Morphine-Resistant Pain Responds to Neurotoxin: Early Trials

FORT LAUDERDALE, Fla--Interest in neurotoxins derived from marinecone snails has led to development of a calcium-channel blockingagent that could potentially be used as an alternative to opioidanalgesics for patients with cancer pain. Early clinical studieswith the agent (SNX-111, being developed by Neurex Corporation,Menlo Park, Calif) have found it to be more potent than morphineand free of opioid side effects, Richard W. Tsien, DPhil, saidat a conference on gene technology organized by the UniversityBiochemistry & Molecular Biology Foundation, Inc. and Bio/TechnologyMagazine.

Dr. Tsien, professor of molecular and cellular physiology, StanfordUniversity, spoke at a session on calcium channel research sponsoredby Boehringer Mannheim.

Among the more than 1 million patients who suffer from cancerpain, a significant proportion, about 100,000 in the US alone,experience severe intractable symptoms of neuropathic origin,Paul Goddard, PhD, chairman and CEO of Neurex, said in an interview.

While no selective treatments for neuropathic pain are currentlyavailable, Dr. Goddard said, SNX-111 appears to block both neuropathicand nociceptive pain (see box below) and to have analgesic effects100 to 1,000 times more potent than those of morphine.

Initial Results

In initial results from phase I/II studies among terminally illcancer patients with severe, morphine-resistant pain, 8 of 9 evaluablepatients responded to therapy with SNX-111 infused intrathecally(1 to 100 ng/kg/hr). Of these patients, 5 received up to 10 monthsof therapy and experienced continued relief.

The drug appears to be safe and well-tolerated, Dr. Goddard said.The majority of patients experienced partial or complete painrelief without common opioid side effects. "Most terminallyill patients want both pain relief and lucidity," Dr. Goddardsaid. Importantly, he added, tolerance to SNX-111 has not developedin preclinical studies.

Continuing expanded trials with 30 patients are showing similarbenefits to those seen in the first patients, he said.

A double-blind, crossover phase II/III safety and efficacy trialof SNX-111 for treatment of intractable pain in patients withcancer or AIDS, initiated in January of this year, includes along-term treatment phase among 200 patients in more than 30 UScenters.

For this study, the FDA is no longer restricting enrollment toterminally ill patients, Dr. Goddard pointed out. Additionally,controlled studies for SNX-111 for nonmalignant pain are expectedto begin later this year.

Delivery by Implanted Pump

Neurex is developing SNX-111 in collaboration with Medtronic,Inc., Minneapolis, a medical device manufacturer, for intrathecaladministration through an implantable pump (SynchroMed). The infusionpump requires a 20- to 30-minute procedure for implantation intothe abdomen, and has a battery that lasts 5 years.

Dr. Goddard said that Neurex, in collaboration with Warner Lambert,is devoting extensive efforts to the development of second-generationneuron specific calcium blocking compounds suitable for intravenousor oral administration.

A Neuron-Specific Calcium Blocker

A subset of peptides isolated from marine cone snails--calledconopeptides or conotoxin peptides--were shown to specificallyblock calcium channels, Dr. Richard Tsien said at a Florida conference(see story above).

After 6 years' research into the 300 to 400 compounds identifiedin the snail venom, Neurex Corp. was able to synthesize the neuron-specificN-type calcium channel blocker, SNX-111.

The first intended use of SNX-111, Dr. Paul Goddard, of Neurex,said in an interview was to protect stroke, head trauma, and cardiacarrest victims from excitotoxic events following lack of oxygento the brain. In such events, cells become overexcited when, ascalcium flows in, regulatory mechanisms are destroyed. SNX-111blocks specific calcium receptors, preventing calcium influx andprotecting the cell.

During preclinical work, investigators found that the compoundbound to neurons in parts of the spine responsible for transmissionof pain signals from the periphery to the brain, and that it appearedto block both nociceptive and neuro-pathic pain.

"The key challenge in treating pain in cancer patients isthat most ultimately develop both kinds of pain," Dr. Goddardsaid.