1. Hasn't Zadaxin had a pretty long checkered history, which explains why it has never been approved in the U.S.? 2. Since it is an old drug, presumably there isn't much patent life left for SCLN. What is the best they could hope for if Zadaxin pans out in CF? 3. Is there no one else targeting thymosin alpha 1 in general? Isn't it odd as long as Zadaxin has been around that there do not seem to be others that have, or are currently, pursuing this target?]
Peptide Drug Seen as Possible Cystic Fibrosis Tx Polypeptide thymosin alpha-1 fixed molecular defect, cut inflammation
by Salynn Boyles Contributing Writer April 11, 2017
The naturally occurring polypeptide thymosin a1 (Ta1) effectively corrected a protein misfolding that drives cystic fibrosis, and reduced inflammation, according to preclinical studies. In mouse and in vitro studies, Ta1 rectified multiple tissue defects in a mouse model of cystic fibrosis (CF), and in cells from people with the most common genetic mutation associated with cystic fibrosis, p.Phe508del, reported Allan Goldstein, PhD, of George Washington University in Washington, Enrico Garaci, MD, of the University of Rome Tor Vergata, and colleagues.
This mutation results in the production of a misfolded protein "with residual activity that is degraded by the ubiquitin-proteasome system during biogenesis," they wrote in Nature Medicine. The results suggest that a Ta1-agent approved for use outside the U.S. may be a useful single-molecule-based treatment for the disease.
A synthetic version of the thymosin alpha 1 peptide, marketed as Zadaxin by California-based SciClone Pharmaceuticals, has been used for more than 15 years and is approved in close to three dozen countries for the treatment of viral infections, HIV, and other immunodeficiency diseases, and cancer. Ta1 has been shown to have an excellent safety profile in clinical use when given as an adjuvant or immunotherapeutic treatment, Goldstein told MedPage Today. Goldstein is among the researchers who discovered Ta1, which was first isolated from the thymus, and synthesized it more than three decades ago.
Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its ability to channel chloride from cell to cell.
"Because of the inherent complexity of the pathogenetic mechanisms involved in cystic fibrosis, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious cystic fibrosis therapy," the researchers wrote. "Corrector drugs rescue trafficking of p-Phe508del-CFTR to the plasma membrane by directly targeting the mutant protein." "However, in site of their high efficacy in vitro, CFTR correctors show modest clinical benefits in individuals with CF who harbor the p-Phe508del mutation, even when these correctors are combined with the CFTR potentiator ivacaftor," they stated.
Ta1 has been shown to potentiate immune tolerance in the lung, reducing lung inflammation in some studies.
"This led us to hypothesize that administration of Ta1 could be beneficial in cystic fibrosis to alleviate inflammation at an early stage of the disease and/or in individuals who are newly diagnosed," the researchers wrote.
In the current studies, Ta1 was shown to improve inflammation and immune tolerance in a cystic fibrosis mouse model and in vitro, as well as improve the location and stability of mutant CFTR. The polypeptide was also shown to rescue CFTR protein and rescue p.Phe508del-CFTR in mice and human bronchial epithelial (HBE) cells.
"We found that intravenous administration of Ta1 corrected the misfolded (CFTR) protein that occurs because of this mutation which inhibits the ability of cells to regulate chloride ions," Goldstein said. The researchers noted that while the corrector activity of Ta1 has yet to be verified in human studies, "the excellent safety profile and cost effectiveness of Zadaxin in adults and children suggest that Ta1 could be tested in clinical trials for possible pulmonary and extra-pulmonary benefits in individuals with cystic fibrosis."
Goldstein told MedPage Today that Garaci and others in Italy hope to soon obtain approval for a phase I study of the agent in patients with cystic fibrosis. If approved, the small study is expected to include adolescent (age 12 to 18) patients with cystic fibrosis and the study duration will be around 2 months, he said.
"Thousands of adults and children [outside the U.S.] have used this agent and it has a very good safety profile," Goldstein said. "I do expect this phase I trial to be approved."
He added that the first children were treated with Ta1 in the mid-1970s.
"It is exciting to think that all these years later, this synthetic peptide may prove effective as a one-drug treatment for both children and adults with this serious, deadly disease."
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