Drs. Iwao Ojima, left, and Martin Kaczocha in a Stony Brook University laboratory. Photo by John Griffin, Stony Brook University
A non-opioid investigational drug with promising pre-clinical results in treating neuropathic pain has passed an important hurdle after the study’s safety review committee (SRC) reviewed the data from initial volunteers and recommended to progress into the next dose level in a first-in-human clinical trial.The drug, ART26.12, is being developed by Artelo Biosciences, Inc, based in Solana Beach, Calif.
The compound was discovered and initially developed by Stony Brook University’s Iwao Ojima, PhD, and Martin Kaczocha, PhD. The technology is based on a class of fatty acid binding proteins (FABPs) inhibitors, including what is now ART26.12, and was licensed to Artelo in 2018 by the Research Foundation for the State University of New York.
Neuropathic pain is estimated to affect about eight percent of the U.S. population, which translates to approximately 20 million people. ART26.12 is being developed specifically for chemotherapy-induced peripheral neuropathy, which remains a serious adverse problem for patients during cancer therapy and post therapy.
Dr. Ojima and colleagues selected FABPs as drug targets of the body’s endocannabinoid system to modulate lipids within the cell for a potentially promising way to treat pain, inflammation and cancer. According to Artelo, ART26.12 is the lead compound in Artelo’s proprietary FABP platform and is believed to be the first-ever selective FABP5 inhibitor (5 indicates a specific protein) to enter clinical trials.
The SRC completed its initial clinical safety review of ART26.12 in early January for the first cohort of eight volunteers. With that, the phase 1 clinical trial of this drug will advance to the next step, which will include more subjects and an evaluation of higher doses of the investigational drug.
Artelo says that other potential indications with the lead compound and other FABP5s in development include treatments related to cancer, osteoarthritis, psoriasis and anxiety.
Dr. Ojima, SUNY Distinguished Professor in the Department of Chemistry at Stony Brook University, and Director of the Institute of Chemical Biology and Drug Discovery, and Dr. Kaczocha, Associate Professor in the Department of Anesthesia in the Renaissance School of Medicine, led the Stony Brook team in its work developing inhibitors to various FABPs.
They continue to consult with Artelo regarding the advancement of these compounds in clinical trials.
For more about the FABP inhibitor story, see this 2024 press release. For more about Artelo’s successful completion of the first cohort in the phase 1 study of ART26.12, see this press release.
From left, Iwao Ojima, Ashna Garg and Maurizio Del Poeta.
Photo by Kathryn Takemura
By Daniel Dunaief
It worked for mice and now, several years later, has shown promise for cats.
Researchers from Maurizio Del Poeta’s lab, working closely with those from Iwao Ojima’s team at Stony Brook University, have demonstrated that an experimental treatment against a fungus resistant to the current standard of care can work with cats battling a ferocious infection, albeit on a small sample size.
The Stony Brook team, along with scientists and veterinarians in Brazil, used a drug they created in 2018 called D13 to treat 10 cats with severe forms of a fungus that affects cats and humans called sporotrichosis.
With this treatment, which the researchers introduced as a powder into the cat’s food, half of the 10 felines whose skin was under insidious attack from the fungus staged remarkable recoveries, offering a potentially promising development that could one day also offer an alternative care for cats and for people.
“The prevalence in South America is 25 to 20 cases per 100,000 people, which is not low,” explained Del Poeta, Distinguished Professor of Microbiology and Immunology. “It affects mostly immunocompromised people and particularly people who have cats or people taking care of infected cats.”
Tis cat presented no improvement of the tumor-like lesion and of an ulcerated lesion on the nasal region upon treatment with ITC. After adding D13, the cat significantly improved, even though clinical cure was not achieved after 4 weeks of treatment with ITC and D13 combination.
Typically, people get superficial infections, but a person who is severely immunocompromised could have an infection that spreads and becomes fatal.
The work taps into the expertise of Ojima, a Distinguished Professor in the Department of Chemistry. Ojima worked on the structure elucidation, the structure activity relationship and development of efficient synthetic methods for large scale synthesis of the drug.
Recent Stony Brook PhD graduate Ashna Garg contributed to this ongoing effort.
Ojima described the work as “solidly encouraging” and added that the scientists have “even better compounds in the same series for human use” that are more potent and more selective to fungi compared to humans which makes systemic toxicity “very low.”
