather as much data [as possible] on chronic exposure to Promacta for long-term efficacy and safety, is called the EXTEND study," he said. "The EXTEND study is for patients who have had prior exposure to Promacta, and then we put them into this study as an open-label extension study."

To date, more than 90 subjects have been enrolled. "The efficacy that we are seeing is generally consistent with what we saw in the initial exposure to Promacta," Roychowdhury noted. Data from EXTEND will be presented in an abstract at the 2007 meeting of the American Society of Hematology.

"The next area that we are investigating is hepatitis C virus-associated thrombocytopenia," he said. The goal of Promacta therapy in that setting is "to increase platelet counts to initiate and maintain antiviral therapy, leading to curative antiviral outcome."

Two placebo-controlled Phase III studies - ENABLE 1 and 2 - are slated to begin in the third quarter. Patients will receive antiviral therapy for up to 48 weeks, with the primary endpoint being sustained virologic response 24 weeks after the end of antiviral treatment. The design has been agreed upon with global regulatory authorities, Roychowdhury noted.

The other area where GSK is studying Promacta is chemotherapy-induced thrombocytopenia. "Our initial proof of concept study did not achieve its primary endpoint of improving the native platelet counts," Roychowdhury stated. "This was we believe due to two reasons. One, the chemotherapy regimen chosen, although causing thrombocytopenia, was mildly thrombocytopenic and therefore didn't go down to really low native platelet counts. Second, we may not have had the optimum Promacta dose and schedule."

"But it did show increasing platelet counts, which helped us in designing the two other studies, one of which is ongoing and one is planned."

The dosing and schedule of Promacta in CIT is being studied in an ongoing trial with chemotherapy for sarcoma; the planned FUSION study will use different dosing schedules with various chemotherapies.

- Mary Jo Laffler (m.laffler@elsevier.com)

GSK Looks To Build On Supportive Care Presence With Promacta And Rezonic

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