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Microsoft word - pexiganan nonconf document updated 1.20.10Liquidating Trust
(Genaera Corporation MSI-78, formerly LOCILEX)
active against multi-drug resistant bacteria Argyce LLC
The Genaera Liquidating Trust (the “Trust”) seeks to divest or otherwise monetize all its rights topexiganan, a drug candidate developed by Genaera Corporation, the Trust’s predecessor ininterest. Pexiganan is a novel, small peptide anti-infective developed in a topical cream form fortreatment of patients with mild diabetic foot infection.
Pexiganan represents a unique drug development opportunity: Higher than average probability of approval – one new phase 3 study required.
Product launch reasonably achievable within three years after funding; Unmet need – no topical antimicrobial compounds are specifically approved for mild diabetic foot ulcers; local treatment avoids toxicities and exposures of systemic therapy; Ability to treat drug resistant pathogens; Favorable risk reward ratio -- total development funding required from start to launch is estimated to be in the $5 million to $7.5 million range; and Highly credible pharmaceutical executives with the right experience are available to properly develop the compound picking up from the progress made to date.
Pexiganan is the subject of an open IND and a pending NDA for diabetic foot infection 1998 - 2006: In clinical trials conducted by Genaera, over 1000 human subjects were exposed topexiganan without safety concerns, including 418 patients who received pexiganan in two Phase3 clinical trials submitted in a New Drug Application to the U.S. Food and Drug Administration(FDA) in 1998. In the Phase 3 trials 835 patients were randomized to pexiganan cream 1% ororal ofloxacin. The FDA judged the primary clinical endpoint of one of the two Phase 3 trials tohave been achieved. The other Phase 3 clinical trial, which did not meet its specified endpoint,provided strong supportive data indicative of the clinical benefit of pexiganan. Additionally, morethan half of the FDA advisory committee felt the Phase 3 studies should have been placebocontrolled even though significant thought leaders in the medical community at the time assertedthat placebo use in infected diabetic foot ulcers was potentially unethical. Difficulties withChemistry Manufacturing & Controls (CMC), principally water separation, and an FDA requestfor one additional controlled Phase 3 study precluded approval at that time. As described in“Licensing History” below, pexiganan was subject to an agreement with SmithKline Beechamuntil late 2006, during which time Genaera took no further steps to develop the compound.
Current: By 2007 the environment to complete clinical development of pexiganan had improvedon a number of fronts and continues to improve: significant advances in peptide manufacturing; improved understanding of the treatment of diabetic foot infections; improved clinical study design and execution for anti-infective compounds – a placebo controlled study can be designed to be safe for patients and acceptable to physicians; greater clarity around regulatory requirements for anti-infectives e.g. a recent Zyvox study that lead to FDA approval validated Infectious Disease Society of America (IDSA)guidelines for mild, moderate and severe infections.
On February 12, 1997, Genaera Corporation (then known as Magainin Pharmaceuticals, Inc.)entered into a Development Supply and Distribution Agreement with SmithKline BeechamCorporation (later GSK) that gave SmithKline exclusive rights to Pexiganan and an option tocontrol and distribute another Magainin product of its choosing if Pexiganan were not approved.
In July 1999 Magainin received a not approvable letter from the FDA citing cGMP deficiencies inthe manufacturing of the drug product. The FDA recommended conducting a single additionalclinical trial for the NDA to be approvable in the US market and described steps required tocorrect CMC issues. In the meantime, SmithKline had other anti-infective products on themarket and in its development pipeline. Magainin shifted scientific/clinical priorities for its verylimited resources away from anti-infectives, changed its top management and changed its nameto Genaera. The SmithKline Agreement had the effect of keeping Pexiganan “on the shelf” untilNovember 27, 2006 when Genaera obtained a termination letter from GSK.
Genaera sold an option to license Pexiganan to MacroChem Corporation for $250,000 in July2007. MacroChem exercised the option in October 2007, subsequently paid $1,000,000 toGenaera and assumed all costs related to clinical development, manufacturing and regulatoryactivities. The royalties and subsequent milestones in the license were redacted in SEC filingsbut may be disclosed under a confidentiality agreement.
During 2008, MacroChem Corporation defined a course of action to go forward with the FDA andbegan to address the CMC issues to the point of preparing small batch GMP material. Thoseefforts included generating interest in and taking advice from medical thought leaders, publishingthe clinical trial results for the first time and evaluating the environment in which to run a finalPhase 3 study in subjects with infected diabetic foot ulcers that could lead to FDA approval.
In July 2008 MacroChem agreed to be acquired by Access Pharmaceuticals in an acquisitionprincipally motivated by MacroChem’s oncology assets, oncology being Access’ strategic focus.
The transaction closed in Q1-2009. Citing limited resources Access ceased development ofMacroChem’s dermatology products including pexiganan.
On October 20, 2009, the Trust notified Access Pharmaceuticals and MacroChem Corporationthat the licensing agreement would terminate November 20, 2009 and that the program assetsare to be returned to the Trust.
Pexiganan is a 22-amino acid linear peptide. It is formulated as a cream and has a novelmechanism of action based on its ability to disrupt the integrity of bacterial cell membranes. Ithas antimicrobial activity against Gram positive (methycillin resistant staphylococcus aureus(MRSA)) and Gram negative organisms that commonly infect skin and soft tissue. It has a lowpotential for induction of resistance and no cross-resistance with existing therapeutic antibioticsas a consequence of its mechanism of action.
