MGI Aloxi Launch Set For September; Indications Include Delayed Nausea

MGI Pharma plans to differentiate the antiemetic Aloxi (palonosetron) from other 5HT3 antagonists by highlighting a unique indication for delayed nausea in chemotherapy patients.

"We are going to focus on a drug that has superb clinical results and has a differentiated labeling claim," CEO Lonnie Moulder said during a July 28 conference call. The product "lasts longer, and that is a big part of what we will be talking about."

FDA approved Aloxi July 25 for the "prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic chemotherapy" and for the "prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy" (¹ 'The Pink Sheet' July 28, 2003, In Brief).

Aloxi is the first 5HT3 antagonist indicated for the prevention of delayed chemotherapy-induced nausea and vomiting. Three 5HT3 antagonists - GlaxoSmithKline's Zofran (ondansetron), Roche's Kytril (granisetron) and Aventis' Anzemet (dolasetron) - are approved only for acute nausea.

"The overall strategy for the product will focus on the clinical differentiation, a different label claim and of course not only the clinical benefit, but the pharmacoeconomic benefit that may exist within the different practice segments with a product that can be administered as a single I.V. dose and prevent [CINV] over multiple days," Moulder said.

The recommended dose of Aloxi is .25 mg infused intravenously over 30 seconds approximately 30 minutes before the start of chemotherapy. "Repeated dosing of Aloxi within a seven day interval is not recommended because the safety and efficacy of frequent (consecutive or alternate day) dosing in patients has not been evaluated," labeling states.

Labeling for market-leader Zofran recommends multiday administration for moderately emetogenic chemotherapy.

Merck's substance P antagonist Emend (aprepitant) was the first agent approved for both acute and delayed chemo-induced nausea. Emend is indicated for combination use with other antiemetics during initial and repeat courses of highly emetogenic chemotherapy, including high-dose cisplatin (² (Also see "Emend Risk Program To Ensure Prescribers Understand Approved Indication" - Pink Sheet, 31 Mar, 2003.), p. 3).

Moulder suggested that Aloxi could be used in combination with Emend.

MGI plans to launch Aloxi by mid-September. The overall market for chemotherapy-induced nausea is estimated at $800 mil.

The company is forecasting sales of $5 mil.-$10 mil. in 2003, $40 mil.-$55 mil. during the first 12 months following launch, and annual sales of at least $250 mil. within four years.

Cost of sales as a percentage of revenue is expected to range from 35% to 37%.

Aloxi is expected to be priced at a premium to the other 5HT3 antagonists. "We have a differentiated product per our labeled indication and we think this will bring a great deal of value to the overall oncology marketplace in addition to real benefits for patients," Moulder said.

Aloxi ³ labeling includes data from three Phase III trials comparing palonosetron with Zofran and Anzemet in approximately 1,800 patients. The results include several statistically significant findings of superiority for Aloxi.

During the acute phase after moderately emetogenic chemotherapy (0-24 hours), 81% of Aloxi patients achieved a complete response versus 69% on Zofran. In the Anzemet trial, 63% of Aloxi patients had a complete response versus 53% on Anzemet, not a statistically significant difference.

During the delayed phase after moderately emetogenic chemotherapy (24-120 hours), 74% of Aloxi patients reported a complete response compared to 55% on Zofran, labeling states. In the Anzemet trial, 54% of Aloxi patients reported no nausea/vomiting versus 39% on Anzemet.

In a third study with highly emetogenic chemo, 59% of Aloxi patients had a complete response during the acute phase versus 57% on Zofran, a non-significant difference. "Clinical superiority over other 5HT3 receptor antagonists has not been adequately demonstrated in the acute phase," labeling says.

FDA's approval letter for Aloxi indicates that the agency wants to keep a close eye on potential gastro-intestinal and cardiovascular side effects of the drug.

MGI will submit all spontaneous reports of constipation requiring hospitalization or emergency room visit, and cardiovascular adverse events as 15-day reports, the approval letter states.

The 15-day reports are also required for "all spontaneous reports of possible complications of constipation such as obstruction, perforation, intestinal ulceration, toxic megacolon, ileus, or impaction resulting in hospitalization or emergency room visit."

Labeling notes that there were two cases of severe constipation reported in clinical trials of Aloxi for uses outside the approved indication. The reports followed "a single palonosetron dose of approximately 0.75 mg, three times the recommended dose," labeling states.

Constipation was reported by 5% of Aloxi patients in chemotherapy trials, compared to 2% of Zofran patients and 6% of Anzemet patients. The most common adverse event associated with Aloxi was headache, at 9% (compared to 8% for Zofran and 16% for Anzemet).

A precaution in Aloxi labeling states that the drug "should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc."

"In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration," labeling states. "In clinical trials, the dose-response relationship to the QTc interval has not been fully evaluated."

"Palonosetron has been safely administered to 192 patients with pre-existing cardiac impairment in the Phase III studies," labeling adds. "The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in clinical trials."

MGI is supporting the launch of Aloxi with a promotional effort comparable to that of other antiemetics, Moulder said. The firm has increased its sales force to 80 reps from 50.

"We have scaled-up our oncology sales force so we have approximately 80 highly experienced oncology sales professionals [and] we are targeting an oncology audience of over 10,000" physicians, he said.

MGI's sales force will have a share of voice equal to "where the main players are," Moulder maintained. "that reach and frequency puts us in an extremely competitive position."

In addition, the company plans a significant increase in promotional spending. "Our SG&A last year was $29 mil. and we gave guidance that it will be $49 mil. this year, so clearly there is a substantial advertising and promotion spend in there."

The Aloxi NDA (21-372) was submitted Sept. 26, 2002. The product's approval ahead of the 10-month user fee deadline continues FDA's recent strong showing in first-cycle approvals of new molecular entities (⁴ (Also see "FDA Approves 9 NMEs, 6 BLAs In First Half ‘03, On Track To Exceed 2002 Total" - Pink Sheet, 28 Jul, 2003.), p. 6).

Aloxi was in-licensed from the Swiss pharmaceutical company Helsinn Healthcare. Helsinn acquired worldwide rights to palonosetron from Syntex (Roche) in 1998 when the drug was in Phase II.

Helsinn's business strategy is to in-license early-stage NCEs, complete their clinical development and attain marketing approval in the U.S. and Europe.

"Helsinn's products are eventually out-licensed to its marketing partners for distribution. The active pharmaceutical ingredients and the finished dosage forms are manufactured at Helsinn's cGMP facilities and supplied worldwide to its customers," the company says.

MGI plans to pursue more product acquisitions using the proceeds from an upcoming 4 mil. share secondary stock offering. The company hopes to raise $120 mil. to $150 mil. from the offering.

"We are looking to acquire...differentiated oncology products," Moulder said. "We mean an outright purchase of products, in-licensing of products or co-promotion."

MGI previously acquired the second-line ovarian cancer agent Hexalen (altretamine) from MedImmune (⁵ (Also see "MGI Pharma Hexalen" - Pink Sheet, 20 Nov, 2000.), In Brief). MGI also markets Salagen (pilocarpine) for radiation-induced xerostomia and for dry mouth associated with Sjogren's syndrome. The company's first product is the hypercalcemia of malignancy therapy Didronel I.V. (etidronate), licensed from Procter & Gamble.