A Pakistani boy who could walk on burning coals propelled drugmakers on a quest for the ultimate pain treatment that can ease an ailment as old as life itself without harmful side effects.
Geoffrey Woods, a geneticist at the University of Cambridge, was studying families that had intermarried in northern Pakistan when he heard about the boy, who felt no pangs as he performed stunts on the street. Research on other children in the area uncovered a faulty gene among them. They all were healthy and had a normal sense of touch.
Woods’s findings, published in the journal Nature, spurred Pfizer Inc, AstraZeneca Plc and Merck & Co to study drugs that work like the gene mutations by interrupting a channel that transmits pain signals. While that research is at an early stage, Newron Pharmaceuticals SpA of Italy has a product in human tests. Those studies may lead to treatments that have fewer side effects than many painkillers, which London-based Datamonitor Plc says generated $24.3 billion in sales in 2007.
“It’s the ultimate target,” said John Wood, a professor of molecular neurobiology at University College London who co- wrote the Nature article with Woods in December 2006. “The people that don’t have the channel are not ill, they have no problems, so if you find a drug that blocks it, they should be pain-free and also free of side effects.”
Pain is one of the body’s natural defenses, intended to compel a retreat from danger or force rest to allow healing.
While a variety of painkillers exist, none is perfect. Non- steroidal anti-inflammatory drugs, a group that includes aspirin and ibuprofen, can irritate the stomach. Merck withdrew its Vioxx medicine from the market in 2004 because of a potential link to heart attacks and strokes. Opioids, which are derived from the opium poppy and include morphine, are among the most- abused prescription medicines.
The sodium 1.7, or Nav1.7, channel is a protein found in nerve cells. When a cell receives a stimulus, the tube-like channel opens and sodium ions flow into it, activating the nerves. They send an electrical signal to the spinal cord and the brain, which interprets it as pain.
In people with the gene mutations found in the Pakistani children, the sodium channel is incomplete, interrupting the chemical cascade that leads to pain sensation.
Early research on the channel, first identified in the mid- 1990s, had found gene mutations that heightened the sense of pain. Woods’s work, funded by Pfizer, the University of Cambridge and the London-based Wellcome Trust, was the first to establish a link between loss of the channel and an absence of distress.
“Geoff’s paper demonstrated that you can basically live without having Nav1.7, and for a drug company that is the most important finding they can have in defining a drug target,” said Sulayman Dib-Hajj, a neurology researcher at the Yale School of Medicine in New Haven, Connecticut, who was involved in early studies of the channel.
While scientists have identified nine sodium channels, the 1.7 target is one of only three found in peripheral neurons, or nerve cells outside the heart and central nervous system.
“The mere fact that the Nav1.7 sodium channel is primarily expressed in peripheral neurons means you’re not going to worry about an effect on the heart or on the brain or on the spinal cord,” Dib-Hajj said. “And that’s why it has become a very important target in the quest for new painkillers.”
Pfizer, based in New York, is developing compounds that block the sodium 1.7 channel, though they have yet to be tested in people. The channel is “high profile for us and we believe we’re making great progress,” said Gillian Burgess, head of the pain group at Pfizer.
AstraZeneca, based in London, is also in early development of such compounds, said Neil McCrae, a company spokesman.
Merck of Whitehouse Station, New Jersey, aims to use the channel to treat different types of pain, said Stefanie Kane, senior director in Merck’s pain research unit.
“We have initially identified compounds that in preclinical analysis are at least 100 times more potent than currently available drugs as inhibitors of this target,” Kane said in an e-mailed response to questions. She declined to say how advanced development is.
From 80 per cent to 90 per cent of experimental drugs fail to get through preclinical tests, the phase that occurs before human trials, according to the US National Institutes of Health, in Bethesda, Maryland. It takes an average of eight years to get a drug through human testing and regulatory review, according to the Tufts Center for the Study of Drug Development, in Boston.
The approach isn’t limited to big drugmakers. Newron has developed a compound that works, in part, by targeting the channel. The Milan-based company’s Ralfinamide is in the last stage of human testing generally needed for regulatory approval, with about 400 patients participating in Austria, Germany, India, Italy, Romania and the UK Results are due in the first half of 2010, said Chief Financial Officer Stefan Weber.
Positive results from the trial would make Newron a takeover candidate, said Olav Zilian, a Geneva-based analyst for Helvea SA who recommends buying Newron shares. The company has a market value of 143.4 million Swiss francs ($132.3 million).
“The data so far on Ralfinamide have been robust because it’s got a unique mode of action and is unlikely to cause the side effects seen with other painkillers,” Zilian said.
Besides inhibiting several sodium channels, including the Nav1.7, Ralfinamide acts on calcium channels, which play a similar role in signaling pain. The drug also controls the release of a chemical messenger called Substance P.
Newron plans to market the drug for neuropathic lower back pain, which is caused by damage to the nervous system. The company may seek regulatory approval in 2012, and the drug may have peak annual sales of more than $1 billion, Weber said.
Standard painkillers have shown limited effectiveness for neuropathic back pain. Pfizer’s Lyrica is the best-selling drug for the condition, while the company’s Neurontin epilepsy medicine and Eli Lilly & Co’s Cymbalta antidepressant and painkiller are also prescribed.
It’s important that Ralfinamide acts on more than one chemical pathway to pain and also that it doesn’t completely shut the sodium 1.7 channel, the company said.
“Losing normal pain sensitivity is dangerous, so it is important to have compounds able to potently inhibit the key ion channels, including Nav1.7, only during pathological pain,” Patricia Salvati, vice president of preclinical research and development and one of Newron’s founders, said in an interview.
All of the Pakistani children Woods studied had injuries to their lips or tongues, some requiring surgery, caused by biting themselves in the first four years of life, according to his article in Nature. Most had fractured bones, which were diagnosed later because of limping or inability to use an arm or leg. The firewalker died on his 14th birthday, before Woods could see him, after jumping off a roof.