Del Poeta’s lab has been studying sphingolipids metabolism and signaling in fungal and mammals cells to identify new markers for early diagnosis and microbial enzymes/ molecules essential to cause infections in the attempt to develop new antifungal targets.
To be sure, in the cat research, five out of the 10 cats didn’t complete the study. One of them died, although the cause of death was unknown, and four of the other cats abandoned the study.
Additionally, one of the cats for whom the drug worked showed an elevated level of a liver enzyme, which returned to normal within weeks of the conclusion of the study.
Still, the results were promising and provided encouraging improvements for cats battling an infection that threatened their health.
“I am very pleased with the efficacy of D13 on cats in Brazil,” explained Ojima, adding that it is “a compelling result.”
Additionally, in other preliminary studies, D13 works against various fungal infections, including cryptococcosis, aspergillosis and candidiasis. A new derivative of D13 is more effective for those other infections, the scientists said.
Del Poeta explained that the scientists chose to do the research in Brazil because of the prevalence of sporotrichosis in the area and because he had established collaborations in the country in earlier research.
‘Proud and grateful’
For her part, Garg was thrilled to contribute to research that provided a remedy to a deteriorating condition in an animal some of her friends own as pets.
Cat owners often reacted emotionally when she told them about her work, appreciating the significance of the results.
“I am deeply proud and grateful to have contributed to this work,” said Garg. “Its remarkable effectiveness continues to inspire and motivate me.”
A significant part of her PhD revolved around taking the initial lead compounds and developing second and third generation compounds to enhance their effectiveness and bioavailability.
With three bromine atoms, D13 is an unusual therapeutic treatment.
Bromine is “relatively rare among the top 200 pharmaceuticals,” Garg explained. “Bromine can be toxic or can act as an irritant. Part of my work involved exploring ways to reduce the bromine content” to make the treatment more viable in drug development. The scientists are working to understand why and how this treatment works.
“The exact mechanism of action of D13 is not fully understood yet but we are getting very close,” Garg explained.
With the third generation of D13, the team identified compounds that are highly fungal specific with broad spectrum activity, effectively eradicating 100 percent of the three malignant type of fungi.
“It’s important to note that some first and second generation compounds also demonstrated excellent antifungal activity at very low drug concentrations, even if they did not achieve complete eradication on one of the three fungal strains,” Garg added.
While promising, this study does not indicate a new human treatment will be on the market in the short term.
The scientists are doing toxicology studies and hope a new therapeutic option might be available as soon as five years, Del Poeta estimated.
From Delhi to Stony Brook
Garg, who defended her thesis in December, grew up in Delhi, India, where she pursued her undergraduate studies in Chemistry at Delhi University.
After that, she earned her Master’s in Chemistry at Vellore Institute of Technology in Tamil Nadu, India.
Garg arrived at Stony Brook in 2019 and joined Ojima’s lab in early 2020, just at the start of the pandemic.
“It was indeed a challenging time to start a new position,” Garg acknowledged.
Currently a resident of Poquott, Garg enjoys living on Long Island, where she visits beaches, drives around the area and cooks.
Garg, who attended meetings in the labs of both Professors Ojima and Del Poeta, is grateful for the support of these senior scientists, who were also part of her thesis committee.
Del Poeta described Garg as a “dedicated scientist” with an “impeccable” work ethic.
“Drug synthesis can be very challenging,” Del Poeta described. “She is tirelessly resilient.”
Garg is staying at Stony Brook for another year as a post-doctoral researcher.
Del Poeta is pleased with the productive collaboration he’s had with Ojima, whom he described as “passionate, intellectually stimulating, dedicating, inspiring and hard working.”
If Del Poeta sends an email on Saturday night, Ojima typically replies by Sunday morning.
“It is an honor to collaborate with him,” Del Poeta explained. Ojima’s work “makes these impressive results possible.”
Iwao Ojima and Martin Kaczocha (foreground) led the Stony Brook team in developing its class of Fatty Acid Binding Proteins (FABPs) a promising set of drug targets for new therapies.
Photo by John Griffin, Stony Brook University
The “FABP” inhibitor is part of a series of compounds that uses the body’s natural marijuana-like substances to curb pain and inflammation
Six years ago Stony Brook University through the Research Foundation for the State University of New York licensed a promising technology to Artelo Biosciences that identified Fatty Acid Binding Proteins (FABPs) as drug targets of the body’s endocannabinoid system for a potentially promising way to treat pain, inflammation and cancer. Now the first one of these compounds has been cleared by the Food and Drug Administration (FDA) for human clinical trials.
