Drug Discovery and Development

From gene therapy to vaccines to mitochondrial rescue, the quest for more effective neurodegenerative therapies faces mixed outcomes in 2024

From gene therapy to vaccines to mitochondrial rescue, the hunt for more effective neurodegenerative therapies has yielded a mix of promising breakthroughs and frustrating setbacks in 2024.

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Illustration of the thought processes in the brain

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Nine months into 2024, the search for effective neurodegenerative disease therapies continues, yielding a mix of promising advances and frustrating setbacks. After something of a lull in the 1990s and early 2000s, research into novel treatments for neurodegenerative diseases has surged back to life. One factor propelling the trend is the uptick in neurodegenerative disease incidence. Conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) pose a significant and growing threat to public health, with millions affected. In the US alone, nearly 7 million people are living with AD, 1 million with PD, and 31,000 with ALS.

The overarching issues that plague many of these drugs are typically a lack of safety or efficacy. For instance, the first clinical trial for an AD drug took place in 1987 using the acetylcholinesterase inhibitor tacrine. FDA approved the therapy in 1994, but pulled it from the market in 2013 due to side effects such as abdominal pain, nausea, vomiting, diarrhea, blurred vision, liver damage, and other symptoms.

Not only did tacrine cause significant side effects, acetylcholinesterase inhibitors like tacrine have failed to decrease the aggregation of tau and amyloid plaques in the brain, the chief AD pathology. Another adverse side effect of anti-amyloid AD drugs is known as amyloid-related imaging abnormalities (ARIA). Physicians have observed these abnormalities in patients taking aducanumab, the first monoclonal antibody for Alzheimer’s, which its manufacturer Biogen discontinued earlier this year. Despite controversy surrounding the therapy, the company has maintained that safety concerns did not influence the decision.

Alzheimer’s disease is not the only neurodegenerative condition facing challenges in treatment development. The primary treatment for Parkinson’s disease, for instance, L-DOPA, also comes with side effects. Despite long remaining a principal therapy for Parkinson’s thanks to its ability to mitigate the decrease of dopamine in the brain resulting from the death of dopaminergic neurons, the effect is short-lived. It wears off in one to three hours. This unpredictability is known as the “on-off phenomenon,” where periods of improved motor control (“on” time) alternate with times of reduced mobility and increased symptoms (“off” time”). FDA has approved seven medications to treat ALS, but only one of them, riluzole, extends the lifespans of patients, and only by a few months. Pharmaceutical companies are thus continuing to hunt for more effective novel therapeutics.

Genetic approaches

ANEW Medical has patented a Klotho gene therapy for AD, PD, and ALS. The s-KL RNA splice variant of the Klotho gene, which is involved in aging and cognition, supports healthy neurological functioning. ANEW’s theory, which existing evidence backs, is that high concentrations of Klotho lengthens one’s life and improves health. Conversely, lower concentrations are a risk factor for the development of neurodegenerative diseases. ANEW thus aims to create a diagnostic test to measure Klotho gene and protein concentrations in patients to assess their eligibility for clinical trials and their need for this form of treatment as well. QIAGEN and Eli Lilly are also coming together to create a diagnostic test for Alzheimer’s; however, the purpose of this test is to find APOE genotypes that result in an increased chance of developing Alzheimer’s disease. The test, known as QIAstat-DX, can identify the APOE2, APOE3, and APOE4 genotypes in approximately one hour. The APOE4 genotype carries the greatest risk for developing the disease.

Immunizations for AD and PD

In contrast with ANEW, Vaxxinity is developing a vaccine aimed at freeing the brain of the “toxic beta-amyloid aggregates” that are a traditional hallmark for the disease. UB-311 boasts not only efficacy in a Phase 2a clinical trial, but increased safety compared to older monoclonal antibody treatments, as no cases of ARIA-E and a small number of asymptomatic ARIA-H cases were identified. The same company is also developing a similar vaccine treatment, UB-312, for PD. The vaccine was shown to decrease concentrations of alpha-synuclein associated with PD pathology and promote the creation of antibodies in twelve of thirteen patients, which were correlated with significant increase in motor ability in a Phase 1 trial.

Potential New Dopaminergic and Glutamatergic Treatments for PD

Amneal Pharmaceuticals’ Crexont is an orally administered combination of levodopa and carbidopa that FDA approved in August. It was found to increase “on” time compared to immediate-release levodopa, meaning that fewer doses are required in a given period of time. It is also associated with relatively mild side effects, the most frequent being nausea and anxiety.

Another company, Allyx Therapeutics, announced in March of this year their plans for their AD and PD drug ALX-001 to advance to Phase 2 clinical trials for AD following favorable results regarding safety from its Phase 1b trial involving healthy participants. ALX-001 is a “silent allosteric modulator of mGluR5”, which serves to lessen the dysfunction and degradation of synapses resulting from the misfolded proteins characteristic of AD and PD. The first Parkinson’s patient was dosed with ALX-001 earlier this month in a new Phase 1 trial funded by the Michael J. Fox Foundation for Parkinson’s Research.

Targeting the “powerhouse of the cell” in ALS

Some progress has been made on the ALS front as well. The Target ALS Foundation awarded a grant to NRG Therapeutics to further develop mitochondrial permeability transition pore (mPTP) inhibitors as a possible method of treatment. Mitochondria cease to function properly in patients with ALS due to a faulty form of the TDP43 protein, which is especially detrimental to energetically costly cells such as neurons. The co-founder and CEO of NRG Therapeutics, Dr. Neil Miller, stated that the goal of this project is to test their mPTP inhibitor in a more gradually-progressing mouse model of ALS in order to better assess its impact. The study will also investigate the extent to which the mPTP inhibitors restore muscle strength and functioning.

What hasn’t worked?

Unfortunately, not all medications have been enjoying the same level of success. In May of this year, Biogen and Ionis Pharmaceuticals announced that they would halt development of their ALS-focused antisense oligonucleotide BIIB105 after it failed to decrease neurodegeneration or improve breathing in a Phase 1/2 trial.

Athira Pharma’s fosgonimeton for AD also did not show significant efficacy compared to placebo in a Phase 2/3 clinical trial, following similar failures in Phase 2 trials in 2022 and 2023 and resulting in plummeting stock price. However, the treatment appeared to be more effective in participants as opposed to the placebo when the participants had moderate AD or the APOE4 allele. Following this trial, Athira made the decision to not only let 70% of their employees go, but also to pivot their focus towards ATH-1105, a potential ALS treatment, which is scheduled to begin testing on human patients next year.

Conclusion

Overall, recent clinical trials for neurodegenerative disorder treatments have had mostly promising findings. Although not all tentative treatments enjoy success, pharmaceutical companies continue to strive for safe and effective solutions in order to hopefully decrease the suffering of those afflicted with such diseases and increase their quality of life.

Emma San Filippo graduated from Vassar College with a Bachelor of Arts in Neuroscience and Behavior. During her time at Vassar, she was a General and Lay Editor for the college’s chapter of the Grey Matters Journal, a student-run neuroscience publication.

References

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