LEAP Publications

A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable

Date:

8/25/23

Citation:

Perazzolo, Simonea; Stephen, Zacharya; Eguchi, Masaa; Xu, Xiaolina; Fratte, Rachele Dellea; Collier, Ann C.b; Melvin, Ann J.c; Ho, Rodney J.Y.a,d. A novel formulation enabled transformation of 3 HIV drugs tenofovir-lamivudine-dolutegravir (TLD) from short-acting to long-acting all-in-one injectable. AIDS ():10.1097/QAD.0000000000003706, August 25, 2023. | DOI: 10.1097/QAD.0000000000003706

Using drug-combination-nanoparticle (DcNP) technology to stabilize multiple HIV drugs, the 3 HIV drugs TLD, with disparate physical-chemical properties, are stabilized and assembled with lipid-excipients to form TLD-in-DcNP. TLD-in-DcNP is verified to be stable and suitable for subcutaneous administration. To characterize the plasma time-courses and PBMC concentrations for all 3 drugs, single subcutaneous injections of TLD-in-DcNP were given to nonhuman primates (NHP, M. nemestrina).

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study

Date:

4/1/23

Citation:

Smith J, Bansi-Matharu L, Cambiano V, Dimitrov D, Bershteyn A, van de Vijver D, Kripke K, Revill P, Boily MC, Meyer-Rath G, Taramusi I, Lundgren JD, van Oosterhout JJ, Kuritzkes D, Schaefer R, Siedner MJ, Schapiro J, Delany-Moretlwe S, Landovitz RJ, Flexner C, Jordan M, Venter F, Radebe M, Ripin D, Jenkins S, Resar D, Amole C, Shahmanesh M, Gupta RK, Raizes E, Johnson C, Inzaule S, Shafer R, Warren M, Stansfield S, Paredes R, Phillips AN; HIV Modelling Consortium. Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study. Lancet HIV. 2023 Apr;10(4):e254-e265. doi: 10.1016/S2352-3018(22)00365-4. Epub 2023 Jan 12. PMID: 36642087; PMCID: PMC10065903.

Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa.

Antiviral supramolecular polymeric hydrogels by self-assembly of tenofovir-bearing peptide amphiphiles

Date:

1/17/23

Citation:

Monroe MK, Wang H, Anderson CF, Qin M, Thio CL, Flexner C, Cui H. Antiviral supramolecular polymeric hydrogels by self-assembly of tenofovir-bearing peptide amphiphiles. Biomater Sci. 2023 Jan 17;11(2):489-498. doi: 10.1039/d2bm01649d. PMID: 36449365; PMCID: PMC9894536.

The development of long-acting antiviral therapeutic delivery systems is crucial to improve the current treatment and prevention of HIV and chronic HBV. We report here on the conjugation of tenofovir (TFV), an FDA approved nucleotide reverse transcriptase inhibitor (NRTI), to rationally designed peptide amphiphiles (PAs), to construct antiviral prodrug hydrogelators (TFV-PAs).

A Holistic Review of the Preclinical Landscape for Long-Acting Anti-infective Drugs Using HIV as a Paradigm

Date:

11/21/22

Citation:

Megan Neary, Andrew Owen, Adeniyi Olagunju, A Holistic Review of the Preclinical Landscape for Long-Acting Anti-infective Drugs Using HIV as a Paradigm, Clinical Infectious Diseases, Volume 75, Issue Supplement_4, 1 December 2022, Pages S490–S497, https://doi.org/10.1093/cid/ciac685

Decisions about progressing new drug candidates to clinical development are guided by evidence from preclinical studies. These are the cornerstone of new drug development and clinical translation, providing the critical data that inform first-in-human trials. The landscape for long-acting (LA) anti-infective development over the past 12 months was marked by some significant developments, particularly for human immunodeficiency virus (HIV), which will be used as a paradigm to discuss the preclinical development of LA anti-infective drugs.

What Clinicians Need to Know About the Development of Long-Acting Formulation

Date:

11/21/22

Citation:

Charles Flexner, David L Thomas, Polly Clayden, Susan Swindells, What Clinicians Need to Know About the Development of Long-Acting Formulations, Clinical Infectious Diseases, Volume 75, Issue Supplement_4, 1 December 2022, Pages S487–S489, https://doi.org/10.1093/cid/ciac749

When thinking about the potential impact of long-acting formulations on the treatment and prevention of infectious diseases, it is important to first define what is meant by “long-acting.” In most clinical circumstances, the concept of long-acting is a relative one, based on the frequency of dosing of other treatments available for the same disease. For example, although intramuscular procaine penicillin G has an apparent half-life in plasma of 3.4 hours, and might be considered long-acting when compared to the 30 minute half-life of unaltered penicillin G, neither compares to the 672 hour apparent half-life of intramuscular benzathine penicillin G.

Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19

Date:

8/12/22

Citation:

Assmus F, Driouich JS, Abdelnabi R, Vangeel L, Touret F, Adehin A, Chotsiri P, Cochin M, Foo CS, Jochmans D, Kim S, Luciani L, Moureau G, Park S, Pétit PR, Shum D, Wattanakul T, Weynand B, Fraisse L, Ioset JR, Mowbray CE, Owen A, Hoglund RM, Tarning J, Lamballerie X, Nougairède A, Neyts J, Sjö P, Escudié F, Scandale I, Chatelain E. Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19. Microorganisms. 2022 Aug 12;10(8):1639. doi: 10.3390/microorganisms10081639. PMID: 36014057; PMCID: PMC9460261.

The coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative pathogen of COVID-19, one of several coronaviruses that can infect humans, along with SARS-CoV and MERS-CoV. Due to its high infectivity and ability to cause severe disease and death, COVID-19 became a public emergency of international concern and was classified as a pandemic by the World Health Organization (WHO) in March 2020. At the time of writing, over 537 million confirmed cases and more than 6 million deaths have been recorded globally, contributing to 14.9 million excess deaths associated with the COVID-19 pandemic.

The future of long acting agents for PrEP

Date:

7/1/22

Citation:

Flexner C. The future of long-acting agents for preexposure prophylaxis. Curr Opin HIV AIDS. 2022 Jul 1;17(4):192-198. doi: 10.1097/COH.0000000000000735. PMID: 35762373; PMCID: PMC9467455.

Why should we pursue long-acting approaches to drug delivery for HIV pre-exposure prophylaxis (PrEP) when co-formulated daily oral antiretrovirals are widely available and work so well? Injectable cabotegravir provides an immediate answer to this question. Recent large randomized prospective controlled clinical trials clearly demonstrate the superior efficacy of this agent, as compared to daily oral PrEP.

Supramolecular Nanomedicines through Rational Design of Self-Assembling Prodrugs

Date:

6/1/22

Citation:

Wang H, Monroe M, Leslie F, Flexner C, Cui H. Supramolecular nanomedicines through rational design of self-assembling prodrugs. Trends Pharmacol Sci. 2022 Jun;43(6):510-521. doi: 10.1016/j.tips.2022.03.003. Epub 2022 Apr 19. PMID: 35459589; PMCID: PMC9106924.

he clinical application of small molecule drugs such as cancer chemotherapeutics is often limited by their poor solubility in aqueous environments, lack of delivery specificity, low therapeutic index, insufficient therapeutic efficacy, short circulation lifetime, and severe adverse effects. Encapsulation of drugs within nanocarriers of well-defined size and shape has been demonstrated to increase the solubility of hydrophobic drugs, improve the pharmacokinetics of the drug with the promise of reducing adverse side effects, and promote targeting efficiency.

Lack of antiviral activity of probenecid in Vero E6 cells and Syrian golden hamsters: a need for better understanding of inter-lab differences in preclinical assays

Date:

3/3/22

Citation:

Box H, Pennington SH, Kijak E, Tatham L, Caygill CH, Lopeman RC, Jeffreys LN, Herriott J, Sharp J, Neary M, Valentijn A, Pertinez H, Curley P, Arshad U, Rajoli RK, Rannard S, Stewart JP, Biagini GA, Owen A. Lack of antiviral activity of probenecid in Vero E6 cells and Syrian golden hamsters: a need for better understanding of inter-lab differences in preclinical assays. bioRxiv [Preprint]. 2022 Mar 3:2022.03.03.482788. doi: 10.1101/2022.03.03.482788. PMID: 35262084; PMCID: PMC8902890.

A concerted global effort over the first two years of the pandemic has sought to rapidly evaluate antiviral drug candidates to complement the highly successful, rigorously validated but still highly unequitable vaccination programmes.

An Open Label, Adaptive, Phase 1 Trial of High‐Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS‐CoV‐2

Date:

3/1/22

Citation:

Walker LE, FitzGerald R, Saunders G, Lyon R, Fisher M, Martin K, Eberhart I, Woods C, Ewings S, Hale C, Rajoli RKR, Else L, Dilly-Penchala S, Amara A, Lalloo DG, Jacobs M, Pertinez H, Hatchard P, Waugh R, Lawrence M, Johnson L, Fines K, Reynolds H, Rowland T, Crook R, Okenyi E, Byrne K, Mozgunov P, Jaki T, Khoo S, Owen A, Griffiths G, Fletcher TE; AGILE platform. An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2. Clin Pharmacol Ther. 2022 Mar;111(3):585-594. doi: 10.1002/cpt.2463. Epub 2021 Nov 13. PMID: 34699618; PMCID: PMC8653087.