Nomlabofusp (CTI-1601)

Dr. Mark Payne  who first described the possibility of frataxin replacement therapy via TAT-Frataxin, has been developing this exciting prospect for FA therapy. A recombinant fusion frataxin protein is partnered with a unique delivery system (a protein fragment called a Trans-Activator of Transcription or TAT) to get the frataxin protein to the mitochondria. Dr. Payne has tested TAT-frataxin in FA mice and demonstrated proof of principle and compelling results. (See publication below).

Dr. Payne’s approach increases the life span and weight of FA mice and improves their cardiac function. Dr. Payne formed a company, Chondrial Therapeutics, to further develop this approach and generate preclinical data. Chondrial is now Larimar Therapeutics.

January 13, 2016: Chondrial Therapeutics announces that the company’s lead drug candidate for the treatment of Friedreich’s Ataxia (FA), TAT-Frataxin (TAT-FXN) has been accepted for further development by Therapeutics for Rare and Neglected Diseases (TRND) program researchers at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health. This support from the TRND program provides Chondrial with access to additional expertise and resources to complete IND-enabling studies and advance the program to Phase 1 human studies.

February 2017: Chondrial Therapeutics announces that it secured up to $22.6 million in Series A financing led by Deerfield Management. Also, Chondrial expects to file an Investigational New Drug (IND) application for CTI-1601 (TAT-FXN) with the U.S. Food and Drug Administration (FDA) and, upon acceptance of the IND by the FDA, initiate Phase 1 clinical trials of the compound.

August 2017: Chondrial Therapeutics announces that it has received Orphan Drug Designation for CTI-1601, a novel investigational therapy for FA. In its press release, Chondrial reports that the IND-enabling studies are ongoing.

November 2019: Chondrial Therapeutics begins a first-in-human study of CTI-1601, Single Ascending Dose Study of CTI-1601 versus Placebo in Subjects with FA. As a phase 1 study, the primary goals of the study are to evaluate safety and dose, beginning with single doses. Cohorts of 6-8 individuals with FA are enrolled and evaluated a specific dose levels. The study enrolls individuals with FA who are 18 yrs and older who are able to go the distance of 25 feet with or without an assistive device or pushing oneself using a manual wheelchair. This study required a 4 night/5 day stay at the study site.

May 2020: Chondrial Therapeutics does a reverse merger with Zafgen, Inc. The combined, publicly traded clinical-stage biotechnology company begins operating under the name Larimar Therapeutics, Inc.

November 2020: Larimar completes the single ascending dose (SAD) study of CTI-1601 in FA patients. The multiple ascending dose (MAD) study began enrollment in late 2020. Patients who completed the single ascending dose (SAD) and/or MAD clinical trials will be eligible to screen for an open-label extension clinical trial, the Jive study, which Larimar expects to initiate in the first half of 2022. Larimar also expects to initiate a MAD clinical trial in patients under 18 years of age in the first half of 2022. Patients completing this pediatric trial would also be eligible to screen for the Jive study.

May 2021: Larimar shares top line data from the Phase 1 placebo controlled single and multiple ascending dose (SAD and MAD) studies of CTI-1601. The key findings are that CTI-1601 was generally well tolerated at doses up to 100mg administered daily for 13 days and frataxin levels measured in buccal cells, skin and blood are increased more than 2-fold into the range of phenotypically normal heterozygous carriers in the 50mg and 100mg dose groups. As the safety and pharmacokinetic data meets the criteria for moving forward, the company states that these data represent a proof of concept and a critical step forward in CTI-1601’s development as a frataxin replacement therapy for patients with FA. This is the first time a frataxin replacement therapeutic approach has been tried in FA patients.

May 25, 2021: The United States Food and Drug Administration (FDA) places a clinical hold on the CTI-1601 clinical program following the Company’s notification to the FDA of mortalities which occurred at the highest dose levels in an ongoing 180-day non-human primate (NHP) toxicology study, which was designed to support extended dosing of patients with CTI-1601. In the clinical hold letter, the FDA states that it needs a full study report from the ongoing NHP study and Larimar may not initiate additional clinical trials until the company has submitted the report and received notification from the FDA that additional clinical trials may commence. At the time of the notice, the Company had no interventional clinical trials with patients enrolled or enrolling.

August 2021: The Company reports completion of the 180-day NHP toxicology study discussed above. The Company is currently collecting and analyzing data from the study. While there is no way to predict the FDA’s response or whether they will require additional data or testing before lifting the clinical hold on CTI-1601 in full or in part, the Company expects to initiate its Jive open-label extension and pediatric MAD trials in the first half of the next year.

February 2022: Larimar announces that it has received feedback from the U.S. Food and Drug Administration (FDA) regarding the clinical hold on the company’s CTI-1601 program. FDA states it is maintaining its clinical hold at this time and that additional data is needed to resolve the clinical hold. Larimar will further analyze previously completed studies and evaluate if additional studies were warranted. The Company also intends to engage FDA to determine how best to provide these data.

