Mois : janvier 2025

Cyclarity Therapeutics is pleased to announce regulatory approval to begin its first-in-human clinical trial. The trial will be conducted at CMAX, one of Australia’s leading clinical research centers, in partnership with Monash University. This effort will be led by Dr. Stephen Nicholls of the Victorian Heart Institute (VHI), a distinguished leader in cardiovascular medicine. In addition to a traditional SAD/MAD phase 1 trial, the authorization includes an allowance to enroll 12 patients with Acute Coronary Syndrome (ACS) to assess the safety of UDP-003 in individuals with plaque buildup, as well as to explore anecdotal evidence of efficacy. This represents a critical first step in evaluating the potential impact of our therapy in a population with high unmet need.

Key performance indicators (KPIs):

Clinical Trial Material (CTM): Manufacture is complete, with all supporting documentation and analysis finalized. UDP-003 is in vials and ready for administration to human participants.
Investigational New Drug (IND) Enabling Studies: All studies have been successfully completed with no predicted toxicological liabilities, ensuring a safe path forward.
Clinical readiness: All materials necessary for clinical trial authorization have been submitted and are in place.

This milestone marks a significant moment for Cyclarity as the trial joins Dr. Nicholls’ legacy of innovative clinical research. His previous work includes the SATURN trial for Crestor in the early 2000s, the CLEAR Outcomes trial in the 2020s that introduced bempedoic acid as a statin alternative, and the recent Muvalaplin trial targeting Lp(a), a major innovation in cardiovascular health.

“We are excited to be working with Dr. Nicholls on a groundbreaking advancement in cardiovascular care,” said CEO of Scientific Affairs Matthew O’Connor. “As we advance into being a clinical stage company, Cyclarity is focused on bringing truly disease-modifying treatments for the world’s deadliest disease into reality.”

We deeply appreciate the support we’ve received to reach this important stage and invite you to stay tuned as we continue to push the boundaries of therapeutic development. For more information, please contact press@cyclaritytx.com or visit https://cyclaritytx.com/.

In a journal called Small, researchers have described a new targeting mechanism for delivering senolytic compounds where they need to go.

Finding the right nanoparticle

This paper begins with a discussion of the well-known features of cellular senescence and laments that, despite all the work done in this area, no senolytic has yet been approved for clinical use. The researchers provide evidence that this is due to both efficacy and targeting: senolytics do not always solely affect senescent cells [1].

Previous work has focused on using galactose as a carrier for such potential drugs [2], as senescent cells are characterized by the presence of SA-β-gal, a compound that naturally cleaves galactose. This approach has, in early studies, been found to reduce the toxicity of navitoclax, the senolytic that is the focus of this study [1].

However, much of that previous work was focused on encapsulating porous silica with galactose as a nanocarrier for the drug, and these researchers note that porous silica can be toxic [3]. Trying to directly modify drugs with galactose changes is also not perfect, as this process changes their structure and is difficult to accomplish [4].

The soap approach

Instead of silica, these researchers chose to encapsulate their drug in amphiphilic micelles, which are very similar to soap bubbles and have been previously examined in drug delivery [5]. Here, the micelles have the water-attracted (hydrophilic) portion facing outwards and holding the galactose, with the water-repellent (hydrophobic) portion facing inwards to contain the navitoclax. The researchers go into detail regarding the chemistry of how they accomplished this, using a variety of branches extending from the central component and then assembling those molecules together to form a bubble.

Of these three approaches, the branched variant was found to be the most effective, as shown by an in vitro test using fluorescent Nile Red dye. Furthermore, the bubble was found to be protective: in the absence of β-galactosidase, only 6% of the total fluorescence was reduced 24 hours after exposure, while in its presence, 50% of it was gone within 6 hours and 90% within 24 hours.

Effective in cells

The researchers then tested their compound against actual senescent cells, specifically cells derived from lung cancer (A549) and melanoma (SK-MEL-103) lines. The senolytic index, which measures efficacy versus off-target effects, was much stronger in the encapsulated variant versus raw navitoclax alone: the micelle-encapsulated drug was more selective against senescent cells, particularly in the A549 line.

However, this paper is only a cellular study, and there were no animals involved. Furthermore, the experiments were conducted solely on cell lines derived from cancer, and it has yet to be experimentally determined how other cells or living organisms might respond to these micelles in the body. Still, this paper serves as a useful proof of concept, explaining how a drug can be targeted to the cells that need it most.

Literature

[1] González‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson III, J. R., González‐López, C., … & Muñoz‐Espín, D. (2020). Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging cell, 19(4), e13142.

[2] Muñoz‐Espín, D., Rovira, M., Galiana, I., Giménez, C., Lozano‐Torres, B., Paez‐Ribes, M., … & Serrano, M. (2018). A versatile drug delivery system targeting senescent cells. EMBO molecular medicine, 10(9), e9355.

