Experimental drug cuts pain at the source, company says

Boston-based Vertex Pharmaceuticals announced Tuesday that it has developed an experimental drug that relieves moderate to severe pain and blocks pain signals before they can reach the brain. It only works on peripheral nerves – those outside the brain and spinal cord – making it different from opioids. Vertex says the new drug is expected to prevent opioids from leading to addiction.

The company reported that it had completed two randomized trials, the first in 1,118 people who had had tummy tucks and the other in 1,073 people who had bunion surgery. The two procedures are often used in studies of people with acute pain, the temporary type of pain caused by, for example, a surgical procedure that is likely to decrease over time.

In its clinical trials, Vertex measured the drug's effect using a standard pain scale where patients rated the severity of pain from 1 to 10, with 10 being the most severe. Those who took the drug had a statistically and clinically meaningful reduction in pain, the report notes. A third study looked at the safety and tolerability of the drug in people experiencing pain from various conditions.

Buoyed by the results, which have yet to be published or presented at a meeting, Vertex plans to apply to the Food and Drug Administration mid-year for marketing approval of the drug, a pill that provisionally called VX-548.

“This has the potential to be a blockbuster,” said Dr. Stephen Waxman, professor of neurology, neuroscience and pharmacology at Yale. Dr. Waxman was not involved in the research, but received a significant honorarium from the company. He predicted that the Vertex drug would be just the first foray into this new field.

“I like to think this is the beginning of non-addictive pain medications,” he said.

For now, most people who need relief from moderate to severe pain have two options: medications like ibuprofen and COX-2 inhibitors, or opioids. Drugs like ibuprofen are not very effective and the opioids are known to be addictive because of the way they work. There is no way to separate the effects of opioids – pain relief – from the side effects: changes in thinking, cognition, energy and emotions.

The opioid crisis, one of the largest public health problems in the United States, began more than two decades ago and included people who started taking the drugs for pain but became addicted. As states tightened regulations on prescription opioids, many turned to illegal street drugs like heroin and fentanyl. Although doctors are more cautious about prescribing opioids these days, many still do so because there are few alternatives.

Efforts to develop a new class of pain-relieving drugs began in earnest in the 1990s. Researchers asked whether there were sodium channels specific to peripheral nerves. These are portals that open to send pain signals from the nerves to the brain and then close to stop sending. If there were portals that only controlled signals from peripheral nerves, that suggested the ability of drugs to block them and control pain without affecting the brain and without causing addiction. Pain can be stopped at the source.

So researchers began scouring the world for people with genetic mutations that prevent peripheral nerves from transmitting pain signals, or that cause peripheral nerves to signal pain almost constantly. If they found those mutations, the genes involved could be targeted with drugs.

Ultimately, they found both types of mutations.

In Alabama, one gene mutation caused a family to develop a condition known as Burning Man syndrome, which causes peripheral nerves to become overloaded. People feel a burning pain that some say is like hot lava inside them. Any kind of heat can cause it – wearing socks or a sweater or going outside when it's 70 degrees Fahrenheit.

“It's a tragic disease,” said Dr. Waxman. “It literally drives some people to suicide.”

After years of searching, researchers found people with a gene mutation that led to the opposite effect. The discovery started with a teenage boy in Pakistan. He earned money by walking on coals or cutting himself with sharp knives during street performances. His relatives had the same mutation, with “painless fractures, painless burns, painless tooth extractions and painless deliveries,” said Dr. Waxman.

It's not that people with such mutations felt less pain, he said; “They felt no pain.”

Those mutations and subsequent research led researchers to discover that two genes are needed to transmit pain, known as Nav1.7 and 1.8. The race was on to find a drug based on one of those genes.

“Every major company has been working on it,” says Dr. David Altshuler, Chief Scientific Officer of Vertex Pharmaceuticals.

But finding a drug that worked proved to be a difficult task. Vertex, said Dr. Altshuler, spent twenty years on the project.

The result is VX-548. It inhibits Nav1.8, temporarily blocking the gene so it can't make the protein needed for the nerves to transmit pain signals.

The studies involved people with acute pain. But the company is now studying people with chronic pain due to diabetic peripheral neuropathy and patients with a type of back pain called lumbosacral radiculopathy, caused by damage or injury to a nerve in the lumbar spine.

For now, the Vertex drug, if approved, would only be used in a fairly limited number of conditions. The greater need is for non-addictive medications to manage chronic pain, and while studies are underway, for now only people with acute pain would benefit.