Monday, February 22, 2010

Javelin Pharmaceuticals' good fortunes continue - Ereska meets its pain-reduction end point but will it overcome the stigma of adverse events and drug

Javelin is one of a few companies that is reformulating existing drugs to address unmet needs in the pain management market. Candidates in development include Dyloject, Ereska and an intranasal morphine formulation known as Rylomine.

Dyloject was initially launched by Javelin in the UK in December 2007 for the treatment of acute pain, including postoperative pain. Dyloject differs from other IV formulations of diclofenac in that it employs a proprietary solubilizing agent that reduces irritation to veins and therefore does not require dilution or slow infusion. Movement towards the market in other geographies has taken longer with the company filing an MAA through the Mutual Recognition Procedure in 2009 and an NDA in December 2009. Last week we announced in DailyUpdates that the FDA had accepted the IND for review and that a PDUFA date had been set for October, 2010.

The NDA acceptance came after further good news for Javelin a few days earlier. On February 11th, 2010 the company announced that an external review of Phase III data for Ereska had found previously negative top-line results for its primary endpoint to be statistically significant. This randomized, placebo-controlled study assessed the safety and analgesic efficacy of repeated doses of Ereska over 6 hours in 259 patients with acute moderate to severe pain following orthopedic surgery. The primary end-point, pain intensity over the 6 hour period was reduced from 78.5 ± 12.4 to 47.3 ± 12.3 units (p=0.046)

While the revised analysis offers renewed hope for the company, doubts over Ereska must remain due to ketamine's association with drug abuse and its well-documented hallucinatory effects. Both factors represent key weaknesses in the market place, despite Ereska's proven efficacy.

Prior to the third-party reassessment of pain score measurements, Javelin Pharmaceuticals reported that Ereska (intranasal ketamine) had narrowly missed the principal goal of a late-stage trial. However, a third-party biostatistics company verified the presence of inconsistencies in the previously disclosed top-line results (based upon data captured by an external vendor). Indeed, the company has benefited from a share increase of around 6% since the announcement of the re-examined data.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been in use for over 25 years as an anesthetic, although is not approved for use as a pain reliever. Nevertheless, low-dose ketamine has been used off-label for the treatment of various pain complexes and the safety and efficacy of ketamine as an anesthetic and analgesic is well documented. According to IMS Health, ketamine achieved total sales of over $8m across the seven major markets (US, Japan, France, Germany, Italy, Spain and the UK) in 2008.

The market research company, Datamonitor believes that an FDA-approved formulation of ketamine for the treatment of moderate to severe pain will provide physicians with an accepted and regulated alternative to off-label use and opioids. Breakthrough pain, which affects approximately 42% of cancer patients across the seven major markets, is typically treated with opioids. In 2008, the opioids market was valued at an estimated $9.6 billion across the seven major markets and is forecast to grow in the future as a result of the launch of rapidly acting fentanyl products. However, opioids are associated with several adverse events and patients who use opioids chronically may display tolerance. For this reason, Datamonitor believes that there is a market for a non-opioid agent to treat breakthrough pain.

That said, pain specialists interviewed for today's featured report, stakeholder insight report into cancer pain, expressed concerns related to potential safety issues despite ketamine's potential as an alternative to opioids. Therefore, Javelin will need to carefully monitor the hallucinatory side effects of ketamine in future trials of Ereska. Pain specialists also proposed that use of ketamine and an opioid such as Actiq (fentanyl citrate; Cephalon) in combination represents an interesting avenue of research.

As the only non-opioid in the current breakthrough pain pipeline, and being of an intranasal formulation, Ereska is well positioned to compete against Cephalon's Actiq and Fentora in this market. However, a substantial challenge for Javelin will be to tackle the negative perception of ketamine as a dangerous drug that is associated with narcotics abuse. In order to overcome this barrier, Javelin would benefit from seeking the marketing resources of a larger company with experience in the narcotic analgesics market.

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