New Branched Polymers Excipients and Emulsions for Enhanced Drug Delivery

Lead Research Organisation: University of Liverpool
Department Name: Institute of Translational Medicine

Abstract

The poor absorption of many orally-dosed medicines results in the use of higher doses per administration than would be ideally delivered to maintain lower production costs, storage issues, and manufacturing capacity. For HIV and other chronic diseases, patients require a life-long commitment to therapy meaning that costs accumulate over time. This has considerable impact in low- and middle-Income countries where many chronic infectious diseases require lifelong dosing to minimise further spread and maximise the quality and length of life for infected patients, which has a knock-on effect for productivity and wider economic considerations. HIV is a specific example where doses greater than 900mg per-patient-per-day are common, leading to a considerable cost burden for healthcare providers (often local governments as well as the international community) and the prevention of wide spread access to therapy due to cost constraints. In many cases, these high doses are only required because a limited amount of the drug that is swallowed actually enters the bloodstream to provide the explicit pharmacological benefits. In some cases, the drug that stays in and passes through the gut may cause the patient considerable side-effects such as gastrointestinal disturbances. Within this grant we aim to progress a new approach to therapy formulation through to demonstration of actual benefits in healthy volunteers and establish the potential to reduce administered doses whilst maintaining the amount of drug available within the bloodstream to exert its therapeutic effect after oral dosing.
This will require the full demonstration of the potential to take our new materials technology through to pharmaceutical and regulatory approved manufacturing processes and use the material to generate a new therapy candidate. After approval for human pharmacokinetic evaluation, a small study will establish the data required to de-risk pharmaceutical and material industry investment to develop new medicines. The proposed research, therefore, considerably accelerates the outcomes of previous research towards actual impact that could provide healthcare benefits around the world. While the programme is specifically targeted at a new HIV medicine, we expect the validated platform technology to be widely applicable across indications, saving costs of treatment, enabling delivery of drugs that could otherwise not be delivered orally, and generating wealth for the UK economy through commercialisation in high income contexts.

Planned Impact

The introduction of new pharmaceutical excipients and the clear demonstration of their value and benefits may impact widely upon academia and industry, thereby having demonstrable scientific, economic and societal benefit. Academically, new approaches to drug delivery with clear evidence of benefits in human studies are well known to spur considerable new activity and investment. The combination of concepts used within the translational pathway outlined in this research is potentially highly synergistic, encouraging researchers to engage in translation and deliver new impact through material developments that may be progressed through relevant manufacturing processes. As such, the strategy for taking model systems with academic proof-of-concept through to actual healthy volunteer demonstration will inspire other researchers to progress their healthcare innovations and create evidence that will de-risk their engagement with pharmaceutical companies and development partners alike.
Achieving matching PK from reduced concentrations of drugs in orally administered therapies has the potential to revolutionise healthcare system costs for a range of diseases, but specifically the growing cost for treatment of chronic indications. The value for HIV alone is huge (see letters of support), but a validation of the core technology opens opportunities for much more widespread uptake, and will enable us to generate additional impact from engagement with our existing (and new) commercial partners. In addition, the dossier of information generated for the new copolymer excipient will make this material a viable and scale-able option for wider provision to the drug formulation community - pharmaceutical excipients are predicted to reach an estimated $8.1bn dollar global market in coming years, thereby providing an exciting opportunity for a material company to exploit. The interest in this market is clear from the engagement of Itaconix in this programme, and if successful this offers an opportunity for a UK company to learn more within this expanding market.
It is expected that the research presented here may impact on a wide range of communities and, eventually, offer financial, economic and societal benefits. Through careful selection of the candidate therapy, the pharmacological target and the oral administration route, the team have shortened the pathway to clinical impact to potentially as little as 2 years post completion of this research - a clear acceleration of healthcare impact from initial fundamental research, which is only possible because of the foundations set by our previously EPSRC-funded research.
The laboratory researchers involved in this study will witness the translation of novel concepts through to industrial evaluation and scale-up and evidence formation through healthy volunteer studies. It is our strong hope that the impact of experiencing translation of their research will help further cement the need for truly interdisciplinary and ambitious research in the next generation of UK scientists.
 
Description A CMO has been contracted and initial bench scale polymer synthesis has successfully been translated to the CMO under GMP conditions. Polymer synthesis was being scaled for GMP formulation to precede confirmatory pharmacokinetic studies in animals and GLP toxicology but was negatively impacted by the pandemic.

For the main project formulations were selected for in vivo studies and pharmacokinetics characterised after oral, intravenous and intramuscular administration to rats. Results of these studies indicated that profound benefits in posology were not likely to arise from the selected drugs. Ongoing discussions are underway to explore different drugs and formulations for evaluation that may include options currently under consideration for COVID-19. A new strategy will be agreed in the coming weeks.

