Can New Pain Drugs Break Through To A Growing Cancer Market and Beyond?

Two new drug approvals represent the latest innovations in the emerging area of breakthrough cancer pain, designed to ease intense, short-term waves of heightened suffering in patients who are already taking opioids for persistent background pain.

Both Archimedes Pharma Ltd.’s Lazanda and Nycomed International Management GmbH’s Instanyl are new intranasal formulations of well-known painkiller fentanyl. With its June 30 approval by FDA, Lazanda will be the first fentanyl nasal spray to reach U.S. shores, a year after it made its debut in the European market. A few days later on July 4, Instanyl received European approval in a new single-dose nasal spray, complementing Nycomed’s existing multi-use spray.

As new entrants jostle against entrenched and generic competitors in a fairly new, still-growing disease category, the market winners will be those products that can successfully differentiate themselves among physicians and payers, with potential to expand their remits beyond oncology into other emerging pain indications. Breakthrough pain was formally defined just two decades ago and has generally remained the province of specialty pharmas. Recently Archimedes attracted substantial venture funding, signaling investors’ view of the space as a possible growth opportunity.

Estimates vary widely as to how many cancer patients have breakthrough pain episodes, from less than half to about 90%, with a wide range of experiences among those that do.

Although time to onset and duration can vary, breakthrough pain is generally defined as an episode of especially excruciating pain that appears quickly and lasts less than an hour, temporarily “breaking through” the analgesic effects of opioids that mollify the persistent, longer-lasting pain felt by cancer patients. To deal with the debilitating bursts of pain, specialty pharmas have developed drugs to match the rapid onset and short duration of the episodes. "Lazanda is designed to have an onset and offset which closely matches the pain itself," Archimedes CEO Jeff Buchalter told “The Pink Sheet.”

The first drug approved to treat breakthrough pain, Cephalon Inc.’s fentanyl lozenge-on-a-stick Actiq (oral transmucosal fentanyl citrate), sold well after its 1999 approval, reaching $550 million in peak global sales before losing U.S. patent protection in 2006. Its successor, Fentora (fentanyl buccal tablet), faces competition from generic versions of Actiq, but grew to $181.6 million in 2010 sales worldwide.

While Fentora is currently the market leader among breakthrough pain medications, alternatives have entered the category in the hopes of capturing market share. Generally, those competitors are aiming to provide a faster-acting or more conveniently administered formulation.

Sweden’s Meda Pharmaceuticals Inc. launched Onsolis (fentanyl citrate film), a thin strip that dissolves in the patient’s cheek, in the U.S. late in 2009, and has since received European and Canadian approval. Meanwhile, Orexo AB’s Abstral (fentanyl sublingual tablet), received FDA approval in January; ProStrakan Group PLC, which licensed the drug in the U.S., began selling it this spring.

For Archimedes, the U.S. market entry for Lazanda expands on its existing presence in Europe, where it sells the same product as PecFent. The nasal spray is already marketed in five EU countries – by Archimedes in the U.K., Ireland, Germany and Spain, and in Italy by a marketing partner, following its European approval in September 2010. PecFent uses the company's PecSys technology, which is based on the fruit-derived polysaccharide pectin, a compound often used as a gelling agent in jam. The drug is administered as a fine mist that turns into a gel when it comes into contact with the nasal mucosa. Fentanyl is then rapidly absorbed into the patient's bloodstream.

Funding Boost Underscores Opportunity

Although it’s not Archimedes’ only product – the company has licensed oncology and Parkinson’s drugs, among others – the company has spent considerable effort bringing it to market over the past two years. Venture investors, including Novo Growth Equity and Warburg Pincus, showed great confidence in the young startup, supplying a £65 million ($100 million) round in March 2010. The cash was intended to support continued development of Lazanda/PecFent as well as to establish a U.S. presence and hire a new CEO, which the company did by tapping Buchalter (Also see "Archimedes Raises £65 million for Leap to U.S." - Scrip, 1 Mar, 2010.).

At the time of the funding, Novo managing partner Ulrik Spork told "The Pink Sheet” that Archimedes could grab “a couple of hundred million dollars” of an overall $2 billion market, according to his estimates. That would include the U.S. expansion, for which Archimedes is currently hiring its own sales force and commercial infrastructure to market Lazanda when it launches before year’s end.

To reach Spork’s estimates, however, Archimedes will need to differentiate Lazanda in an increasingly crowded market that includes inexpensive generic competition. Moreover, the entire breakthrough pain category will have to grow substantially, as oncologists and pain specialists have been relatively slow to prescribe separate medications for short-term pain in opioid-tolerant patients.

Arvind Narayana, a medical director in Cephalon’s medical affairs division who has worked closely on Fentora since its origination, described breakthrough pain as “an under-recognized disease” for which medications are underutilized to date. The company estimates that 275,000 cancer patients suffer breakthrough pain, but only 10,000 are currently on rapid-onset opioids. (Estimates vary widely as to how many cancer patients have breakthrough pain episodes, from less than half to about 90%, with a wide range of experiences among those that do. A 2009 American Pain Foundation survey indicated that a fifth of pain flare sufferers experience breakthrough episodes multiple times a day, while about a third have them less than once a week.)

Buchalter said that Archimedes’ research showed that many oncologists simply treat those occurrences with more aggressive doses of the same opioids used to treat background pain, typically morphine derivatives. Use of fentanyl via Johnson & Johnson’s Duragesic (fentanyl transdermal system) patch is common for breakthrough pain as well, although the drug’s onset is slower and duration lasts much longer. Buchalter acknowledged that a “very low” percentage of potential breakthrough treatment users are currently prescribed a separate drug. “There’s still some education to be done,” he said, adding, “There is no diagnosis for breakthrough pain – you can’t quantify that.”

Seeking Differentiation

Yet, the introduction of more new treatments suggests that the therapeutic benefit of fast-acting opioids will lead to a growing market opportunity. Each is touted with its own benefits, from ease of administration to speed of onset. Cephalon says a Fentora tablet wedged in the cheek provides a more passive administration with improved dissolution compared to Actiq, for example, while Buchalter says Lazanda’s pectin-based mist adheres to the nose better than Instanyl’s aqueous spray, and can be delivered quickly with high bioavailability. “Physicians will see what attributes they value” in each, said Narayana, who also pointed to Cephalon’s longer experience in dealing with pain specialists as a differentiator.

Thus far, Fentora is far and away the market leader among patent-protected drugs. Abstral sold $26.4 million worldwide in 2010, while PecFent brought in minimal sales in the year’s waning months, according to IMS Health statistics.

Some clarity could come to the market soon, as FDA finalizes a class-wide Risk Evaluation and Mitigation Strategy program for transmucosal opioids. The agency announced its intent to standardize a REMS for multiple pain relief products as it approved Abstral in January, while individual drugs still have their own REMS, largely addressing abuse prevention (Also see "Abstral REMS Sets Stage For Risk Reduction Plans For Similar Fentanyls" - Pink Sheet, 17 Jan, 2011.).

The class could also see further growth if the drugs gain approval for breakthrough pain in non-cancer indications, according to Narayana. Sufferers of chronic back pain, for example, experience acute flare-ups that could be treated with medications separate from opioids for background pain.

Either way, the new formulations represent a continued life for fentanyl, a potent drug which has been around for a half century. Whether that leads to a new success story in breakthrough pain depends on whether its reformulators can create a broader drug category for the disorder that has, to date, been only modest in size.

By Paul Bonanos, John Davis