Daily Dosing of CTI-1601 Appears to Rescue Frataxin Levels

Daily dosing of CTI-1601, a lab-made, modified version of frataxin — the protein lacking in people with Friedreich’s ataxia (FA) — for 13 days led to a dose-dependent increase in frataxin levels compared to placebo, top-line data from a Phase 1 study show.

Patients treated with the two highest doses of CTI-1601 tested, 50 mg and 100 mg, saw their frataxin levels reach similar or even surpassing the levels of carriers — those with approximately 50% of the frataxin levels seen in healthy people.

Moreover, the increase in frataxin was detected in several tissues in the body, including in mouth (buccal) cells, skin, and platelets (tiny blood cells involved in blood clotting).

“Daily subcutaneous CTI-1601 administration resulted in median frataxin levels in buccal cells that are similar to, and even exceed, the levels we would expect to see in phenotypically normal heterozygous carriers,” Nancy M. Ruiz, MD, chief medical officer of Larimar Therapeutics, which is developing the therapy, said in a press release.

“The ability of CTI-1601 to elevate frataxin in the evaluated tissues strongly supports its continued clinical evaluation, as frataxin levels in buccal cells and blood have been shown to be associated with disease severity in FA patients,” Ruiz added.

Frataxin is a key protein for the proper function of mitochondria, the organelles inside cells that generate energy. Mutations in the FXN gene lead to a defective frataxin protein, which underlies the nerve and muscle damage seen in patients.

The modified frataxin of CTI-1601 was designed to enter the mitochondria, and is expected to ease FA symptoms and halt or slow disease progression by restoring frataxin levels.

In the multiple-ascending dose (MAD) Phase 1 trial (NCT04519567), 27 adult patients (18 or older) were randomly assigned to receive multiple subcutaneous (under-the-skin) injections of CTI-1601, at 25, 50, or 100 mg, or a placebo for 13 days.

Those in the 25 mg dosing groups were given a daily dose of CTI-1601 or a placebo for four days, and then every three days until the end of the treatment period. In the 50 mg group, the daily dosing was performed for seven days, and then once every other day. The 100 mg group was given CTI-1601 or a placebo daily for 13 days.

The study’s primary endpoint was to assess the therapy’s safety and tolerability. Additional (secondary) endpoints included its pharmacokinetics — the therapy’s absorption, distribution, metabolism, and excretion — and changes in frataxin levels from baseline (start of the trial) in different tissues.

Now, topline data from the trial has shown that the treatment was well-tolerated with no treatment-related serious adverse events reported. Mild to moderate injection site reactions were the most common adverse events reported by all patients treated with CTI-1601 and 43% of those given a placebo.

One patient in the 50 mg group discontinued the study after experiencing mild to moderate nausea and vomiting. All other 26 patients completed the study.

The pharmacokinetics analysis showed that CTI-1601 was quickly absorbed, with a mean half-life of 11 hours. Half-life is the time required to reduce the amount of a compound by half and is an indicator of how long its benefits last.

Dose-dependent increases in frataxin levels were seen in all evaluated tissues.

“These findings are exciting and represent a critical step forward in CTI-1601’s development as a frataxin replacement therapy for patients with FA,” Ruiz said. “We believe CTI-1601 has the potential to address a critical unmet need, as FA is caused by patients’ inability to produce sufficient amounts of frataxin and current treatment options for this progressive and devastating disease are limited to symptom management.”

“It is also important to note that CTI-1601 is the only drug candidate that we are aware of in clinical development that is designed to supplement frataxin levels in patients with FA, thus addressing the root cause of the disease,” she added.

Results of this and other trials are to be presented at a future meeting.

“We look forward to sharing additional quantitative analyses from our Phase 1 clinical trials at a future scientific meeting,” said Carole Ben-Maimon, MD, president and CEO of Larimar. “We anticipate this data will inform the design of our planned future clinical trials for CTI-1601.”

Participants from previous single-ascending dose trials and from the MAD trial are eligible for an open-label extension trial, called Jive, expected to begin by the end of the year. According to Larimar, during this period, a new MAD trial will also open for patients younger than 18.

“We are thrilled with these data, which demonstrate proof-of-concept for CTI-1601 and highlight its safety and tolerability profile,” Ben-Maimon said. “Our ability to generate these results amid the pandemic speaks to the commitment of the patients who participated in the trials and the broader FA community.”