Mois : septembre 2024

Insilico Medicine, a clinical-stage generative AI-driven drug discovery company, announced positive preliminary results from its Phase IIa clinical trial evaluating ISM001-055. ISM001-055 is a first-in-class small molecule targeting TNIK (Traf2- and Nck-interacting kinase) and was designed utilizing generative AI to treat idiopathic pulmonary fibrosis (IPF). The study met both its primary endpoint of safety and its secondary efficacy endpoints, demonstrating dose-dependent response in forced vital capacity (FVC), a critical measure of lung function in IPF patients.

Insilico’s proprietary AI platform facilitated ISM001-055’s target identification and molecular design. Its development was recently described in a March 2024 Nature Biotechnology paper, which detailed TNIK’s identification as a novel therapeutic target in IPF and ISM001-055 subsequent design. This comprehensive paper showcased ISM001-055’s preclinical evaluation and positive Phase 0 & Phase I clinical studies justifying this intervention’s potential as a disease-modifying agent for IPF.

ISM001-055’s Phase IIa study (NCT05938920) was a randomized, double-blind, placebo-controlled trial that enrolled 71 patients with IPF across 21 sites in China. Patients were randomized to receive either placebo, 30mg once daily (QD), 30mg twice daily (BID), or 60mg QD for 12 weeks. Patient enrollment was initiated in April 2023, and the last subject’s follow-up visit was completed in August 2024. A parallel Phase IIa (NCT05975983) clinical trial in the U.S. is ongoing and actively enrolling patients.

In this 12-week Phase IIa study, ISM001-055 met its primary endpoint of safety and tolerability across all dose levels. Positive results were also reported for the secondary efficacy endpoint, wherein a dose-dependent FVC improvement was observed. Patients receiving 60mg QD of ISM001-055 demonstrated the largest improvement in FVC.

Complete topline data will be released at the upcoming medical conference and clinical trial results will be submitted for publication in a peer-reviewed journal.

“These results are very encouraging, particularly the dose-dependent response in FVC. IPF is a devastating disease, and seeing improvements in lung function over just 12 weeks of treatment is a promising indication that ISM001-055 may provide a new therapeutic option for patients. Our Phase IIa in the U.S. is actively recruiting patients,” said Toby M. Maher, MD, PhD, a leading expert in interstitial lung disease and an investigator in the trial.

“Last year, I presented a lecture on how generative AI can help with end-to-end drug discovery from disease modeling and target identification to generation of novel drugs with the desired properties and purposing it to a specific disease. I used Insilico’s TRAF2 and NCK-interacting kinase (TNIK) inhibitor as a case study going from 0 to Phase I. The fact that this same drug demonstrated efficacy in addition to safety in a Phase IIa study is extraordinary and represents a true first in this new era of AI-powered drug discovery,” said Michael Levitt, PhD, 2013 Nobel Laureate in Chemistry.

“With all the hype that surrounds the potential of generative AI in drug discovery and many other potential applications, it is thrilling see to the dose dependence of ISM001-055 in Insilico Medicine’s phase IIa IPF clinical trial. This is strong evidence that the drug is truly effective and that favorable results will continue to be seen in future trials,” said Charles Cantor, PhD, a renowned geneticist and advisor to the company since 2014.

“This is great news for the field of AI for drug discovery. The fact that this molecule is safe and has a dose-dependent response means that there is a green light for further studies. I am hopeful it continues its path to making a difference,” said Alan Aspuru-Guzik, PhD, Professor of Chemistry and Computer Science at the University of Toronto and CIFAR AI Chair at the Vector Institute.

“This study result represents a critical milestone in AI-powered drug discovery and in my life to date,” said Alex Zhavoronkov, PhD, co-CEO of Insilico Medicine. “While we expected the drug to be safe, we did not expect to see such a clear dose-dependent efficacy signal after such a short dosing period. IPF is a very diverse disease and it is very rare to see improvement in FVC. With our novel TNIK inhibitor, we attempted to go after what we think is a common mechanism in fibrotic diseases and in aging to maximize indication expansion potential.”

