Alzheimer’s disease drug-development pipeline: few candidates, frequent failures

Introduction

Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.

Methods

We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.

Results

During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).

Conclusions

The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.

Full Article

(Image: Shutterstock)

Researchers find clue to stopping Alzheimer’s-like diseases

Tiny differences in mice that make them peculiarly resistant to a family of conditions that includes Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob Disease may provide clues for treatments in humans.

Amyloid diseases are often incurable because drug designers cannot identify the events that cause them to start.

Professor Sheena Radford, Astbury Professor of Biophysics at the University of Leeds, said: “Amyloid diseases are associated with the build-up of fibrous plaques out of long strings of ‘misfolding’ proteins, but it is not clear what kicks the process off. That means the normal approach of designing a drug to destroy or disable the species that start the disease process does not work.

“We have to take a completely different tack: instead of targeting the cause of the disease, we need to disrupt the plaque building process.”

The University of Leeds-led team’s study, published in the journal Molecular Cell, looked to mice for a way forward.

“We already knew that mice were not prone to the build up of some of these plaques. This study, for the first time, observed the building happening and saw the differences between the mice proteins and their almost identical human equivalents,” Professor Radford said.

She added: “We mixed the mice and human proteins and found that the mice protein actually stopped the formation of the plaque-forming fibrils by the human protein.”

The research was conducted completely in the test-tube using human and mice beta-2 microglobulin proteins produced in the laboratory. Plaques made up of beta-2 microglobulin are associated with Dialysis Related Amyloidosis (DRA). Instead of being a neurodegenerative condition like Alzheimer’s or Parkinson’s, DRA primarily affects the joints of people on kidney dialysis.

The team observed differences in the formation of the plaque-forming fibrils in samples containing only mice protein, samples with only the human protein and samples containing mixtures of the two.

The lead researcher, Dr Theodoros Karamanos, said: “These two versions of the proteins are almost exactly the same, with very slight differences in structure, but the outcomes are completely different. If I put a misfolding-prone protein in the human sample, I see the formation of fibrils in two days in the right conditions. If I do the same in the mouse sample, I can leave it for weeks and there are no fibrils.

Dr Karamanos added: “The exciting thing is that if you mix the proteins—with only one mouse protein for every five human proteins—you see a significant disruption of the formation of fibrils.”

The study used Nuclear Magnetic Resonance spectroscopy to look at a molecular level at the interactions of the different proteins and identified tiny differences in the physical and chemical properties of the surfaces that made a great difference to whether plaques are formed.

The results showed that the mouse protein binds to the human protein more tightly than the human protein binds to its misfolded form. Interestingly, subtle differences in the driving forces of binding (i.e. the balance of hydrophobic and charge-charge interactions) in the binding interface govern the outcome of assembly.

Dr Karamanos said: “We can’t just load up a syringe and inject mouse protein into patients. But if we know the properties of the interface between the two proteins that are responsible for the inhibition effect, we can ask the chemists to design small molecule drugs which mimic what the mouse protein does to the human protein. That may be a key insight into how to stop the plaque building process.”

Blocking brain’s ‘internal marijuana’ may trigger early Alzheimer’s deficits

When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input — such as might accompany falling into a hole, burning one’s finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell “cat” — are firmly stored in the brain’s memory vaults and more accessible to retrieval.

These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells — effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of “wet blanket” nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells’ transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance — the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.

Passing along the message

But when the news is particularly significant, pyramidal cells squirt out their own “no, this is important, you shut up!” chemical — endocannabinoids — which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.

A-beta is known to impair pyramidal-cell plasticity. But Madison’s research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron’s endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.

While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ’s sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer’s disease.

Exactly how A-beta blocks endocannabinoids’ action is not yet known. But, Madison’s group demonstrated, A-beta doesn’t stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car’s ignition switch won’t do much good if your battery is dead.)

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb’s active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.

“Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”

Besides, flooding the brain with external cannabinoids induces tolerance — it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids’ ability to do their crucial job of opening the gates of learning and memory.

How a new approach to funding Alzheimer’s research could pay off

Rescue of Alzheimer’s Memory Deficit Achieved by Reducing ‘Excessive Inhibition’

A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a Professor of Biology and the Verne M. Willaman Chair in Life Sciences at Penn State University. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found. A scientific paper describing the discovery will be published in Nature Communications on 13 June 2014. 

Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. “Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,” Chen said. The research behind those drugs had targeted the long-recognized feature of Alzheimer’s brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die. “The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,” Chen explained.

