Analgesic drugs have reached a painful point. Unwanted side effects and abuse potential have made existing drug categories such as non-steroidal anti-inflammatories and opioids unappealing prescriptions for patients in chronic pain. But a new class of antibodies that inhibit the crucial protein nerve growth factor could spell relief for millions of chronic pain sufferers - if they can demonstrate safety and efficacy.

First identified in the 1950s by the Washington University/St. Louis researchers Stanley Cohen and Rita Levi-Montalcini, naturally occurring NGF is essential for both nerve cell growth and maintenance. In addition, production of NGF rises sharply in response to injuries and certain diseases, mediating pain sensations within the body. Inhibiting NGF receptors appears to dampen that response, potentially opening the door for a new anti-NGF drug class that would treat chronic pain.

A new pharmaceutical category could have an especially large market impact due to ongoing concerns about alleviating pain with existing prescription remedies. NSAIDs can elevate risk of gastrointestinal bleeding, unwanted renal effects, and cardiovascular disorders, while opioids produce physical dependence and carry high abuse potential.

In some indications, and for some patients, early research suggests that an NGF inhibitor could prove effective with fewer risks. "These could be the first really different alternatives in the pain market," said Datamonitor Group health care analyst Trung Huynh.

It's an area ripe for improvement. Since Pfizer's Celebrex (celecoxib) added a black-box warning about side effects and Merck pulled its Vioxx (rofecoxib) drug off the market in 2004, many innovations in pain drug categories haven't lived up to expectations.

An FDA panel has just declined to recommend approval for NicOx's naproxcinod, a new formulation of the NSAID naproxen touted to have fewer cardiovascular risks, citing a lack of evidence that it does not raise a patient's blood pressure (¹ Also see "Naproxcinod Effective But Safety Concerns Remain, Advisory Committee Says" - Pink Sheet, 12 May, 2010..) And in April, another FDA panel overwhelmingly rejected the oxycodone formulation Acurox , a product of Acura Pharmaceuticals and King Laboratories, citing the addition of niacin as insufficient to prevent abuse (² Also see "Acurox Approval Could Be Impossible Given Combination Drug Regs" - Pink Sheet, 3 May, 2010.).

Chronic joint and back pain sufferers could be the first to benefit from anti-NGF drugs.

"[A biologic drug] would be most differentiated for the treatment of moderate-severe chronic low back pain, but is also particularly interesting for patients with moderate to severe osteoarthritis pain," said Seamus Hernandez of the health care equity research firm Leerink Swann, which termed new anti-NGFs as potential "game-changers" in a recent report.

The firm estimates that more than 2 million patients in the U.S., and millions more around the globe, could benefit from anti-NGF treatments if approved by regulators. Beyond back pain and osteoarthritis, other indications undergoing clinical investigations include pain related to bone cancer, pancreatitis, thermal injuries, interstitial cystitis, endometriosis and hip injuries.

Pfizer Takes An Early Lead

Pfizer's monoclonal antibody, tanezumab, acquired via its 2006 acquisition of the South San Francisco, Calif.-based biotech Rinat Neuroscience, is the drug candidate that has progressed the furthest in the clinic.

Currently undergoing Phase III trials for osteoarthritis, with significant data expected later this year or early in 2011, tanezumab could be ready for the market as soon as 2012. Although an intravenous anti-NGF formula to treat osteoarthritis is the first of several projects for which Pfizer is pursuing approval, the company already is gathering Phase II data on other indications including diabetic peripheral neuropathy, lower back pain and interstitial cystitis, as well as a subcutaneous injection for osteoarthritis.

Huynh said the large population of osteoarthritis patients - 80 million in the world's seven largest markets - made it a good first target.

Analysts are optimistic that tanezumab will provide increased efficacy, but are still worried about its safety and side effects. Leerink Swann's report flagged peripheral nerve symptoms including paresthesia, which have been found in 10 percent to 20 percent of test subjects, as a concern since they could reflect the possibility of peripheral nerve damage.

According to Datamonitor's Huynh, the long-term safety of tanezumab will be better known in the fall or early 2011, when the results from longer-term studies are revealed. "The longest anyone has been on these drugs is about six months," he said.

Pfizer's trials are expected to demonstrate proof of concept, potentially opening the door to further research by other drug developers.

Two other compounds are roughly 18 to 24 months behind Pfizer's drug, in terms of their development. Ortho-McNeil-Janssen Pharmaceuticals is acquiring Phase II data on the compound JNJ-42160443, which is being studied as a subcutaneous injection, while Sanofi-Aventis is conducting mid-stage trials on REGN-475. Both drugs are addressing multiple indications including osteoarthritis and lower back pain. With clinical data far from complete, it's not yet clear how either will differentiate itself, although Huynh said dosing regimes and efficacy could vary.

