RT001 for Friedreich’s ataxia

Last updated Oct. 2, 2023, by José Lopes, PhD
 Fact-checked by Patrícia Silva, PhD

What is RT001 for Friedreich’s ataxia?

RT001 for Friedreich’s ataxia (FA) is an experimental treatment that originally was developed by Retrotope. It was intended to protect against oxidative damage — a process that’s common to FA and other serious degenerative diseases — to certain fat molecules in mitochondrial and cellular membranes. Mitochondria are the cell compartments involved in energy production, and as such, are key to cellular function.

Retrotope filed for bankruptcy in March 2022, selling some of its development assets. The Friedreich’s Ataxia Research Alliance (FARA) now lists RT1001 as a compound not part of the currently active therapeutic research pipeline in FA.

Therapy snapshot

How does RT001 work in FA?

RT001 is a stabilized version of linoleic acid, an omega-6 fatty acid. Linoleic acid is a polyunsaturated fatty acid, or PUFA — a type of healthy fats — essential to human diet, that can be found in vegetable oil, nuts, and seeds.

Among other cellular alterations, FA is characterized by oxidative stress — a type of cellular damage in which there is an imbalance between toxic reactive oxygen species and the antioxidant molecules needed to counteract them. Oxidative stress is tightly linked to dysfunction of mitochondria.

In FA, reactive oxygen species cause damage to PUFAs that are essential for the proper functioning of cellular and mitochondrial membranes. RT001 was designed to replace PUFAs so as to protect cells from oxidative stress.

How will RT001 be administered in FA?

In clinical trials with FA patients, RT001 was being given as oral capsules. In a Phase 2/3 study, it was administered as three capsules three times a day, for a total of nine capsules daily. The medication was given with meals for the first month of treatment, and subsequently as three capsules with breakfast and three more with dinner, for a total of six capsules. Each capsule contains 960 mg of RT001.

RT001 in clinical trials

A Phase 1b/2a study (NCT02445794) had tested the safety and effectiveness of RT001, given orally to 18 people with FA. Two doses were tested: 1.8 g once a day (two capsules per day) and 4.5 g twice a day (9 g total; nine capsules per day).

The primary objective of the study was to assess the number of participants who developed adverse reactions at the end of 28 days, or about one month, of treatment. Other objectives included the study of the pharmacokinetics of RT001 — how it moves into, through, and out of the body — at different timepoints, as well as changes in the timed 25-foot walk test, which assesses mobility and leg function.

The results showed that treatment with RT001 was safe and well tolerated. The only treatment-related adverse event reported in more than one participant was diarrhea. One patient with a low body mass index experienced excessive fat in the stool, known as steatorrhea, while on a high dose of the medication, and discontinued the study. RT001 reached steady blood levels within the 28 days of treatment.

Although biological activity was not a primary objective, treatment with RT001 was associated with improvements in peak workload, or cardiorespiratory fitness, compared with healthy individuals who served as controls. The therapy also was associated with improvements in peak oxygen consumption, and in stride speed.

A Phase 2/3 trial (NCT04102501) intended to evaluate the therapy in 65 FA patients over 11 months of treatment. The participants’ age range was 12 to 50 years and the trial’s main goal was to assess changes in peak workload using cardiopulmonary exercise testing, comparing treatment with a placebo. A secondary outcome measure was to assess changes in timed 1-minute walk distance.

RT001 was given as three capsules three times a day (nine capsules total) with meals for the first month of treatment, and later as three capsules with breakfast and three more with dinner. A total of 45 participants completed treatment and all study visits.

The therapy was well tolerated, with no serious side effects related to it use. The most frequent treatment-emergent adverse events included abdominal discomfort, nausea, and loose stools. Steady-state levels of RT001 and its primary breakdown product were reached by four months.

However, the results further showed that RT001 and the placebo did not differ significantly in primary, secondary, or exploratory outcome measures. An additional analysis suggested minimal effects of RT001 at the dosages used in the study.

Upon being informed about these data, FARA stated its disappointment, but noted that the results might help inform the development of other potential therapies.

Common side effects of RT001

In the Phase 1b/2a trial, the only treatment-emergent adverse event reported in more than one patient was diarrhea, deemed probably or possibly related to RT001. One underweight patient taking high-dose RT001 discontinued the study within the first week because of excessive fat in the stool. This side effect resolved upon stopping treatment.

In the subsequent Phase 2/3 study, digestive symptoms such as abdominal discomfort, nausea, and loose stools were the most common treatment-emergent adverse events reported.

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