June 15, 2006 (Vol. 26, No. 12)
Improving Long-term Pain Relief by Reducing Dependency and Tolerance
Remi Barbier started Pain Therapeutics(www.paintrials.com) in 1998 with the singular vision of creating the next generation of painkillers to treat severe chronic pain. “It boggles my mind that the drugs in use today for severe chronic pain are exactly the same ones used by our great, great grandparents,” says Barbier. He is referring to opiates, the gold standard for pain control, which include opium used 2,000 years ago and morphine, its modern derivative.
In fact, opioid painkillers have improved little since morphine became available, more than 100 years ago. Patients taking opiates still become physically dependent on the drugs and need increasingly higher doses to relieve the same amount of pain. Pain Therapeutics’ mission is to design new painkillers that reduce dependency and tolerance, while preserving or improving long-term pain relief. “That outcome is the holy grail of opioid research,” says Barbier, president and CEO of this S. San Francisco-based company.
The company’s two lead candidates, Oxytrex and Remoxy, are in Phase III pivotal trials. Oxytrex, an oral painkiller for severe chronic pain associated with osteoarthritis, cancer, or back problems, is being developed as an effective substitute for oxycodone, a narcotic painkiller widely used today. “Oxytrex represents the first new mechanism of action by an opiate drug since morphine was discovered,” says Barbier.
All in the Dose
Oxytrex contains a combination of oxycodone, an opioid agonist, and an ultralow dose of naltrexone, an opioid antagonist. In the brain, opioid drugs inhibit the transmission of signals from neuron to neuron. However, with chronic use, the brain adapts to opioids, and the signals switch from being predominantly inhibitory to predominantly excitatory. This results in tolerance, or patients needing escalating doses of opioids to mask pain. Moreover, even when the pain stops, the brain continues to desire opioids, a process called physical dependence. Patients must endure unpleasant withdrawal symptoms to free themselves of the adverse effects of opiates.
Researchers at Albert Einstein College of Medicine discovered that combining an ultralow dose of the opioid antagonist naltrexone with an opioid agonist prevents the physiological switch from the inhibitory to excitatory state. In general, opioid agonists reverse the actions of opoid antagonists. “But it’s all about the dose,” says Barbier. At high doses, an antagonist and agonist do counteract each other, “but at ultralow doses an opioid antagonist actually turbo charges the performance of the opioid agonist,” Barbier explains. Scientists at Pain Therapeutics translated this academic insight into a novel opiod painkiller called Oxytrex. Oxytrex provides pain relief with minimal physical dependence.
When the results of a large Phase III trial of Oxytrex were unblinded in 2005, “we saw that the drug really worked as intended,” states Barbier. In the three-month study of 700 patients, Oxytrex reduced physical dependence by 55% and in the subset of patients older than age 50, physical dependence was reduced fivefold. Cases of severe physical dependence were reduced sixfold. The patients had severe osteoarthritis pain, and many were waiting for knee or hip replacement surgery.
The company’s second candidate, Remoxy, is an abuse-resistant formulation of long-acting oxycodone. Long-acting oxycodone is currently on the market under the brand name, Oxycontin. A number of government studies and media report Oxycontin is a highly abused drug because crushing the tablets destroys the time-release substance. Then, the drug, intended to work over 12 hours, is injected or snorted to produce a highly addictive, short-term euphoria.
In Remoxy, Pain Therapeutics created a safer, abuse-resistant form of twice-daily oxycodone. The sticky, high-viscosity composition of Remoxy resists injection or snorting. When frozen, crushed, or mixed in alcohol, only a small fraction of oxycodone is released compared to Oxycontin. This discourages recreational drug abuse and prevents accidental misuse by patients.
Remoxy received a Special Protocol Assessment (SPA) from the FDA in February 2006, which specifies the Phase III trial objective, design, clinical endpoints, and analyses needed to support regulatory approval. Under the terms of the SPA, just one pivotal trial is required to file a New Drug Application.
The randomized, double-blinded, placebo-controlled, multicenter trial will enroll 400 patients with moderate-to-severe osteoarthritic pain in the U.S. Patients will be randomized to either Remoxy (10 milligrams daily) or placebo for 12 weeks.
After Remoxy receives marketing approval, Pain Therapeutics has a strategic alliance with King Pharmaceuticals (www.kingpharm.com) to develop and commercialize Remoxy and other abuse-resistant opioids.
Barbier describes Pain Therapeutics’ business strategy as a “high-quality clinical development shop” that “brings in a mix of low-risk, high-reward compounds and high-risk, high-reward compounds.” Remoxy, for instance, is a low-risk compound, whereas Oxytrex is a high-risk compound. “Our business strategy is to build a blended pipeline,” Barbier says. “We want biotechnology and specialty pharmaceutical products under the same roof. To us, drug development is drug development. We’re indifferent whether it involves testing a reformulated version of a known compound or testing the safety and efficacy of an entirely new compound. The skills required to excel in drug development are similar in both scenarios. I think this is a unique strategy in our industry.”
Pain Therapeutics scouts out programs in the pre-IND stages to in-license and develop. They maintain close ties with academic researchers who have projects in the early stages of development. “When a project is ready for prime time, we in-license it,” says Barbier. This model cuts down on the high costs of early-stage research, one of the pharmaceutical industry’s greatest inefficiencies.
“Early-stage research requires a lot of smarts but also a lot of luck. Even the brightest people fail in drug discovery, which is why big pharma has not been able to corner the market for novel drugs. In contrast, drug development requires a lot of hard work, people skills, teamwork, and a laser-like focus. These are precisely our strengths,” says Barbier.
For example, some aspects of the formulation used in Remoxy were in-licensed for $1 million, and Pain Therapeutics spent $12 million more to develop it. Then, King Pharmaceuticals paid $400 million plus a 20% royalty rate to develop and commercialize Remoxy.
“Our approach is highly efficient by industry standards,” says Barbier, and it allowed the company to move three new compounds through Phase III trials in just six years. Pain Therapeutics expects its first product to come to market in 2008.