Novel treatments for neurodegenerative diseases

Currently, around 50 million people worldwide are suffering from various neurodegenerative diseases, out of them about 7 million are in the USA. Brain diseases are devastating and severely impact the quality as well as the duration of life of affected individuals and put both psychological and financial strain on them and their families. Neurodegeneration robs people of their memories, relationships, skills, usual everyday activities, and even their personalities. Various treatment strategies have been developed, but despite the considerable efforts and vast funds that have been invested in this endeavor, none of more than 600 existing neurodegenerative diseases are currently curable. Therefore, the need for new medicines and therapeutic approaches remains acute. During 2023 three new drugs that specifically tackle this aim were approved by the FDA’s (The United States Food and Drug Administration) Center for Drug Evaluation and Research: Leqembi, Skyclarys, and Wainua.

Alzheimer’s disease is the most widespread cause of dementia, and according to the special report prepared by the Alzheimer’s Association in 2023 around 6.7 million Americans were living with it. In the majority of cases, first symptoms are observed after the age of 65, but in rare cases, even people in their 30s and 40s can already show signs of mild cognitive impairment, one of the signs of the first stage of Alzheimer’s. Its irreversible symptoms progress from memory loss, apathy and depression to problems with communication and decision-making, eventually making the affected individual bed-bound due to damage to the cortex areas that control all movements. Not only walking but even speaking and swallowing are severely impaired in the latest stage of Alzheimer’s disease. All of these symptoms result from neuronal death in various brain regions that is caused by abnormal accumulation of just two proteins – beta-amyloid and tau protein. A newly approved drug, Leqembi (Lecanemab), is an antibody that directly targets one of them, beta-amyloid. Thus, this new therapeutic agent targets the important part of the underlying pathophysiology of the disorder and represents a significant breakthrough in the ongoing battle for treating this disease. 

Results of Phase 3 clinical trial of Leqembi showed significant benefits for patients who were diagnosed with mild cognitive impairment or mild dementia stage of disease, delaying cognitive decline by 5.3 months compared to placebo after 18 months of treatment. While not curing the disease, it gave patients and their families additional time when they could enjoy normal everyday activities, hobbies, traveling, and time spent with loved ones when it is most valuable. 

Amyloid beta forms depositions in the brain called plaques that are quite significant in volume. Thus removing them not only has positive effects but also contributes to side-effects of Leqembi, which include swelling and/or bleeding in certain brain areas. Normally these adverse effects resolve over few months, but in rare cases can cause long-term damage. Therefore, the condition of patients taking this medication must be monitored closely and systematically. 

Initially, Leqembi was approved by FDA via the Accelerated Approval pathway in January 2023, which means that the third phase of the clinical studies had not been conducted at that moment. The drug had been made commercially available earlier than it normally would have been due to the urgent and unmet need for such medication and the positive results of the preclinical research and the first two phases of the clinical studies. Upon receiving and processing the positive results of Phase 3 clinical studies half a year later (in July 2023) the FDA approval of this medicine has been converted to the traditional one. This made it much easier for patients to get access to this treatment since before this CMS (the Centers for Medicare and Medicaid Services), which operates Medicare, reimbursed the cost of this medication (full price is $26,500 per patient per year) only for those participating in the clinical trials. Now 80% of costs can be reimbursed by Medicare for patients who receive this drug via prescription, outside of a clinical trial, but there is a mandatory requirement for their doctors to be enrolled in the “coverage with evidence development” (CED) registry, created by CMS for collecting data about safety and efficiency of Leqembi. The problem is that to be enrolled in the CED registry the healthcare provider must have direct access to the full clinical team, required for follow-up care and it is not possible at every location. Therefore, numerous patients who need Leqembi are still facing availability issues.

While representing a considerable breakthrough in treating Alzheimer’s, Leqembi is not classified by the FDA as “First in class” for a simple reason – it has a predecessor with a similar mechanism of action, Aduhelm (Aducanumab). It has been demonstrated that Aduhelm reduces the buildup of beta-amyloid and that led to the Accelerated Approval by the FDA in 2021, but conversion to the traditional approval has never happened. There has been a lot of controversy over the drug and concerns about its safety and efficacy, voiced by scientists and healthcare providers. Its manufacturer, Biogen, announced that it will be discontinued in 2024 “to reprioritize company’s resources”, but Aduhelm is still on the market. According to Biogen for patients who are now obtaining it as a part of a clinical trial, Aduhelm will be available until May 1, 2024, and those who are prescribed it by their physicians will have access to this drug until November 1, 2024.

Donanemab, the third and most recent chemical that clears beta-amyloid plaques from the brain has been recently developed and is currently in the late stage of clinical research. Results of Phase 3 clinical trial for this drug have been reported in July 2023 and are highly promising. Almost half (47%) of study participants, who were administered this drug showed no clinical progression of Alzheimer’s disease one year after the study started (compared to 29% of patients receiving placebo). Manufacturer (Eli Lilly and Company) has already applied for FDA approval and expects it to be issued in the first half of 2024.

Unlike Leqembi, the next two described drugs, Wainua and Skyclarys, were developed for treating rare diseases, hereditary transthyretin-mediated amyloidosis and Friedrich’s ataxia. Friedrich’s ataxia affects approximately 5,000 people in the USA and the prevalence of hereditary transthyretin-mediated amyloidosis is estimated to be around 50,000 individuals worldwide. Availability of new safe and effective medication for such disorders is highly important since people who have such rare conditions usually have no or very few treatment options.

