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AV411 – Potential indications include:
   – Chronic neuropathic pain
   – Opioid withdrawal
   – Opioid and methamphetamine addiction

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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 opioid withdrawal and drug addiction. The active pharmaceutical ingredient in AV411 is ibudilast – a drug developed about 20 years ago in Japan for asthma.

What is AV411's mechanism of action?

AV411 is a glial cell regulator.  In particular, an attenuator of glial cell activation.  It accomplishes this, at least in part, by reducing proinflammatory factor activation of glial cells.  For example, it reduces the activity of MIF and also TLR-4 activation.  Pain researchers at Avigen and collaborators at University of Colorado 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.   Importantly, the Drs. Watkins and Hutchinson, in collaboration with Avigen scientists, have identified that glial activation contributes to rewarding properties and withdrawal symptoms of opioid administration and that AV411 treatment can reduce signs of dependence and potentially represent a new pharmacotherapy approach for opioid and other drug addiction. 

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 about 18 years for the treatment of bronchial asthma and more recently to treat dizziness secondary to cerebral stroke. It was originally developed by Kyorin Pharmaceuticals and approved under the trade name Ketas®. The compound is not approved for use in any indication in the U.S. or Europe.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 or 20 mg TID compared to placebo for a treatment duration of at least one year (MediciNova Press Release, February 5, 2006).

Moreover, as described in Avigen’s recent press releases, AV411 has completed Phase 1 and 2a clinical trials in the U.S. and Australia under their procedures allowing mutual recognition of approved Japanese products. We have established safety and tolerability and PK profiles at doses never before described and have observed indications of potential treatment benefit in painful diabetic peripheral neuropathy.  AV411 is currently being tested with opioid dependence research experts at Columbia University in a Phase 2a trial of morphine withdrawal which is largely funded by NIDA. 

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. 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.

No Avigen patents have been issued although a method of use application is nearing potential issuance. Additional method filings are in review stages and Avigen believes it will ultimately have a combination of use patents for various indications.  Additionally, an analog program developing second-generation compounds has identified one development candidate, AV1013, and advanced leads from another novel class of glial attenuators. 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.

Avigen’s AV411 Published Patent Applications

1. Application Title:  METHOD FOR TREATING NEUROPATHIC PAIN AND ASSOCIATED SYNDROMES   (click here for copy of this patent)

Publication Number:  WO 2006/063048

Filing Date:  6 December 2005

Publication Date:  15 June 2006

 

2. Application Title:  METHOD FOR TREATING DRUG AND BEHAVIORAL ADDICTIONS   (click here for copy of this patent)

Publication Number:  WO 2007/038551

Filing Date:  26 September 2006

Publication Date:  5 April 2007

 

3. Application Title:  SUBSTITUTED PYRAZOLO [1,5-α] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE  [Analog of AV411]   (click here for copy of this patent)

Publication Number:  WO/2007/146087

Filing Date:  6 June 2007

Publication Date:  21 December 2007

 

4. Application Title:  METHODS FOR TREATING ACUTE AND SUBCHRONIC PAIN   (click here for copy of this patent)

Publication Number:  WO/2008/094571

Filing Date:    29 January 2008

Publication Date:  7 August 2008

 

5. Application Title:  METHOD FOR TREATING DELIRIUM   (click here for copy of this patent)

Publication Number:  WO/2008/057496

Filing Date:  2 November 2007

Publication Date:  15 May 2008

 

6. Application Title:  MIF INHIBITORS FOR TREATING NEUROPATHIC PAIN AND ASSOCIATED SYNDROMES    (click here for copy of this patent)

Publication Number:  WO 2007/142923

Filing Date:  29 May 2007

Publication Date:  13 December 2007

 

7. Application Title:  METHOD FOR ANTAGONIZING MIF ACTIVITY    (click here for copy of this patent)

Publication Number:  WO/2007/142924

Filing Date:  29 May 2007

Publication Date:  13 December 2007

 

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