Moxatag approval a crucial first for MiddleBrook

The approval not only bolsters the US therapeutic armoury by offering patients the first once-daily formulation of an antibiotic widely used for throat infections. It also makes a considerably more attractive proposition of a company whose rocky path to the marketplace has forced management to consider a sell-off. Investors agreed, nearly tripling the value of MiddleBrook's shares in response to the FDA's decision. "We now look forward to continuing our ongoing strategic evaluation process from a position of greater strength with this approval in hand​," commented president and chief executive officer Dr Edward Rudnic. The full indication for the extended-release amoxicillin product is for pharyngitis and/or tonsillitis secondary to Streptococcus pyogenes​ infection - commonly known as strep throat - in adults and children aged 12 years and over. The approval was based on a Phase III clinical trial with more than 600 patients, in which a once-daily, 775mg dose of Moxatag given for 10 days was shown to be effective at eradicating the bacteria responsible for strep throat and demonstrated statistical non-inferiority to a four times daily dose of penicillin over the same period. Once-daily dosing is expected to improve compliance in a condition for which the most commonly prescribed treatment is 500mg of amoxicillin dosed three times daily over 10 days. "With the FDA approval of Moxatag, physicians now have available the first once-daily product in the aminopenicillin class for the treatment of pharyngitis while utilising approximately once-half the amount of amoxicillin currently used,​" MiddleBrook pointed out. A US launch is expected this autumn or winter. The company cited IMS Health data to the effect that around one quarter of amoxicillin prescriptions are written for pharyngitis, strep throat and tonsillitis in adults and children. Total retail sales of amoxicillin in the US were worth more than $650m in 2006, with some 60 million prescriptions written. The Pulsys technology is based 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 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​", MiddleBrook 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. 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, MiddleBrook notes, they afford a more consistent GI transit than other solid dosage forms such as sustained-release tablets. Based in Germantown, Maryland and focused on developing and marketing anti-infectives for substantial unmet medical needs, MiddleBrook (formerly Advancis Pharmaceutical) originally filed a US New Drug Application (NDA) for its Amoxicillin Pulsys formulation in December 2006. Last February, however, the FDA sent the company a 'refusal to file' letter explaining that the NDA was incomplete as it did not include a proposed commercial batch record or a detailed commercial process description with process parameters and in-process controls. A revised NDA was submitted the following month. That was the latest in a run of setbacks that included Amoxicillin Pulsys failing to meet its microbiological and clinical endpoints in a Phase III non-inferiority trial versus the comparator therapy, penicillin. Subsequent to that announcement, in June 2005, the same thing happened with a 'sprinkle-dosed' paediatric formulation of Amoxicillin Pulsys. In late July 2005, MiddleBrook said it was cutting its staff by around 38%, including six corporate officers. The company, which was obliged to change its name from Advancis Pharmaceutical in June 2007 after Sanofi-Aventis filed a patent infringement lawsuit, has also been through several rounds of financing. One of these involved selling to a major shareholder, Deerfield Management, US rights to the first-generation cephalosporin antibiotic Keflex (cephalexin), which MiddleBrook acquired from Eli Lilly in July 2004. Keflex has provided MiddleBrook with a revenue stream as it pursues its Pulsys development programme. The line was extended with a 750mg capsule formulation in July 2006. Following the initial disappointment with Amoxicillin Pulsys in both the adult and paediatric populations, the paediatric version was put on hold but MiddleBrook started enrolling for a new Phase III trial in adults and adolescents, extending the treatment period for Amoxicillin Pulsys from seven to 10 days (a seven-day regimen was also used in the paediatric trial; in both cases penicillin was given for 10 days). Positive results from the redesigned trial were announced in August 2006. MiddleBrook postponed all other clinical development programmes using the Pulsys system while it made a determined push to get Moxatag approved for adults and adolescents. It also 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. As part of a post-marketing commitment for Moxatag, and in accordance with the requirements of the US Pediatric Research Equity Act, Middlebrook has agreed with the FDA further to evaluate the Amoxicillin Pulsys formulation in paediatric patients aged under 12 years with pharyngitis and/or tonsillitis. It must submit a completed study report and data set for Moxatag in this population within the next five years. MiddleBrook is ready to go with a new Phase II trial for paediatric Moxatag (using a 10- rather than a seven-day dosing regimen) but has made it clear that, as with the company's Keflex Pulsys product candidate, it would need additional capital or a partner to help initiate the next stage. The paediatric indication might be a significant draw for a potential suitor: according to MiddleBrook, amoxicillin is the most prescribed drug among all therapeutic classes for paediatricians. Last June the company reported a positive outcome from a pre-Phase III meeting with the FDA on Keflex Pulsys as a once-daily treatment for uncomplicated skin infections and adolescents. The non-inferiority trial, if it went ahead, would compare 1,200 milligrams of Keflex Pulsys administered once daily for 10 days with 250 milligrams of Keflex given four times daily for 10 days. Just after gaining FDA approval for Moxatag, MiddleBrook announced agreements with institutional investors to raise around $21m gross through a private placement of 8,750,000 shares of common stock. The proceeds will be used to support the manufacture of Moxatag and for working capital and general corporate purposes. Dr Rudnic said the latest round of financing should provide "sufficient capital to operate our business in 2008 and afford the company greater flexibility and leverage as we seek to complete a strategic transaction over the coming months"​.