Genaera Corporation scientific staff and clinical prepared a detailed overview of preclinical workincludes the following description that remains both accurate and relevant to this day: Liquidating Trust
“…the distinguishing characteristic of pexiganan is its ability to cause membrane disruption in a broad spectrum of microbes, including gram-negative and gram-positive aerobicbacteria, anaerobic bacteria and certain species of fungi. This distinction, combined with thefact that the peptide-cell interaction is not receptor mediated, suggests that pexigananpossesses characteristics that reduce the potential for microorganisms to develop resistance.
Preclinical studies failed to elicit resistance to pexiganan following repeated-passage studiesof strains including S. aureus, S. epidermidis, E. cloacae, K. pneumoniae, P. aeruginosa, A.
baumanii, and S. maltophilia. Additionally, efforts to induce resistance in strains of E. coliand S. aureus through use of chemical mutagens failed. In contrast to some antimicrobialdrugs, no evidence has been reported documenting the transfer of a resistance phenotypethrough either plasmid or chromosomal genetic transfer for a magainin peptide or any closelyrelated molecule.
There is no cross-resistance between pexiganan and commonly used antimicrobialsincluding penicillins, cephalosporins, carbapenems, quinolones, macrolides, lincosamides,sulfonamides, nitromidazoles, polymyxin B and polymyxin E. Pexiganan is active againstpathogens that are resistant to these antibiotics.” Manufacturing
Pexiganan may be produced by a solid or solution phase processes. Pexiganan API isextremely stable. The main CMC deficiencies raised by the FDA in the context of Magainin’sNDA filing concerned formulation, principally water separation. Genaera scientists alsodeveloped an Escherichia coli based recombinant manufacturing process for efficient, high levelexpression of pexiganan that has been demonstrated and replicated at laboratory scale.
Genaera Corporation has maintained the recombinant process as a trade secret.
Pexiganan is covered in the US by a composition of matter patent that will expire in August 2016,but which can be extended under Hatch Waxman until late 2019 at the earliest and potentiallyuntil August of 2021 at the latest. The patent is issued to Scripps Institute and held by the Trustpursuant to a fully paid up license.
According to the Centers for Disease Control and Prevention (CDC), the estimated incidence ofdiabetes in the US exceeds 1.5 million new cases annually, with an overall prevalence of nearly24 million people (2008), or more than 7% of the US population. It is estimated that as many asone in four persons with diabetes will develop a foot ulcer in their lifetime of which about 60%become infected. Diabetic foot ulcers generally result from the consequences of peripheralneuropathy. Peripheral vascular disease, increased biomechanical stress and acute traumafurther increase the risk of foot ulcers. It typically takes several months for an ulcer to heal, andduring this period there is a continual risk of foot infection. Infected foot ulcers can result in boneinfection (osteomyelitis) or progressive gangrene. Diabetes is now the top cause of non- Liquidating Trust
traumatic leg amputations in the developed world. Additionally, foot ulcers are now the mostfrequent cause of diabetes-related hospitalizations. The total annual cost of foot ulcer care in theUS has been estimated to be as high as $5 billion. Thus, diabetic foot infection is a majorburden to patients resulting in long-term disabilities and continuing high demands on thehealthcare system.
Remarkably, pexiganan may prove to be an especially timely product in spite of time lost.
Currently, no topical antimicrobials are specifically approved for the treatment of diabetic footinfections. Concern as to treatment of antibiotic resistant pathogens has only grown over time.
Moreover, the economics of treating mild diabetic foot infections with a topical antimicrobial favorpexiganan. Even an expensive topical for resistant pathogens at the “mild” stage shouldcompare to favorably to treating more advanced infections. Pfizer’s Zyvox was recentlyapproved for diabetic foot infection. Zyvox, labeled for “certain serious bacterial infections thatare often resistant to other antibiotics” can cost over $2,000. Even so, in a study presented tothe IDSA in 2005 total treatment costs using Zyvox were much lower than other antibiotics forserious infections. Pexiganan has the potential to be an initial therapy for resistant pathogens inmild diabetic infections and to augment systemic therapy in more serious infections.
Pexiganan sales potential is estimated to exceed $100 million annually with some estimates over$500 million. The Trust is commissioning a study of the market potential for pexiganan. [Forinitial discussions we assume a number closer to the $100 million for the approved indication].
Other potential indications for which pexiganan may provide beneficial therapy include: MRSA -cutaneous and systemic methicillin-resistant Staphylococcus aureus; central venous catheterinfections; Infections of prosthetic/skin interfaces and acne. Genaera received expert advice tothe effect that a lower concentration level, <0.2% w/w, pexiganan has the potential to be includedin over-the-counter (OTC) and/or cosmetic applications for the treatment of acne.
The Trust can provide detailed information from public sources and confidential records,including IND and NDA documents, FDA communications, a wide range of scientific andpreclinical data and scientific journal articles including Phase 3 results published in the ClinicalInfectious Diseases Journal on December 15, 2008. Interested parties should contact: Argyce LLC,Trustee of the Genaera Liquidating TrustAttn: John Skolasjskolas@argyce.comOffice: 267 988 4075Mobile: 267 303 0834
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