AD focus shifts to treating agitation/aggression

After years of fruitless search for new therapies to slow the deadly progression of Alzheimer’s disease (AD), researchers are having more success with experimental treatments for the neuropsychiatric symptoms associated with AD, such as agitation and aggression.

A case in point is Avanir Pharmaceuticals (NASDAQ:AVNR), which reported positive results in mid-September from a Phase 2 clinical trial of its AVP-923 in lowering agitation in patients with AD.

Another company, Transition Therapeutics (NASDAQ:TTHI; TSX:TTH), is in a major Phase 2 trial with its ELND005 drug candidate for the treatment of agitation and aggression in AD patients. Enrollment of up to 400 patients should be completed in the first quarter, with data released in mid-2015. With its high level of patient enrolment, the study may qualify as one of two Phase 3 trials required for approval.

The Avanir trial, which enrolled 220 patients at 87 sites in the U.S., showed that AVP-923 significantly reduced agitation, compared with placebo, as measured by the primary endpoint, the agitation/aggression domain score of the neuropsychiatric inventory (NPI). In addition, improvements were seen in a majority of secondary endpoints, including measures of caregiver burden.

The news sent Avanir’s shares soaring on Sept. 15. The stock price doubled to $12.49 from $6.74, adding some $1-billion to its market cap, on volume of almost 89 million shares, or 40 times the average daily volume.

“With no FDA-approved drugs for the treatment of agitation in AD, we believe these results represent a breakthrough for patients,” Dr. Joao Siffert, CMO of Avanir, said at the time. “We are extremely excited with the prospect of bringing a potential treatment that can provide clinically meaningful relief to these patients and reduce caregiver burden.”

Based on the Phase 2 results, Avanir hopes to meet with both the FDA and the European Medicines Agency in order to discuss moving into pivotal studies for the treatment of agitation in patients with AD.

At the American Neurological Association meeting last month, Avanir provided details of the Phase 2 data that Piper Jaffray analyst, Charles Duncan, described as better than expected and having potential to open the door for a billion dollar opportunity. He reiterated an “overweight” rating on the stock, with a $21 price target. Avanir closed at $11.85 on Friday.

AVP-923 is a differently formulated combination of the ingredients in Avanir’s Nuedexta, the only FDA-approved treatment for pseudobulbar affect (PBA). PBA occurs secondarily to a variety of otherwise unrelated neurological conditions and is characterized by involuntary, sudden and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion to a patient’s underlying emotional state.

An estimated six million Americans have AD, a number that 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 dementia patients and in more than 80% of patients with dementia living in nursing homes. As the disease progresses, the risk of these complications approaches 100%.

Aggression is usually characterized by verbal insults and shouting, as well as physical manifestations, such as hitting, biting and throwing objects. They are particularly common during personal care. Other symptoms of agitation include restlessness and pacing, excessive fidgeting, motor activities associated with anxiety, such as hand wringing or following a caregiver around the home, and verbal signs of distress like shouting and screaming.

In almost all individuals, agitation and aggression significantly affect patients’ daily lives. They are often distressing for the patients themselves, as well as their caregivers, and result in increased care burden and the likelihood of depression in caregivers. Psychological symptoms of dementia are also associated with a reduced quality of life and are commonly a main factor in the decision to move a person to an institutional care setting.

The other leading player in the AD agitation/aggression landscape is Transition Therapeutics with its ELND005 oral drug candidate, a small molecule that crosses the blood-brain barrier. In clinical studies, ELND005 has demonstrated an acceptable safety and tolerability profile.

The FDA granted fast track designation to ELND005 in 2013 for the treatment of neuropsychiatric symptoms associated with AD.

An earlier Phase 2 study, which evaluated ELND005 in more than 350 mild-to-moderate AD patients, was published in the peer-reviewed journal, Neurology. In the completed study, ELND005 appeared to decrease the emergence and severity of specific neuropsychiatric symptoms, an effect that seemed to correlate with drug exposure for some symptoms, according to Transition.

Currently, ELND005 is being investigated for multiple neuropsychiatric indications on the basis of its proposed dual mechanism of action. These include a reduction of brain myo-inositol levels in the brain, which are associated with mood/behavioral changes, an effect that is shared by other approved neuropsychiatric drugs, such as lithium and valproic acid. In addition, ELND005 is associated with a reduction in the levels of beta amyloid and tau proteins in the cerebrospinal fluid.

Transition’s ongoing Phase 2 study in agitation/aggression plans to enroll more patients for an extended treatment period, compared with Avanir’s Phase 2 study. The primary endpoint in the Transition study, which is a change in the NPI-Clinician (NPI-C) agitation/aggression combination score, is also clinician-based and broader than Avanir’s change in NPI agitation/aggression domain score.

The NPI was developed to provide a means of assessing neuropsychiatric symptoms and psychopathology of patients with AD and other neurodegenerative disorders. It is used to characterize the neuropsychiatric symptom profiles in a variety of neurological diseases and to capture treatment-related behavioral changes in patients.

In 2010, researchers revised NPI into a new NPI-C rating scale to include expanded domains and items as well as a clinician-rating methodology. It is a comprehensive instrument to measure neuropsychiatric symptoms in dementia, consisting of delusions, hallucinations, agitation, aggression, dysphoria/depression, elation/euphoria, apathy, irritability/lability, motor disturbances, sleep disorders, appetite and eating disorders, and aberrant vocalizations.

In a statement earlier this year, Dr. Tony Cruz, CEO of Transition, said ELND005 is a unique drug candidate that has been shown to have an acceptable safety profile in six clinical studies and to have reduced the emergence of multiple neuropsychiatric effects, including agitation, aggression, depression and anxiety. “We believe ELND005 provides a unique opportunity to achieve therapeutic benefit for patients with neuropsychiatric symptoms.”