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Peptide leads new class of drugs

For the past 40 years, there has been no —which is arising from major addition to the repertoire of drugs for nerve injury—affects over a million North treating severe, chronic pain. Nonsteroidal Americans, and no good treatment exists. anti-inflammatory drugs, including COX-2 ( and other are usually inhibitors, or opioids have been the treat- ineffective.) Chronic, inflammatory pain ments of choice. Now, two drugs with a affects millions more. Ziconotide, approved completely different mechanism of action, for severe chronic pain resistant to other targeting N-type calcium channels, namely treatments, specifically targets N-type cal- Elan’s ziconotide (Prialt) and cium channels, which are crucial for trans- Pfizer’s small molecule (Lyrica), mitting pain signals from sensory neurons

are making their market debuts in the US to the spinal cord and then to the brain. A Elan and Europe—milestones that have received thousand times more potent than morphine, remarkably little attention. Although these ziconotide works by preventing neurotrans- Pacific Ocean whose venom was the drugs may change the way pain is treated, mitter release at the synapse, thus blocking basis for the new pain drug ziconotide several competing companies are at work pain sensation. to develop orally available small molecules Although ziconotide is likely to bridge a that promise, in particular, fewer side effects gap in the pain market segment, other play- ecules offering “a quantum leap in improve- than ziconotide. ers should eventually supersede this new bio- ment.” McGivern agrees: “All the companies On February 22, the European Commission tech drug because of its delivery system—a are in a race to identify the small molecule approved the first peptide, ziconotide, a pump implanted in the patient’s spinal cord. drug that would make it to the market first”.

http://www.nature.com/naturebiotechnology month after its US debut. Ziconotide’s Because of this restriction, Elan estimates Orally bioavailable small molecules should be approval for chronic pain “paves the way peak sales for ziconotide at only $150–250 superior painkillers, he adds. With the most for the next generation of pain killers,” million per year. By comparison, the new advanced small molecule N-type calcium says Joseph McGivern, principal scientist at neuropathic pain treatment pregabalin in phase 1, however, prod- Amgen of Thousand Oaks, California. A pep- (Lyrica), which was approved for post-her- ucts are still many years away. tide derived from the venom of a fish-hunt- petic neuralgia and , has One of the strategies competitors could ing Pacific Ocean cone snail, ziconotide was the potential to reach $2.7 billion in sales. adopt is to try and reduce the toxicity of isolated by Salt Lake City-based University of That’s what blockbuster epilepsy drug gaba- ziconotide. Indeed, though it lacks mor- Utah scientists in 1979 but never patented. pentin (Neurontin), a less potent version of phine’s addictive potential and tendency The biotech company Neurex in Menlo Park, pregabalin developed by New York-based to depress breathing, ziconotide can have California, which was acquired by Irish bio- Pfizer, achieved in 2003, before going off- some severe side effects, mainly neuro- pharmaceutical company Elan of Dublin patent. Both target N-type calcium channels psychiatric disturbances, as well as confu- in 1998, developed a synthetic version and but work differently from Elan’s peptide. sion, and dizziness. That’s mainly 2005 Nature Publishing Group Group 2005 Nature Publishing

© brought it to the clinic. Already companies are aggressively devel- because the drug sits on calcium channels, Ziconotide’s approval “is probably the oping competing products (see Table 1). blocking not only pain transmission but ultimate proof of concept of a new mecha- Elan biochemist and research fellow George also other nerve functions. In theory, small nism of action for targeting neuropathic and Miljanich in S. San Francisco, California, who molecule N-type blockers chronic pain,” says Terrance Snutch, CSO conceived the idea of using the original snail should avoid the worst of these side effects, at Canadian pain therapeutics company toxin to treat pain, predicts that ziconotide is because they’re ‘state-dependent’—they act Neuromed in Vancouver, British Columbia. destined for replacement by future small mol- only on nerves that are firing in response to painful stimuli. Another target of interest is the voltage- gated known as Nav1.8. Table 1 Companies targeting N-type calcium channels for pain Unlike a calcium channel block, which Company Compound Stage stops the pain signal at the synapse, block- Elan Prialt (ziconotide; synthetic conopeptide) Approved, ing Nav1.8 prevents the nerve from firing to Dec. 2004 begin with. “If you can get sufficiently selec- Pfizer Lyrica (pregabalin; alpha2-delta ligand) Approved, tive and potent blockers, you should be able Dec. 2004 to knock out the pain signal with out getting Amrad (Melbourne, Australia) AM-336 (synthetic conopeptide) Phase 2b any of the side effects that are often associ- Neuromed NMED-1600, small molecule Phase 1 ated with sodium channel block,” says Iain Ionix IX-2000, small molecule Preclinical James, director of at Ionix Scion SCI-860, small molecule Preclinical Pharmaceuticals in Cambridge, UK. Barry Astra-Zenecaa (London) Small molecule Undisclosed Berkowitz, CEO of Scion Pharmaceuticals Mercka (Whitehouse Station, New Jersey) Small molecule Undisclosed in Medford, Massachusetts, fully expects ion aCompound patents and/or patent applications recorded, but programs unconfirmed. bSuspended since 2003, channel blockers to provide “the next gen- up for licensing. eration of compounds” for pain. Ken Garber, Ann Arbor, Michigan

NATURE BIOTECHNOLOGY VOLUME 23 NUMBER 4 APRIL 2005 399