[3] Lin, Y. S., & Haynes, C. L. (2010). Impacts of mesoporous silica nanoparticle size, pore ordering, and pore integrity on hemolytic activity. Journal of the American Chemical Society, 132(13), 4834-4842.

[4] Guerrero, A., Guiho, R., Herranz, N., Uren, A., Withers, D. J., Martínez‐Barbera, J. P., … & Gil, J. (2020). Galactose‐modified duocarmycin prodrugs as senolytics. Aging Cell, 19(4), e13133.

[5] Parshad, B., Prasad, S., Bhatia, S., Mittal, A., Pan, Y., Mishra, P. K., … & Fruk, L. (2020). Non-ionic small amphiphile based nanostructures for biomedical applications. RSC advances, 10(69), 42098-42115.

In a new study, researchers have found that lithocholic acid, a metabolite found in the serum of calorically restricted mice, can mimic the effects of caloric restriction [1].

Restricting calories to live longer

Caloric restriction without malnutrition improves healthspan and extended lifespan in multiple model organisms and has been found to have health benefits in human studies. We have covered the many benefits of caloric restriction on longevity and healthspan, including a recently published interview in which we discussed one of the longest-running caloric restriction experiments on monkeys.

Mimicking caloric restriction

Restricting calories changes many aspects of an organism’s metabolism [2]. One of its well-documented effects is the activation of AMP-activated protein kinase (AMPK). AMPK is an essential regulator of multiple signaling pathways, including aging-related pathways and cellular processes, and mediates many of these beneficial effects [3]. In this study, the researchers used AMPK as a proxy to identify metabolites that mimic caloric restriction.

The researchers subjected mice to 4 months of caloric restriction. Then, they treated a few cell lines with serum from calorically restricted mice. The serum activated AMPK in those cell lines, suggesting that this serum mimicked the effects of caloric restriction. The activation of AMPK was also possible in the liver and muscle cells of normally fed mice treated with the serum of calorically restricted mice.

Finding ‘the one’

Being able to mimic the effects of caloric restriction without restricting caloric intake is an intriguing idea. However, using a whole serum from mice to achieve it is not a practical solution, especially since, most likely, only one or a few molecules from the serum are responsible for the effect of AMPK activation. The researchers went on a quest to identify those molecules.

They employed mass spectrometry-based approaches to identify over a thousand specific metabolites in the serum, and almost seven hundred that were altered by caloric restriction. After performing a few more tests to narrow the list, they performed a screen on cell cultures using AMPK activation as a biomarker.

In the initial screening, the researchers identified six metabolites that increased after caloric restriction and activated AMPK in cell cultures. However, the concentrations needed to activate AMPK by most of those metabolites were too high to be used in physiological conditions.

Only one of the identified metabolites, lithocholic acid (LCA), one of the bile acids (but not its derivatives), activated AMPK when administered at a concentration similar to that in the serum.

Late-life intervention

The researchers asked whether LCA can improve aging-related phenotypes when administered later in life. To test it, they gave aged mice LCA for one month. They noted that while mice and humans differ in their bile acid composition, LCA concentrations are similar in both species [4, 5].

The authors observed many improvements following LCA treatment in mice, including increased running distance, duration, and grip strength, and positive impact on other molecular measures, such as NAD+ levels, mitochondrial content, mitochondrial respiratory function, glucose tolerance, and insulin resistance.

LCA also didn’t cause muscle loss, a phenotype observed in mice and humans when restricting calories [6], suggesting that LCA treatment may be more beneficial. Additionally, muscle regeneration after damage was accelerated in aged mice following the LCA treatment.

Extending lifespan

As AMPK is an essential player in mediating lifespan extension [3], the researchers tested if LCA can mimic the effects of caloric restriction and extend lifespan in the model organisms C. elegans (worms) and D. melanogaster (fruit flies).

LCA treatment in worms and flies activated AMPK and extended their mean lifespans. In hermaphroditic C. elegans, lifespan was extended from 22 to 27 days. Lifespan extension from LCA was similar to that of caloric restriction and consistent with previous reports showing LCA-mediated lifespan extension in flies [7]: from 47 to 52 days in males and from 52 to 56 days in females.

The positive effect of LCA treatment was also evident in healthspan markers in worms and flies, for example, in a few measurements of resistance to different stresses or NAD+ levels. The activity of AMPK was necessary for those improvements since inactivating the AMPK gene in worms or flies abrogated those anti-aging effects.

The effects of LCA were more modest in mice, resulting in “a consistent, albeit nonsignificant, increase in median lifespan” when LCA was started at one year of age. Depending on the cohort, the increase was between 5.1% and 9.6% for male and between 8.3% and 12.5% for female mice.

The authors suggest that altering the LCA dose or the age at which LCA was administered might improve lifespan extension.

The role of gut microbes

The authors point to gut microbes’ role in LCA metabolism. LCA precursors are secreted from the liver to the intestine, where microbes, specifically by Lactobacillus, Clostridium, and Eubacterium species, convert it to LCA. Those microbes are known to be increased after caloric restriction [8, 9].