“I am excited to see that ISM001-055 demonstrated obvious clinical efficacy in IPF patients in only 3-months treatment. While preliminary, this clinical data is certainly encouraging, and provides the clinical validation of AI-powered drug R&D for both novel target and novel molecule,” said Feng Ren, PhD, co-CEO and CSO of Insilico Medicine. “ This is a significant milestone for Insilico Medicine and the AI driven drug discovery Industry. The milestone is achieved due to the contribution of both the capabilities of our proprietary generative AI platform and the efforts of our multidisciplinary R&D team. We will continue to fully commit to provide breakthrough solutions for the benefit of the patients globally.”

Following the positive results from this Phase IIa trial, Insilico Medicine will engage regulatory authorities to discuss the design of a Phase IIb study. The company aims to explore extended treatment durations and larger patient cohorts to further investigate ISM001-055’s therapeutic potential in IPF.

About ISM001-055 and TNIK

ISM001-055 is a potentially first-in-class small molecule targeting TNIK utilizing generative AI. In IPF, the activation of TNIK drives pathological fibrosis in the lungs, contributing to the progressive decline in lung function. By inhibiting TNIK, ISM001-055 aims to halt or reverse fibrotic processes, offering a disease-modifying treatment for patients with IPF. In February 2023, ISM001-055 received Orphan Drug Designation from the FDA for treating Idiopathic Pulmonary Fibrosis.

About the Phase IIa Study

The double-blind, placebo-controlled Phase IIa clinical trial (NCT05938920) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of 12-week oral ISM001-055 dosage in 71 subjects with IPF. Patients from 21 sites were randomized into four parallel cohorts: 30mg QD, 30mg BID, 60mg QD, and placebo. Preliminary results from the study show ISM001-055 demonstrated a good safety profile and dose-response trend in lung function in IPF patients.

About Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, scarring lung disease characterized by a progressive and irreversible decline in lung function. Affecting approximately 5 million people worldwide, IPF carries a poor prognosis, with a median survival of 3 to 4 years. Current treatments, including antifibrotic drugs, can slow disease progression but do not stop or reverse it, leaving a significant unmet need for more effective, disease-modifying therapies. IPF is an age-related disease, with the average age of onset typically between 60 and 70 years, and it is most commonly diagnosed in older adults. The disease is rare in individuals under the age of 50.

About Insilico Medicine

Insilico Medicine, a global clinical-stage biotechnology company powered by generative AI, connects biology, chemistry, and clinical trial analysis using next-generation AI systems. The company has developed AI platforms that utilize deep generative models, reinforcement learning, transformers, and other modern machine learning techniques to assist novel target discovery and the generation of novel molecular structures. Insilico Medicine is developing breakthrough solutions to discover and develop innovative drugs for cancer, fibrosis, immunity, central nervous system diseases, infectious diseases, autoimmune diseases, and aging-related diseases. www.insilico.com

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Yes I will donate

Researchers have published a review of the current state of combination therapies that address multiple Hallmarks of Aging [1]. Some of these combined therapies were found to induce greater lifespan extension than single treatments.

A complex phenomenon calls for complex treatments

The complexity of aging cannot be underestimated. It is unlike individual diseases, which primarily affect single organs. Aging affects the entire body and does so by affecting countless molecular processes. Therefore, to slow down or reverse it, it must be attacked from multiple directions, such as by using a combination of therapies.

While there is broad research in model organisms on genetic and pharmaceutical approaches that target aging, most of the approaches result in modest lifespan increases in mammals.

The authors of the review state that “this outcome is to be expected if we consider that even if one aging process is successfully treated, other aging pathways may remain intact” and limit the organism’s lifespan. Therefore, multiple aspects of aging must be addressed at once.

More therapies are better than one

The researchers reviewed the literature to gather data on existing combination therapies targeting pathological processes in aging. They used the Hallmarks of Aging as a reference point and focused on mouse studies, since mice are the most commonly studied mammalian model organism.

