Among drugs for the consequences of chemo, those with the highest profile are Amgen Inc.'s erythropoietin stimulating agents, Epogen (epoetin alfa) and Aranesp (darbepoetin alfa), and Ortho Biotech Products LP's Procrit (epoetin alfa) - all lately dogged by safety concerns that have led to label changes and lessened reimbursements due to concerns about safety.
Amgen also has Neulasta (pegfilgrastim), used to decrease infection during chemo. Yet another compound from the same company for chemo's various, dismal side effects is Kepivance (palifermin), the keratinocyte growth factor for patients with blood cancers who get bone marrow transplants.
But nobody is forgetting the best-known, odious add-on involved with chemo: CINV, or chemo-induced nausea and vomiting. Over the summer, A.P. Pharma Inc. raised $35 million for its Phase III CINV compound APF530 (granisetron), a 5HT3 antagonist that deploys A.P.'s polymer-based Biochronomer bioerodible drug delivery system. One subcutaneous shot before chemo is designed to provide therapeutic plasma levels of granisetron for four to five days.
Granisetron, sold under the brand name Kytril in oral and intravenous forms by F. Hoffmann-La Roche Inc., also is the active ingredient in the transdermal patch that, as Phase III trials neared, became the center of a potential $21 million marketing deal in March between Abeille Pharmaceuticals Inc. and SymBio Pharmaceuticals Ltd., which gained rights in Japan, China, Korea, Taiwan and Singapore.
The drug to beat in CINV is Aloxi (palonosetron), from MGI Pharma Inc. and Swiss partner Helsinn Healthcare SA. Injected Aloxi is cleared by the FDA for the prevention of acute nausea and vomiting associated with moderately and highly emetogenic cancer chemotherapy and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic (prone to cause vomiting) chemo.
Included in the 5HT3 antagonist class of CINV drugs are compounds for acute onset and for delayed onset, as well as those for moderately and highly emetogenic chemo. Aloxi is approved for acute and delayed onset in highly and moderately emetogenic chemo, but not for delayed onset in highly emetogenic chemo, which makes up between 60 percent and 90 percent of patients, noted Stephen Dunn, analyst with Dawson James. This is where APF530 might have an edge, while providing longer-lasting relief - up to five days (the same target as Abeille's patch). Most emetogenic chemo falls into the "high" or "extremely high" category.
Aloxi, which only works for as long as three days, recorded third-quarter sales of $66.3 million, 37 percent higher than sales in the second quarter of this year, as the compound snatched patient share from GlaxoSmithKline plc's 5HT3 antagonist ondansetron, sold in injectable, tablet and liquid forms as Zofran, also available as a generic.
Lazard Capital Markets forecast a 14 percent sequential growth in Aloxi revenues for the fourth quarter, which Lazard estimated could reach $75.3 million. Last month, MGI and Helsinn filed a supplemental new drug application for Aloxi capsules to treat post-operative nausea and vomiting, based on results from two randomized, multicenter, Phase III trials evaluating the safety and efficacy of three doses of Aloxi compared to placebo. Yet another 5HT3 antagonist CINV is tablet and liquid-form Anzemet (dolasetron) from Sanofi-Aventis Group.
A notable setback in the CINV space struck Hana Biosciences Inc., which earlier this year withdrew the NDA filing for Zensana, an oral spray version of ondansetron. Hana filed for approval under Section 505 (b)(2) in late June 2006 and was hoping for a decision in April of this year, but in February, the company reported a precipitation issue in manufacturing and warned that the approval might be delayed. During a March conference call, Hana's President and CEO Mark Ahn told investors that Hana had "ruled out the feasibility of options that would make this an easy fix" and would quit developing the formulation.
Ahn said partner NovaDel Pharma Inc. (from which Hana acquired U.S. and Canadian rights in 2004) had developed an alternative formulation. But in August, Hana licensed Zensana to Par Pharmaceutical Cos. Inc., in a deal that brought a $5 million investment in Hana, $1 million upon Zensana's approval and as much as $44 million in sales-based milestone payments.
The apparent lockup held by MGI's Aloxi on the CINV market despite competition from generic Zofran left Robert Baird & Co. "genuinely impressed," according to a research report published on MGI's third-quarter earnings. Still, Baird kept its "neutral" rating on MGI shares because of "potential scrutiny [of] Dacogen's competitive position on the horizon." Dacogen is approved for myelodysplastic syndromes.
But here comes A.P. Pharma's APF530, for which Phase III data are expected in the third quarter of 2008, with a launch possible in the second half of 2009. The Abeille patch could reach the market before APF530 - as early as next year, if the company's plans pan out - but subcutaneous APF530 might be deemed an easier route for patients, even though it involves a subcutaneous injection, since patients on chemo are less likely to balk at a needle.
A company that already has its granisetron patch already in Phase III trials is ProStrakan Group plc, but it's for acute-onset CINV, Dunn said. "The reality of patches is that they don't stay on for five days," he told BioWorld Financial Watch, adding that the "bioavailability is too variable."
Even more enthusiastic about A.P.'s APF530 is Russell McAllister, analyst with Merriman Curhan Ford, who believes the "stage is set" for APF530 to take Aloxi's place as the best-in-class therapy for CINV. In a research report last week, McAllister called A.P. "ridiculously undervalued relative to its peers," and estimated a fair market value of $6 to $11 per share. The stock was trading at just under $2 Thursday.
"I do not believe most of the analysts following MGI Pharma are even aware of A.P. Pharma," McAllister told BioWorld Financial Watch, and positive results from the APF530 study - which compares the drug head to head against Aloxi - "would be a major negative shock" for holders of MGI shares.
Also in the A.P. pipeline are APF112 (mepivacaine) for post-surgical pain relief up to 36 hours, slated to start a Phase IIb trial in the second half of next year, and APF580, an undisclosed opiate for pain relief lasting at least a week, due to enter Phase I around the same time.