Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Roche paid Aileron $25 million up front for this technology in a deal worth over $1 billion.

On August 26, Aileron Therapeutics announced a deal with Roche that could eventually bring the Cambridge, MA, biotech company $1.1 billion. Roche paid Aileron $25 million up front to develop a class of drugs called stapled peptides, based on Aileron’s stabilization technology, to treat a range of illnesses including inflammation and metabolic diseases.

Once hailed as the next great thing in drugs, peptides have failed to live up to their blockbuster promise due to delivery and formulation problems, lack of efficacy, toxicity, manufacturing hurdles, and cost constraints. High-volume synthetic peptide drugs on the market include insulin, calcitonin, and Amylin Pharmaceuticals and Eli Lilly’s Byetta for the treatment of diabetes.

Recent progress in lowering production expenses has driven renewed interest in peptide therapeutic development. Clever chemistry and fundamental advancements in stabilizing their structure to improve their properties as drugs have proven equally enabling.

Peptide-based therapeutics now represent one of the fastest growing classes of new drugs. While they currently account for only 2% of drugs on the market, they comprise roughly 50% of drugs in the pipelines of major drug manufacturers. Additionally, the market for peptide drugs is growing at a compound annual rate of 7.5% and has been estimated to be in excess of $13 billion this year.

Roche’s Currently Marketed Peptide Drug

Roche’s Fuzeon provides a good example of the complexities involved in producing a successful peptide drug. FDA approval in March 2003 made it the first member of an anti-HIV drug class known as HIV fusion inhibitors. Fuzeon is a synthetic peptide version of one of the C-peptides derived from the HIV-1 envelope glycoprotein gp41. Its active ingredient, enfuvirtide, interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes.

The peptide has a total of 36 amino acids in its chain and requires 106 separate manufacturing steps to produce 3,700 kg annually, or 60–300 times the annual production volume for synthetic peptides like calcitonin and leuprolide, a gonadotropin-releasing hormone analog containing a mere 10 amino acids. The need for high-concentration doses of Fuzeon to achieve biological activity necessitates high-volume production. Not suprisingly the price for one year of therapy with Fuzeon, about $20,000, is much higher than for any other approved anti-HIV treatments. 

It takes 44 raw materials to make Fuzeon, compared to the usual 15 for most drugs, with a six-month production time. Roche says it invested nearly $600 million in the drug’s development and manufacturing, a big reason why its price is so high. Some analysts believe that less complex, orally available drugs will force Fuzeon off the market.

Originally developed by Trimeris and licensed to Roche for $10 million, Fuzeon is manufactured and distributed by Roche. The companies share gross profits equally from sales in the U.S. and Canada. Trimeris also receives a royalty based on net sales of Fuzeon outside these two countries.

Trimeris reported royalty revenue for the quarter ended June 30, 2010, was $1.6 million compared with $2.1 million for the same period last year. This was driven by diminished net sales of the drug outside the U.S. and Canada. Net sales of Fuzeon in the U.S. and Canada for the second quarter of this year also dropped; it was $8 million, down 18% from $9.7 million in the second quarter of 2009.

Betting on Stapled Peptides

Why, then, is Roche making a play for more peptide-based therapeutics? Complexity aside, multiple factors have sparked interest in peptides including the decreasing number of approved drugs produced by the pharmaceutical industry, increasing R&D expenses, and demands for alternative approaches to improve pharmaceutical R&D productivity.

An unmet challenge in peptide drug development has been to access intracellular target space, according to Tomi K. Sawyer, Ph.D., Aileron’s CSO and svp, drug discovery and innovative technologies.  Further requirements include achievement of good pharmacokinetic properties and preservation of the peptide’s unique 3-D structural integrity to effect molecular recognition including protein-protein interactions.

“Over the past 30 years lead peptides were successfully identified and chemical manipulations including now classic types of macrocyclization and restricted conformational approaches were used to stabilize them,” Dr. Sawyer pointed out to GEN. “But from the drug development standpoint they didn’t provide the big home run that large pharma or biotech was looking for. Small molecules have been a major competition as peptides have generally lacked the combination of key properties such as metabolic stability, oral absorption, and good pharmacokinetics of small molecule drugs.”

New synthetic strategies for limiting peptide breakdown and allowing oral administration have emerged in recent years. Aileron’s stapled peptide platform stabilizes these molecules into biologically active alpha-helical conformations, reportedly endowing them with good drug-like properties including resistance to proteolytic degradation, improved pharmacokinetics, and cell penetration. The chemistry to achieve a novel peptide structure using hydrocarbon stapling is exquisitely simple, Dr. Sawyer explained.

“We start with a peptide, an alpha-helical conformation, and identify the amino acid residues that are nearest neighbors in the helical conformation, even though they may be separated by a single or double turn. We then replace the helically defined neighboring amino acids with novel side chains that incorporate terminal double bonds (olefins), which,  when reacted with special catalysts, generate hydrocarbon macrocycles.”

Dr. Sawyer noted that Aileron is advancing its lead stapled mimetic peptide program to target and modulate intracellular BCL-2 target families/pathways, which are recognized, he said,  as very promising targets for cancer treatment. Roche is betting on Aileron’s technology in the hope that hydrocarbon stapling and other innovative strategies for enhancing stability, efficacy, and intracellular delivery may usher in a new era in peptide therapeutics.

Patricia F. Dimond, Ph.D. (email: [email protected]), is a principal at BioInsight Consulting.

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