The combined therapies that showed improvements compared to single treatment in rodents included rapamycin and metformin; rapamycin and acarbose (an anti-diabetic drug); simvastatin and ramipril (cardiovascular disease drugs); glycine plus N-acetylcysteine (both ameliorate age-associated glutathione deficiency and reduce oxidative stress); elevated expression of the oncosuppressors p53 and Arf, with telomerase reverse transcriptase improving them even further; PROP1 gene deficiency and caloric restriction; suppression of growth hormone and caloric restriction, and the overexpression of the antioxidant enzymes catalase and superoxide dismutase.

Some of those combinations were effective not only in lifespan extension but also in improving some age-related phenotypes, such as cognitive impairment. However, some of them had sex-specific effects.

Being strategic

The authors of this review believe that a good way to approach the design of combination therapies is by using several therapies that attack different Hallmarks of Aging.

In their paper, they mention that “the current availability and diversity of lifespan-promoting therapies allows the possibility to design studies in mice targeting at least thirteen hallmarks of aging simultaneously” and nine of them don’t require genetic manipulations of embryos.

Combination therapies are also investigated by the LEV Foundation, which is testing a combination of rapamycin, a senolytic navitoclax, hematopoietic stem cell transplantation (HSCT), and telomerase expression [2]. This strategy targets six Hallmarks of Aging.

Since there are many possible combinations, but resources and time are limited, the authors elaborate on guidelines on which combination therapies to prioritize in testing, such as cost, effectiveness, feasibility, ability to be sustained for longer periods (caloric restriction is not easily sustained), and effectiveness when applied to already-aged organisms.

The authors suggest a few strategies that can be utilized in designing combination therapies. They wish to focus on therapies that have shown the best lifespan extension individually and combine them, attempting to target a maximum of hallmarks with few treatments and then bolstering that combination with underused lifespan-extending treatments that target further hallmarks. They wish to screen combination pairs that target different Hallmarks of Aging, with a focus on widely-used therapies with proven safety in humans.

Limitations

The researchers note that one of this review’s limitations is that most of the research is done on mice. The results of those experiments often depend on the animals’ living conditions, genetic backgrounds, etc. While animal research is essential, not all of it might translate to humans.

Additionally, using the Hallmarks of Aging framework is limiting; for example, this framework doesn’t differentiate between primary and secondary causes of aging. If a better framework is created, it can aid in the improved selection of therapies for combinatorial treatments.

While combination therapies are promising anti-aging approaches, the authors also point out possible drawbacks, one of the most important being possible adverse effects, especially for healthy people for whom the risks might outweigh the benefits. They also admit that many of these therapies have not been carefully evaluated for side effects, and combining therapies adds complexity and could offset or combine side effects.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Yes I will donate

Literature

[1] Panchin, A. Y., Ogmen, A., Blagodatski, A. S., Egorova, A., Batin, M., & Glinin, T. (2024). Targeting multiple hallmarks of mammalian aging with combinations of interventions. Aging, 16(16), 12073–12100.

[2] Lewis, C. J., & De Grey, A. D. (2024). Combining rejuvenation interventions in rodents: a milestone in biomedical gerontology whose time has come. Expert Opinion on Therapeutic Targets.

Scientists have found a correlation between the intensity of nighttime outdoor lighting, which can disrupt sleep, and Alzheimer’s disease [1].

Light pollution – heavy consequences

Outdoor lights help us with a lot of things, such as illuminating our streets and highways, discouraging crime, and so on. City nightlines and views of Earth at night from the orbit are among the most iconic images of our civilization. However, bright lights during nighttime are also quite unnatural for our biology, which is built around circadian rhythms.

Excessive levels of artificial outdoor light are called “light pollution” and have been linked to sleep disruption, obesity, depression, anxiety, memory dysfunction, atherosclerosis, and cancer [2]. Indoor light was found to be a problem as well [3]. Laws exist in certain states and countries that limit light pollution levels.