August 2022: Larimar announces that it has received meeting minutes from the FDA following a recent Type C Meeting. The purpose of the Type C Meeting was to obtain FDA feedback on the information needed to resolve CTI-1601’s current clinical hold in full or in part, as well as to discuss a proposed change in CTI-1601’s clinical development plan. The proposed change is to introduce a Phase 2 dose exploration study to precede initiation of an open label extension study. The Phase 2, four-week dose exploration study in FA patients would start at the lower dose levels tested in the Company’s Phase 1 multiple-ascending dose clinical trial. This study was to provide data on extended dosing of lower doses of CTI-1601, including additional data on safety and tolerability as well as whether lower doses for longer periods of time can increase frataxin levels while maintaining acceptable exposures. The Company plans to submit a complete response to the CTI-1601 clinical hold in the third quarter of 2022.

September 14, 2022: Larimar announces that the FDA cleared the initiation of the 25 mg cohort of a Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in FA patients. In a written communication to Larimar, the FDA indicated it was lifting its full clinical hold on the CTI-1601 program and imposing a partial hold. The design of the Phase 2 trial is identical to the design proposed by Larimar, with the exception of a requirement for the FDA to review data from the 25 mg cohort prior to escalating the dose in the second cohort. Larimar expects to begin the Phase 2 trial in Q4 2022, with top-line data expected in 2H 2023.

May 15, 2023: Larimar announces preliminary data from the Phase 2 four-week placebo-controlled, 25mg dose exploration trial of CTI-1601 showing increases in frataxin levels in individuals with FA. Participants in the trial (n=13) were randomized to receive subcutaneous injections of 25 mg CTI-1601 (n=9) or placebo (n=4) daily for 14 days and then every-other-day thereafter until day 28. Data from the cohort indicate CTI-1601 was generally well tolerated and showed increases in frataxin levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14. One patient had an allergic reaction, most likely to the drug, which resolved with standard treatment. About half of those receiving placebo and all of those receiving CTI-1601 had a mild to moderate injection site reaction that resolved in 24 hours. Steady state levels of the drug were achieved by day 14. Larimar submitted the data to FDA for review and a meeting was scheduled with the Agency for later in the quarter to discuss the information needed to gain clearance to initiate a 50 mg cohort in the Phase 2 trial. Larimar expects to provide an update on the next steps for the CTI-1601 program in the third quarter of 2023, after it receives feedback from the upcoming FDA meeting. The update expects to include plans for upcoming trials, including the open label extension trial (JIVE), which would be open to participants in the SAD, MAD and four-week dose exploration studies; and MAD trial in patients 2-17 years of age; and the global double-blinded, placebo-controlled pivotal trial.

July 25, 2023: Larimar Therapeutics, Inc. announces that the U.S. Food and Drug Administration (FDA) cleared the Company’s four-week, placebo-controlled, Phase 2 dose exploration trial of CTI-1601 in patients with Friedreich’s ataxia (FA) to proceed to a 50 mg cohort in which participants will be dosed daily for the first 14 days, and then every other day until day 28. In addition, Larimar’s open label extension (OLE) trial is cleared for initiation by the FDA. Participants in the OLE will receive 25 mg of CTI-1601 daily. CTI-1601 is a novel protein replacement therapy designed to deliver frataxin to the mitochondria of patients with FA who have low levels of frataxin.

Participants who complete treatment in the Phase 2 dose exploration trial, or who previously completed a prior clinical trial of CTI-1601, are eligible to screen for Larimar’s OLE trial. Participants in the OLE trial will receive subcutaneous injections of 25 mg of CTI-1601 administered daily. The trial is expected to begin in Q1 2024 with interim data expected in Q4 2024. Click here to read the full press release or watch the webcast update.

February 12, 2024: Larimar Therapeutics, Inc. announces top-line data from the four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp (CTI-1601) in FA. This completes the dose exploration study. Nomlabofusp was generally well tolerated. Dose dependent increases in frataxin were seen in the evaluated tissues (skin and buccal cells). The press release provides detailed information on the changes in frataxin levels. Briefly, skin cells showed a mean increase in frataxin levels of 2.81mg in the 25 mg cohort (a 33% increase) and 5.57 pg/mg in the 50mg cohort (59% increase) at 14 days of dosing, with slightly lower levels at 28 days of dosing. Note that doses are given every day from day 1-14 and every other day from day 15-28. The majority of patients also showed increases in buccal cell frataxin levels, but these data were more variable. This may be due to the faster turnover rate of buccal cells vs skin cells and due to the lower level of frataxin in the buccal cells.

There were no severe adverse events in the 50mg cohort. One person in the 25mg cohort had an allergic reaction that resolved with standard treatment. This allergic reaction was reported as a severe adverse event and this person withdrew from the study. Other mild to moderate injection site reactions were reported. The final phase 2 data are expected to be presented at a conference in the second half of 2024.