Artelo announced this week that the FDA’s initial approval of one of the FABP5 (5 indicates a specific protein) selective compounds called ART26.12 enables the company to initiate its first human phase 1 single ascending dose study of the drug. The company states that ART26.12 will address a critical need for cancer patients, treating chemotherapy-induced peripheral neuropathy. Phase 1 clinical trials are expected to be launched internationally during the first half of 2025.
ART26.12 is the lead compound in the series of FABP5 inhibitors under development. In 2018, Artelo received an exclusive license to the intellectual property of all FABP inhibitors for the modulation of the endocannabinoid system.
The work on FABPs originated with Iwao Ojima, PhD, SUNY Distinguished Professor in the Department of Chemistry at Stony Brook University, Martin Kaczocha, PhD, Associate Professor in the Department of Anesthesiology in the Renaissance School of Medicine at Stony Brook University, and Dale Deutsch, PhD, Professor Emeritus in the Department of Biochemistry and Cell Biology at Stony Brook University, a research collaboration affiliated with the Institute of Chemical Biology and Drug Discovery (ICB & DD). They identified the action of FABPs as drug targets. Specifically, FABP5 was identified as the intracellular transporter for the endocannabinoid anandamide (AEA), a neurotransmitter produced in the brain that binds to cannabinoid receptors.
The research group demonstrated in the laboratory that elevated levels of endocannabinoids can result in beneficial pharmacological effects on stress, pain and inflammation and also ameliorate the effects of drug withdrawal. Drs. Ojima (also Director of the ICB & DD), Kaczocha, Deutsch and colleagues discovered that by inhibiting FABP transporters, the level of AEA is raised. The finding provided the basis for the drug development approach to elevate the levels of AEA.
Artelo took this concept and approach to further develop the compounds. Their scientists collaborated with the Stony Brook team to reach new findings that has led to the commercialization and use of the first drug (ART26.12) in a potential pipeline of drugs to treat pain and inflammation.
After the license to Artelo was finalized, Drs. Ojima and Kaczocha under a contract with Artelo synthesized and evaluated compound candidates with high FABP5 potency and selectivity, an effort that culminated in the development of the lead candidate, SB-FI-1621, which Artelo named ART26.12.
“This is the first clinical stage compound targeting the FABP pathway, an important and exciting milestone,” says Sean Boykevisch, PhD, Director of Intellectual Property Partners in Stony Brook’s Technology Transfer Office. “The fundamental and translational research conducted by the Stony Brook team and their subsequent collaboration with Artelo resulted in a true bench-to-bedside program with the goal of better patient experiences and outcomes.”
“We look forward to sharing the initial clinical results with ART26.12 next year,” says Gregory D. Gorgas, President and CEO of Artelo Biosciences. “As the leading company pursuing FABP inhibition we are committed to building on the unique, lipid-modulating mechanism of our FABP inhibitor platform to address life-altering pathologies for which there are few, if any, safe and effective pharmaceutical treatments.”
For more about the Stony Brook research that developed FABP inhibitors and the grant to support years of research, see this news.
For more details on the FDA clearance news of the drug, and Artelo’s R&D plan, see this news.
From left, Martin Kaczocha, Robert Rizzo, Iwao Ojima and Lloyd Trotman. Photo from SBU
By Daniel Dunaief
Pulling together experts from a variety of fields, scientists at Stony Brook University and Cold Spring Harbor Laboratory have demonstrated promise in their efforts to tackle prostate cancer in a new way.
Led by Iwao Ojima, a distinguished professor of chemistry and director of the Institute of Chemical Biology and Drug Discovery at SBU, and Martin Kaczocha, an assistant professor in the Department of Anesthesiology at SBU, the multidisciplinary team recently received a five-year, $4.2 million grant from the National Cancer Institute.
The team is following up on its preliminary success with inhibitors of fatty acid binding protein 5, or FABP5. By tamping down on this protein in prostate cancer cells grown in the lab and in mouse models of the disease, these researchers treated metastatic cancer cells.
The scientists, who received a Translational Research Opportunities Seed Grant from the Renaissance School of Medicine at Stony Brook, were pleased with the next steps in their research.
