Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Researchers are targeting different pathways with small and large molecules in their quest for a new pain killer.

A hundred years have passed “without having really a major new pain drug,” according to Thomas Schnitzer, M.D., Ph.D., a professor of medicine at Northwestern University. Dr. Schnitzer made those comments to Nature Biotechnology in commenting on FDA’s December 2010 decision to place a hold on most clinical trials involving therapies targeting nerve growth factor (NGF).

On March 13, 2012, though, the Arthritis Advisory Committee to the FDA unanimously concluded that the potential benefits of anti-NGF drugs outweighed the risks associated with their use. They voted 21 to 0 to allow Pfizer and other developers to resume testing, despite cases of joint destruction and osteonecrosis associated with their use.

The FDA advisory panel concluded that there is a role for the ongoing development of NGF inhibitors to manage pain associated with conditions other than osteoarthritis for which there are no agents with demonstrated analgesic effect. The panel’s recommendations are not binding on the FDA, which will make the final determination on the partial clinical hold. The agency will weigh in on dosing and trial designs for companies planning to restart clinical testing.

NGF Pathway

Anti-NGF pain therapeutics are thought to work by preventing the perception of pain and inducing analgesia. NGF, a neurotrophic factor, plays a key role in neuropathic and inflammatory-induced pain and promotes hyperalgesia.

FDA stopped Pfizer’s Phase III study exploring tanezumab in patients with osteoarthritis of the knee or hip in June 2010 because some patients experienced worsening of the disease necessitating, in some cases, joint replacements. The firm said this adverse effect had not been recorded in nonosteoarthiritis patients receiving tanezumab.

Johnson & Johnson also halted studies of its experimental anti-NGF antibody fulranumab because of concerns over the risk of joint damage in 2011. And due to the Pfizer findings, AstraZeneca voluntarily stopped early-stage studies of its anti-NGF drug candidate medi578. The suspension was not requested by regulators and the company has not seen similar cases of bone-tissue death.

Additionally, Regeneron and partner Sanofi suspended clinical trials of their anti-NGF compound REGN475/SAR164877. Nonetheless, anti-NGF drugs showed promise in treating pain from severe osteoarthritis, offering good pain control in ongoing trials.

Ion Channels

GEN asked Russell Herndon, CEO of Hydra Biosciences, which is also developing antipain medications, how he thought the favorable ruling on anti-NGF pain killers might affect the chances of developing new pain medications. “The FDA’s stance on anti-NGF drugs is welcomed and underscores the increasing recognition of the need for new pain therapeutics. Additional study will allow for a more informed judgment on the safety and efficacy of these products.

“The approach that we are taking differs significantly from anti-NGF antibodies. We are looking at small molecule modulators of ion channels involved in pain rather than monoclonal antibodies directed at growth factor pathways. Thus we do not expect to see similar side effects to what has been reported with anti-NGF antibodies.”

Last January Cubist Pharmaceuticals and and Hydra announced plans to begin a Phase I trial for a small molecule antagonist of the human transient receptor potential ankyrin repeat 1 (TRPA1) ion channel, CB-625. The compound was discovered under the companies’ collaboration.

CB-625 acts by blocking peripheral TRPA1 channels and attenuates surgically induced and inflammatory-mediated pain in animal models. The firms point out that it represents a novel, nonopioid method of treating peri-operative pain.

Hydra also announced in February that it will collaborate with Zalicus to advance the latter’s preclinical ion channel modulator compounds for pain treatment into the clinic over the next two years. Zalicus’ clinical-stage ion channel modulators are not included in the collaboration. They include Z-160, an N-type calcium channel blocker, and Z944, a novel T-type calcium channel blocker, both in Phase I.

Hydra’s technology platform rests on the transient receptor potential (TRP) ion channel pathway family. Ion channels function to maintain normal cellular homeostasis and transmission of information into and out of the cell as well as acts as multimodal signal integrators.

Hydra explains that the gene family encoding TRPs represents about 20% of all ion channels found in the body. Since TRP channels are only distantly related to voltage-gated channels, they present an opportunity to identify selective first in class drugs. Because the homology among TRP family members is quite low, specific modulators can be more readily identified in this family than in other ion channel families, limiting the potential for off-target effects, which have plagued other ion channel families.

