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Calibr at Scripps Research Logo Bill and Melinda Gates Medical Research Institute Logo Calibr transitions investigational compound CLB073 to Gates MRI to advance development LA JOLLA, Calif. and CAMBRIDGE, Mass., Feb. 15, 2023 /PRNewswire/ -- Calibr, a division of Scripps Research dedicated to the "bench to bedside" development of transformative medicines, and the Bill & Melinda Gates Medical Research Institute (Gates MRI), today announced a strategic licensing agreement to advance development of a novel investigational compound for tuberculosis treatment. Under the agreement, Calibr is granting Gates MRI an exclusive license to continue the development of the investigational compound CLB073 for tuberculosis treatment. Calibr will transition CLB073 to Gates MRI for further development. "Eradicating tuberculosis will require enhancing the world's current therapeutic options—meaning shortening treatment duration and overcoming drug resistance," says Case McNamara, PhD, senior director of Infectious Disease at Calibr. "At Calibr, we have been working with collaborators, through the support of the Bill & Melinda Gates Foundation, to discover and develop novel medicines for diseases that require improved treatment regimens, such as tuberculosis. We hope our collaboration with Gates MRI to advance CLB073 will ultimately be able to help the millions of people who contract this deadly disease." Calibr transitions investigational compound CLB073 to Gates MRI to advance development Tweet this Tuberculosis is a severe disease caused by the bacterium Mycobacterium tuberculosis (Mtb). Mtb is known to sequester in lung macrophages following infection. Macrophages are a type of immune defense cell that typically kill infecting microorganisms. Mtb has the ability to establish a prolonged infection in these cells and, under certain conditions, relies on the macrophage's cholesterol supply as a key carbon source for growth. To develop a drug capable of targeting Mtb in a new way, scientists at Calibr collaborated with researchers at the Cornell University College of Veterinary Medicine, including David Russell, PhD, the William Kaplan Professor of Infection Biology, and Brian VanderVen, PhD, an associate professor of Microbiology & Immunology. Together, they discovered and pre-clinically studied CLB073, which uses a novel mechanism to weaken Mtb's intramacrophage survival. CLB073 works by modulating cholesterol catabolism and eliminating the bacteria's carbon source. CLB073 activates adenylyl cyclase (Rv1625c), which ultimately blocks the ability of Mtb to metabolize cholesterol. With this novel mechanism, CLB073 holds the potential to complement and potentiate the current tuberculosis standard of care, with the intent of improving efficacy and shortening the duration of treatment time. This is especially critical for multidrug-resistant Mtb, which has compromised many frontline drugs. This work was executed through the TB Drug Accelerator, a partnership for tuberculosis (TB) drug discovery and development funded by the Bill & Melinda Gates Foundation. In preclinical mouse studies, CLB073 significantly enhanced efficacy of the Nix-TB drug regimen1—the tuberculosis standard of care for drug-resistant tuberculosis. "Tuberculosis is one of the world's most significant infectious causes of human disease and death," said Emilio Emini, PhD, chief executive officer of the Bill & Melinda Gates Medical Research Institute. "CLB073, discovered by Calibr scientists and now licensed to the Gates MRI for further development, may represent a potentially important constituent of future TB therapeutic regimens." About Tuberculosis Tuberculosis (TB) is a major global cause of illness and disability, and it is one of the leading causes of death from an infectious disease worldwide, responsible for an estimated 1.5 million deaths per year. The most commonly used drug regimen for the treatment of drug-sensitive TB requires patients to take multiple drugs usually for a minimum of six months with routine clinical monitoring. Patients with drug-resistant forms of the infection can face longer and more complex treatment journeys, often with significant side effects that require increased monitoring. The need for drug-resistance testing prior to treatment initiation is an added challenge. A substantially shorter drug regimen for the treatment of both drug-susceptible and drug-resistant forms of TB could provide a significant benefit to both patients and health systems and may overcome the need for accompanying drug-resistance testing. About Calibr Calibr was founded on the principle that the creation of new medicines can be accelerated by pairing world-class biomedical research with state-of-the-art drug discovery and development capabilities. Leveraging the unique scientific framework of Scripps Research, Calibr has created a portfolio of drug candidates based on Scripps technologies and is shaping a new paradigm for advancing nonprofit biomedical research to impact patients. About the Bill & Melinda Gates Medical Research Institute (Gates MRI) The Bill & Melinda Gates Medical Research Institute is a non-profit medical research organization dedicated to the development and effective use of novel biomedical interventions addressing substantial global health concerns, for which investment incentives are limited, including malaria, tuberculosis, enteric and diarrheal diseases, and diseases that impact maternal, newborn, and child health. For further information please visit . Contact: [email protected] [email protected] SOURCE Calibr at Scripps Research; The Bill & Melinda Gates Medical Research Institute

