What Is Plan B If A-Beta Alzheimer's Hypothesis Is Void?

August 19, 2010 Therapeutic focus - What is plan B if A-beta Alzheimer's hypothesis is void?

Amy Brown

The failure of Eli Lilly’s gamma secretase inhibitor, semagacestat, which targets the main amyloid-beta (A- beta) hypothesis of Alzheimer's disease (AD), raises once more the worrying possibility that targeting A-beta plaques may not be the breakthrough pathway to developing the first disease-modifying drug (Will gamma secretase Alzheimer's class survive the fall of semagacestat?, August 18, 2010).

Worrying because the bulk of current research dollars is being spent on agents that target A-beta – a review of pipeline data from EvaluatePharma shows that of the 139 clinical stage candidates in development for Alzheimer's, 30% are adopting the A-beta approach (see tables below). As such, although the most money is being spent on A-beta candidates, there remains a decent portion of products adopting slightly different pathways which could offer hope should the main hypothesis be proved wrong.

Approaches to treat Alzheimer's disease

Targeting A-beta Targeting neurotransmitters (symptomatic)

Anti- Beta Beta Gamma Beta Other beta RAGE Tau Status amyloid amyloid secretase secretase A- amyloid modulator inhibitor (serotonin) inhibitor vaccine inhibitor inhibitor beta MAb

Phase - 2 - 1 - - 1 - III

Phase 4 1 2 2 1 2 1 1 II

Phase 5 4 6 5 2 - 3 1 I

Class 9 7 8 8 3 2 5 2 total

A- beta 42 total

Null hypothesis?

AD therapeutics fall into two broad categories. The first targets nervous signalling in the CNS, and is generally associated with improving cognition and symptomatic AD, although has not been shown to slow or alter disease progression. The second, more recent class, elucidates the underlying causes of its pathology, and include drugs that target A-beta plaque build-up in nervous tissue.

Classic treatments for AD are based on the rationale that increasing levels and longevity of serotonin (5-HT) and/or the neurotransmitter acetylcholine (ACh) in the brain improves cognition and memory. Therefore, drugs such as Eisai’s Aricept, an acetylcholinesterase (AChE) inhibitor, which blocks the enzyme that breaks down ACh, improve cognition.

The 5-HT-based drugs are normally associated with treating depression and anxiety, by inhibiting 5-HT re- uptake in synapses, thereby increasing its levels. A rationale currently exists for the development of specific 5- HT6 receptor antagonists in treating AD. The 5-HT6 receptor exists almost solely in the brain, localised to areas responsible for cognition and memory; antagonists of the receptor, such as GSK’s phase II candidate 742457, therefore increase 5-HT levels specifically in those areas.

Alternatives

An alternative approach to the AChE pathway is targeting the glutamate pathway, an excitatory neurotransmitter in the brain and CNS. Antagonists of the NMDA (N-Methyl-D-Aspartate) receptor, a glutamate receptor, like Forest Laboratories’ Namenda (memantine), are also marketed as AD therapeutics, as overactivation of receptors induces toxic effects implicated in AD. NMDA receptor antagonists were classically used as anaesthetics, and include recreationally-used psychotropic agents like phencyclidine (PCP) and ketamine. As such, they can incur unfavourable side effects.

Providing a similar rationale, but attacking the glutamate pathway from the other side, so as not to directly inhibit NMDA receptors and therefore limit side effects, is in the development of H3 histamine receptor antagonists. H3 receptors, found in the CNS, release histamine in the brain, which in turn triggers the release of glutamate. This upstream inhibition of NMDA receptor activation is being harnessed in AD drugs programmes from Merck & Co, Sanofi-Aventis, GSK and Cephalon.

Johnson & Johnson and Addex Pharmaceuticals’ metabotropic glutamate receptor 2/3 (mGluR2/3) agonist, ADX-71149, in phase I, is another glutamate-derived alternative, and works by similar mechanism to the NMDA receptor antagonist.

Other studies have been conducted, including one in association with Johnson & Johnson, assessing a two- pronged approach on the ACh and glutamate pathways together, using a combination of AChE inhibitor Razadyne (galantamine) and NMDA antagonist memantine. One similar combination, however, Pfizer’s Dimebon, reported negative phase III data recently, and may mean that AD drug development moves away from targeting neurotransmitters (Dimebon explodes on Medivation, March 3, 2010).

Variations on A-beta

On the other side of the fence are programmes targeting the disease itself, and blocking A-beta plaque accumulation has been for some time the most popular and validated target.

Interestingly though, a new variation on this method is currently being developed by Pfizer and TransTech Pharma, with their phase II compound TTP488 (PF-4494700), a RAGE (receptor for advanced glycated endproducts) modulator. RAGE is a multi-ligand receptor expressed in most tissues on cell surfaces, including cortical neurons, and is found to increase with age. Being so ubiquitously expressed, it interacts via various signalling pathways with a range of different peptides, including A-beta.

