Effective therapies for neurodegenerative diseases like Alzheimer’s are urgently needed. But developing new drugs is difficult, time-consuming, and expensive, with a high risk of failure. Strategic partnerships can help biotech companies manage costs and access the latest technologies to drive innovation and advance novel therapy ideas.
Serious unmet medical need
Finding treatments for neurodegenerative disorders such as Alzheimer’s disease is one of today’s largest unmet medical needs. Around 50 million people worldwide have some form of dementia, and numbers are expected to almost double every 20 years. “Brain disease poses the third-largest health burden globally and deserves a suitable research focus,” says Fraser Murray, CEO of Pandeia Therapeutics, a biotech developing drugs for Huntington’s disease.
Developing effective therapies is difficult, as neurodegenerative disease profiles are heterogeneous, and despite following many leads over the last decades, researchers don’t fully understand the underlying pathophysiologies. Diagnosis adds further complications, often involving an extensive medical review, psychological tests, neurological exams, and brain scans.
One theory for Alzheimer’s, limited success
Most scientists agree that two proteins in the brain – beta-amyloid and tau – are involved in Alzheimer’s disease. The amyloid hypothesis proposes that abnormal levels of beta-amyloid form plaques between neurons in the brain, disrupting cell function. Then tau accumulates and forms neurofibrillary tangles inside the neurons, blocking their transport system.
Why these proteins accumulate, how they relate to each other, and what other factors are involved is unclear. Most efforts to develop therapies have focused on this hypothesis and failed. The few available drugs aimed to prevent damage in patients’ brains offer little tangible benefit.
Many experts question the amyloid hypothesis because plaques and tangles have also been found in people with no symptoms. Some researchers believe we need to investigate causative mechanisms more widely to understand the potential roles of inflammation, the immune system, the gut microbiome, and energy metabolism.
Looking for genetic links and new targets
New technologies are enabling researchers to shift their search for new genetic links and therapeutic targets beyond beta-amyloid. “Astrocytes have been overlooked in drug discovery and are potentially an untapped source of new targets. Astrocytic processes are fundamental to CNS homeostasis, and their dysfunction is both a consequence and cause of neurodegeneration,” according to Jamie Bilsland, CSO of AstronauTx, a UK biotech that is taking an alternative approach to fighting Alzheimer’s disease.
Treatments that can delay or prevent the onset of Alzheimer’s disease symptoms are the major goal, but these require biomarkers to identify which people will develop Alzheimer’s and might benefit from therapies. The genetic links to Alzheimer’s disease are mostly undefined. Some risk genes are known, but how and when they cause disease is still not understood and is likely multi-factorial. Nevertheless, research continues to correlate genetic data with Alzheimer’s disease patient samples and brain scans.
One promising biomarker and therapeutic target is the aggregatin protein, which attaches to amyloid-beta. Suppression of the protein in a mouse model reduced plaques and improved inflammation and cognitive impairment. Another novel biomarker, neurofilament light chain protein, could be used in early detection Alzheimer’s disease blood tests because it starts accumulating in the blood up to 16 years before symptoms appear.
Various RNA regulators could also be biomarkers or therapeutic targets. Genomic and transcriptomic studies comparing Alzheimer’s disease and healthy states will advance this area and further the understanding of the disease pathology.
The Alzheimer’s disease drug pipeline
In 2019, Alzheimer’s disease clinical trials included 132 agents aimed to modify the disease or ease symptoms. Small molecules and biologics such as monoclonal antibodies, oligonucleotides, and cell therapies are all under investigation. Mechanisms vary and include preventing the build-up of disease-causing proteins, suppressing specific transcripts, expressing therapeutic proteins, and using stem cells to replace damaged brain cells.
But to date, 99% of Alzheimer’s disease clinical trials have shown no difference between the drug and placebo effects. Roche, Eli Lilly, AstraZeneca, and Merck all recently halted the development of drug candidates due to a lack of efficacy. There is a desperate need for new hypotheses and new strategies and tools to test these hypotheses, in pre-clinical discovery, with translational studies, and ultimately in clinical trials.
Sophisticated end-to-end solutions
How can small or young biotech companies advance innovative hypotheses? Strategic partnerships with global solutions providers, for example, offer access to the latest technologies. The WuXi AppTec open-access platform provides an extensive offering of high-quality R&D and manufacturing services.
“We have built an open, enabling, platform to support any organization involved in drug discovery, across all modalities, from target identification and validation all the way to commercial manufacture,” explains Dave Madge, Vice President of the Research Services Division at WuXi AppTec.
The in vitro hit-finding platform developed by WuXi AppTec accelerates drug discovery by leveraging a broad suite of technologies to deliver novel, tractable, chemical matter. Having diverse platforms, such as affinity selection mass-spectroscopy, DNA-encoded library screening, fragment screening, and biochemical screening, ensures that a suitable assay technology is available for all target types.
These assays are enabled by extensive protein production and cell-line development capabilities and further supported by orthogonal assay techniques such as biophysics and visualization of ligand-protein interactions by x-ray crystallography. Sophisticated computational chemistry, virtual screening, and machine learning platforms inform and accelerate discovery programs.
WuXi AppTec provides a fully integrated solution for medicinal chemistry, in vitro biology, in vivo biology, and drug metabolism pharmacokinetics (DMPK) studies to rapidly transform screening hits into clinical candidates. The platform also includes a variety of sophisticated animal models for Alzheimer’s disease, Parkinson’s disease, encephalomyelitis, and amyotrophic lateral sclerosis.
“The expertise we have developed and the facilities we have built give our collaborators access to the tools they need when they need them. This provides rapid, timely, and economical access to technologies and accelerates our collaborators’ discovery programs,” said Dave.
Alzheimer’s disease drug development has faced limited success so far, but as researchers combine new technologies and strategic partnerships, the expectation is that they can accelerate innovation and improve outcomes.
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