Clinical Trials Archives |

Results of the RISCA study: gaining a better understanding of how ataxia symptoms first appear in at-risk patients

Written By Dr. David Bushart Edited by Celeste Suart

The RISCA study will help researchers design smarter, more efficient clinical trials by teaching us about the very early stages of SCA

Ataxia research has grown significantly in recent years. Although much work still remains, we are gaining a better understanding of how ataxia affects patients. Several exciting, new therapies are currently being studied. These advances would not be possible without the involvement of ataxia patients in clinical research studies. Some clinical studies are drug trials, where patients are enrolled to help researchers determine whether new therapies are effective at treating ataxia. However, other equally important types of clinical studies also exist. Ataxia patients play a critical role in the success of these studies.

What would an ideal treatment for ataxia look like? Ideally, we would be able to treat patients when their symptoms are very mild, or perhaps even before their symptoms appear at all. However, there are several obstacles to developing and testing this kind of hypothetical treatment:

First, it can be hard to know which patients to treat if symptoms are not yet present! There are many people who descend from patients affected by SCA of some kind. They have a 50% chance of being affected. While some of these people have been genetically tested, many have not. This makes it difficult to predict whether they will eventually develop SCA at all.

Second, along those lines, it could be very difficult to predict whether a drug is working to prevent symptoms from appearing if we don’t know precisely when symptoms should appear. It is much easier to tell if a drug is working when it is given to a patient with obvious symptoms – if their symptoms improve, the drug works.

Third, it can be difficult for researchers to enroll enough patients into clinical trials to get a meaningful result. This is complicated by the fact that we don’t know the answers to the first two questions above. Until recently, it remained unclear how a trial to test such a hypothetical treatment would need to be designed.

Thankfully, recent work has helped us better understand the answers to these questions. Results from the RISCA study were recently released. RISCA, which is a prospective, longitudinal, observational cohort study, was designed to study individuals who are at-risk for developing SCA, and how SCA symptoms might first appear.

Doctor and patient discussing something while sitting at the table — The RISCA study was designed to give doctors and patients more information about when ataxia symptoms first start to appear. This information is incredibly important for future ataxia clinical trials. Photo used under license by S_L/Shutterstock.com.

Fishing for a solution to SCA38 – are omega-3 fatty acids the key to symptom relief?

Written by Dr. Siddharth Nath Edited by Dr. Sriram Jayabal

SCA38 results in a deficiency of an omega-3-fatty acid called docosahexaenoic acid (DHA). Scientists from Italy had shown previously that short-term DHA supplementation reduces disease symptoms. Now, new research from the same group finds that this impact continues with long-term DHA supplementation.

What is SCA38?

One of the rarer forms of ataxia, SCA38 is an autosomal dominant SCA that occurs as a result of mutations in the ELOVL5 gene. This gene contains the recipe for the protein called elongase. It is responsible for building long-chain fatty acids in the brain, including docosahexaenoic acid (DHA), a process key for normal cellular function. Importantly, this protein is found mostly in Purkinje cells, a special type of neuron found within the cerebellum of the brain.

In SCA38, mutant elongase is found primarily in a part of the cell called the Golgi apparatus, which is responsible for packaging proteins and finalizing production, similar to a quality-control technician in an assembly line. Normally, elongase is found at the endoplasmic reticulum, which is further up the assembly line, more akin to the fabrication section.

This mislocation of the protein may explain why it is unable to produce sufficient amounts of long-chain fatty acids to support healthy Purkinje cell function. Deficiencies in DHA resulting from mutations in elongase are detectable by blood tests.

spilled bottle of yellow capsule pills — Photo by Pixabay on Pexels.com

Docosahexa-what?

You’ve probably heard of omega-3-fatty acids. Omega-3 fatty acids are part of a larger group of molecules called polyunsaturated fatty acids to which the omega-6 fatty acids also belong. DHA is a type of omega-3 fatty acid. Omega-3 fatty acids and omega-6 fatty acids are often touted as a key component of a healthy diet.

Omega-3-fatty acids are important building blocks of the cellular membrane, which is part of all cells in the body. Humans aren’t able to make omega-3-fatty acids ourselves, we need to get them from our diet. That is why many food guides have recommended intakes of omega-3 and omega-6 fatty acids from oily fish and nuts. Vegetarians can also supplement their diet with flaxseed or algae capsules to get these fatty acids in their diet.

DHA is just one of many omega-3-fatty acids and it is most prevalent in the membranes of brain cells, where it plays a key role in normal brain function. Thus, when there is a disturbance or deficiency in the level of DHA, we can expect brain function to become impaired, as is the case in SCA38.

Snapshot: What is Omaveloxolone?

A new therapeutic compound shows promise to treat Friedrich’s ataxia.

What is Friedrich’s ataxia (FA)?