Pre-clinical models have shown that inflammation, stress and A-beta aggregation in neuronal tissue is augmented by the RAGE-A-beta interaction, and it is suggested that RAGE mediates a proinflammatory neuronal pathway that commonly underwrites neurodegenerative diseases. In one study, using mouse models in an A-beta-rich environment, expression of RAGE increased pathologies and behaviours normally associated with AD, more so than in mice that overexpressed only the pathological mutant precursor to A-beta peptide. Furthermore, by blocking the RAGE-A-beta interaction, A-beta load was reduced, and cognitive and synaptic functions in the mice were improved.

Allon Therapeutics' activity dependent neuroprotective protein (ADNP)-based candidate AL-108 (davunetide) also offers an alternative approach to protecting against beta-amyloid plaque damage, by preventing degradation of tau and protecting the microtubule network holding neuronal cells together. The drug is currently in phase II.

Tau tangles

TauRx Therapeutics, however, is considering a related, but wholly different target altogether, with its phase II drug Rember, and phase I candidate LMT-X, targeting tau-protein aggregation.

Tau tangles, a form of neurofibrillary tangle (NFT), similar to A-beta plaques, are aggregated fibrils made up of polymerised tau, a protein associated with microtubule formation and stabilisation. They were originally found in regions of the brain that are normally the source of cognitive impairment in AD.

Tau undergoes large conformational changes and phosphorylation when forming NFTs, but the reasons for NFTs naturally evolving is not properly understood. However, what has been found of significance in the case of tau pathologies, like AD, is that the tau molecule is specifically truncated, and that certain truncations lead to more toxic aggregates. Furthermore, a mutation in the tau gene has since been found to cause frontotemporal dementia, and demonstrated a direct link between tau pathology and neurodegeneration.

It has therefore been suggested that tau is only pathological when truncated in a particular way, and that an ordered sequence of cuts from both ends of the molecule quickly forms more filaments, or stabilises them as they form.

Another theory is that the state of tau in NFTs is also echoed in surrounding cells that cannot bear these tangles. While NFT-bearing cells actually collect up toxic tau, it is the pre-fibrillar protein in non-tangle-bearing neuronal cells that causes their death.

Immunoglobulin surprise package

Another alternative to conventional approaches comes in the form of Gammagard, from Baxter International, a long-standing immunoglobulin-based therapy that stimulates an immune response from the patient; it is proposed that newly-replenished antibodies will attack A-beta plaque formation. Positive initial phase III data were released in April.

Gammagard has been found to significantly alleviate symptoms of AD and sustain improved cognitive function much more persistently than the AChE inhibitors. Other studies have shown Gammagard recipients to be half as likely to develop dementias versus those who received a placebo. The major drawback of Gammagard is that it is a human plasma-manufactured product, meaning supplies will be limited and expensive.

Finally, the first AD gene therapy, Ceregene, BioSante Pharmaceuticals and Roche’s CERE-110, aims to introduce an NGF (nerve growth factor) gene directly into regions of the brain associated with AD, stimulating nerve cells to function properly and survive longer. Only 50 mild-onset patients are being tested currently in a phase II, double-blind, placebo-controlled study. The therapy does, however, require surgical injection directly to the affected region, a potentially hazardous operation involving drilling a hole in the patient’s skull.

Therefore, while gamma-secretase may not prove to be the best route to targeting A-beta, there are several alternative paths being explored and indeed validated, and studies into factors such as neural microtubule networks and tau aggregation show that not all the eggs are being placed in one basket. Selected late stage pipeline candiidates for Alzheimer's disease using non-A-beta WW Annual approach Sales ($m)

Generic Pharmacological Launch Product Company 2009 2016 Name Class WW

immune Phase Gammagard globulin Immunoglobulin Baxter International - - - III Liquid/KIOVIG (human)

Acetylcholinesterase Dimebon latrepirdine inhibitor & NMDA Pfizer/Medivation 2013 - 278 receptor antagonist

Phase Alpha-7 nicotinic RG3487 - Roche 2013 - 89 II agonist

PF-4494700 - RAGE modulator Pfizer 2015 - 30

PF-5212365 5-HT6 (serotonin) - Pfizer 2013 - 28 (SAM-531) antagonist

Tau aggregation Rember - TauRx Therapeutics - - - inhibitor

TTP488 - RAGE modulator TransTech Pharma - - -

Ceregene/BioSante CERE-110 - NGF gene therapy - - - Pharmaceuticals

AZD3480 Alpha 4 & beta 2 ispronicline AstraZeneca/Targacept - - - (TC-1734) nicotinic agonist

Activity-dependant AL-108 davunetide neuroprotective Allon Therapeutics 2013 - - protein (ADNP)

H3 receptor MK-0249 - Merck & Co - - - antagonist