As part of the emergency response to the COVID-19 pandemic, a portion of funding was repositioned with approval from UKRI to explore evaluation of candidates therapeutics for COVID-19. This work has been highly productive and has led to several candidates that are now progressing into various stages of development with additional funding from other agencies.
Exploitation Route Several of the candidates identified with the repositioned COVID-19 funding are now in clinical trials nationally and internationally as a direct outcome of the funding but with specific budgets covered from other agencies. In addition, a new formulation was identified for a putative COVID-19 application on which patent have been filed, a publication was recently accepted, and is now being translated to GMP manufacture again with funding from another agency.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Data arising from the utilisation of the reposition funding for COVID-19 have directly resulted in selection of candidate therapeutics for several ongoing clinical trials in UK (AGILE), South Africa and Nigeria. Discussions are also underway with trialists in Mexico. In addition, a candidate formulation of a putative antiviral for SARS-CoV-2 has been identified and is being translated for GMP manufacture with funding from another source. There are also ongoing discussion with several potential commerical and charitable partners to establish a viable route to market.
First Year Of Impact 2020
 
Description DNDi 
Organisation Drugs for Neglected Diseases initiative (DNDi)
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution Our team have identified drugs that are potentially repurposable as antiviral interventions for SARS-CoV-2. Weekly meetings with DNDi have resulted in rapid sharing of data with them and planning experiments to plug knowledg gaps and identify a route to phase III evaluation.
Collaborator Contribution The team at DNDi have organised complimentary preclinical evaluations to refine Liverpool candidates for evaluation in their phase III ANTICOV platform trial. A candidate identified by Liverpool as part of the repositioned funding from this award has now been selected for evaluation in ANTICOV.
Impact Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID-19 Therapeutic Development. Boffito M, Back DJ, Flexner C, Sjö P, Blaschke TF, Horby PW, Cattaneo D, Acosta EP, Anderson P, Owen A. Clin Pharmacol Ther. 2020 Oct 28. doi: 10.1002/cpt.2099. Online ahead of print. PMID: 33113246
Start Year 2020
 
Description Ezintsha 
Organisation Ezintsha
Country South Africa 
Sector Charity/Non Profit 
PI Contribution Candidates identified in Liverpool have directly progressed into two phase II trials in South Africa looking at utility in treatement or prevention of COVID-19. These candidates were identified directly using the repositioned funding from this award.
Collaborator Contribution The team in South Africa were instrumental in development of the protocols, approvals and drug supply.
Impact None yet
Start Year 2020
 
Description Liverpool School of Tropical Medicine 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution At the start of the pandemic, a cross-campus COVID-19 community was established and preclinical assessments were conducted harmoniously as part of a collaboration with the Liverpool School of Tropical Medicine. The repositioned funding from this award was instrumental in establishing this collaboration. Our team contributed pharmacokinetic modelling and in vivo preclinical evaluation of candidate medicines for COVID-19.
Collaborator Contribution The LSTM team contributed in vitro assessments of candidate drugs for COVID-19
Impact Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2? Stachulski AV, Taujanskas J, Pate SL, Rajoli RKR, Aljayyoussi G, Pennington SH, Ward SA, Hong WD, Biagini GA, Owen A, Nixon GL, Leung SC, O'Neill PM. ACS Infect Dis. 2020 Dec 22:acsinfecdis.0c00478. doi: 10.1021/acsinfecdis.0c00478. Online ahead of print. PMID: 33352056 Free PMC article. Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. Rajoli RKR, Pertinez H, Arshad U, Box H, Tatham L, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, Aljayyoussi G, Pennington SH, Hill A, Boffito M, Ward SA, Khoo SH, Bray PG, O'Neill PM, Hong WD, Biagini GA, Owen A. Br J Clin Pharmacol. 2020 Oct 21. doi: 10.1111/bcp.14619. Online ahead of print. PMID: 33085781 Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. Rajoli RK, Pertinez H, Arshad U, Box H, Tatham L, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, Aljayyoussi G, Pennington SH, Hill A, Boffito M, Ward SA, Khoo SH, Bray PG, O'Neill PM, Hong WD, Biagini G, Owen A. medRxiv. 2020 May 6:2020.05.01.20087130. doi: 10.1101/2020.05.01.20087130. Preprint. PMID: 32511548 Free PMC article. Updated. Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics. Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, O'Neill PM, Aljayyoussi G, Pennington SH, Ward SA, Hill A, Back DJ, Khoo SH, Bray PG, Biagini GA, Owen A. Clin Pharmacol Ther. 2020 Oct;108(4):775-790. doi: 10.1002/cpt.1909. Epub 2020 Jun 14.
Start Year 2020
 
Description Obafemi Awolowo University 
Organisation Obafemi Awolowo University
Country Nigeria 
Sector Academic/University 
PI Contribution Work conducted in Liverpool as part of the repositioned funding from this award directly resulted in identification of a potential combination for SARS-CoV-2, which has progressed into a phase II trial in partnership with the Nigerian collaborator.
Collaborator Contribution The team in Nigeria were instrumental in developing the clinical protocol and securing approvals and drug supply for the NACOVID trial.
Impact Efficacy and safety of nitazoxanide plus atazanavir/ritonavir for the treatment of moderate to severe COVID-19 (NACOVID): A structured summary of a study protocol for a randomised controlled trial. Olagunju A, Fowotade A, Olagunoye A, Ojo TO, Adefuye BO, Fagbamigbe AF, Adebiyi AO, Olagunju OI, Ladipo OT, Akinloye A, Adeagbo BA, Onayade A, Bolaji OO, Happi C, Rannard S, Owen A. Trials. 2021 Jan 4;22(1):3. doi: 10.1186/s13063-020-04987-8.
Start Year 2020
 
Description Due diligence 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Friday 24th August 2018 - Due diligence meeting with PCI Synthesis 9 Opportunity Way, Newburyport, MA 01950, USA
Year(s) Of Engagement Activity 2018
 
Description Due diligence 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Friday 15th February 2019 - Due diligence meeting with ChemConnection B.V., Kloosterstraat 9, 5349 AB Oss, Netherlands
Year(s) Of Engagement Activity 2019
 
Description Due diligence 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Thursday 13th December 2018 - Due diligence meeting with ChemCon GmbH, Engesserstraße 4B, 79108 Freiburg im Breisgau, Germany
Year(s) Of Engagement Activity 2018