The resubmission under Section 505 (b) (2) of the Federal Food, Drug and Cosmetic Act - used for versions of marketed drugs that are not exactly identical to the original - followed the receipt of a "refusal to file" letter from the Food and Drug Administration (FDA) on 12 February, asking for additional information on Advancis' planned commercial manufacturing process for Amoxicillin Pulsys.
The company met with the FDA on 26 February to clarify these requirements and believes it has responded "fully and directly" to the agency's requests in the amended NDA. Advancis originally filed for US approval of Amoxicillin Pulsys on 14 December 2006. The FDA now has 60 days to decide whether the NDA is acceptable for filing and substantive review. If it is acceptable, Advancis expects an action date 10 months from the date of submission, in January 2008.
The FDA's "refusal to file" letter did not cite any clinical deficiencies with Amoxicillin Pulsys, the company has noted. Rather, the objection was that Advancis' NDA "did not include a proposed commercial batch record or a detailed commercial process description with process parameters and in-process controls".
The focus on manufacturing issues should come as some relief to the company's shareholders, who saw Advancis' net losses for 2006 deepen to US$42 million (€31.6 million) compared with US$33 million in 2005.
The company is pursuing capital-raising initiatives with the aim of securing enough cash to see it through to 2008. It is also taking steps to reduce costs, including staff cuts and postponing all other clinical development programmes using the Pulsys system. Moreover, Advancis has hired an investment bank to help it review "a full range of strategic options available to the Company", which might include a merger or the sale of some or all of its assets.
The technology underlying these business manoeuvres rests on the finding that, due to their relatively short natural lifecycle, bacteria exposed to antibiotics in staccato bursts or 'pulses' - specifically, three to five pulses within the first six to eight hours of initial dosing - are eliminated more efficiently and effectively than with standard treatment regimens.
The resulting Pulsys oral drug delivery system, coupled with MAPS - a proprietary analysis and design technology that uses the physical, chemical, biological and microbiological properties of each specific antibiotic to design the optimal Pulsys product - has the potential to "redefine bacterial infection treatment", Advancis claims. In preclinical trials, pulsatile dosing of certain antibiotics not only killed more bacteria and better prevented the development of resistant strains, it did so at significantly lower drug concentrations.
A Phase III clinical trial of Amoxicillin Pulsys, in adults and adolescents with pharyngitis/tonsillitis due to Group A streptococcal infections, compared 775mg of the Advancis formulation, given once-daily for 10 days, with 250mg of penicillin VK, dosed four times daily for 10 days.
Amoxicillin Pulsys showed statistical non-inferiority to its comparator in the trial's primary endpoints - bacterial eradication at the post-therapy 'test-of-cure' visit for patients who fully complied with the trial protocol, as well as in a larger patient population. It also achieved non-inferiority for secondary endpoints, including clinical cure at the test-of-cure visit and bacterial eradication at the late post-therapy visit.
The most commonly prescribed treatment for the management of Group A streptococcal pharyngitis is 500mg of amoxicillin, dosed three-times daily for 10 days, Advancis points out. Amoxicillin is not currently approved in the US for once-daily dosing to treat pharyngitis.
The Pulsys dosage form is a compressed, film-coated tablet containing pellets that release the incorporated drug in 'pulses' at various stages of its passage through the gastrointestinal (GI) tract. The multiple pellets (up to six in total) with different release profiles are combined in such a way as to provide a constant escalation in plasma drug levels during the first few hours of the once-daily dosing. As the pellets travel along the lumen wall of the small intestine, Advancis notes, they afford a more consistent GI transit than other solid dosage forms such as sustained-release tablets.