Hydra has shown in animal models that targeting TRPA1 relieves pain without side effects including depression and stomach upset and shouldn’t cause the addiction associated with opioid use.

Opioid Receptors

In February Scripps Florida scientists were awarded $3.1 million by the National Institute on Drug Abuse to study and develop several new compounds that could prove to be effective in controlling pain without the unwanted side effects common with opiate drugs. Thomas Bannister, Ph.D., associate professor chemistry and associate director of translational research at Scripps, told GEN that he and his colleagues had been looking for “functionally selective” compounds that act at the mu opioid receptor; i.e., molecules that activate the receptor differently than current opiate drugs.

“For a long time, it was thought that any compound that activated the opioid receptor would produce analgesia but with all the baggage that went with it—potential for addiction, respiratory effects, and constipation. But Laura (Laura Bohn, Ph.D., associate professor of molecular therapeutics at Scripps) had thought recently that her work suggested this isn’t the case— the mu receptor can be activated in slightly different ways; differentially starting the pathways associated with pain relief and other pathways lead to the side effects.

“Laura’s work focused on one particular pathway associated with side effects, involving a protein called beta arrestin, first studying knock-out animals . These animals experience pain relief from opiate analgesics with lessened side effects. Then we started looking for molecules that would do the same thing in normal mice. We are targeting the same opiate receptor targeted by other drugs but trying to selectively eliminate from activation at least one of the pathways that would lead to side effects.”

Dr. Bannister said that until recently it was thought that that these receptors were either on or off, but “our research suggests that the ‘on switch’ is much more complicated, with many pathways involved, and the right molecules may activate just the pathways leading to pain relief. This represents a new way of thinking about pain therapy.”

He believes that he and his colleagues will spend about five years funded by the grant “optimizing the compounds for potency, selectivity, safety in animals, and in general finding out exactly which side effects normally seen with opiates our best compounds do not show and why. Once we get to that point, we can start talking to a potential pharma partner with the clinical expertise needed to make it a reality. It’s a long road from verifying an idea to actually having pills in a bottle, but at this point we are very encouraged that it will work.”


And in the early-but-interesting category, Scripps Research Institute scientists reported the laboratory synthesis of conolidine, a scarce, naturally occurring compound originally isolated from the stem bark of Tabernaemontana divaricata, a tropical flowering plant used in traditional Chinese, Ayurvedic, and Thai medicine. Reporting in Nature Chemistry, Michael A. Tarselli and colleagues at the departments of chemistry and neuroscience, said that the compound’s synthesis would enable study of its chemical and pharmacological properties.

The researchers say that although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. They described the first de novo synthetic pathway to this “exceptionally rare” C5-nor stemmadenine natural product, the first asymmetric synthesis of any member of this natural product class, and the discovery that (±)-, (+)-, and (−)-conolidine are potent and efficacious nonopioid analgesics in an in vivo model of tonic and persistent pain.

Pharmacologic studies showed that the new synthetic compound had surprisingly potent analgesic properties. “While it’s not an opiate, it’s nearly as potent as morphine,” said Glenn Micalizio, an associate professor in the department of chemistry.

But Dr. Bohn noted, “While the pain-relieving properties are encouraging, we are still challenged with elucidating the mechanism of action. After pursuing more than 50 probable cellular targets, we are still left without a primary mechanism.”

So far, the compound has shown remarkably few, if any, side effects, but that is something of a double-edged sword, she added. “The lack of side effects makes it a very good candidate for development. On the other hand, if there were side effects, they might provide additional clues as to how the compound works at the molecular level.” That remains a mystery.

And despite the long time lines on the horizon, the arduous search for new analgesics may be worth the pain. The pain-management market is growing, albeit relatively slowly, according to GlobalData, providing ample motivation for drug developers. The value of the osteoarthritis therapy market alone was estimated at $4.4 billion in 2010, with expected growth to $5.9 billion in 2018.

Opioid analgesics remain medical mainstays of drug interventions for severe pain. But their liabilities include addiction and tolerance as well as depression of breathing, nausea, and chronic constipation. Due to their suboptimal therapeutic profile, the search for nonopioid analgesics to replace these well-established therapeutics remains a critical pursuit for pharma companies.

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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