“We’re happy that the National Cancer Institute validated our target,” said Kaczocha. It will help us “move forward and expand the scope of our work.”
From left, Robert Rizzo, Iwao Ojima, Martin Kaczocha and Lloyd Trotman. Photo from SBU
To be sure, scientists are generally cautiously optimistic about the translation between basic discoveries about mechanisms involved in cancer and the ability of doctors to use these findings in future therapies. Indeed, numerous promising early efforts haven’t always led to treatments. “Many tumors develop resistance to existing therapies through a variety of mechanisms,” said Kaczocha.
Still, the researchers involved in the current study hope the findings will eventually provide another tool in the treatment of prostate cancer.
The inhibitors scientists including Lloyd Trotman, a professor at Cold Spring Harbor Laboratory, are testing “appear to work in a context where [other treatments] lose efficacy. We hope this will translate” to a setting in which the researchers test their treatment in a mouse model of prostate cancer, explained Kaczocha. One of the goals of the NCI grant is to find further validation of this benefit.
Eventually, any possible treatment that utilizes these findings would involve a combination of inhibitors and existing therapeutics, Kaczocha said.
To create a product that might target this molecule, Ojima screened more than one million commercially available compounds on a computer. Out of over 1,000 compounds designed and analyzed, he selected about 120 for chemical synthesis and biological assay.
Artificial intelligence helps dig out known matters from a huge data, but not for newly created substances. Ojima found more than 30 compounds from the ones he synthesized and tested that were more advanced than the original project.
“It’s an ongoing process,” Ojima explained, adding that he believes he will find a more efficacious inhibitor. Ojima and Kaczocha are working with Robert Rizzo, a professor in the Department of Applied Mathematics & Statistics at SBU to develop these inhibitors.
Indeed, that process involves determining the stability, bioavailability and many other factors to minimize any adverse side effects
The side effects from this treatment connect to the original focus of the scientific team. As it turns out, inhibiting FABP5 causes pain relief because it reduces the breakdown of anandamide, or AEA, which is part of the body’s natural pain relief system. The inhibitors also have anti-inflammatory properties.
“This compound’s side effect is pretty beneficial for patients,” said Ojima.
The Long Island team is continuing to pursue the use of these compounds to manage pain as well.
Indeed, Kaczocha’s mother Zofia, who has pain associated with arthritis, asks him at least once a month when his drug will be available. The NCI grant will enable him and his colleagues to continue to build on their earlier work as they hope to translate their scientific discoveries into a clinical option.
“We are continuing our original research on the use of FABP5 inhibitors for pain control,” Ojima explained in an email.
As for their work with cancer, the inhibitors are “less cytotoxic,” Ojima said, and, in animal models, have been able to kill metastatic cancer cells that have become resistant to drug treatment. He suggested that the hope of this treatment is that it can sensitize the cancer cells or tumor to other therapies, which is a “promising approach.”
So far, Ojima, Kaczocha, Trotman and colleagues have tested this treatment only on tumors that haven’t yet metastasized, and not on tumors that have spread to other organs. “Our hope is that it may have some preventive effect in the early stages” of metastasis, Ojima said.
Ojima and Kaczocha were grateful for the seed grant from the medical school, which helped push the research forward. “A seed grant is very important for basic research,” Ojima added.
Other cancers, such as breast cancer, also have over expression of the same fatty acid binding protein. While the scientists are starting with prostate cancer, they hope to expand their work to other cancers as well, once they start gathering results.
La Jolla, California-based Artelo Biosciences partnered with these researchers starting in the spring of 2018. Artelo is licensing the patents for the target as well as the patents for lead compounds. Moving any compound through the beginning of the Food & Drug Administration testing is something Artelo will eventually take over, Kaczocha said. “They will have the financing to pursue this further,” he added.
As a researcher and a pharmacologist who is involved in basic and translational studies, Kaczocha said his hope is always to develop something in his career that will help patients.
Other research groups are also developing small molecule inhibitors to reduce the prevalence or activity of fatty acid binding proteins, but these other scientists have generally not focused on the role of these proteins in cancer. Fatty acid binding protein 4, for example, has a role in metabolic disorders.
“We have a relatively unique position where we are targeting prostate cancer” by reducing the activity and effect of this protein, Kaczocha said.
Trotman, whose lab has a unique animal model of prostate cancer that is a close mimic to the progression of prostate cancer in humans, offers an advantage in their research work, added Kaczocha.
