Simonsen, L. | Search bioRxiv

bioRxiv2023

Sustained Delivery of GLP-1 Receptor Agonists from Injectable Biomimetic Hydrogels Improves Treatment of Diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone and neurotransmitter secreted from intestinal L-cells in response to nutrients to stimulate insulin and block glucagon secretion in a glucose-dependent manner. GLP-1 in itself is rapidly degraded, but long-acting GLP-1 receptor agonists (GLP-1 RAs) have become central in the treatment of T2D because of the beneficial effects extending also beyond glucose control. Currently, these therapeutics must be injected either daily or weekly or taken daily orally, leaving room for technological innovations that enable less frequent administrations, which will reduce patient burden and increase patient compliance. An ideal GLP-1 RA drug product would provide continuous therapy for upwards of four months from a single administration to match the cadence with which T2D patients typically visit their physician. In this work, we leveraged an injectable hydrogel depot technology to develop a long-acting GLP-1 RA drug product. By modulating the hydrogel properties to tune GLP-1 RA retention within the hydrogel depot, we engineered formulations capable of months-long GLP-1 RA delivery. Using a rat model of T2D, we confirmed that a single injection of hydrogel-based therapies exhibits sustained exposure of GLP-1 RA over 42 days, corresponding to a once-every four month therapy in humans. Moreover, these hydrogel therapies maintained optimal management of blood glucose and weight comparable to daily injections of a leading GLP-1 RA drug molecule. The pharmacokinetics and pharmacodynamics of these hydrogel-based long-acting GLP-1 RA treatments are promising for development of novel therapies reducing treatment burden for more effective management of T2D. Progress and PotentialWhile insufficient access to quality healthcare is problematic for consistent management of Type II diabetes (T2D), poor adherence to burdensome treatment regimens is one of the greatest challenges for disease management. Glucagon-like peptide 1 (GLP1) drugs have become central to the treatment of T2D due to their many beneficial effects beyond improving glucose control. Unfortunately, while optimization of GLP1 drugs has reduced treatment frequency from daily to weekly, significant patient burden still leads to poor patience compliance. In this work we developed an injectable hydrogel technology to enable GLP1 drugs only requiring administration once every four months. We showed in a rat model of T2D that one injection of a hydrogel-based therapy improves management of blood glucose and weight when compared with daily injections of the leading drug used clinically. These hydrogel-based GLP1 treatments are promising for reducing treatment burden and more effectively managing T2D. Future ImpactA GLP-1-based drug product providing four months of continuous therapy per administration could be transformational for the management of Type II diabetes (T2D). One of the most challenging aspects of diabetes management with GLP-1 mimics is maintenance of consistent levels of the drugs in the body, which is complicated by poor patient compliance on account of the high frequency of dosing required for current treatments. By leveraging a unique sustained release hydrogel depot technology we develop a months-long GLP-1 drug product candidate that has the potential to reduce patient burden and improving diabetes management. Overall, the hydrogel technology we describe here can dramatically reduce the frequency of therapeutic interventions, significantly increasing patient quality of life and reducing complications of diabetes management. Our next steps will focus on optimization of the drug formulations in a swine model of T2D, which is the most advanced and translationally-relevant animal model for these types of therapeutics. The long-term vision for this work is to translate lead candidate drug products towards clinical evaluation, which will also require comprehensive safety evaluation in multiple species and manufacturing our these materials according to Good Manufacturing Practices. The months-long-acting GLP-1 drug product that will come from this work has the potential to afford thus far unrealized therapeutic impact for the hundreds of millions of people with diabetes worldwide.

bioengineering↗

bioRxiv2018

Challenges in estimating the impact of vaccination with sparse data

BackgroundThe synthetic control (SC) model is a powerful tool to quantify the population-level impact of vaccines, because it can adjust for trends unrelated to vaccination using a composite of control diseases. Because vaccine impact studies are often conducted using smaller subnational datasets, we evaluated the performance of SC models with sparse time series data. To obtain more robust estimates of vaccine effects from noisy time series, we proposed a possible alternative approach, \"STL+PCA\" method (seasonal-trend decomposition plus principal component analysis), which first extracts smoothed trends from the control time series and uses them to adjust the outcome.\n\nMethodsUsing both the SC and STL+PCA models, we estimated the impact of 10-valent pneumococcal conjugate vaccine (PCV10) on pneumonia hospitalizations among cases <12 months and 80+ years of age during 2004-2014 at the subnational level in Brazil. The performance of these models was also compared using simulation analyses.\n\nResultsThe SC model was able to adjust for trends unrelated to PCV10 in larger states but not in smaller states. The simulation analysis confirmed that the SC model failed to select an appropriate set of control diseases when the time series were sparse and noisy, thereby generating biased estimates of the impact of vaccination when secular trends were present. The STL+PCA approach decreased bias in the estimates for smaller populations.\n\nConclusionsEstimates from the SC model might be biased when data are sparse. The STL+PCA model provides more accurate evaluations of vaccine impact in smaller populations.

epidemiology↗

bioRxiv2018

Do pneumococcal conjugate vaccines (PCVs) reduce childhood pneumonia mortality? An assessment across socioeconomic groups in Brazil

BackgroundUnderstanding the real-world impact of pneumococcal conjugate vaccines (PCVs) on pneumonia mortality is critical, given the expectation that PCVs can substantially reduce the burden of pneumonia deaths in children under five years. However, surprisingly few post-vaccine introduction studies have estimated the benefit of PCVs for childhood mortality, and results have been inconsistent.\n\nMethodsWe investigated the long-term trends in child pneumonia mortality in Brazil (1980-present) and assessed the impact of PCV10 on childhood pneumonia mortality, both nationally and in municipalities stratified by socioeconomic status (SES), after the vaccine was introduced in Brazil in 2010.\n\nFindingsBetween 1980 and 2010, a period when Brazils Human Development Index (HDI) rose from 0.55 to 0.71, national pneumonia mortality in children under five decreased 10-fold. Despite rapid uptake of PCV10 following its introduction in 2010, our primary analytical method found no significant decline in national childhood pneumonia mortality, although a secondary analysis found a 10 percent decline in some but not all strata. However, at the municipal level we found significant reductions in childhood pneumonia mortality of up to 24% in low SES strata.\n\nInterpretationContrary to expectations, we found that PCV use led to at best modest savings in childhood pneumonia mortality at the national level in a middle-income country. In contrast, we found evidence that PCV led to larger reductions in low-income settings; a similar benefit might occur when PCVs are introduced in other low-SES settings. The long-term findings underscore that improvements in nutrition, hygiene, education, and healthcare play a major role in reducing pneumonia mortality.\n\nFundingThis work was funded by a grant from the Bill & Melinda Gates Foundation (OPP1114733). DMW also acknowledges support from the Bill and Melinda Gates Foundation (OPP1176267) and the National Institute of Allergy and Infectious Diseases (R01AI123208)

epidemiology↗