It was supposed to be a year with a wealth of novel antibiotics, but regulatory concerns turned 2008 from a year of banner antibiotic approvals into a sizeable crop of action letters. Now the delays are taking a serious toll, causing some sponsors to drastically restructure in the face of uncertain and evolving regulatory standards.

The Office of Antimicrobial Products had an unusually busy 2008, reviewing a large number of antibiotic applications. Yet only two new molecular entities made it through OAP with a marketing approval - Sirion's ocular anti-inflammatory Durezol and Tibotec's HIV therapy Intelence - and neither were antibiotics (¹ Pharmaceuticals Approval Monthly January 2009, p. 12). At least seven antibiotic NMEs are still in the review process.

For small companies - a quality shared by many of the firms backing the crop of novel antibiotics - delay quickly escalates to disaster, especially if that delay entails requests for costly additional clinical work.

In the first month of 2009, two of the companies affected by the delays announced restructuring plans. A third company opted to move ahead with a different regulatory path, submitting another NDA for its antibiotic in a new indication in an area with clearer guidance from FDA.

Delays Can Carry High Costs

Arpida was the first of the antibiotic sponsors to be thrown into a tailspin by the adverse regulatory experience with its antibiotic iclaprim.

The company went into something of a quiet period after the Nov. 20, 2008 advisory committee 17-2 vote against its complicated skin and skin structure infection application. The first comment from Arpida after the meeting was that it was cutting three-quarters of its staff (including the research and development heads) and trimming R&D - and that it would seek an external consult on future development of iclaprim (² 'The Pink Sheet,' Dec. 22, 2008, In Brief).

On Jan. 19, just days after the user fee goal date for iclaprim - which FDA met with a "complete response" letter - Arpida announced the restructuring is progressing as planned and that it is reducing the size of the board of directors.

"The drastic cost-saving measures that we've recently implemented should buy us sufficient time to consider and develop strategic options for progressing iclaprim's development," CEO Jurgen Raths said in a press release. FDA has requested additional clinical data to demonstrate iclaprim's efficacy.

An additional Phase III program has also been requested for Targanta's oritavancin, another casualty of the Nov. 18-20 advisory committee meeting. Targanta executives expressed surprise at receiving FDA's Dec. 8 "complete response" letter (³ Also see "Targanta’s Oritavancin Gets FDA “Complete Response”; Additional Phase III Needed" - Pink Sheet, 9 December, 2008.).

Because of the hefty cost associated with the new clinical trials that will have to be done to get oritavancin to the market, the company is having discussions to determine whether a partnership or a different strategic option is necessary.

Basilea is another antibiotic sponsor that was forced into restructuring efforts, with the aim of bringing costs in line with an unclear regulatory future for its cephalosporin ceftobiprole.

The Swiss biotech announced Jan. 27 that as a result of the regulatory delay for ceftobiprole, it is reducing operations in its U.S. organization and focusing resources on commercialization and high priority programs.

The ceftobiprole application was issued a second "complete response" letter Nov. 26, citing integrity issues with the application for cSSSI (⁴ Also see "J&J/Basilea’s Ceftobiprole Gets Another Setback" - Pink Sheet, 26 November, 2008.).

Although U.S. operations are being scaled back and approximately 30 positions at headquarters from low-priority research programs are being cut, Basilea is adding 100 positions to its worldwide organization. Ceftobiprole is marketed as Zeftera in Canada and Zevtera in Switzerland with partner Johnson & Johnson, and received a positive recommendation from the EMEA in late November.

The application delay may also affect planned follow-on filings for ceftobiprole for both hospital-acquired and community-acquired pneumonia.

Trying A Different Tack

Evolving approval standards regarding appropriate use of non-inferiority trials for antibacterial drugs have led at least one sponsor to try its hand at a different indication, hoping to hit on an easier path to approval.