Even though rare, Friedrich’s ataxia is the most widespread form of hereditary ataxia in the USA. It is a neurodegenerative disease, characterized by progressive damage of the peripheral nervous system and, consequently, impairment of muscle functioning throughout the whole body. Nerve fibers that make up the spinal cord and peripheral nerves become thinner and lose myelin sheath. Neurodegeneration occurs in the cerebellum as well, further impacting the coordination of movements. First symptoms occur between the ages of 5 and 15, but the disease might also begin in patients who are older than 25 in case of late-onset Friedrich’s ataxia. Heart problems, impairment of speech, hearing, and vision, loss of sensation in limbs that progresses to the rest of the body, and scoliosis are also common symptoms and complications of this disease. Skyclarys (Omaveloxolone), granted traditional approval by the FDA in February 2023, is the first drug ever to treat this disease. Mitochondrial dysfunction is believed to be the pathophysiological basis of Friedrich’s ataxia, leading to the increased production of reactive oxygen species, which are highly reactive and toxic molecules. Skyclarys slows down the progression of this disease by boosting the ability of cells to neutralize reactive oxygen species. It also has an anti-inflammatory effect, which helps to reduce already existing damage to the cells and tissues. Clinical studies have shown that treatment with Skyclarys slowed the progression of Friedrich’s ataxia by at least 50% compared to the placebo group during each of the 3 years of the study, demonstrating positive and lasting effects of this medication. Prevalent side effects include headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain, as well as usually asymptomatic and reversible increase in the level of liver enzymes in the blood. All of these generally are not dangerous but have to be monitored throughout the treatment.

Skyclarys is currently available for patients via prescription for $370,000 per year. Its developer, Reata Pharmaceuticals, offers access to this medicine via the patient support program, ReataReach. This program offers support for both insured and uninsured patients not only by helping to find a way to reduce costs but also by providing long-term counseling support for patients and their caregivers. According to Dawn Bir, chief commercial officer of the company, none of the patients will face more than a nominal pay for this medicine.

Skyclarys has proven to be effective, but it does not target the core reason for Friedrich’s ataxia, which is caused by a mutation of the gene that codes a protein called frataxin. Frataxin is required for normal functioning of mitochondria in the cells and its decreased production due to gene mutation leads to elevated production of reactive oxygen species. While preventing the cell and tissue damage that these highly active molecules can do is a good treatment strategy, decreasing frataxin levels in the cells might be much more effective. For this reason, two chemicals that have this effect are currently tested for safety and efficiency. DT-216, developed by Design Therapeutics, is currently in the stage of Phase 1 clinical testing, and CTI-1601, from Larimar Therapeutics’, already entered Phase 2 clinical study. Information about CTI-1601 has already been submitted to FDA and the company is working together with the federal agency to gather all necessary data and documents for approval of this new drug.

Hereditary transthyretin-mediated amyloidosis is another hereditary neurodegenerative disease, which usually manifests in the age from 20 to 40 years old. Fibrils of misfolded transthyretin accumulate mainly in the peripheral nerves but are also found in the heart, kidneys and eyes. This makes hereditary transthyretin-mediated amyloidosis a severe, multisystem, and life-threatening disease, which is challenging to diagnose due to the great variability in its clinical course and presentation between patients. This disease mostly manifests as polyneuropathy, leading to nerve damage, or cardiomyopathy, which leads to heart failure. In December 2023 FDA issued traditional approval for Wainua (Eplontersen) after the Phase 3 clinical trial demonstrated consistent and sustained improvement of patients’ health upon its regular administration. At the core of this chemical compound is an oligonucleotide, that binds to RNA molecules that are used by the cell to produce transthyretin. This triggers the destruction of these RNA molecules and decreases the concentration of transthyretin in the cells and tissues of the patient, which halts the progression of the disease. The most common side effects include vitamin A deficiency as well as vomiting which can be managed with the help of additional medication and dietary supplements.

Wainua has been available for patients since January 2024 from its developers, AstraZeneca and Ionis Pharmaceuticals. The drug has to be administered once per month, and since a single injection costs $43,797, the annual price per patient for this medication is a little over half a million – $525,564. It is possible for commercially insured patients who have a prescription to have a $0 copay, but receiving this medicine is more complicated for patients who have state- or federally-funded insurance. Developers offer a support program WainuaWay, which provides counseling for patients regarding the availability and functioning of this drug. 

Wainua is not the only available medication for treating hereditary transthyretin-mediated amyloidosis. There is another drug, Onpattro (Patisiran), which was approved by the FDA in August 2018. The yearly cost of this medication currently is around $185,634. The mechanism of action is quite similar to Wainua, targeting and destroying matrix RNA of an abnormal transthyretin form. Nevertheless, side effects can be quite dangerous and include not only flushing of skin, back pain, nausea, stomach pain, and headache, but also difficulty breathing. 

Both Wainua and Onpattro have shown significant efficacy in slowing down the progression of hereditary transthyretin-mediated amyloidosis, but none of them can cure it. This is because even when the level of pathological protein is decreased, this harmful protein is still being produced due to the mutation of its gene. Researchers at Intellia Therapeutics are currently working on testing NTLA-2001, the first in the world experimental in vivo gene editing therapy, based on CRISPR technology. FDA approved the company’s application for Phase 3 clinical trial of NTLA-2001 in October 2023 and it is scheduled to begin at the end of this year. If its usage is approved, it can start a new era in medicine, because it has the potential to cure this genetic disease just after administration of the single dose of medication. 

Neurodegenerative diseases take undoubtedly a heavy toll on humanity, causing lots of suffering for affected people and their loved ones. None of them is curable at the moment, but scientists have come incredibly close to changing that for good. There are still multiple gaps in the knowledge about the pathophysiology of these diseases and a long way to go in improving the tools available for dealing with them. But as long as each day at least the tiniest of steps is taken in this direction, one day all of these diseases will be conquered. 

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