| |
Effects of tesamorelin on hepatic transcriptomic
signatures in HIV-associated NAFLD
|
| |
| |
JCI Insight.July 23 2020
Lindsay T. Fourman 1, James M. Billingsley 2, George Agyapong 3, Shannan J. Ho Sui 2, Meghan N. Feldpausch 1, Julia Purdy 4, Isabel Zheng 1, Chelsea S. Pan 1, Kathleen E. Corey 3, Martin Torriani 5, David E. Kleiner 6, Colleen M. Hadigan 4, Takara L. Stanley 1, Raymond T. Chung †3, Steven K. Grinspoon 1
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV with a more aggressive course than in the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analogue tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over one year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the HIV population. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using Gene Set Enrichment Analysis (GSEA), we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of growth hormone action on the liver and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.
In summary, among individuals with HIV-associated NAFLD, GH axis augmentation with tesamorelin led to changes in hepatic gene expression that reflect an overall return toward liver health. We found that tesamorelin upregulated oxidative phosphorylation genes, and downregulated genes involved in inflammation, tissue repair, and cell turnover compared to placebo. Further, tesamorelin shifted hepatic gene expression toward a profile associated with a favorable HCC prognosis. By expanding our knowledge of the effects of GH axis augmentation on hepatic biology, our findings raise the possibility of novel clinical benefits of this strategy in the treatment of NASH that should be evaluated in future large-scale efforts.
---------------------
THERATECHNOLOGIES REPORTS THAT TESAMORELIN IMPROVES LIVER HEALTH
Download the PDF here
pdf publication
Sub-analysis of MGH study helps better demonstrate how tesamorelin reduces liver fat
Positive impact of tesamorelin on oxidative phosphorylation, inflammation, tissue repair and cell division
Montreal, Canada - July 23, 2020 - Theratechnologies Inc. (Theratechnologies) (TSX: TH) (NASDAQ: THTX), a commercial-stage biopharmaceutical company, is pleased to announce new data that further support the potential role of tesamorelin in the treatment of HIV-associated nonalcoholic steatohepatitis (NASH).
The new data were published in the recent online edition of JCI Insight and are derived from a sub-analysis of the Phase 2 study evaluating the effect of tesamorelin on the transcriptome of the liver biopsies in people living with HIV-associated nonalcoholic fatty liver disease (NAFLD) conducted at Massachusetts General Hospital and the National Institute of Allergy and Infectious Diseases and led by Dr. Steven Grinspoon. The results of the Phase 2 study were previously published in the December 2019 issue of The Lancet HIV Journal.
"The data from this sub-analysis show that tesamorelin improves oxidative phosphorylation gene expression, and decreases gene expression involved in inflammation, tissue repair, and cell division. In addition, tesamorelin shifted hepatic gene expression toward a profile associated with a favorable HCC prognosis. These findings suggest potential novel clinical benefits of tesamorelin in liver health," said Dr. Christian Marsolais, Senior Vice President and Chief Medical Officer, Theratechnologies Inc. "The data also support the clinical relevance for the development of tesamorelin as a potential treatment for liver diseases."
The sub-analysis of paired liver biopsy specimens from patients participating in the Phase 2 study using Gene Set Enrichment Analysis (GSEA) assessed the effect of tesamorelin on hepatic transcriptomic signature of HIV-associated NAFLD/NASH. Results demonstrated that tesamorelin had a positive effect on gene expression related to oxidative phosphorylation and decreased gene expression related to inflammation, tissue repair and cell division. Furthermore, treatment with tesamorelin led to improvement of genes associated with favorable hepatocellular carcinoma (HCC) prognosis.
"These data demonstrate for the first time how tesamorelin reduces the accumulation of liver fat and improves hepatic gene expression that reflect an overall return toward liver health in people living with HIV-associated NAFLD/NASH," said Dr. Steven Grinspoon, Professor of Medicine at Harvard Medical School, Chief of the Metabolism Unit at Massachusetts General Hospital, and a scientific consultant to Theratechnologies Inc.
About Theratechnologies
Theratechnologies (TSX: TH) (NASDAQ: THTX) is a commercial-stage biopharmaceutical company addressing unmet medical needs by bringing to market specialized therapies for people with orphan medical conditions, including those living with HIV. Further information about Theratechnologies is available on the Company's website at www.theratech.com, on SEDAR at www.sedar.com and on EDGAR at www.sec.gov
Forward-Looking Information
This press release contains forward-looking statements and forward-looking information, or, collectively, forward-looking statements, within the meaning of applicable securities laws, that are based on our management's beliefs and assumptions and on information currently available to our management. You can identify forward-looking statements by terms such as "may", "will", "should", "could", "would", "outlook", "believe", "plan", "envisage", "anticipate", "expect" and "estimate", or the negatives of these terms, or variations of them. The forward-looking statements contained in this press release include but are not limited to statements regarding the novel clinical benefits of tesamorelin and the development of tesamorelin as a potential treatment for liver diseases.
Forward-looking statements are based upon a number of assumptions and include, but are not limited to, the following: the efficacy and results obtained from the administration of tesamorelin reported herein will not change when tesamorelin will be administered to a large patient population, no unknown adverse side effects will develop from the long term use of tesamorelin and tesamorelin will yield positive results when developed for the potential treatment of liver diseases and will gain approval from regulatory agencies for the treatment of liver diseases.
Forward-looking statements are subject to a variety of risks and uncertainties, many of which are beyond our control that could cause our actual results to differ materially from those that are disclosed in or implied by the forward-looking statements contained in this press release. These risks and uncertainties include, among others, the risk that the administration of tesamorelin in a large patient population does not return the same results as those reported herein, the risk that the development of tesamorelin for the treatment of liver diseases does not occur because of difficulty in enrolling patients, the current pandemic, the discovery of untoward side effects and, even if the development of tesamorelin for the potential treatment of liver diseases occurs, the risk that results obtained do not allow the filing of a supplemental biologic license application or that the regulatory agencies refuse to approve tesamorelin for such treatment.
We refer potential investors to the "Risk Factors" section of our annual information form dated February 24, 2020 and to our Form 40-F dated February 25, 2020 filed on EDGAR for additional risks regarding the conduct of our business and Theratechnologies. The reader is cautioned to consider these and other risks and uncertainties carefully and not to put undue reliance on forward-looking statements. Forward-looking statements reflect current expectations regarding future events and speak only as of the date of this press release and represent our expectations as of that date.
We undertake no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise, except as may be required by applicable law.
For media inquiries:
Denis Boucher
Vice President, Communications and Corporate Affairs
514-336-7800
| |
| |
| |
|
|
|
