Remember FDA-stalled oritavancin?

The hospital-based glycopeptide antibiotic acquired in 2001 by InterMune Inc. from Eli Lilly and Co. (which developed the compound as a replacement for vancomycin, which still takes an estimated 80 percent share of the market) was bought by Targanta Therapeutics Inc around Christmas four years later.

Now it seems that, despite some early problems, oritavancin might turn out to be something of a gift for patients suffering gram-positive infections, and the opportunity for Targanta could be particularly strong in complicated skin and skin structure infection (cSSSI) - all the more so, since Targanta has bargained Lilly down on the royalty rate.

Elsewhere in cSSSI therapy, Theravance Inc. and partner Astellas Pharma US Inc. last month said the FDA issued an approvable letter for their once-daily, injectable antibiotic telavancin. The companies said no more trials would be required to provide a complete response, which could include a revised label, reanalysis of existing data or more data.

Especially, and increasingly, unnerving for physicians treating infection is the ever more prevalent methicillin-resistant Staphylococcus aureus (MRSA) bug. The more weaponry the better against that enemy, most agree. Enter oritavancin - again.

In two Phase I trials, injection-site phlebitis caused the FDA to put the drug on clinical hold in 2004, but Targanta scientists have managed to prove to the agency that the condition was caused not by the drug but by the rate of administration, as also can happen with vancomycin. Oritavancin has finished with flying colors two Phase III trials that met the specified primary endpoints, including one study that showed an improved adverse event rate versus vancomycin. A new drug application is expected in the second half of next year.

The drug might have two advantages over existing therapies. One is mechanism of action. Oritavancin binds to two types of peptidoglycan rather than a single type (as with other compounds), and inhibits cell-wall synthesis (as others don't), while anchoring its anti-bug power in the bacterial membrane. The upshot could be faster action and lower incidence of resistant strains than vancomycin, efficacy of which has been steadily weakening.

A second advantage of oritavancin could be the dosing regimen, noted Lazard Capital Markets, which - along with Cowen & Co. - initiated coverage of Targanta last week. Lazard believes oritavancin's half-life is about 200 hours, compared to less than 10 hours with vancomycin and the same with Theravance/Astellas' telavancin, which means oritavancin dosing might be once daily for 3 to 7 days, compared to twice daily for 10 to 14 days, as with vancomycin.

"The hallmark is the short duration of therapy," said Mark Leuchtenberger, president and CEO of Targanta.

There could be a third benefit: safety, per the fewer adverse events in one of the Phase III trials. Oritavancin fans note the drug has not shown significant QT-interval prolongations or hepatic or renal issues, which could set it apart from others in the glycopeptide-antibiotics class. "Importantly for patients, it's excreted largely through the bile, unchanged," Leuchtenberger said.

CSSSI, though, is a competitive market, with vancomycin already in place, as well as injected Cubicin (daptomycin), from Cubist Pharmaceuticals Inc. The growth of Cubicin, which the FDA approved for cSSSI in 2003 and which brought in third-quarter net revenues of $76.3 million this year, stands as an indicator of the hunger for new therapies.

Since the first FDA clearance, Cubist has expanded Cubicin's label into bloodstream infections, including right-sided infective endocarditis, while working with partners for international approvals. The firm is working with the compound in more indications, too, such as prosthetic joint infections and high-dose, short-term treatment of cSSSI.

Others are coming up fast. The FDA is reviewing the cephalosporin antibiotic ceftobiprole and dalbavancin, a semisynthetic glycopeptide. Ceftobiprole is being developed by Basilea Pharmaceutica Ltd. in partnership with Johnson & Johnson, and Pfizer Inc. owns dalbavancin.

Arpida Ltd. is nearing a regulatory filing with iclaprim, its diaminopyrimidine antibiotic, which achieved its primary endpoint in two pivotal trials. That new drug application is expected later this year. Ceftaroline acetate, which Forest Laboratories Inc. gained in its January buyout of Cerexa Inc., has reached the Phase III stage.

Another firm with a potential cSSSI drug is Paratek Pharmaceuticals Inc., which last month reaped $22 million in the first tranche of its $40 million Series H financing round. The second and final tranche, worth the remaining $18 million, is expected to close in early 2008, and the money will be used to complete ongoing Phase II trials with the tetracycline derivative PTK 0796. The trials compare oral and intravenous formulations of the drug to Pfizer's Zyvox (linezolid) for hospital-based treatment of cSSSI.

Also due for the clinic next year is Paratek's derivative of PTK 0796, designed for community settings. Like the original, the derivative is broad-spectrum, designed to go after many common bacteria as well as resistant strains such as MRSA, vancomycin-resistant Enterococci and penicillin-resistant Streptococcus pneumoniae. But the derivative also could treat bronchitis, flu and other diseases.

Yet another player in the space: Tygacil (tigecycline), Wyeth's intravenous, tetracycline-like antibiotic for hospital-based infections, which became the subject of a supplemental NDA in July, asking the FDA to clear Tygacil for community-acquired pneumonia and for additional, resistant pathogens in the approved indications of cSSSI as well as complicated intra-abdominal infection.

Wyeth plans to finish new Phase III trials with Tygacil for hospital-acquired pneumonia prior to filing for that use, since the first study for this indication met only one of two primary endpoints. New trials are expected early next year.

Cowen predicts Targanta will launch oritavancin for gram-positive infections in the second half of 2009, and in the meantime will have started a follow-on Phase II study to Lilly's work in bacteremia. Targanta also has preclinical data with the compound in a model of osteomyelitis, where a Phase II trial could start next year. In collaboration with the U.S. Army, the company is trying the drug as a prophylactic treatment after anthrax exposure. First results in preclinical work suggest oritavancin works as well as the standard anthrax blocker, ciprofloxacin.

Targanta investors, though, might worry about the prospect of four would-be competitors over the next year and a half, plus regulators' requirements for antibiotics - guidelines that have changed in 2001 and 2003, when the Phase III oritavancin trials were done. The first trial, known as ARRD, was designed to hit a 15 percent non-inferiority margin, but the FDA since has decided the margin should be 10 percent.

"That actually happened between our first Phase III and our second Phase III," Leuchtenberger said. Lilly consulted with the FDA regarding the second trial, and "overachieved with respect to efficacy" in that one, he said.

Targanta has discussed the matter of the non-inferiority margin with regulators, and the FDA wants Targanta to include in its NDA package any available support from the medical literature showing the 15 percent margin is worthy. If the agency finds Targanta's justification incomplete, it could ask for another Phase III trial.

Leuchtenberger doesn't expect that to happen. "We pressed that point with the FDA as sharply as it's possible for one to do," he told BioWorld Financial Watch. "We feel very confident about our position." Tygacil, he said, won approval based on two 15 percent trials and no 10 percent trial in cSSSI.

Also, noted a Cowen report, there might not be enough MRSA cases in the existing Phase III study results to satisfy the FDA. ARRD trial have not been disclosed, but the second study, called ARRI, enrolled 138 MRSA patients, 88 treated with oritavancin for a 64 percent cure rate, and 38 given vancomycin, for a 68 percent cure.

Still, for investors willing to make the risk, the reward could be substantial. Cowen projects oritavancin worldwide sales could reach $240 million by 2013, $150 million of that in the U.S., assuming a 5 percent share of the fast-expanding IV MRSA market. Targanta went public in October, netting almost $60 million for the oritavancin push.