BETHESDA, Md., Feb. 14, 2023 /PRNewswire-HISPANIC PR WIRE/ -- WHAT: In a mouse study, researchers funded by the National Institutes of Health have identified a potential non-hormonal contraceptive that men could take shortly before sexual activity and have fertility restored the next day. Researchers gave male mice a compound that temporarily disables soluble adenylyl cyclase, the enzyme essential for activating a sperm cell's ability to swim and mature so that it can travel through the female reproductive tract and fertilize an egg. In several tests, the researchers showed that the compound TDI-11861 rendered mouse sperm cells immobile and prevented them from maturing. The compounds did not interfere with the animals' sexual functioning. Although male mice mated with females, no pregnancies were observed. Sperm recovered from female mice remained incapacitated. The authors did not observe any side effects in the male or female mice. The compound wore off three hours later, and males recovered their fertility. The study was conducted by Melanie Balbach, Ph.D., a postdoctoral fellow in the laboratories of coauthors Jochen Buck, Ph.D., and Lonnie Levin, Ph.D., at Weill Cornell Medical College, New York City, and colleagues. It appears in Nature Communications. Funding was provided by NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging, and National Cancer Institute. The researchers say their work provides proof of concept that soluble adenylyl cyclase inhibitors have the potential to provide a safe, on-demand, non-hormonal and reversible oral contraceptive for men. WHO: Christopher C. Lindsey, Ph.D., a program official in the NICHD Contraception Research Branch, is available for comment. ARTICLE: Balbach, M. Research Letter: On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature Communications.2022. About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit . About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit . SOURCE Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (NIH)

An experimental contraceptive drug temporarily stops sperm in their tracks and prevents pregnancies in preclinical models. The study demonstrates that an on-demand male contraceptive is possible. An experimental contraceptive drug developed by Weill Cornell Medicine investigators temporarily stops sperm in their tracks and prevents pregnancies in preclinical models. The study, published in Nature Communications on Feb. 14, demonstrates that an on-demand male contraceptive is possible. The discovery could be a "game-changer" for contraception, according to the study's co-senior authors Dr. Jochen Buck and Dr. Lonny Levin, who are professors of pharmacology at Weill Cornell Medicine. Drs. Buck and Levin noted that condoms, which have existed for about 2000 years, and vasectomies have been men's only options to date. Research on male oral contraceptives has stalled, partly because potential contraceptives for men must clear a much higher bar for safety and side effects, Dr. Levin said. Because men don't bear the risks associated with carrying a pregnancy, he explained, the field assumes men will have a low tolerance for potential contraceptive side effects. Drs. Buck and Levin did not initially set out to find a male contraceptive. They were friends and colleagues with complementary skill sets. But when Dr. Levin challenged Dr. Buck to isolate an important cellular signaling protein called soluble adenylyl cyclase (sAC) that had long eluded biochemists, Dr. Buck couldn't resist. It took him two years. Drs. Buck and Levin then shifted their research focus to studying sAC and eventually merged their laboratories. The team discovered that mice genetically engineered to lack sAC are infertile. Then in 2018, Dr. Melanie Balbach, a postdoctoral associate in their lab, made an exciting discovery while working on sAC inhibitors as a possible treatment for an eye condition. She found that mice that were given a drug that inactivates sAC produce sperm that cannot propel themselves forward. The team was reassured that sAC inhibition might be a safe contraceptive option by another team's report that men who lacked the gene encoding sAC were infertile but otherwise healthy. The new Nature Communications study demonstrate that a single dose of a sAC inhibitor called TDI-11861 immobilizes mice sperm for up to two and half hours and that the effects persist in the female reproductive tract after mating. After three hours, some sperm begin regaining motility; by 24 hours, nearly all sperm have recovered normal movement. TDI-11861-treated male mice paired with female mice exhibited normal mating behavior but did not impregnate females despite 52 different mating attempts. Male mice treated with an inactive control substance, by contrast, impregnated almost one-third of their mates. "Our inhibitor works within 30 minutes to an hour," Dr. Balbach said. "Every other experimental hormonal or nonhormonal male contraceptive takes weeks to bring sperm count down or render them unable to fertilize eggs." Additionally, Dr. Balbach noted that it takes weeks to reverse the effects of other hormonal and nonhormonal male contraceptives in development. She said that since sAC inhibitors wear off within hours, and men would take it only when, and as often, as needed, they could allow men to make day-to-day decisions about their fertility. Drs. Balbach and Levin noted that it took substantial medicinal chemistry work to develop TDI-11861, and this was accomplished in partnership with the Tri-Institutional Therapeutics Discovery Institute (TDI). The TDI works with investigators from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center and The Rockefeller University to expedite early-stage drug discovery. "This highly productive collaboration between TDI and the Buck/Levin lab clearly illustrates the power of partnering pharma-trained drug discovery scientists with academic innovators," said Dr. Peter Meinke, Sanders Director of the TDI. The Buck/Levin lab's collaboration with TDI was fostered and nurtured by Weill Cornell Medicine Enterprise Innovation, the office that accelerates the translation and commercialization of technologies arising from research conducted by Weill Cornell faculty and trainees. In addition, Enterprise Innovation is leading the out-licensing of this discovery to their start-up company. "The team is already working on making sAC inhibitors better suited for use in humans," Dr. Levin said. Drs. Buck and Levin launched Sacyl Pharmaceuticals with colleague Dr. Gregory Kopf, who serves as the company's Chief Scientific Officer. The next step for the team is repeating their experiments in a different preclinical model. These experiments would lay the groundwork for human clinical trials that would test the effect of sAC inhibition on sperm motility in healthy human males, Dr. Buck said. If the drug development and clinical trials are successful, Dr. Levin said he hopes to walk into a pharmacy one day and hear a man request "the male pill."