NASH

Prolonged inflammation and liver damage related to steatosis can cause fibrosis of the liver. NASH patients with fibrosis have a higher risk of progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.¹ Although there is currently no approved treatment for NASH fibrosis, it is possible for NASH to be reversible.² Current potential therapeutic options are focused on the reduction of steatosis and fibrosis. In an exploratory study of NASH, leronlimab 350mg was shown to decrease both steatosis and fibrosis.

The CCR5 receptor exists in the liver on the surface of hepatocytes and stellate cells. Stellate cells are the cells that produce scar tissue in the liver, which can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. It is critical to have therapeutic options to resolve NASH before it progresses to later life-threatening stages. There are multiple comorbidities associated with NASH including a higher cardiovascular mortality rate.

¹European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol, 2016;64(6):1388-1402.

²Rinella ME, Sanyal AJ. Management of NAFLD: a stage-based approach. Nature. 2016;13:196-205.

NASH/HIV

Liver-related morbidity remains high among HIV-infected patients, despite advances in the treatment of HIV and viral hepatitis. Approximately 25% of the U.S. Population will have non-alcoholic fatty liver disease (NAFLD) and approximately 5% will develop Non-Alcoholic Steatohepatitis (NASH). In the HIV population, the prevalence of NAFLD is up to 50%¹. NASH and liver-related fibrosis are higher in patients living with HIV. This may be related to increased metabolic comorbidities, hepatoxic effects of antiviral therapy, and chronic HIV infection².

Liver Disease is one of the leading causes of non-AIDS-related death.³ The vast majority of patients with HIV are excluded from clinical trials for NASH making HIV/NASH an unmet medical need. We believe leronlimab is unique in its ability to potentially control HIV viral load while concurrently aiming to decrease steatosis and fibrosis. We believe the CCR5 receptor plays a crucial role in macrophage-mediated inflammation and hepatic stellate cell activation, which are key drivers of progression at multiple stages of NASH.

¹van Welzen BJ, Mudrikova T, El Idrissi A, Hoepelman AIM, Arends JE. A Review of Non-Alcoholic Fatty Liver Disease in HIV-Infected Patients: The Next Big Thing? Infect Dis Ther. 2019 Mar;8(1):33-50. doi: 10.1007/s40121-018-0229-7. Epub 2019 Jan 3. PMID: 30607807; PMCID: PMC6374241.

²Cervo A, Shengir M, Patel K, Sebastiani G. NASH in HIV. Curr HIV/AIDS Rep. 2020 Dec;17(6):601-614. doi: 10.1007/s11904-020-00531-0. PMID: 32984925.

³Kaspar MB, Sterling RK. Mechanisms of liver disease in patients infected with HIV. BMJ Open Gastroenterol. 2017;4(1):e000166. Published 2017 Oct 26. doi:10.1136/bmjgast-2017-000166

ONCOLOGY

Upon malignant transformation, pathological expression of CCR5 occurs in many types of cancer. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness.¹ CCR5 expression induced by transformation imbues the cell with dramatic alteration in motility, gene expression, and homing behavior to metastatic sites.² CCR5 augments the pro-inflammatory pro-metastatic immune phenotype and enhances DNA repair, providing aberrant cell survival and resistance to DNA damaging agents.²

It is believed that CCR5 may play an integral role in tumor progression in a variety of cancers. CCR5 is overexpressed in breast cancer, prostate cancer, colorectal carcinoma, melanoma, head and neck cancer, gastric cancer, esophageal cancer, pancreatic cancer, and other tumors.¹Increased CCR5 expression is an indicator of disease status in several cancers.

