AVP-923 for Agitation in Patients with Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of dementia and is a progressive neurodegenerative disease eventually leading to death. An estimated 5.4 million Americans have AD, this number has doubled since 1980, and is expected to be as high as 16 million by 2050.
AD is generally characterized by cognitive decline, impaired performance of daily activities, and behavioral disturbances. Behavioral and psychiatric symptoms develop in as many as 60% of community-dwelling people with dementia and in more than 80% of patients living in nursing homes; the lifetime risk of such complications approaches 100%.
Frequent and severe dementia-related behavioral symptoms can be extremely distressing to the individual, the family, and caregivers. Agitation is defined as a state of poorly organized and purposeless psychomotor activity characterized by at least one of the following types of behaviors:
- Aggressive verbal (e.g., screaming, cussing)
- Aggressive physical (e.g., destroying objects, grabbing, fighting)
- Non-aggressive physical (e.g., pacing)
These behavioral disturbances have been associated with more rapid cognitive decline, institutionalization, and increased caregiver burden. Reduction or elimination of such disruptive agitated behaviors could therefore improve the ability of caregivers to manage patients at home, and perhaps postpone the need for institutionalization. With no currently approved drugs for treatment of agitation in Alzheimer’s disease, there remains a great unmet medical need for these patients.
In June 2012, Avanir initiated a Phase II clinical trial to investigate the efficacy, safety and tolerability of AVP-923 for the treatment of symptoms of agitation in patients with Alzheimer’s disease. Details on the clinical trials can be found on the NIH website or Avanir’s clinical study site.
AVP-923 – Central Neuropathic Pain for Multiple Sclerosis patients
Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) characterized by disabling symptoms, including abnormalities of movements, coordination, gait, sensation, vision and affect. Experts believe MS is caused by an abnormal function of the immune system leading to inflammation of the nervous system. It is usually characterized by multiple exacerbations and remissions, with symptoms determined by the location of lesions in the brain and spinal cord called “MS plaques.” Among the many symptoms associated with MS chronic pain can be particularly disabling. Chronic pain has a substantial impact on daily life of MS patients, including their ability to function and work. MS patients experience pain of several types including musculoskeletal pain, painful tonic spasms and neuropathic pain, including trigeminal neuralgia, Lhermitte’s sign and central neuropathic pain affecting the limbs. Central neuropathic pain is caused by lesions of sensory pathways in the brain and spinal cord and is estimated to affect up to 30% of MS patients. It is characterized by moderate to severe painful sensations described as burning, pricking, electric shocks and squeezing generally overlying areas of numbness. Common analgesics usually provide inadequate relief for neuropathic pain and there are no FDA-approved drugs indicated for the treatment of central neuropathic pain.
In November 2011, Avanir initiated a phase II trial to investigate the safety, tolerability and efficacy of three doses of AVP-923 for the treatment of central neuropathic pain in patients with multiple sclerosis. Details on the clinical trial can be found on the NIH website or on Avanir's clinical study site.
AVP-923 is an investigational drug consisting of a combination of two well-characterized compounds: the active ingredient dextromethorphan hydrobromide (DM), an uncompetitive NMDA receptor antagonist and sigma-1 agonist and the enzyme inhibitor quinidine sulfate (Q), a CYP450 2D6 inhibitor, which serves to increase the bioavailability of dextromethorphan. Over 1,635 patients were exposed to AVP-923 in doses up to 60 mg of DM with 60 mg Q in 19 clinical trials in various diseases as well as healthy volunteers. Across this safety database, the most common adverse events reported were dizziness, headache and nausea which tended to improve within a few weeks of continued dosing in most patients. AVP-923 DM 20mg/Q 10 mg capsules was approved for treatment of pseudobulbar affect (PBA) in October 2010 under the trade name NUEDEXTA ® (dextromethorphan hydrobromide and quinidine sulfate). NUEDEXTA is not approved for the treatment of agitation in Alzheimer’s patients.