"We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients," Chen said. He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called "reactive astrocytes" in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.  

Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped “astrocyte” cells which, in a healthy individual, surround and support individual neurons in the brain. “Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,” Chen said. 

Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice). “Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,” Chen said. His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

Importantly, Chen said, “After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.”

Is glaucoma a brain disease?

Findings from a new study published in Translational Vision Science & Technology (TVST) show the brain, not the eye, controls the cellular process that leads to glaucoma. The results may help develop treatments for one of the world’s leading causes of irreversible blindness, as well as contribute to the development of future therapies for preserving brain function in other age-related disorders like Alzheimer’s.

In the TVST paper, Refined Data Analysis Provides Clinical Evidence for Central Nervous System Control of Chronic Glaucomatous Neurodegeneration, vision scientists and ophthalmologists describe how they performed a data and symmetry analysis of 47 patients with moderate to severe glaucoma in both eyes. In glaucoma, the loss of vision in each eye appears to be haphazard. Conversely, neural damage within the brain caused by strokes or tumors produces visual field loss that is almost identical for each eye, supporting the idea that the entire degenerative process in glaucoma must occur at random in the individual eye — without brain involvement. 

However, the team of investigators discovered during their analysis that as previously disabled optic nerve axons — that can lead to vision loss — recover, the remaining areas of permanent visual loss in one eye coincide with the areas that can still see in the other eye. The team found that the visual field of the two eyes fit together like a jigsaw puzzle, resulting in much better vision with both eyes open than could possibly arise by chance.

“As age and other insults to ocular health take their toll on each eye, discrete bundles of the small axons within the larger optic nerve are sacrificed so the rest of the axons can continue to carry sight information to the brain,” explains author William Eric Sponsel, MD, of the University of Texas at San Antonio, Department of Biomedical Engineering. “This quiet intentional sacrifice of some wires to save the rest, when there are decreasing resources to support them all (called apoptosis), is analogous to pruning some of the limbs on a stressed fruit tree so the other branches can continue to bear healthy fruit.” 

According to the researchers, the cellular process used for pruning small optic nerve axons in glaucoma is “remarkably similar to the apoptotic mechanism that operates in the brains of people afflicted with Alzheimer’s disease.” 

“The extent and statistical strength of the jigsaw effect in conserving the binocular visual field among the clinical population turned out to be remarkably strong,” said Sponsel. “The entire phenomenon appears to be under the meticulous control of the brain.” 

The TVST paper is the first evidence in humans that the brain plays a part in pruning optic nerve axon cells. In a previous study, Failure of Axonal Transport Induces a Spatially Coincident Increase in Astrocyte BDNF Prior to Synapse Loss in a Central Target, a mouse model suggested the possibility that following injury to the optic nerve cells in the eye, the brain controlled a pruning of those cells at its end of the nerve. This ultimately caused the injured cells to die.

“Our basic science work has demonstrated that axons undergo functional deficits in transport at central brain sites well before any structural loss of axons,” said David J. Calkins, PhD, of the Vanderbilt Eye Institute and author of the previous study. “Indeed, we found no evidence of actual pruning of axon synapses until much, much later. Similarly, projection neurons in the brain persisted much longer, as well.” 

“This is consistent with the partial recovery of more diffuse overlapping visual field defects observed by Dr. Sponsel that helped unmask the more permanent interlocking jigsaw patterns once the eyes of his severely affected patients had been surgically stabilized,” said Calkins. 

Sponsel has already seen how these findings have positively affected surgically stabilized patients who were previously worried about going blind. “When shown the complementarity of their isolated right and left eye visual fields, they become far less perplexed and more reassured,” he said. “It would be relatively straightforward to modify existing equipment to allow for the performance of simultaneous binocular visual fields in addition to standard right eye and left eye testing. 

Authors of the TVST paper suggest their findings can assist in future research with cellular processes similar to the one used for pruning small optic nerve axons in glaucoma, such as occurs in the brains of individuals affected by Alzheimer’s. 

“If the brain is actively trying to maintain the best binocular field, and not just producing the jigsaw effect accidentally, that would imply some neuro-protective substance is at work preventing unwanted pruning,” said co-author of the TVST paper Ted Maddess, PhD, of the ARC Centre of Excellence in Vision Science, Australian National University. “Since glaucoma has much in common with other important neurodegenerative disorders, our research may say something generally about connections of other nerves within the brain and what controls their maintenance.”

(Image: iStock)