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October 04, 2010

Innovations in Peptide Structure Pushing Candidates through Development

Companies are taking aim at otherwise untractable targets.

Innovations in Peptide Structure Pushing Candidates through Development

Companies are taking aim at otherwise untractable targets. [Anchor Therapeutics and Arkitek Studios]

  • Apolipoprotein

    Also revamping peptide structures for therapeutic applications is LipimetiX, which was formed in April with rights from the University of Alabama to two preclinical drug candidates. The licensed compounds mimic the structure and function of the receptor binding and lipid binding domains of apolipoprotein E. The peptides, because of their structures, can insert into lipid-rich lipoproteins and direct them to receptors on the liver, where they are internalized and degraded, thereby decreasing blood cholesterol levels.

    The company's two lead product candidates, AEM-28 and AEM-18, have demonstrated selective non-HDL cholesterol clearance, excretion of excess cholesterol, and rapid restoration of vasorelaxation in    animal models, according to the company. 

  • Erythropoietin

    Another peptide in development with a novel structure is Hematide (peginesatide), but the drug recently triggered some safety issues in Phase III testing. In June Affymax and Takeda Global Research & Development Center reported preliminary results for Hematide in the treatment of anemia in chronic renal failure patients. Affymax’ shares fell 69% after the company released the disappointing results.

    Hematide, a pegylated synthetic peptide-based erythropoietin agonist, binds to and activates the erythropoietin receptor and thus acts as an erythropoiesis stimulating agent (ESA). While the peptide proved as good as Amgen’s Epogen and Aranesp in hitting the study’s primary endpoint of maintaining hemoglobin levels in chronic renal failure patients, it also produced some concerns about its cardiovascular safety in the nondialysis patient group.

    When a subgroup analysis of the trial results was conducted, 22% of nondialysis patients taking Hematide had a cardiovascular complication, compared with 17% of those taking Aranesp. The biggest difference was seen in the number of patients who died of a heart-related problem: 8.8% among the Hematide users compared with 6.7% of those taking Aranesp.

  • Marching into the Clinic

    Pioneers in the field have different opinions about what has impeded therapeutic development.  “Peptides come in and out of favor about every 10 years,” Richard Houghten, founder and president of Torrey Pines Institute for Molecular Studies, told GEN.

    In general it seems that optimism trumps disappointment. To date, 54 therapeutic peptides have been marketed worldwide, with 26 of these in the U.S., according to the Peptide Therapeutics Foundation. And four U.S.-approved peptides reached over $1 billion in global sales.

    Dr. Houghten also noted that once peptides make it to the clinic, they enjoy a higher rate of success than small molecule drugs. And it looks like the every ten years has come around again. According to the Tufts Center for the Study of Drug Development 2010 report on the state of the therapeutic peptide field, the number of new peptides entering clinical testing doubled in the past decade.

    The Tufts Center found that of the 334 peptides known to have undergone some clinical testing by commercial firms, half entered the clinic in the last decade. There has been an average of about 17 new clinical candidates in each of the last 10 years compared to fewer than 10 in the decade before that and under five in the 1980s.

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