The study demonstrated proof-of-concept, demonstrating a sustained delivery system of 3 highly-potent antiretroviral therapies and drug-polymer matrices.
Andrew Bellinger, MD, PhD
Investigators from the Massachusetts Institute of Technology (MIT), Brigham and Women's Hospital (BWH), and Lyndra Inc. have announced the publication of a feasibility study of an oral, once-weekly drug delivery platform for HIV antiretroviral therapy (ART).
The study, published in Nature Communications, demonstrates proof-of-concept in swine models of a sustained oral, novel drug delivery system of 3 key potent anti-HIV therapies, dolutegravir, rilpivirine and cabotegravir, and 3 drug-polymer matrices, a polyether, polyanhydrides and polyester.
“We are hopeful that Lyndra will provide the HIV community with a new, easier option for their antiretroviral therapy,” Andrew Bellinger, MD, PhD, co-founder and chief scientific officer, Lyndra, told MD Magazine. “By decreasing dosing from daily to weekly, Lyndra’s aims to help decrease the chances for non-adherence within this patient population and to improve the overall outcomes.”
Based on the proof-of-concept findings, the initial development has begun of the ultra-long-acting, sustained release oral dosage form that could be taken weekly.
In the study, mathematical models were used to simulate HIV viral dynamics in the body under several levels of patient adherence to therapy.
The polymer matrices achieved systemic drug levels of all 3 antiretrovirals for up to 7 days after a single administration. Researchers selected the 3 antiretrovirals drugs because of their supporting efficacy either alone or in combination of maintenance therapy.
Animals were evaluated twice daily clinically and radiographically. Dosage forms deployed in the intestine began disintegrating within 24 hours and were completely removed by 6 days post-administration.
To evaluate the potential clinical and public health impact of long-acting oral antiretrovirals, researchers established mathematical modeling frameworks that predicted the impact on patient outcomes and epidemiologic trends.
Mathematical modeling allowed researchers to conclude that the formulation delivered via a novel oral dosage form has great potential to reduce therapeutic failures and prevent new HIV cases. Clinical translation could represent a paradigm shift in HIV treatment and prevention.
Evidence from other medications prescribed for long-term use, and for which both daily and weekly oral dosage forms are available, implies that adherence to weekly administration is substantially higher.
To gauge whether such use could make an impact on combating the spread of the infection in high-burden countries, modeling was used to estimate how many new infections could be prevented with the use of a long-acting oral antiretroviral dosage form for PrEP, compared to currently available daily oral PrEP.
A recent meta-analysis was reviewed that estimated the difference in adherence to daily versus weekly dosage forms of similar medications that were prescribed for the same condition.
Assuming the availability of a weekly regimen influences efficacy and not coverage, the model predicts that about 200,000—800,000 additional infections could be prevented throughout 20 years, a 3.4% cumulative reduction, if the weekly PrEP formulation is made available for high-risk populations ages 15–29.
Limitations in the feasibility study include the use of the swine model that was used to study the gastric residence and antiretroviral pharmacokinetics, as the anatomy of the pig stomach closely resembles that of a human. The animals were fed a broad diet, however, it’s possible certain diets may impact the gastric residence of the dosage form, which needs to be examined in future development.
Another limitation of utilizing the pig model is that it precludes evaluating the dosage form in the context of HIV, and therefore further testing in other large mammals including non-human primates is essential.
Researchers are working on adapting this technology to other diseases which could benefit from drug dosing. The way that researchers designed the polymer arms of the capsule, it allows for a fairly easy swap of different drugs, since the pill can hold multiple drugs at one time, accommodating a different medication on each of its 6 arms.
The development of the formulation is partially supported by a 5-year grant from the National Institute of Allergy and Infectious Disease (NIAID) of the National Institutes of Health (NIH). The grant provides more than $3.6 million throughout 5 years, funding the formulation and preclinical development.