TERT

The treatment combines MSD’s islatravir with Gilead’s lenacapavir. Credit: Ground Picture via Shutterstock. Gilead Sciences and MSD are advancing their once-weekly HIV treatment regimen to Phase II trials, following promising results from a 48-week study. The treatment combines MSD’s islatravir, an experimental nucleoside reverse transcriptase inhibitor, with Gilead’s lenacapavir, marketed as Sunlenca for use in combination with other antiretroviral drugs to treat people with multidrug-resistant HIV infection. In contrast to currently available daily HIV medications, such as Gilead’s Biktarvy (bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg), this new option could offer a long-acting alternative for people living with HIV. In the Phase II trial (NCT05052996), 104 virologically suppressed adults on Biktarvy were randomly assigned to either continue their daily regimen or switch to the once-weekly islatravir/lenacapavir combination. At the 24-week mark, 94.2% of patients on the experimental treatment maintained viral loads below 50 copies m/L – a key threshold for HIV suppression – matching the Biktarvy group. By week 48, the new regimen continued to demonstrate non-inferior efficacy, with 94.2% of participants achieving sustained viral suppression, compared to 92.4% of those who remained on Biktarvy. These results suggest that the once-weekly combination could provide a more convenient option for patients, potentially reducing the burden of daily medication. Currently, the only long-acting HIV treatment available in the US is Viiv Healthcare’s Cabenuva, which is administered as a monthly or bi-monthly injection. This could make Gilead and MSD’s new pill an attractive alternative to those seeking a less frequent oral regimen. See Also: Editas and Genevant team up to develop gene editing therapies World Osteoporosis Day calls for urgent action to prevent fragility fractures Biktarvy is approved as a once-daily pill to treat patients living with certain types of HIV. The drug generated $11.9bn in global sales in 2023, as per Gilead’s financials. According to GlobalData’s Pharma Intelligence Center, Biktarvy will generate $15.3bn in sales in 2030. GlobalData is the parent company of Pharmaceutical Technology. In the announcement accompanying the results, Elizabeth Rhee, vice president of global clinical development of Merck Research Laboratories said: “Daily single-tablet regimens have helped to transform HIV care but can be challenging for some people to maintain. Novel HIV treatment options that allow for less frequent oral dosing have the potential to help support adherence, and address stigma faced by some individuals taking daily oral therapy.” MSD previously tried to develop a higher dose of islatravir, however it had to pause development after it led to a drop in counts of lymphocytes and CD4+ T cells in clinical trials in 2021. In MSD and Gilead’s Phase II study, there were no differences in immune cell count changes between the Biktarvy and experimental groups. Additionally, no participants discontinued because of a decrease in CD4+ T-cell or lymphocyte counts. Encouraged by these results, Gilead and MSD are now advancing the treatment in Phase III trials. Gilead is also advancing lenacapavir as a PrEP medication, a group of drugs that HIV-negative people can take to minimise the risk of contracting HIV. The company plans to use the data from two Phase III clinical trials – PURPOSE-1 (NCT04994509) and PURPOSE-2 (NCT04925752) – to support a series of global regulatory filings for lenacapavir for PrEP that will begin by the end of 2024.

Pictured: Sign at Gilead's corprate headquarters in Silicon Valley/iStock, Sundry Photography The Biden administration last week appealed a 2023 jury decision , which found that Gilead did not infringe on key government patents in its HIV prevention regimen consisting of the drugs Truvada (emtricitabine/tenofovir disoproxil fumarate) and Descovy (emtricitabine/tenofovir alafenamide). In May 2023, a Delaware jury overwhelmingly took Gilead’s side, noting that the U.S. government did not have enough evidence to establish that using the HIV drugs violated three key patents. The jury also unanimously agreed with the pharma that these patents were invalid in the first place, in part because the technologies they protect were obvious to professionals knowledgeable in the space. In March 2024, a Delaware court gave the government some breathing room when it granted the state’s motion to “upset the jury’s findings” of direct infringement and the invalidity of these patents. In particular, the court ruled against the jury’s verdict that the patents were not infringed but upheld the view that the patents were invalid. The government’s appeal last week—filed by the Department of Justice for the Department of Health and Human Services—seeks to reverse the previous rulings on the invalidity of their patent claims over Truvada and Descovy. First approved in 2004 for the treatment of HIV, Truvada is a combination of two drugs—emtricitabine, a nucleoside reverse transcriptase inhibitor, and a prodrug of tenofovir, which is a nucleotide reverse transcriptase inhibitor. Both of its active ingredients allow Truvada to prevent the HIV virus from infecting a cell and embedding its genetic material into the host’s DNA. In July 2012, the FDA signed off on the preventative use of Truvada, allowing its administration to reduce the risk of sexually acquired HIV. Descovy is a newer generation drug that the FDA approved for HIV prevention in October 2019. It also uses emtricitabine, but combines it with tenofovir alafenamide, another tenofovir prodrug. In November 2019, the Trump administration sued Gilead over the use of Truvada and Descovy, alleging that the combination regimen was first invented by scientists at the Centers for Disease Control and Prevnetion in the early 2000s. “To date, the government has spent hundreds of millions of dollars on clinical studies of these treatment regimens,” the Justice Department wrote in its announcement at the time, adding that Gilead “has repeatedly refused to obtain a license for use of the patented drug regimens, while continuing to profit from hundreds of millions of dollars of publicly funded research.” Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Researchers have demonstrated that therapeutically restoring 'youthful' levels of a specific subunit of the telomerase enzyme can significantly reduce the signs and symptoms of aging in preclinical models. If these findings are confirmed in clinical studies, there may be therapeutic implications for age-related diseases such as Alzheimer's, Parkinson's, heart disease and cancer. Researchers at The University of Texas MD Anderson Cancer Center have demonstrated that therapeutically restoring 'youthful' levels of a specific subunit of the telomerase enzyme can significantly reduce the signs and symptoms of aging in preclinical models. If these findings are confirmed in clinical studies, there may be therapeutic implications for age-related diseases such as Alzheimer's, Parkinson's, heart disease and cancer. The study, published today in Cell, identified a small molecule compound that restores physiological levels of telomerase reverse transcriptase (TERT), which normally is repressed with the onset of aging. Maintenance of TERT levels in aged lab models reduced cellular senescence and tissue inflammation, spurred new neuron formation with improved memory, and enhanced neuromuscular function, which increased strength and coordination. The researchers show that TERT functions not only to extend telomeres, but also acts as a transcription factor to affect the expression of many genes directing neurogenesis, learning and memory, cellular senescence, and inflammation. "Epigenetic repression of TERT plays a major role in the cellular decline seen at the onset of aging by regulating genes involved in learning, memory, muscle performance and inflammation," said corresponding author Ronald DePinho, M.D., professor of Cancer Biology. "By pharmacologically restoring youthful TERT levels, we reprogrammed expression of those genes, resulting in improved cognition and muscle performance while eliminating hallmarks linked to many age-related diseases." Loss of TERT is connected with aging through multiple mechanisms Aging is associated with various epigenetic changes that influence functional and physiological decline. One of the hallmarks of aging is the gradual shortening of telomeres, the chromosomal end structures that help maintain their stability. Free radicals also can modify and harm telomere sequences. When telomeres become extremely short or modified, they trigger a continual DNA damage response, which can lead to cell senescence -- a phenomenon in which cells release inflammatory factors that can cause tissue damage, prompting aging and cancer. Telomerase is a protein complex responsible for synthesizing and extending telomeres. However, its activity is reduced over time due to the epigenetic silencing of TERT, particularly at the onset of natural aging or Alzheimer's and other age-related diseases. The DePinho laboratory previously showed that deactivating the TERT gene in vivo led to premature aging, which could be reversed through TERT reactivation. The researchers also observed that certain cells, such as neurons and cardiac cells, were rejuvenated without undergoing the normal cell division required to synthesize telomeres. Their observations led them to hypothesize that TERT had other functions beyond synthesizing telomeres and that overall telomerase levels were important in the aging process. Based on these findings, the researchers, led by DePinho and first author Hong Seok Shim, Ph.D., aimed to develop a drug to restore TERT levels. Small molecule restores TERT levels, reversing hallmarks of aging A high-throughput screen of over 650,000 compounds identified a small-molecule TERT activating compound (TAC) that epigenetically de-represses the TERT gene and restores physiological expression present in young cells. In preclinical models equivalent to adults over age 75, TAC treatment for six months led to new neuron formation in the hippocampus (memory center) and improved performance in cognitive tests. Additionally, there was an increase in genes involved in learning, memory and synaptic biology, consistent with TERT's ability to interact with and control the activity of transcription factor complexes regulating diverse genes. TAC treatment also significantly reduced inflammaging -- an age-related increase in inflammatory markers linked with multiple diseases -- in both blood and tissue samples and also eliminated senescent cells by repressing the p16 gene, a key senescence factor. TAC improved neuromuscular function, coordination, grip strength and speed in these models, reversing sarcopenia -- a condition under which muscle mass, strength and performance naturally worsen with advancing age. Additionally, TAC treatment in human cell lines increased telomere synthesis with reduced DNA damage signal at telomeres and extended the proliferative potential of these cells, demonstrating the activity of TAC in ex vivo human models. "These preclinical results are encouraging, as TAC is easily absorbed by all tissues, including the central nervous system. Yet further studies are needed to properly assess its safety and activity in long-term treatment strategies," DePinho said. "However, our deeper understanding of the molecular mechanisms driving the aging process has uncovered viable drug targets, allowing us to explore opportunities to intercept the causes of a variety of major age-related chronic diseases." This study was supported by the National Institutes of Health (R01 CA084628, P30 CA016672 and S10 RR029552), the G. Harold and Leila Y Mathers Charitable Foundation and the Belfer Family Foundation Neurodegeneration Consortium. This study was a collaborative effort with Peter Schultz and Michael Bollong at the Scripps Institute.