DOR said a Phase I safety, tolerability and pharmacokinetic study with leuprolide, incorporated in the company's Lipid Polymer Micelle (LPM) drug delivery technology, should begin "around mid-year 2007".
In preclinical studies, it noted, the LPM system significantly enhanced the capacity of leuprolide, a synthetic peptide agonist of gonadotropin releasing hormone, to pass through the intestinal epithelium compared with leuprolide alone. DOR believes its oral delivery technology could be applicable to a large number of peptides and other water-soluble drugs with poor gastrointestinal permeability.
LPM is a proprietary lipid-based system that incorporates the drug of interest in a thermodynamically stable configuration known as a reverse micelle. This is a structure formed when certain classes of lipids come into contact with small amounts of water. In the resulting delivery vehicle, a stable clear dispersion of the water-soluble drug can be evenly distributed within the lipid phase.
The platform technology is thought to promote intestinal absorption due to the ability of micelles to open up small channels through the epithelial layer of the intestines that allow only molecules of a certain size to pass through, while blocking much larger molecules such as bacteria and viruses. Non-specific enzyme inhibition by surfactants in the LPM formulation also means the reverse micelles guard against rapid inactivation of peptides by enzymes in the upper gastrointestinal pact, DOR explained.
As the company noted, one of the major limitations of drugs derived from synthetic peptide chemistry or recombinant DNA technology is that they must be given by injection, due to the molecules' inability to penetrate the intestinal epithelium.
Leuprolide, which generated worldwide sales of around US$1.8 billion last year under brand names such as Lupron (TAP Pharmaceutical Products) and Eligard (Sanofi-Aventis), is currently available only in injectable, injectable depot and subcutaneous implant formats. The drug is used not only to treat prostate cancer but for non-cancer indications such as endometriosis, uterine fibroids and central precocious puberty.
Oral bioavailability of leuprolide in an aqueous solution is less than 5 per cent, the company said. However, delivering the drug with the LPM system in rats and dogs pushed bioavailability up to an average of 30 per cent, compared with just 2.2 per cent for a control oral solution.
DOR's biotherapeutics pipeline is led by orBeC, an oral formulation of the corticosteroid beclomethasone dipropionate for the treatment of gastrointestinal graft-versus-host disease (GI GVHD), a common and potentially life-threatening complication of bone marrow transplantation. Approval applications for this indication have been filed with the US Food and Drug Administration (FDA) and the European Medicines Agency, while DOR recently secured FDA clearance to conduct a Phase II clinical trial with orBec for the prevention of GVHD.
The company also has a biodefence pipeline, comprising bioengineered vaccines to protect against ricin toxin and botulinum toxin. A Phase I clinical trial with RiVax, which could be the world's first vaccine against ricin toxin, showed the vaccine to be well tolerated and capable of inducing neutralising antibodies against the toxin.