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Lifting the fog

Despite numerous setbacks, the hunt for an Alzheimer's disease cure is still ongoing

A foggy forest pathThe debilitating neurological condition Alzheimer's disease (AD) affects one in ten people over 65 years of age and half of people over 85. The development of AD is characterised by the deposition of amyloid plaques and neurofibrillary tangles, as well as demyelination, which results in the death of nerve cells in the brain.

The cause of AD continues to be a subject of debate; there is strong evidence that the disease has a genetic component, as shown by the incidence of familial AD. This is attributed to an inherited gene mutation and to the presence of genetic risk factors that make particular individuals more susceptible to developing AD later in life. However, AD can also be attributed to changes in an individual's brain, which result in reduced synthesis of the neurotransmitter acetylcholine. This hypothesis was the basis from which currently approved drug therapies for AD were developed.

Despite significant progress in research into this complex disease, the discovery of a single cure continues to be elusive. Current treatments therefore focus on maintenance of mental function, management of behavioural symptoms and delaying the progression of the disease.

Treating the symptoms, not the cause
Research into symptomatic treatments for AD has been partially successful. Orally administered acetylcholinesterase inhibitors, such as rivastigmine (Exelon, Novartis) and donepezil (Aricept, Eisai), are marketed worldwide.

Rivastigmine is indicated for the treatment of mild-to-moderate AD. Results of clinical trials of rivastigmine showed the drug provides cognitive and non-cognitive benefits, such as improved quality of life, increased independence and improvements in the ability to perform everyday tasks. As well as being administered orally, rivastigmine is also available as a transdermal patch in the US, Canada, the UK and Ireland.

Donepezil is indicated for the treatment of moderate-to-severe AD. A once-daily, sustained-released (SR) formulation of donepezil was approved for use in moderate-to-severe AD by the US Food and Drug Administration (FDA) in July 2010, suggesting that the drug continues to be effective in this population. Additionally, a patch formulation of donepezil is in development.

Also approved for the treatment of moderate-to-severe AD is memantine (Namenda, Forest Laboratories), which was the first NMDA receptor antagonist to be approved for this indication. The NMDA receptor, a glutamate receptor, controls synaptic plasticity and memory function. In clinical trials, memantine was associated with an increase in functional brain activity: this suggests utility of the drug for the reversal of cerebral metabolic decrease, which occurs as the disease worsens. Memantine recipients also showed a significant increase in glucose metabolism in several regions of the brain associated with language and attention — the same regions in which placebo recipients showed metabolic decline.

Nevertheless, the drug is still considered to be modestly effective and new treatments are eagerly anticipated.

Semagacestat
Many drugs for AD initially appear promising but fail when they reach late-stage development. The failure of these drugs can be attributed to a number of factors, including the incorrect optimal dose being determined early in development. It is often found in hindsight that efficacy seen in animal models could not be translated in human subjects, as animal models are rarely representative of the disease in humans. The best researchers can do is estimate the amount of drug needed for human subjects to demonstrate the same effect seen in animal models. Often this is where the drug falls short or leads to unacceptable toxicity. Combined with the complexity of working with the human brain, it is not surprising that even the most promising drugs can fail.

A recent example of this late-stage failure was the discontinuation of Eli Lilly's semagacestat. In this case, phase III trials were halted after preliminary results suggested worsening of cognitive decline, as well as the development of skin cancer in recipients of the drug. Semagacestat is a gamma-secretase inhibitor of the final step in amyloid-beta protein synthesis: the negative results seen in this trial indicate that there is little potential for this class of drugs. This discovery has put at risk other drug development programmes operating in the same area.

Other late-stage failures
Another drug that is close to treading the same path as semagacestat is ELND005 (Elan). This drug appears to break down neurotoxic fibrils to allow clearance of beta-amyloid (Aß) peptides, which are responsible for the development of amyloid plaques, in the brain. In a phase II trial, low-dose ELND005 failed to outperform placebo in primary cognitive and functional endpoints. Elan and Transitional Therapeutics intend to press forward with phase III trials regardless.

Another drug that initially showed potential in the treatment of early-stage AD was dimebolin (Dimebon, Medivation). The phase III CONNECTION trial failed to meet its primary endpoints of cognition, memory and global function in patients with mild-to-moderate AD; nevertheless, Medivation remains committed to determining whether dimebolin can offer clinical benefits to these patients in the phase III CONCERT trial.

A different approach to the treatment of AD comes in the form of immune globulin (Gammaguard, Baxter). The compound is being evaluated in a phase III pivotal trial in patients with mild-to-moderate AD and is also being used to treat a range of other neurological conditions, such as peripheral nerve disorders. The mechanism of action of the compound, which is thought to comprise natural antibodies against the Aß peptide, is not clear but is thought to be neuroinflammatory or antibody-related.

If it proves to be successful in preventing the downstream effects of Aß, Gammaguard may be one of the first drugs with a disease-modifying effect to be approved for the treatment of AD.

Early detection
Another question also being addressed is that of whether treating late-stage disease is the right approach. Current treatments target patients with symptomatic AD, when irreparable damage has already been done. Generally, however, the key to treating a disease effectively is early detection. Therefore the best time to treat AD is likely to be prior to the development of symptoms such as memory loss. This is difficult to model in animals, and most human subjects involved in clinical trials are often close to developing, or have already developed, the first signs of the disease.

According to the Alzheimer's Prevention Initiative, it currently takes too many cognitively 'normal' people, too much money and too much time to evaluate pre-symptomatic AD treatments in randomised clinical trials. Preventative trials would have to run for years to show any clinical benefit, resulting in huge costs. However, it may be possible to develop screening methods to choose candidates most at risk of developing AD by using biomarkers such as changes in cerebral glucose metabolism and measurements of brain shrinkage, among others. Also, identifying individuals with predisposing genetic factors would greatly contribute to the success of preventative trials in the future.

As lifespans extend, there is no doubt the demand for therapies to treat late-onset diseases such as AD is growing. However, very few currently approved treatments are effective as long-term solutions as they cannot change the underlying disease process, meaning that these compounds modify only the symptoms and not the cause. Drug therapy relies on an early diagnosis and even then may only be effective for a few months to a few years.

Although a cure for AD is unlikely to be found in the immediate future, some success has been noted for drugs such as memantine, rivastigmine and donepezil, and other drugs in development, such as immune globulin, have considerable potential. However, the failure of promising compounds in late-stage development, such as semagacestat and ELND005, suggests a new approach is needed for the treatment of this irreversible and progressive disease.

 

Drug launches

Generic name Trade Name (Company) Indication  Country
Perflutren protein-type A microspheres injectable suspension Optison (Takeda) Ultrasound contrast agent  US
Darbepoetin alpha Cresp (Dr Reddy's) Anaemia due to chronic kidney disease and chemotherapy India
Trazodone hydrochloride extended-release Oleptro (Angelini Labopharm) Major depressive disorder US
Felodipine sustained-release (Jiangbo Pharmaceuticals) Hypertension  China

 

The Author
Pipeline was written by Chin-Hang Kong of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

To comment on this article, email pm@pmlive.com

15th October 2010

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