Larimar is now in discussions with the FDA about a possible submission of a biologics license application (BLA) for accelerated approval in the later part of 2025, using changes in frataxin levels as the basis of the submission. The open label extension trial (OLE) for the 25mg cohort is underway with interim results expected in Q4 2024. These results add to the safety data for nomlabofusp and will be submitted to the FDA to potentially address the current partial clinical hold. The plans for both a pediatric study and a global double-blind, placebo control study were briefly discussed. A confirmatory study must be underway at the time of the submission of the application for accelerated approval for the FDA to consider granting accelerated approval.

March 11, 2024: Larimar announced that it had initiated dosing the 25mg group in the open label extension (OLE) study. The aim of this study is to understand the long term safety of nomlabofusp, as well as the long term changes in frataxin levels. The results of this study can also support the US regulatory filing (the “BLA” submission) for approval of the drug.

May 20, 2024: Larimar announced that the FDA removed the partial clinical hold for the nomlabofusp program, allowing the company to add a 50 mg dose group to the OLE study. Further dose escalation above 50 mg, if necessary, would require submission of additional data for FDA review to support the increased dose. Interim data from the OLE study is expected in the fourth quarter of 2024. The study remains on track to complete in Q4 2024, with a BLA submission targeted for 2H 2025.

May 30, 2024: Larimar Therapeutics Selected by FDA to Participate in START Pilot Program for Nomlabofusp in Friedreich’s Ataxia

START is a new milestone-driven program designed to accelerate development of novel therapies intended to address an unmet medical need for rare diseases. Nomlabofusp was selected based on potential for clinical benefit in a rare neurodegenerative disease and demonstrated development program readiness.

August 7, 2024: During the Q2 2024 operating and financial presentation (insert link here), Larimar reported that the open label extension (OLE) trial for nomlabofusp is progressing, with an interim data read out expected in Q4 2024. Larimar also plans to initiate a pharmacokinetic (PK) study in children ages 12 to 17 years before the end of 2024. Participants will be eligible to enter an OLE upon completion of the PK study. The company’s plan includes a global confirmatory study to start in mid-2025, the results of which would support an application for accelerated approval in the US in the second half of 2025. Larimar also announced that it has joined FARA’s TRACK-FA Neuroimaging Consortium.

November 18, 2024: Larimar presented additional data from the dose exploration study that supports choice of dose for future studies. Their conclusion from the analyses of the data is that, in most patients with FA, 50 mg of nomlabofusp administered daily is likely to achieve FXN levels that are ≥50% of levels observed in healthy controls and similar to mean FXN levels reported in asymptomatic heterozygous carriers. Additional updates are expected before the end of 2024.

December 16, 2024: Larimar presented data from the open label extension (OLE) study showing increases in frataxin in buccal cell (an average of 30% of healthy volunteer levels) and skin (an average of 70% of healthy volunteer levels) in people receiving 25 mg per day of drug. These data were at 90 days of dosing. Based on the safety data, all participants in the OLE will now receive a daily dose of 50 mg per day. The company also provided information on the plans for studies in pediatric patients (See Clinical Development: Pediatrics below). With demonstrated dose responsive increases in frataxin, FDA acknowledgement that FXN deficiency appears to be critical to the pathogenic mechanism of FA, and the unmet need for treatments that address the underlying disease pathophysiology, the company is in discussions with the FDA to use the accelerated approval pathway with a BLA submission targeted for the second half of 2025. Changes in clinical assessments (mFARS, FARS-ADL, modified fatigue impact scale, and the 9-hole peg test) were also presented. The company noted a trend toward improvement in these measures, but these are data from 90 days and only 8 people.

In the middle of 2025, Larimar is planning on initiating a global confirmatory/registration study and to release the data from 50 mg dose in OLE study. In the second half of 2025, Larimar is planning on a BLA submission to pursue accelerated approval based on increases in frataxin levels.

November 2024: On November 4, 2024, Larimar announced that the company will start enrolling adolescents (12-17 years old cohort) in a clinical trial to study the pharmacokinetics of nomlabofus (Initial Pediatric Study Safety and PK). After a data review, an additional study in children between the ages of 2-11 years old cohort is expected to start. Participants completing the PK studies are eligible to transition into an open label extension (OLE) after the PK study for that cohort is complete.

The company also announced a global phase III study is expected to begin in 2025.

December 16, 2024: Larimar provide information on the nomlabofusp program for children during an investor call. The company is screening adolescents for a pediatric PK run-in study with dosing to initiate early in 2025. The doses for this study will be weight-based dose equivalent of 50 mg adult dose. After collection of the PK data, the plan is to transition adolescents who complete study participation into OLE after analysis of PK and safety data. Additionally, the company announced a plan to enroll children (ages 2-11 years old) in a pediatric PK run-in study in the first half of 2025.