ValanBio Developing New Synthetic Antibiotic to Treat Urinary Tract Infections
It’s often said that success doesn’t happen overnight.
Consider Durham-based anti-infectives startup ValanBio Therapeutics. The journey that led to the development of its new synthetic antibiotic technology – LPC-233 – began about 40 years ago. And it isn’t over yet.
But the experimental drug has proven – so far – to be highly effective at killing gram-negative bacteria like Salmonella, Pseudomonas and E. coli that can cause many urinary tract infections (UTIs).
Animal tests have shown that the small molecule therapy works by interfering with the bacterium’s ability to form its outer lipid layer. The drug’s target is an enzyme called LpxC that is essential to making this outer membrane in gram-negative bacteria.
“If you disrupt the synthesis of the bacterial outer membrane, the bacteria can’t survive,” lead investigator Pei Zhou, Ph.D., said in a recent Duke University news release. “We’re jamming the system. Our compound is very good and very potent.”
Zhou credits his late colleague, former Duke Biochemistry Chair Christian Raetz, MD, Ph.D., with laying the groundwork in the 1980s that eventually led to the discovery of LPC-233. “He actually recruited me to Duke (in 2001) to work on the LpxC enzyme, initially from the structural biology perspective,” said Zhou, who is professor of biochemistry at Duke University School of Medicine.
Raetz established a pathway to a new antibiotic. He and Zhou eventually solved the structure of LpxC. And Zhou and Duke chemistry professor Eric Toone have since worked to make more effective LpxC inhibitors. The efforts of these three scientists, which ultimately resulted in the development of LPC-233, have spanned close to four decades.
Versatile, fast acting, durable
The therapy seems to have all the characteristics you’d look for in a new antibiotic. It has proven effective at killing 285 different strains of bacteria, it’s fast acting (within a few hours), and it’s durable. Studies have shown that LPC-233 – when taken orally – can survive all the way to the urinary tract to attack difficult-to-treat UTIs. At high dosages, It also has demonstrated an extremely low rate of spontaneous resistance mutations that can lead to drug resistance.
The compound works in a two-step process, which adds to its durability, Zhou explained. LPC-233 initially binds to LpxC, then the enzyme-inhibitor complex changes shape to become even more stable. As a result, it outlives the bacteria. “We think that contributes to the potency, as it has a semi-permanent effect on the enzyme,” he added.
In animal studies, the drug has been successfully administered orally, intravenously and through injections into the abdomen.
Zhou and Toone founded ValanBio in 2015 to boost the development and commercialization of LPC-233. Long-time biotech industry executive Clayton Duncan is CEO. The company currently is filing patent applications on a series of compounds and is seeking partners to help fund phase 1 clinical trials to evaluate the drug’s safety and effectiveness in humans.
Early support from NCBiotech
The North Carolina Biotechnology Center provided a $50,000 technology enhancement grant to Duke in 2015 to support preclinical toxicity studies of promising LpxC candidates. Six years later, after ValanBio was established, NCBiotech made a $250,000 loan to the company to help fund formulation, stability and solubility studies for LPC-233.
The technology also has received support from the National Institutes of Health and the National Cancer Institute.
“We have eagerly watched the progression of this research since 2015,” said Robert A. Lindberg, Ph.D., vice president, science and technology development at NCBiotech. “We recognize the steadfast commitment of Dr. Zhou and his team and are proud to have supported the early development and licensing of the technology to ValanBio.”
“Antimicrobial resistance (AMR) continues to be an elusive and massive healthcare challenge, and there is tremendous need for new and innovative drugs to treat a wide range of infections,” Lindberg added. “These most recent results are a significant step towards demonstrating the potential for LpxC inhibition to help address this monumental unmet need.”