“It is reasonable to suggest that the LCA increase that occurs during CR may be caused by changes in these gut microbes.” Current and previous research supports the role of gut microbes in LCA metabolism when calories are restricted. The authors report detecting higher concentrations of LCA in the feces of calorically restricted mice. This was not observed in mice lacking gut microbes or with disrupted gut microbiome due to antibiotic treatment. Similarly, transplanting feces from calorically restricted mice into germ-free mice or antibiotic-treated mice caused an increase in LCA levels, which was higher than when feces were transplanted from normally fed mice.

The role of Clostridioides in increasing LCA levels is also supported by human research, as healthy centenarians with high Clostridioides levels also have high levels of LCA [10].

The authors summarize that their research “provided multiple lines of evidence to show that LCA acts as a CRM [caloric restriction mimetic], recapitulating the effects of CR, including AMPK activation and rejuvenating and anti-aging effects.“

While their research was conducted on model systems, they point to a previous study that observed that LCA was observed to be increased in the serum of healthy humans following 36 hours of fasting, suggesting a link between LCA and fasting in humans [11].

Literature

[1] Qu, Q., Chen, Y., Wang, Y., Long, S., Wang, W., Yang, H. Y., Li, M., Tian, X., Wei, X., Liu, Y. H., Xu, S., Zhang, C., Zhu, M., Lam, S. M., Wu, J., Yun, C., Chen, J., Xue, S., Zhang, B., Zheng, Z. Z., … Lin, S. C. (2024). Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature, 10.1038/s41586-024-08329-5. Advance online publication.

[2] Selman, C., Kerrison, N. D., Cooray, A., Piper, M. D., Lingard, S. J., Barton, R. H., Schuster, E. F., Blanc, E., Gems, D., Nicholson, J. K., Thornton, J. M., Partridge, L., & Withers, D. J. (2006). Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiological genomics, 27(3), 187–200.

[3] Burkewitz, K., Zhang, Y., & Mair, W. B. (2014). AMPK at the nexus of energetics and aging. Cell metabolism, 20(1), 10–25.

[4] Zhao, A., Zhang, L., Zhang, X., Edirisinghe, I., Burton-Freeman, B. M., & Sandhu, A. K. (2021). Comprehensive Characterization of Bile Acids in Human Biological Samples and Effect of 4-Week Strawberry Intake on Bile Acid Composition in Human Plasma. Metabolites, 11(2), 99.

[5] Li, M., Wang, S., Li, Y., Zhao, M., Kuang, J., Liang, D., Wang, J., Wei, M., Rajani, C., Ma, X., Tang, Y., Ren, Z., Chen, T., Zhao, A., Hu, C., Shen, C., Jia, W., Liu, P., Zheng, X., & Jia, W. (2022). Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice. Nature communications, 13(1), 2060.

[6] Heymsfield, S. B., Yang, S., McCarthy, C., Brown, J. B., Martin, C. K., Redman, L. M., Ravussin, E., Shen, W., Müller, M. J., & Bosy-Westphal, A. (2024). Proportion of caloric restriction-induced weight loss as skeletal muscle. Obesity (Silver Spring, Md.), 32(1), 32–40.

[7] Staats, S., Rimbach, G., Kuenstner, A., Graspeuntner, S., Rupp, J., Busch, H., Sina, C., Ipharraguerre, I. R., & Wagner, A. E. (2018). Lithocholic Acid Improves the Survival of Drosophila Melanogaster. Molecular nutrition & food research, 62(20), e1800424.

[8] Cai, J., Rimal, B., Jiang, C., Chiang, J. Y. L., & Patterson, A. D. (2022). Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacology & therapeutics, 237, 108238.

[9] Fraumene, C., Manghina, V., Cadoni, E., Marongiu, F., Abbondio, M., Serra, M., Palomba, A., Tanca, A., Laconi, E., & Uzzau, S. (2018). Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota. Gut microbes, 9(2), 104–114.

[10] Sato, Y., Atarashi, K., Plichta, D. R., Arai, Y., Sasajima, S., Kearney, S. M., Suda, W., Takeshita, K., Sasaki, T., Okamoto, S., Skelly, A. N., Okamura, Y., Vlamakis, H., Li, Y., Tanoue, T., Takei, H., Nittono, H., Narushima, S., Irie, J., Itoh, H., … Honda, K. (2021). Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature, 599(7885), 458–464.

[11] Fiamoncini, J., Rist, M. J., Frommherz, L., Giesbertz, P., Pfrang, B., Kremer, W., Huber, F., Kastenmüller, G., Skurk, T., Hauner, H., Suhre, K., Daniel, H., & Kulling, S. E. (2022). Dynamics and determinants of human plasma bile acid profiles during dietary challenges. Frontiers in nutrition, 9, 932937.