Research has shown multiple key properties of the CCR5’s role in cancer. The first is that the CCR5 receptor on cancer cells potentially plays a role in the migration and invasion of cells into the bloodstream, which may lead to metastasis of breast, prostate, and colon cancer. The second is that blocking the CCR5 receptor on Tregs also turns on anti-tumor fighting properties restoring immune function. The third key finding is that blockage of the CCR5/CCL5 interaction had a synergistic effect with chemotherapy and controlled cancer progression. Chemotherapy traditionally increased expression of CCR5, so blocking CCR5 is expected to reduce the levels of invasion and metastasis. Fourth, animal studies revealed a significant decrease in angiogenesis following administration of leronlimab. Lastly, the CCR5 receptor has been shown to play an integral role in macrophage repolarization due to macrophage plasticity.

¹Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012 Aug 1;72(15):3839-50. doi: 10.1158/0008-5472.CAN-11-3917. Epub 2012 May 25. PMID: 22637726.

²Jiao X, Nawab O, Patel T, Kossenkov AV, Halama N, Jaeger D, Pestell RG. Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology. Cancer Res. 2019 Oct 1;79(19):4801-4807. doi: 10.1158/0008-5472.CAN-19-1167. Epub 2019 Jul 10. PMID: 31292161; PMCID: PMC6810651

HIV

Thirty-seven million people are currently living with HIV. While daily oral antiretroviral therapy limits HIV replication, its use is a lifelong requirement and increases the likelihood for the development of drug-resistant variants¹. HIV drug resistance remains a significant health issue. The World Health Organization emphasized the need for new ART strategies in their Global Action Plan on HIV Drug Resistance². Recent in-vitro research suggests leronlimab maintained full activity in the presence of extensive resistance to the four main antiviral classes³. In addition, leronlimab and maraviroc have been reported to have synergistic activity, further corroborating the different mechanisms of the two drugs despite the same CCR5 target³

Leronlimab belongs to a class of HIV therapies known as viral entry inhibitors that block HIV from entering and infecting healthy cells. Highly Active Antiretroviral Therapy (HAART), the current standard of care for HIV, waits until the virus enters the cell and begins replicating before it attacks the virus. In illustrating the importance of CCR5 in HIV, individuals that lack CCR5 expression due to a natural genetic mutation are naturally resistant to HIV infection¹. Today, five people have been cured of HIV, and all were given transplanted cells deficient in the CCR5 receptor. CytoDyn is currently evaluating the role of leronlimab in HIV cure.

We believe that leronlimab shows promise as a powerful antiviral agent with less frequent dosing requirements compared to certain daily drug therapies currently in use for the treatment of HIV. Combination antiretroviral therapy (ART) has drastically improved survival and increased life expectancy for people living with HIV³. However, it is not curative and requires daily adherence for life¹. We believe the future of HIV treatment is long-acting injectables, and CytoDyn is actively pursuing a long-acting version of leronlimab. This could be potentially used in combination with standard-of-care therapies to treat HIV patients and could prove to be of great use in HIV pre-exposure prophylaxis (“PrEP”). In the absence of prophylactic vaccination, “PrEP” remains a promising approach to control the spread of transmission and slow the HIV epidemic.

¹Chang XL, Reed JS, Webb GM, Wu HL, Le J, Bateman KB, et al. (2022) Suppression of human and simian immunodeficiency virus replication with the CCR5-specific antibody Leronlimab in two species. PLoS Pathog 18(3): e1010396.https://doi.org/10.1371/journal.ppat.1010396

²Global action plan on HIV drug resistance 2017–2021. Geneva: World Health Organization. 2017.

³Stefano Rusconi, Francesco Saladini, Maria Concetta Bellocchi, Laura Galli, Roberta Gagliardini, Lidia Gazzola, Daniela Francisci, Francesca Vichi, Emanuele Focà, Maurizio Zazzi, Maria M. Santoro, Arianna Gabrieli, Antonella Castagna, Leronlimab (PRO 140) in vitro activity against 4-class drug resistant HIV-1 from heavily treatment experienced subjects, Pharmacological Research,Volume 176,2022,106064,ISSN 1043-6618, https://doi.org/10.1016/j.phrs.2022.106064.