AV411 (Treatment of Chronic Neuropathic Pain)

What is AV411?

AV411 is an orally bioavailable, centrally acting molecule that Avigen has identified as having potential utility for the treatment of neuropathic pain and other neurological indications, including opiate withdrawal. The active pharmaceutical ingredient in AV411 is ibudilast.

What is AV411's mechanism of action?

Avigen, in collaboration with Dr. Linda Watkins at Univ. Colorado, Boulder hasve discovered that AV411 has glial cell regulating activity in laboratory cell cultures and in animals.  Pain researchers including Avigen and collaborators have identified that activation of glial cells (astrocytes, microglia, oligodendrocytes) is an important component of the pathogenesis and maintenance of neuropathic pain (Watkins LR, et al., 2001; Watkins LR and Maier SF, 2002; Watkins LR and Maier, 2003; Sutherland S, 2004; DeLeo JA and Yezierski RP, 2001; Watkins L, 1998).  Glial function is markedly altered upon activation, resulting in elevated release of various pro-inflammatory neuroactive substances. Release of factors such as substance P, chemokines such as fractalkine, and cytokines including IL-1 and TNFα play a role in amplifying afferent sensory input and causing or exacerbating painful sensations.  AV411 has been found to suppress the production of pro-inflammatory cytokines (IL-1ß, TNF- α , IL-6), and may enhance the production of the anti-inflammatory cytokine IL-10, and upregulate release of neurotrophic factors (NGF, GDNF, NT-4). While ibudilast was initially developed as a non-selective phosphodiesterase (PDE) inhibitor for the treatment of bronchial asthma, its efficacy in the treatment of neuropathic pain does not appear to be dependent on the PDE activity.   A publication by Avigen and its collaborators describing the clinical-enabling pharmacology of AV411will be published in a special pain issue of a peer-reviewed journal (A. Ledeboer et al., Neuron Glia Biology. In press, 2007).

What is Neuropathic Pain?  Click here to learn more about Neuropathic Pain.

What is the worldwide experience with ibudilast?

Ibudilast has been approved in Japan and other parts of Asia for more than 15 years for the treatment of bronchial asthma and was recently approved to treat dizziness secondary to chronic cerebral stroke. The compound is not approved for use in any indication in the U.S. or Europe.

It was originally developed by Kyorin Pharmaceuticals and approved in 1989 under the trade name Ketas®. The composition of matter patent for the molecule has expired.

Is there any clinical experience with ibudilast in patients?

There is significant clinical and human experience with ibudilast in the indications for which they are approved. For bronchial asthma, a total dose of 20 mg per day (10 mg twice daily) is recommended and for cerebrovascular disorders a total dose of 30 mg per day (10 mg thrice daily) is recommended.

There are clinical publications involving dose regimens higher than those described in the product insert of the marketed products. One study (Kawsaki, 1992) examined 30 patients at 20mg BID for 6 months and another study (Feng 2004) looked at 11 multiple sclerosis patients on 20mg TID for 4 weeks. Neither study reported significant adverse events using these dose regimens.  Recently, ibudilast has also been studied in 297 patients with multiple sclerosis at dose levels of 10 mg TID, 20 mg TID compared to placebo for a treatment duration of one year (MediciNova Press Release, February 5, 2006).

Moreover, as described in Avigen’s recent press release, AV411 is in ongoing clinical trials in Australia under their procedures allowing mutual recognition of approved Japanese products. We have completed a phase I trial in normal volunteers and are enrolling patients in a phase IIa trial for diabetic neuropathic pain.

What is the safety experience with ibudilast?

According to the package insert for Ketas (updated October 2003, version 6), adverse reactions to the drug were reported as 507 (3%) of approximately 15,000 patients treated. The most frequently observed adverse reactions were anorexia (weight loss) in 87 patients (<1%), nausea in 84 patients (<1%), increased AST (GOT) levels in 45 patients (<1%), increased ALT (GPT) in 53 patients (<1%).

The package insert cites occurrences of thrombocytopenia as well as hepatic dysfunction and jaundice. Thrombocytopenia has been reported in only 5 patients over a 15-year period. Likewise, five cases of “liver function anomalies” were reported in a placebo-controlled study of 238 subjects (Shinohara, 2002).

What is the intellectual property and exclusivity status for ibudilast?

The composition of matter patent for ibudilast in the U.S. was filed and has expired. We are not aware of any intellectual property that would be a barrier to Avigen launching AV411 in the U.S. However, Avigen is aware of another company, Medicinova, which is testing ibudilast in Eastern Europe as a treatment for multiple sclerosis.

What intellectual property and exclusivity protection does AV411 have?

No patents have been issued. However, Avigen believes it will have a combination of use patents for various indications.  An analog program developing second-generation compounds is ongoing at Avigen. Compounds developed in this program will be new molecules expected to obtain composition of matter patent protection, in addition to use patents similar to those expected for AV411.

In addition to any patents Avigen may obtain as a New Chemical Entity (NCE) in the U.S., AV411 is eligible for 5-year Hatch-Waxman exclusivity.

(AV411 poster, Nov. 2005) (Watkins and Maier, 2003) (Ledeboer et al, abstract, April 2006) (Ledeboer et al, abstract, May 2006) (Sorkin, book chapter, 2002) (A. Ledeboer et al., Neuron Glia Biology (special pain issue) (Kontinen - Predictive Validity of Neuropathic Pain Models, 2003)