FDA Clears Exploration Trial for Higher Dose of CTI-1601 for Friedreich Ataxia

Carole Ben-Maimon, MD

After the company released positive phase 2 data earlier this year, Larimar Therapeutics announced that the FDA has cleared a 4-week, placebo-controlled exploration trial (NCT05579691) assessing its investigational Friedrich ataxia (FA) agent CTI-1601 in doses of 50 mg. The company’s open-label extension (OLE), which will assess 25 mg of CTI-1601 daily, was also cleared for initiation by the FDA.¹

In the exploration trial, ambulatory and nonambulatory individuals with FA aged at least 18 years old will be randomly assigned 2:1 to either CTI-1601 or placebo daily via subcutaneous injections for the first 14 days, and then every other day until day 28. The trial features 2 cohorts, a 25 mg and 50 mg dosed group. Cohort 1, assessing a 25 mg dose of CTI-1601, includes 13 participants (9 on active treatment, 4 on placebo) while Cohort 2, which is initiating, will include 12-15 participants randomized to either CTI-1601 or placebo in 50 mg dose settings.

The OLE, expected to begin in Q1 2024, will include those who completed treatment in the phase 2 dose exploration trial or a prior trial of CTI-1601. In the OLE, investigators will assess safety, tolerability, and pharmacokinetics of the agent, as well as measures of frataxin (FXN) levels and other pharmacodynamic markers. Other objectives include the evaluation of the effects of long-term subcutaneous administration of CTI-1601 on measures of clinical function. Data from the OLE will be compared with a matched set of untreated patients from the Friedreich’s Ataxia Clinical Outcome Measures Study (FACOMS) database.

"Gaining clearance to advance to a 50 mg cohort in our Phase 2 trial and initiate the OLE trial are crucial steps in CTI-1601’s development as potentially the first therapy to increase frataxin levels in patients with FA,” Carole Ben-Maimon, MD, president and chief executive officer, Larimar, said in a statement.¹ "Given the inability of current treatments to address the frataxin deficiency underlying Friedreich's ataxia, we believe CTI-1601 has the potential to improve the treatment paradigm for this devastating disease. We now look forward to data from our Phase 2 trial’s 50 mg cohort in the first half of 2024, which will help us further characterize the safety and PK profiles of CTI-1601 and its ability to increase frataxin levels in a dose-dependent fashion as seen in our earlier Phase 1 studies."

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In May 2021, the CTI-1601 program was placed on clinical hold by the FDA following Larimar’s notification to the agency of mortalities that occurred at the highest dose levels in a 26-week nonhuman primate toxicology study. The company underwent a Type C meeting with the FDA to determine the next steps, and thus submitted a complete response that included unblinded safety, pharmacokinetic, and pharmacodynamic data from the phase 2 trial’s completed 25 mg cohort. This ultimately led to the FDA’s decision to advance the phase 2 trial to a 50 mg cohort and initiate its OLE.²

CTI-1601 is a recombinant fusion protein intended to deliver human frataxin, the missing protein in FA, into the mitochondria of patients living with the disease. Thus far, the agent has been granted rare pediatric disease, fast track, and orphan drug designations by the FDA.

"We are pleased to have clearance to begin our OLE trial and look forward to what we expect will be important interim data from the study in Q4 2024," Ben-Maimon continued.¹ "Alongside our efforts to advance both our OLE and Phase 2 trials in the United States, we have also begun to engage with regulators and investigators outside the U.S. as we prepare to expand our clinical program to additional geographies. With approximately 75% of individuals with FA living outside the U.S., establishing global clinical trial capabilities is important for addressing the pressing unmet needs of the FA community."

Larimar announced positive topline data from the phase 2 study earlier this year, with CTI-1601 demonstrating a safe profile in doses of 25 mg and observed increases in FXN levels among treated patients. On day 14, a median placebo-adjusted increase from baseline was observed in frataxin levels in skin tissue (3.5 pg/ug) and buccal cells (0.9 pg/ug). Among 7 CTI-1601-treated participants, all demonstrated increases in skin FXN concentrations and 5 had increases in buccal cell FXN concentrations. In comparison, there were no increases in FXN concentrations observed in the skin tissue among the 4 participants on placebo and no increases in buccal cells in the 2 participants on placebo at the end of day 14.³

REFERENCES
1. Larimar Therapeutics receives FDA clearance to proceed to 50 mg cohort in CTI-1601’s phase 2 Friedreich’s Ataxia trial and to initiate open label extension trial. News release. Larimar Therapeutics. July 25, 2023. Accessed September 28, 2023. https://www.globenewswire.com/news-release/2023/07/25/2710268/0/en/Larimar-Therapeutics-Receives-FDA-Clearance-to-Proceed-to-50-mg-Cohort-in-CTI-1601-s-Phase-2-Friedreich-s-Ataxia-Trial-and-to-Initiate-Open-Label-Extension-Trial.html
2. Larimar Therapeutics provided updates on CTI-1601 clinical program following a Type C meeting with the US Food and Drug Administration and reports second quarter 2022 operating and financial results. News release. Larimar Therapeutics. August 11, 2022. Accessed September 28, 2023.
3. Larimar Therapeutics Reports Preliminary Top-line Data from Phase 2 Trial’s 25 mg Cohort Showing Increases in Frataxin Levels in Patients with Friedreich’s Ataxia and First Quarter 2023 Financial Results. News Release. Larimar Therapeutics. Published May 15, 2023. Accessed September 28, 2023. https://www.globenewswire.com/news-release/2023/05/15/2668588/0/en/Larimar-Therapeutics-Reports-Preliminary-Top-line-Data-from-Phase-2-Trial-s-25-mg-Cohort-Showing-Increases-in-Frataxin-Levels-in-Patients-with-Friedreich-s-Ataxia-and-First-Quarter.html