The U. S. Patent and Trademark Office recently issued a patent to the U. S. Department of Health and Human Services involving resiniferatoxin, or RTX, an experimental compound that represents a potential new class of drugs to alleviate the intractable pain that can occur in people with advanced cancer, severe arthritis, and other extremely chronic conditions.
"While RTX remains an investigational drug, the patent licensed to our commercial partner provides further incentive to move the drug through clinical development," said Mark L. Rohrbaugh, Ph.D., J.D., director of NIH's Office of Technology Transfer (OTT), which manages patents and licenses to inventions made by NIH and Food and Drug Administration (FDA) scientists. "The patent increases the likelihood that RTX will not end up on a laboratory shelf as a stalled or lost opportunity, but instead will have the potential to improve the lives of people with intractable pain."
The method patent specifically covers intrathecal administration of RTX, meaning its injection into the spine's thecal sac. The thecal sac is formed from layers of connective tissue and surrounds the spinal cord. Bundles of peripheral nerve roots feed into the fluid-filled sac, where their incoming sensory signals are routed onward along the spine and to the brain.
The patent (U. S. patent number 8,338,457) will be administered through the National Institutes of Health, a component of HHS. The NIH's National Institute of Neurological Disorders and Stroke (NINDS) will lead the early clinical development of intrathecally administered RTX in collaboration with Sherrington Pharmaceuticals, Inc. through a Cooperative Research and Development Agreement. Sherrington, a private biopharmaceutical company focused on the treatment of chronic and refractory pain, will attempt to commercialize RTX under an exclusive license agreement to the newly issued patent.
NINDS presently oversees an early phase clinical study of RTX that investigates the safety and efficacy of RTX administered intrathecally to advanced cancer patients with severe pain. The study continues to recruit patients, and more information can be found at:
RTX first came to the attention of researchers in the mid 1970s when German scientists isolated it as the active compound in a dried white resin and centuries-old folk remedy that is extracted from a spiny, cactus-like plant called Euphorbia resinifera. The discovery soon caught the investigative eye of Dr. Peter Blumberg, a scientist with NIH's National Cancer Institute (NCI). He was intrigued by RTX's unique chemical structure, a natural hybrid between capsaicin, the irritant in red peppers, and daphnane, a unique class of plant-derived, irritant compounds.
Blumberg received several patents in the United States and abroad during the late 1980s and early 1990s related to RTX. He and his colleagues showed among their many discoveries that the compound was a 1,000 times more potent than capsaicin when binding to the surface of certain types of heat-pain sensing neurons. While Blumberg and colleagues laid the scientific groundwork, the optimal means to administer RTX as a new, ultra-potent class of pain medication remained open for discovery.
In the early 2000s, Dr. Michael Iadarola, a basic scientist with NIH's National Institute of Dental and Craniofacial Research (NIDCR), and colleagues began to piece together one such alternative. They had homed in on RTX's reported unique ability to bind to a much studied protein called vanilloid receptor 1 (VR1), which is a channel, or pore, displayed on the surface of certain types of heat-pain-sensing neurons, or nerve cells. RTX attaches to VR1, and, like water flowing through a hose, prompts an influx of calcium ions through the channel, but only in those cells that express VR1.
"Capsaicin is the equivalent of trying to put out a house fire with a low-pressure garden hose," said Andrew Mannes, M. D., a scientist with NIH's Clinical Center, who is involved in RTX's clinical development. "RTX acts like a high-pressure fire hose. Just as the heavy blast of water from the fire hose can extinguish the flames, the heavy influx of calcium that RTX causes overwhelms the specific nerve cells that carry painful sensations and kills them."
Because nerve cells in the peripheral nervous system must first route their sensory signals to the spine, where they then are processed and sent onward to the brain, Iadarola's finding raised an intriguing therapeutic scenario: The cell bodies of these peripheral neurons bundle together in groups near the spine. If RTX were applied intrathecally and directly to the bundles, called dorsal root ganglia, the scientists believed that they could selectively kill specific neurons that express large amounts of the VR1 protein on their surface. By doing this, they also could turn off permanently certain painful sensations, such as noxious heat and certain inflammatory signals that can be involved in severe arthritis, peripheral neuromas, trigeminal neuralgia, and advanced cancer.
The research baton soon passed to NIH's National Institute on Drug Abuse to perform the needed toxicology studies on the intrathecal administration of RTX. Once completed, staff at the NIH Clinical Center painstakingly formulated RTX and produced the needed supply of the drug for NIH's current early-phase clinical study. The investigation is co-supported by NIDCR and NINDS.
"In recent years, NIH scientists have worked to enhance pain research and promote collaboration in the field," said NINDS Director Story Landis, Ph.D. "The unique scientific collaboration of five NIH components leading up to today's announcement has created an opportunity to develop a compound that might one day benefit patients."
"As the nation's medical research agency, NIH has tremendous capability to bring potential drugs to this developmental point," said NIDCR Director Martha Somerman, D.D.S., Ph.D. "We partner with industry to pull in their strengths and further study the drug. I'm happy that a partnership is in place for RTX now to test its potential to help those with intractable pain."
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