While existing targeted colonic-drug-delivery systems (CDDS) are a significant improvement to nonspecific drug delivery, they typically rely on patient physiology such as pH, gut microflora, peristalsis, and transit time to ensure adequate and consistent drug delivery.
This is a limitation as there is significant variation in gastrointestinal physiology which can lead to inconsistencies in drug delivery site, potentially affecting drug safety and efficacy, Dr. Emil Chuang and colleagues explain in a paper in Crohn's and Colitis.
Progenity's drug delivery system, now known as DDS2, is an electronic CDDS that uses anatomy rather than physiology for targeted drug delivery.
DDS2 is a non-degradable capsule housed in a shell that separates an electronics system and actuator from the exterior environment.
"While in transit, outward facing LEDs flash and illuminate the surrounding tissue. When reflected light reaches the photodetectors in the capsule, the internal algorithm determines the correct anatomical location to enable local delivery of the encapsulated drug," the researchers explain.
DDS2 is programmed to recognize transition through the ileocecal valve and into the cecum to trigger drug release. The device is about 11 by 26 mm in size and is similar in material and safety parameters to previously approved electronic GI devices now in use including the SmartPill, Endocapsule and PillCam Colon.
The Progenity team optimized the localization technology of the DDS2 in a trio of studies in healthy volunteers and patients suspected of small intestinal bacterial overgrowth.
They currently have two planned drug/device programs for IBD leveraging the DDS2 technology - PGN-600 and PGN-001.
PGN-600 is a tofacitinib/DDS2 combination. Tofacitinib is a JAK inhibitor approved for the treatment of moderate to severe ulcerative colitis. "This drug was chosen because of its proven efficacy in patients with UC. However, its use is limited by dose-limiting systemic toxicity," the researchers explain.
Studies in mice examining the pharmacokinetic and pharmacodynamic profiles of intracecal (IC) administration of tofacitinib showed equivalent target tissue exposure at 10- to 15-fold lower doses, compared to traditional oral administration. Increased absorption into the mucosa and coverage in the distal colon was also observed.
PGN-001 is an adalimumab/DDS2 combination. Adalimumab is an anti-tumor necrosis factor-alpha drug approved for the treatment Crohn's disease and moderate to severe UC.
In a preclinical study, PGN-001 was delivered directly to the colon through local administration to the cecum in a swine model of induced colitis. Adalimumab was detected in tissue along the length of the colon after intracecal (IC) administration, the company said in a press release (https://bit.ly/36O2WZi).
There was also a significant reduction in TNF-alpha at 24 and 48 hours following repeat IC doses when compared with the induced colitis control group that did not receive treatment.
"No treatment-related adverse events were observed and no measurable adalimumab was detected in the blood, in each case, for animals administered adalimumab by IC catheter," the company said in the release.
"These preclinical results provide further evidence that therapies delivered locally in the GI tract have the potential to transform the treatment of ulcerative colitis by maximizing the available dose at the site of disease while reducing systemic exposure to improve safety," Dr. Harry Stylli, CEO, chairman of the board and co-founder of Progenity, and a coauthor on the Crohn's and Colitis paper, said in the release.
"We now have evidence that this is not just the case for small molecules but also for monoclonal antibodies. This opens the potential for additional candidates for our Targeted Therapeutics program, as well as pharmaceutical and biotech partnerships," said Dr. Stylli.
SOURCE: https://bit.ly/3riQjyW Crohn's and Colitis, online July 7, 2021.
By Reuters Staff
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