Amoxicillin pulsatile - MiddleBrook: APC 111, APC-111, PULSYS-enhanced amoxicillin

MiddleBrook Pharmaceuticals (formerly Advancis Pharmaceutical) is developing an improved version of amoxicillin using its pulsatile oral drug delivery technology, called PULSYS. Amoxicillin PULSYS is intended to provide a lower treatment dose, once-daily alternative to currently approved amoxicillin and penicillin regimens for the treatment of adolescents/adults with pharyngitis and/or tonsillitis. If amoxicillin PULSYS is approved, it will be the first and only once-daily amoxicillin therapy approved for use in the US. Regulatory submissions for the treatment of pharyngitis/tonsillitis have been made in the US. Amoxicillin PULSYS is in clinical development for the treatment of pharyngitis and/or tonsillitis due to group A streptococcal infections in adolescents/adults as a tablet formulation. MiddleBrook was conducting clinical development of a sprinkle formulation for children. However, this has been put on hold for financial reasons. MiddleBrook is seeking regulatory approval for this product as a 505(b)(2) product, which is one that is not considered to be a completely new product, but is also not a generic product. It is a product with some differences from a previously approved product and clinical data to support such differences are required; however, the basic safety and efficacy studies may have been conducted by other organisations. In June 2007, Advancis Pharmaceutical was renamed as MiddleBrook Pharmaceuticals, Inc. MiddleBrook and Par Pharmaceuticals entered a co-promotion agreement for this product in June 2004. Par was to fund future development in exchange for co-exclusive marketing rights and exclusive rights to sell amoxicillin PULSYS. MiddleBrook retained responsibility for the manufacturing programme and also retained all patents and brand names and was responsible for their enforcement. However, this collaboration was subsequently terminated in August 2005 by Par Pharmaceutical. MiddleBrook received the US $4.75 million R&D reimbursement payment due in the third quarter of 2005 and expects no further payments under the collaboration. Under certain circumstances, the termination clauses of the agreement may entitle Par to receive a share of net profits up to 50% of its total US $23 million investment in the development of certain amoxicillin PULSYS products, should a product covered by the agreement be successfully commercialised. Following the end of the first quarter of 2005, MiddleBrook entered into agreements with Clonmel Healthcare Ltd (STADA Group), which will provide MiddleBrook with commercial supply of its amoxicillin PULSYS products being evaluated in phase III trials. MiddleBrook has closed US $24 million in private placement of common equity; funds will be used to support the regulatory approval process for the once-daily amoxicillin pulsatile product. The company conducted phase III trials of this once-daily pulsatile amoxicillin product for the treatment of pharyngitis/tonsillitis due to group A streptococcal infections (commonly referred to as strep throat). Two trials of a 775 mg tablet formulation were conducted in adolescent/adult populations. In December 2006, the company entered into a definitive private placement agreement, raising US $18 million in gross proceeds. It intends to use the proceeds to prepare for the potential commercial launch of amoxicillin PULSYS and to continue the development of other products. The first of the adolescent/adult phase III trials was initiated in October 2004 in the US. This double-blind, non-inferiority, pivotal trial enrolled 510 such patients who received amoxicillin PULSYS 775 mg administered in tablet form once daily for 7 days or the US FDA standard comparator regimen, penicillin 250 mg administered four times daily for 10 days. However, in June 2005, the company reported that amoxicillin PULSYS failed to achieve the primary endpoint of this trial (i.e. bacterial eradication). The company initiated the second adolescent/adult phase III trial in November 2005. This two-arm, double-blind, double-dummy, non-inferiority trial enrolled a total of 620 patients from the US and Canada. Patients received amoxicillin PULSYS (775 mg tablet once daily for 10 days) or the standard penicillin regimen previously mentioned. Top-line results presented in August 2006 showed that the desired microbiological and clinical endpoints were achieved in this trial. In addition, the trial showed that amoxicillin PULSYS achieved 85% bacterial eradication in the per-protocol population, in accordance with the FDA's guidance for approval as a first-line therapy for pharyngitis. MiddleBrook has completed a phase I dose finding trial of its paediatric 'sprinkle' formulation of amoxicillin PULSYS in healthy volunteers. The company commenced a two-arm, investigator-blinded, non-inferiority, US-based, phase III trial in Janary 2005 to evaluate a 'sprinkle' formulation of amoxicillin PULSYS among paediatric patients with acute pharyngitis/tonsillitis caused by group A streptococcal infections. The drug was administered in multiparticulate granules, designed to be sprinkled over food, in two dosages: 475 mg once daily in patients aged 6 months to 4 years, and 775 mg once daily for children aged 5-12 years. Patients were given either 7 days' treatment with amoxicillin PULSYS or penicillin VK four times daily for 10 days. The primary endpoint of the paediatric trial was the same as the adult one. However, in July 2005, the company reported that the product failed to achieve its desired microbiological and clinical endpoints (primary and secondary) in this trial. MiddleBrook was to review the full data and evaluate what steps, if any, could be taken to improve future outcomes.