A spokesman for Regeneron, which first created the compound that became Sanofi's candidate through an ongoing co-development arrangement, described the drug as more specific than tanezumab in its targeting because it binds only to NGF rather than other neurotrophins. In Regeneron's animal studies, the spokesman said, its own formulation of tanezumab (based on Pfizer's published documentation) showed a diminishing of balance in mice, while Regeneron's compound did not.

Two other major pharmaceutical companies also have Phase I entrants under development. AstraZeneca through its MedImmune division recently began Phase I testing for intravenous infusions of MEDI-578, targeting osteoarthritis. Meanwhile, Abbott is conducting Phase I tests in osteoarthritis patients on PG110, originally created by UK-based venture-backed startup PanGenetics and acquired by Abbott last fall (³ Also see "PanGenetics' NGF Antibody Sale Illustrates Index's Asset-Focused Strategy" - Scrip, 1 December, 2009.).

An Area Of Future Deal Making?

NGF has been crucial in several deals thus far, with Abbott's PanGenetics deal the latest to make waves. The largest buyout to date remains Pfizer's April 2006 acquisition of Rinat; although deal terms weren't disclosed, the Big Pharma is believed to have paid $500 million for the biotech. In addition to tanezumab, which was in Phase II at the time of the buy-out, Rinat also had programs for Alzheimer's disease and other neurological disorders (⁴ [See Deal]).

Abbott's recent deal with PanGenetics was an unusually expensive one for a Phase I asset, worth $170 million up front with just $20 million in milestone payouts. The November 2009 acquisition was completed in an unorthodox fashion: PanGenetics was structured as two separate asset-focused companies, one of which was sold to Abbott. (The other targets the protein CD40 in psoriatic arthritis patients.) Rather than rely on downstream royalties, primary PanGenetics stakeholder Index Ventures attained an exit in the deal.

Meanwhile, J&J licensed its drug from Amgen in a 2008 deal worth $50 million up front and $385 million in milestone payouts and royalties. And Sanofi's collaboration with Regeneron stems from an ongoing option arrangement developed in 2007 and extended last fall, under which Sanofi pays for 100 percent of clinical trial costs while Regeneron repays Sanofi in profit-sharing. The anti-NGF antibody is one of five on which the two companies are collaborating (⁵ Also see "Sanofi Makes its Biggest External Play Yet With Long-Term Regeneron Deal" - In Vivo, 1 December, 2009.).

Tracking TrkA And Related Proteins

Whether proof of concept will spur additional deal making remains to be seen, but at least one relevant, unpartnered asset appears to be in play.

Rome-based Lay Line Genomics recently retook possession of a compound that blocks the TrkA receptor, to which NGF typically binds in order to transmit the pain response. While a TrkA inhibitor might block pain in some circumstances, Hunyh said, NGF also binds to other receptors, potentially making such drugs less effective for more general purposes. Lay Line CEO Ennio Esposito said the company has some in vivo animal data on the pre-clinical drug candidate, although research is currently stalled.

Nonetheless, a partner or acquirer could be interested. Lay Line Genomics shares history with others in the pain biologics area already: it was the originator of the anti-NGF acquired by PanGenetics and eventually sold to Abbott. Moreover, PanGenetics investor Index Ventures also was a backer of BioXell of Milan, which licensed Lay Line's TrkA inhibitor, named BXL1H5, in 2006. After the clinical failure of BioXell's overactive bladder drug cast doubts on the company's research platform, it abandoned various projects and pursued a sale, according to Esposito. As Italian firm Cosmo Pharmaceuticals moved to acquire BioXell, Lay Line exercised a termination right and took back the asset. Esposito said Lay Line no longer conducts its own drug development, and intends to "find the best route to the clinic, as fast as possible" for BXL1H5.

There's also a chance anti-NGF or anti-TrkA drugs could be used for other purposes rather than pain relief. The European specialty pharma company Creabilis Therapeutics, for instance, is performing Phase II trials on a topical cream that blocks TrkA to alleviate itching associated with psoriasis and atopic dermatitis, an area also studied by Taisho Pharmaceutical Co.

For now, all eyes remain on Pfizer as tanezumab's clinical profile emerges.

Analysts caution that costs for the new drugs will be high if and when they are approved. Leerink Swann's report said the annual price to medicate a chronic lower back pain sufferer could exceed $10,000, while Hunyh suggested that such drugs initially would be last-line therapies used only if NSAIDs and opioids have failed. Nonetheless, he said that if long-term side effects prove manageable and the price comes down, anti-NGFs could reach a wider market, potentially yielding relief for millions.

- Paul Bonanos ( ⁶ pinkeditor@elsevier.com )

A Painstaking Approach: Can Anti-NGFs Give Relief To Pharma Pipeline Woes?

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