Semagacestat – Gamma Secretase Inhibitor for Alzheimer's Disease (AD)

Semagacestat (LY-450139) is a gamma secretase inhibitor under development by Eli Lilly as a treatment for Alzheimer's disease (AD). Now in advanced-stage development, it is hoped that this new anti-dementia drug will help delay the onset of severe AD and thereby help preserve cognitive and executive functioning and in turn improve patient quality of life.

Moving beyond symptom relief in AD

AD is a devastating neurodegenerative disease and the most common form of dementia to affect the elderly. From early symptoms of memory loss, the disease runs a progressive course of steady cognitive decline accompanied by severe behavioural problems.

Although specific anti-dementia drugs are available for patients with AD, they provide at best only modest symptomatic improvement. Moreover, their effects on cognition, executive functioning and behaviour are only temporary.

None is considered to have disease-modifying effects that can halt the progression of the disease and stop cognitive decline – the hallmark of AD. Many patients also fail treatment with first-line anti-dementia drugs because of poor efficacy and tolerability.

There is an urgent need to find drugs that can address the underlying pathology of AD and help halt the inexorable rise in the prevalence of the disease as the world's elderly population rises.

Gamma secretase inhibitors target beta-amyloid

Pathologically, AD is characterised by the presence of amyloid plaques (neuritic or senile plaques) and neurofibrillary tangles in the brain. The amyloid plaques result from the accumulation of insoluble toxic beta-amyloid (b-amyloid42), derived from amyloid precursor protein (APP).

The production of toxic beta-amyloid is believed to trigger a series of secondary events, giving rise to the so-called amyloid cascade hypothesis. This has spurred the search for drugs to prevent b-amyloid42 formation.

Lilly's semagacestat (LY-450139) is designed to inhibit gamma secretase, an enzyme that is involved in the cleavage of APP to beta-amyloid. By decreasing production of beta-amyloid, it is hoped that gamma secretase inhibitors will exert a disease-modifying effect in AD and thus slow or halt the destruction of nerve cells – the final stage in the amyloid cascade hypothesis.

Phase III IDENTITY trial

In March 2008 semagacestat (LY-450139) advanced to Phase III development, where it was evaluated in the IDENTITY (Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of AmyloId PaThologY) trial, the first Phase III trial for this new anti-dementia drug.

IDENTITY, an international multicentre randomised, double-blind, placebo-controlled trial, enrolled 1,500 patients with mild-to-moderate AD. Integral to the design of this 21-month long study was a randomised delayed start, so that patients initially assigned placebo will receive active drug at some stage before the end of the double-blind treatment period. All patients completing the initial 21-month study period were eligible to continue open-label therapy.

Several different tests were used on a proportion of patients in the IDENTITY trial to measure the effect of semagacestat (LY-450139) on A-beta amyloid and amyloid plaques. For example, a new brain scan capable of taking images of amyloid plaques was used to measure the build up of amyloid plaques, while other tests will measure brain size and functioning. These additional tests helped to further determine the effect of semagacestat (LY-450139) on AD pathology. The results of the clinical trials will be announced after the 21-month period ends.

Phase III IDENTITY 2 trial

In October 2008, Eli Lilly announced the start of the second Phase III study on semagacestat to understand what doses of semagacestat can be given in clinical practice. The study, IDENTITY 2, will enrol 1,100 people suffering from AD.

The treatment period will last for nearly 21 months. During this period, patients will be given either 140mg of semagacestat or placebo. Patients who are currently undergoing symptomatic treatment for AD will also be given semagacestat. They can continue their current treatment while taking semagacestat. The study also includes a 'randomised delayed start' design which will allow even those patients who were initially given the placebo to take semagacestat before the trial period ends.

The results of IDENTITY 2 will be evaluated along with the outcome of the first Phase III trial. The results are expected to give a clearer picture on how semagacestat can be dosed.

Solanezumab

In May 2009, Eli Lilly began two identical clinical trials on another anti-amyloid beta monoclonal antibody. Named solanezumab, the antibody is being tested as a potential medicine for the treatment of mild-to-moderate AD. The trial period will last for 18 months. Referred as EXPEDITION and EXPEDITION 2, the trials will enrol 2,000 patients above 55 years of age from 16 nations.

Marketing commentary

Recent estimates suggest that worldwide between 12 and 15 million people have AD, with about 5 million people affected in the US alone. Primarily a disease of the elderly, prevalence is projected to rise significantly as the proportion of elderly in the world's population increases.

By 2050 there are likely to be more than three times as many people with AD than there are today, unless more effective treatments are discovered. While the search for curative AD therapies continues, any drug that can significantly address underlying disease pathology and slow disease progression would constitute a major advance.

Costs of care increase dramatically as patients advance to severe AD, when they are no longer able to function independently and often become bedridden.

Not surprisingly, the current market for anti-dementia therapies is in its infancy with among the highest growth dynamics in the CNS market.