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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Lower Back pain: New therapeutic opportunities open up for a “new” indication

An estimated 129 million adults suffer from back pain across the seven major markets.

Despite the size of this group of conditions, back pain remains an unmet clinical need characterized in equal measures by developmental challenges and market potential. No therapeutic agents have been specifically indicated for back pain and until recently the regulatory bodies have not even viewed the condition as a specific indication.

Our latest feature “Back Pain - Gain competitive edge by targeting subpopulations” sets out to examine key issues and unmet needs in the diagnosis and management of back pain. The report provides a thorough review of etiology, epidemiology, diagnosis and current treatment options. The report also explores potential commercial opportunities for companies intending to either penetrate, or increase, their share in this competitive market. Analysis is supported by interviews conducted with key opinion leaders in the US and Europe.

For free sample pages contact leaddisc@leaddiscovery.co.uk

Recently published reports in pain:

• Pain Therapeutics - Drugs, Markets and Companies
• Peripheral Neuropathy and Neuropathic Pain, 2008
• Pipeline Insight: Neuropathic Pain - Emerging drugs fail to capitalize in lucrative market
• CNS Market Overview - neurology, pain and psychiatry
• Pipeline and Commercial Insight: Neuropathic Pain
• The Global Pain Market, 2008-2023
• Commercial Insight: Pain Market Overview - Non-traditional analgesics and opioid reformulations to sustain sector growth

Custom analyses of the pain market and pipeline are available on request

The most important unmet need in the treatment of back pain to emerge from opinion leader interviews is for more targeted treatments. Therefore, the challenge to researchers is to provide evidence of which treatment, if any, is of most benefit for subgroups of patients with back pain. In order for this unmet need to be addressed, greater investment in basic science research is required to further our understanding of pain mechanisms.

Broadly speaking however back pain can be split into acute and chronic pain. Two areas of chronic pain under investigation are neuropathic back pain and breakthrough chronic back pain. Targeting back pain subpopulations represents a viable strategy and neuropathic back pain which affects an estimated 18 million adults across the seven major markets represents one such lucrative subpopulation.

Although targeting back pain subpopulations is viable, of the numerous companies are targeting neuropathic pain indications, to date no one product has a specific label for neuropathic back pain. Moreover, few pipeline drugs appear to be to be in development for this condition. This may in part be due to the regulatory bodies failing to recognize neuropathic back pain in its own right; it may also be due to the complexity of diagnosis.

Cephalon has tried and so far failed in breakthrough back pain with the FDA issuing a complete response letter relating to Fentora and its risk management program. Lilly has demonstrated that Duloxetine reduces back pain in individuals with depression. More directly, efficacy has also been reported in a Phase 3 chronic back pain trial with pain scores reduced by 2.4 points from baseline compared to 1.4 points on a standard 10-point rating scale. This effect was significant. Whether Lilly intends to file for a back pain label remains to be seen.

Most recently, Newron announced just this week that it has randomized the first patients to treatment in SERENA, its first phase IIb/III study of ralfinamide in patients with moderate neuropathic low back pain. Newron's ralfinamide now has the potential to become the first drug approved for the treatment of neuropathic low back pain. Ralfinamide is believed to mediate analgesic and anti-inflammatory effects through the modulation of ion channels implicated in pain and the inhibition of substance P.

A small Phase II study has previously shown that 33% of neuropathic low back pain patients demonstrated a 50% improvement following treatment with ralfinamide compared to 10% in a placebo group.

SERENA is one of potentially two large studies that will evaluate the safety and efficacy of ralfinamide compared to placebo. The study is a 12-week randomized trial being conducted in Europe and Asia that will randomize approximately 400 patients with chronic neuropathic low back pain. The primary efficacy measure of the trial will be based on the 11-point Likert Pain Scale. Secondary efficacy measures will include patients’ self ratings of the Visual Analogue Scale as well as responder rates. Patients who complete the 12 weeks of treatment will be eligible to enter a double-blind 40 week extension

Newron is anticipating SERENA data in H1 2010 and in the meantime is expecting to partner, presumably to conduct a similar study in the US and to passage through registration.

During the development of Ralfinamide various health authorities agreed that neuropathic low back pain would be treated as a specific indication. This and the headway being made by Newron suggest that other companies in the pain arena will also focus on back pain. This should hopefully result in new, and much needed treatments becoming available to patients by around 2011.