Theravance submitted its lipoglycopeptide telavancin for cSSSI, but is still waiting after one "approvable" letter, a missed user fee date and a mixed three-day advisory committee meeting on non-inferiority margins (⁵ Also see "Telavancin Back On Road To Approval, Rescued By Sponsor’s Risk Plan" - Pink Sheet, 1 December, 2008., p. 7).

Thus perhaps surprisingly, Theravance submitted a second NDA for telavancin Jan. 26, this time in hospital-acquired pneumonia.

Pneumonia is a space where FDA has attempted to provide clearer advice. In 2008, the agency held public workshops to discuss non-inferiority margins in community-acquired pneumonia (⁶ Also see "FDA Still Needs Convincing On Use Of Non-Inferiority Trials For CAP – Temple" - Pink Sheet, 4 February, 2008., p. 30). That could make pneumonia indications an easier regulatory target for telavancin and perhaps for ceftobiprole.

Same Delay, Different Impact

Pfizer's experience with dalbavancin last year shows that big pharma is not exempt from the struggles of getting an antibiotic approved, although it has an easier time weathering the delays.

Pfizer withdrew its cSSSI application for dalbavancin after FDA refused to accept the company's non-inferiority trial as a basis for approval, and will conduct another trial to support resubmission (⁷ Also see "Dalbavancin Delay: Pfizer Pulls NDA To Conduct Extra Phase III Trial" - Pink Sheet, 9 September, 2008.).

Johnson & Johnson also hit the non-inferiority roadblock for a nosocomial pneumonia indication for Doribax (doripenem), receiving a "complete response" letter in August 2008. Doripenem was first approved in 2007 for complicated intra-abdominal and urinary tract infections. It also is cleared for the pneumonia indication in the EU.

FDA Actively Working To Update Guidances

As the tally of action letters shows, FDA's antimicrobial office was a flurry of activity in 2008. Edward Cox, director of the Office of Antimicrobial Products, cited the whirlwind of activity, from advisory committees and public workshops to developing guidance and evaluating information on non-inferiority margins for several indications.

"We hope that by updating our guidance documents and assembling information on non-inferiority margins, that we will be taking an important step to provide clarity on the types of trial design that are likely to be informative for evaluating the safety and efficacy of antibacterial drugs," Cox said in an interview.

He added that the agency's understanding of non-inferiority trial designs has increased over the last few years as the current crop of drug sponsors have been planning and conducting clinical trials. "This creates a situation where the types of trial designs that a company would plan to perform several years ago may not, in some circumstances, provide that type of trial that is informative."

Cox said this is more likely to occur in trials that enroll patients with less serious illnesses, versus the more serious disease conditions for which the effect of an antibacterial drug is clearer, and "it is likely that previously conducted studies will still be informative."

The agency is working to update guidance documents on recommended types of trials for anti-infectives. In particular, after the three-day advisory committee in November, Cox said FDA is "actively working to update our guidance document on skin infections."

Not Much Glimmer Of Hope For 2009

The process of working out and then applying new standards, especially new parameters for non-inferiority trials, is likely to push back potential approvals of new antibiotics into late 2009 or 2010. Pfizer, for example, predicted an 18-month timeframe for an additional dalbavancin trial. The new clinical trials needed for the others could take even longer.

The best prospect for an NME antibiotic in the near-term would be for the ophthalmic niche. Bausch & Lomb's Optura (besifloxacin), a fluoroquinolone formulated as a suspension for bacterial conjunctivitis, sailed through a December advisory committee and has a first quarter 2009 user fee goal.

There are a couple of other antibiotic user fee dates on the horizon. Salvat's ciprofloxacin solution Cetraxal , for acute otitis externa in pediatric and adult patients, has a May deadline, and Advanced Life Sciences' cethromycin, a second-generation ketolide for once-daily, oral treatment of mild-to-moderate CAP, has an estimated user fee date in late July.

- Becky Jungbauer (r.jungbauer@elsevier.com)

FDA Updating Antibiotic Guidances, But Is It Too Late For Some Sponsors?

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