Some of those conditions, especially sleep disruption and depression, are known comorbidities for Alzheimer’s disease. In a new study, researchers from Rush University Medical Center in Chicago set out to investigate a direct link between light pollution and Alzheimer’s.

One of the strongest factors

The scientists assigned a light pollution score to each US state and retrieved data on Alzheimer’s prevalence in those states, controlling for several known factors that contribute to Alzheimer’s: alcohol abuse, atrial fibrillation, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, obesity, and stroke.

In their analysis, average nighttime light intensity was significantly associated with Alzheimer’s prevalence. This correlation remained strong in both people under and over 65, males and females, and across all races except Asian Pacific islanders.

Average nighttime light intensity was associated with Alzheimer’s prevalence even when accounting for alcohol abuse, chronic kidney disease, depression, heart failure, and obesity. According to the researchers, this suggests that nighttime light intensity has a stronger influence on Alzheimer’s than any of these conditions.

However, other covariates had a stronger association with Alzheimer’s than light intensity. Those included atrial fibrillation, diabetes, hyperlipidemia, hypertension, and stroke, “indicating that nighttime light exposure had a more subtle effect than these disease covariates.” Interestingly, for people under the age of 65, average light intensity was associated with Alzheimer’s even when accounting for all the covariates.

There is, of course, a lot of heterogeneity inside states. Some areas are more populated and some less, which results in corresponding differences in light pollution. For a more fine-grained outlook, the researchers picked 45 counties from across the country and threw in the District of Columbia. Nighttime light intensity was determined for the counties that contain the largest city in each state, and this data was compared to Medicare Chronic Conditions’ county-level data on Alzheimer’s.

The correlation held strong on a county level, too. In fact, it was even stronger than on a state level:

Interestingly, a county’s population size did not seem to define its levels of light pollution:

Possible lifestyle changes

“We show that in the US there is a positive association between AD prevalence and exposure to light at night, particularly in those under the age of 65,” said the first author of the study, Dr. Robin Voigt-Zuwala, an associate professor at Rush University Medical Center. “Nightly light pollution, a modifiable environmental factor, may be an important risk factor for AD.”

Discussing the seemingly stronger correlation between light pollution and Alzheimer’s in the younger population, Voigt-Zuwala suggested that “younger people are more likely to live in urban areas and have lifestyles that may increase exposure to light at night.”

How can this risk factor be mitigated? “Awareness of the association should empower people, particularly those with risk factors for AD, to make easy lifestyle changes,” said Voigt-Zuwala. “Easy to implement changes include using blackout curtains or sleeping with eye masks. This is useful especially for those living in areas with high light pollution.”

Like any populational study, this one does not prove a causal relationship but only shows correlation. It also had several limitations; for instance, it didn’t account for people migrating during their lives. Still, the study highlights the importance of light pollution as part of the exposome, the set of environmental conditions that affect human health.

The analyses reveal that greater average nighttime light intensity (i.e., light pollution) was associated with higher AD prevalence. This was true for 2012–2018 average and each year examined individually, and in those over and under the age of 65 (i.e., 65+, <65), in both sexes, and in each race (except Asian Pacific Island which may be related to power). This finding was observed when examining data on the state level as well as on the county level.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Yes I will donate

Literature

[1] Voigt, R. M., Ouyang, B., & Keshavarzian, A. (2024). Outdoor nighttime light exposure (light pollution) is associated with Alzheimer’s disease. Frontiers in Neuroscience, 18, 1378498.

[2] Bożejko, M., Tarski, I., & Małodobra-Mazur, M. (2023). Outdoor artificial light at night and human health: a review of epidemiological studies. Environmental Research, 218, 115049.

[3] Sweeney, M. R., Nichols, H. B., Jones, R. R., Olshan, A. F., Keil, A. P., Engel, L. S., … & Jackson, C. L. (2024). Exposure to indoor light at night in relation to multiple dimensions of sleep health: findings from the Sister Study. Sleep, 47(2), zsad100.