Friedrich’s ataxia is a genetic neurodegenerative disease that affects many organs, most notably nerves, muscles, and heart. FA is a recessive ataxia. Symptoms typically present in childhood and result in significant physical disability. Cognition (thinking, memory) remains intact.

Some of the symptoms a person with FA may experience include ataxia (loss of movement coordination), fatigue, muscle weakness, cardiomyopathy (heart issues), scoliosis (curvature of the spine) and sensory impairments (vision, hearing). Life expectancy is reduced as a result of the disease.

The genetic change that is present in FA affects the production of a protein called frataxin. Frataxin deficiency leads to abnormal iron accumulation in mitochondria. As mitochondria are critical for energy metabolism and other important functions in cells, their dysfunction causes faulty energy production and undesirable toxicity in the form of reactive oxygen species.

There is currently no treatment available to patients with FA.

white medical pills in the shape of a question mark — What is Omaveloxolone? How could it help people with Friedrich’s Ataxia? Photo by Anna Shvets on Pexels.com

How does Omaveloxolone work?

Omevaloxolone is a synthetic compound. It works by counteracting deficits seen in disease at the cellular level. Omevaloxolone promotes Nrf2, which works to activate a series of defence mechanisms that help cells handle oxidative stress (mentioned above). Nrf2 is also important for improving the energy production machinery mitochondria require to function efficiently. Thus, by activating Nrf2, Omevaloxolone is thought to mitigate oxidative damage, improve energy production, and promote neuroprotection. Additionally, Omevaloxolone and similar compounds exhibit anti-inflammatory action.

What exactly has been validated?

In the MOXIe clinical trial, study participants with FA from several countries were randomized to either daily omaveloxolone (drug) or placebo (control). Their neurological function, activities of daily living, and ataxia were assessed at baseline (at the beginning) and after 48 months of receiving treatment. At the end of this period, the data showed statistically significant improvement in each of these measures. Participants who received omaveloxolone fared better than those who did not (placebo). Additionally, participants who received omaveloxolone saw improvements after treatment compared to their own baseline at the beginning of the study.

What is happening next?

The next step in testing omaveloxolone is to have a long-term study to examine its safety (and any side effects) over the course of a few years. Instead of having a control group in this type of study, called an open-label extension, now everyone enrolled received the same amount of omaveloxolone. This study is already underway and is expected to be completed by 2022. There have been some modifications to the long-term safety study in response to COVID-19, but Reata doesn’t expect there to be a significant delay in their timelines.

If you would like to learn more about omaveloxolone, take a look at these resources by the Reata Pharmaceuticals and ClinicalTrials.gov. To learn more about Friedrich’s Ataxia, visit the Friedrich’s Ataxia Research Alliance website.

Snapshot written by Dr. Judit M. Pérez Ortiz and edited by Larissa Nitschke.

Snapshot: What are Clinical Trials?

How does a medical drug get to patients?

Research is being done every day to discover new or better ways to treat diseases and various medical conditions. In order to determine if these treatments will help patients, studies known as “clinical trials” need to be done before these methods of intervention can be safely and widely used in human patients. Clinical trials are regulated studies that involve volunteer human participants to test how safe and effective a potential new treatment.

doctor writing notes — Physician writing clinical notes. Photo by Pexels.

Treatment interventions being tested can range from medical drugs, to medical devices, to introducing lifestyle changes (diet, exercise). Most clinical trials test new drugs by comparing them to no treatment, to an inactive version of a drug known as a “placebo”, or to a currently available approach. Clinical trials may take months to years to complete and are conducted in a series of steps, known as “phases”, described below.

Phase 1: Is the drug safe?

Healthy volunteers receive different doses of the drug and side effects are evaluated. Safe doses are chosen based on research performed prior to Phase 1, or “pre-clinical research”. The goal is to make sure the drug is not harmful. Usually lasts a few months.

Phase 2: Is the drug effective?

Similar to Phase 1, but the drug is given to a small group of volunteers affected by the medical condition it is intended to treat. This is commonly done by comparing how well participants do with the new drug compared to a placebo. Participants and doctors are typically “blinded”, or prevented from knowing whether the patient received the active drug or the placebo. This is meant to allow for unbiased observations of the participant’s health in response to the drug. Usually lasts a few months to years.

Phase 3: Is the drug still safe? Is it doing what is needed?

Testing becomes a bit more complex. The participant population is expanded while safety and efficacy of the drug continues to be tested. More detailed information about the drug as a treatment is gathered in this phase. Usually lasts several years.

Phase 4: The drug is approved and available on the market.

Long-term effects of the drug will continue to be monitored by pharmaceutical companies and compared to other available drugs and therapies for cost and efficacy.

If you would like to learn more about clinical trials, take a look at these resources by ClinicalTrials.gov and CenterWatch.

Snapshot written by Dr. Claudia Hung edited by Dr. Judit M. Perez Ortiz.