Status: NDA rejected by FDA (complete response letter) in April 2011; marketed in EU

Organizations involved:

Eli Lilly & Co. – R&D; Tech; USA mark.; Parent

Alnara Pharmaceuticals, Inc. - Former

Lonza Biologics plc – Manuf.

Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) – R&D; Tech;

Altus Pharmaceuticals Inc. – Former

Cross ref: See the Pancreatic Enzyme Products entry for further information about digestive enzyme replacements.

Description: Solpura is an aqueous formulation of liprotamase, a mixture of pancreatic digestive enzymes -- amylase, lipase and protease) derived from Escherichia coli (E. coli) bacteria.

One ml contains 100U (equivalent to 3.5mg) insulin lispro (recombinant DNA origin produced in E.coli). Each vial includes 10 ml equivalent to 1000U insulin lispro. Excipients are m-Cresol [3.15 mg/ml]; Glycerol; Dibasic sodium phosphate. 7H2O; Zinc oxide; Water for injections and Hydrochloric acid (and sodium hydroxide maybe used to adjust pH to 7.0 – 7.8). Vials are stored in a refrigerator (2°C - 8°C).

Liprotamase was developed for the treatment of exocrine pancreatic insufficiency (pancreatic enzyme replacement therapy), including the maldigestion, malabsorption and malnutrition that results from exocrine pancreatic insufficiency associated with cystic fibrosis chronic pancreatitis, pancreatic cancer, pancreatectomy and other pancreatic diseases. The drug is particularly targeted to cystic fibrosis (CF) patients.

Note, unlike other current pancreatic enzyme replacement therapy (PERT) pharmaceuticals, Liprotamase is not enteric coated, but these coatings may hinder the enzymes’ ability to be effective in the important areas of the GI tract. There is a high pill burden with the current porcine-derived PERTS, and they have been documented to have substantial variations in formulation, dosage and manufacture of pancreatic enzyme products in addition to poor stability and wide variety in treatment effect.

Nomenclature: Liprotamase [BIO; USAN]; Solpura [TR]; TheraCLEC [TR former]’ Trizytek [TR former]; Amylase -; Lipase, triacylglycerol; Proteinase, aspergillus alkaline [CAS]; 884502-91-4 [CAS RN]; alpha-amylase [SY]; amylase - [SY]; amylase-alfa [SY]; proteinase, aspergillus alkaline [SY]; ALTU-135 [SY]

Companies.: Altus Pharmaceuticals Inc. originally discovered and developed Liprotamase, including through early trials. Due to financial difficulties, Altus discontinued development in Jan. 2009. Unwilling to let this important therapy languish, the Cystic Fibrosis Foundation retrieved rights to the drug from Altus, maintained its clinical progress and searched for a company to see the enzyme through the approval process and marketing.

In March 2009, Alnara Pharmaceutical licensed worldwide rights to liprotamase from the Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) Alnara Pharmaceutical was founded in Oct. 2008 by persons involved with Liprotamase development at Altus (Dr. Margolin and Mr. Gallott), wiht Dr. Margolin responsible for discovery. Investors in Alnara included Third Rock Ventures, Frazier Healthcare and Bessemer Venture Partners.

In Oct. 2009, Alnara concluded a contract with Lonza Biologics plc, Lonza Group, for the manufacture of liprotamase. All related production will be conducted in Lonza’s FDA registered facility in Kourím, Czech Republic.

In July 2010, Eli Lilly acquired Alnara.

FDA class: Drugs NDA

Status: In Jan. 2011, the Gastrointestinal Drugs Advisory Committee, FDA, voted not to support (4 yes, 7 no, 1 abstention) Solpura approval, with the committee not confident that Alnara provides any benefits compared to current FDA-approved porcine-derived pancreatic enzyme products. The committee wanted to see a randomized controlled trial and/or other studies allowing comparison with porcine enzymes. On April 15, 2011, FDA issued a complete response letter (CRL; rejection) to Eli Lilly.

In April 2011, Lilly received a complete response letter (CRL) from FDA for its NDA for liprotamase with this telling Lilly to conduct an additional clinical trial prior to re-submission.

On Jan. 23, 2002, FDA designated as an orphan drug for the “treatment of exocrine pancreatic insufficiency.” FDA revoked the designation on June 28, 2007 based on information showing that the drug could be used in a significantly larger patient population - specifically HIV/AIDS patients who suffer from fat malabsorbtion.

No centralized EU approval - country-by-country in Europe.

Tech. transfer: Related patents apparently include U.S. 6,541,606 and 7,351,798, “Stabilized protein crystals formulations containing them and methods of making them,” Margolin, et al., assigned to Altus Biologics concerning methods for forming and stabilizing enzyme protein crystals for oral delivery. U.S. patents applications assigned to Altus and apparently covering aspects fo Liprotamiase include 6,541,606, “Stabilized protein crystals formulations containing them and methods of making them,” and 7,351,798, “Stabilized protein crystals, formulations comprising them and methods of making them.” Patents applications include 20020045582, 20030175239 and 20080226623, “Stabilized protein crystals formulations containing them and methods of making them;” 20030017144 and 20060128587, “Lipase-containing composition and methods of use thereof;” 20030175239, “Stabilized protein crystals, formulations comprising them and methods of making them;” and 20060121017, “Compositions and methods for treating pancreatic insufficiency.”

Trials: Results from an international, Phase III open-label, long-term safety study presented in Oct. 2009 demonstrated the safety and nutritional benefits of liprotamase in cystic fibrosis (CF) patients. The study showed nutritional maintenance relative to the U.S. population, which is a major finding for this historically challenged patient group, as well as a significantly reduced pill burden. Approximately 90% of CF patients receive PERT to improve nutritional status and bowel-related symptoms related to pancreatic insufficiency.

Medical: See the Pancreatic Enzyme Products entry for further information about digestive enzyme replacements. Approximately 90 percent of CF patients receive PERT to improve nutritional status and bowel-related symptoms related to pancreatic insufficiency.

Liprotamase, as a novel, oral, porcine-free treatment, offers potential advantages over the existing standard of care --- porcine-derived pancreatic enzymes. These often vary in potency and stability and have a high pill burden. Alnara believes liprotamase has the potential to overcome these challenges by providing a first-in-class and best-in-class PERT.

Liprolog is generally administered shortly before meals. When necessary, Liprolog can be given soon after meals. Liprolog preparations should be given by subcutaneous injection or by continuous subcutaneous infusion pump.

Market: The Chairman of the board of Alnara has commented, “We believe the regulatory approval and launch of liprotamase as a non-porcine PERT [pancreatic enzyme replacement therapy] will represent a new paradigm in the treatment of pancreatic insufficiency.” Otherwise, “Alnara believes liprotamase may have the potential to overcome the challenges and issues associated with currently available therapies, by reducing pill burden, providing a formulation for patients unable to swallow capsules and removing the risk for viral contamination thereby providing a first-in-class non-porcine produced PERT.” Also, “[Liprotamase is] The only product with the ability to provide a formulation for pediatric and adult patients unable to swallow capsules, providing a dramatic improvement in both compliance and patient convenience.”

R&D: Alnara also plans to develop a pediatric liquid form of Liprotamase.