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Lexeo Shares Positive Interim Data For FA Cardiomyopathy Gene Therapy
The therapy led to increased frataxin levels and decreased left ventricular mass in patients with Friedreich ataxia (FA) cardiomyopathy, the authors said.
The maker of a gene therapy candidate for the treatment of Friedreich ataxia (FA) cardiomyopathy has released interim data suggesting the therapy is well tolerated and is associated with improvement in key clinical parameters.
Lexeo Therapeutics, which has been working on gene therapies for genetically defined cardiovascular diseases and APOE4-associated Alzheimer disease, released data from a phase 1/2 clinical trial this week. The release also included data from a Weill-Cornell Medicine investigator-initiated phase 1A trial. Taken together, the data suggest the therapy, known as LX2006, is well tolerated and associated with a reduction in mean left ventricular mass index (LVMI) in patients with elevated LVMI at baseline.1
FA is a rare genetic condition that leads to progressive nervous system damage. It can cause muscle weakness and discoordination, among other symptoms. However, the most common cause of death among people with the disease is cardiac complications, such as cardiomyopathy.
Eric Adler, MDImage Credit: Lexeo Therapeutics
Eric Adler, MD, Lexeo's chief medical officer and head of research, said in a conference call with reporters and investors that patients with FA cardiomyopathy have few options.
"Treatment options for FA cardiomyopathy are extremely limited," he said. "Medical therapy has not been shown to be effective, and cardiac transplantation is rarely an option given the comorbidities associated with the disease."
Only one therapy is currently approved to treat FA: omaveloxolone (Skyclarys; Biogen). In clinical trials, it led to meaningful improvement in modified FA rating scale (mFARS) scores.2 However, Adler said it has not been evaluated for the treatment of cardiac dysfunction associated with FA.
LX2006 is specifically focused on cardiac manifestations of FA. The therapy delivers a functional frataxin gene, which promotes the expression of the frataxin protein. The frataxin protein is deficient in patients with FA; these individuals have an estimated 2% or less of the normal level of frataxin in the heart. The company believes improving frataxin levels in the heart can help restore mitochondrial function in myocardial cells.
Adler said it is not yet clear just how much frataxin restoration is needed to improve the cardiac health of people with FA, but he pointed to a newly developed murine model that suggested that achieving even 5% of normal frataxin levels in the heart led to near normal cardiac output.3
"As such, we believe a modest amount of frataxin restoration may be sufficient to restore cardiac function or translate to clinical benefit in FA," he said.
The company's new interim data are based on 8 patients with at least 6 months of follow-up. Authors said all participants exhibited increased levels of frataxin compared with baseline following treatment with LX2006. They found that three-quarters of patients with elevated LVMI at baseline achieved a reduction of at least 10% at 12 months; there were also mean reductions of 11.4% at 12 months and 18.3% at 18 months. Left ventricular lateral wall thickness was reduced at 12 months, by an average of 13.6% in all patients, they said. High-sensitivity troponin levels, which indicate myocardial injury, were reduced by an average of 53.3% at 12 months.
In terms of safety, the company said neither study has identified any treatment-related serious adverse events thus far, and all adverse events were transient and resolved. The company said there are no signs of complement activation, nor are there any cardiac or hepatic safety signals thus far. No patients have discontinued either study.
Adler said Lexeo is "very encouraged" by the early results and hopes to explore expedited clinical development of the therapy. The press release said the company expects to share further details of their interim results in the fall of this year. Meanwhile, the Weill-Cornell investigator-initiated trial is currently enrolling a second cohort of patients.
References
1. Lexeo Therapeutics announces positive interim phase 1/2 clinical data of LX2006 for the treatment of Friedreich ataxia cardiomyopathy. News release. Lexeo Therapeutics. July 15, 2024. Accessed July 16, 2024. Https://ir.Lexeotx.Com/news-releases/news-release-details/lexeo-therapeutics-announces-positive-interim-phase-12-clinical
2. Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann Neurol. 2021;89(2):212-225. Doi:10.1002/ana.25934
3. Gérard C, Archambault AF, Bouchard C, Tremblay JP. A promising mouse model for Friedreich Ataxia progressing like human patients. Behav Brain Res. 2023;436:114107. Doi:10.1016/j.Bbr.2022.114107
Hypertrophic Cardiomyopathy: New Rules Say You Can Exercise
In HCM, the heart muscle is abnormally thick, causing issues that can even result in sudden death. — AFP
About 1 in 500 people have hypertrophic cardiomyopathy (HCM).
It's a condition where the heart muscle becomes abnormally thick.
HCM is one of the most common causes of sudden death among young athletes and otherwise healthy adults.
In the past, athletes and other patients with hypertrophic cardiomyopathy were told to sit on the sidelines.
But it may be time to get back into the game.
The American Heart Association and the American College of Cardiology recently released new guidelines on this condition.
The guideline's writing committee chair and Mayo Clinic Hypertrophic Cardiomyopathy Clinic medical director Dr Steve Ommen says that with exercise and proper medication management, patients can return to their normal daily routines.
"Hypertrophic cardiomyopathy should not be an automatic disqualification from pursuing sports," he says.
Patients with HCM might benefit from being active, he notes.
"Our current recommendations are that patients with hypertrophic cardiomyopathy participate in low to moderate intensity exercise as part of a healthy lifestyle, and that it's reasonable for them to do more vigorous activities as well," he says.
A new class of medications is on the roster, giving patients more options to manage their disease.
"Usually, there's some simple medications the patient may try first, and then, if that's not effective, they will have an option of this medication; an older medication called disopyramide; an operation called surgical myectomy; or a catheter-based solution, alcohol septal ablation," Dr. Ommen explains.
It's a good idea to check with your healthcare team before making changes to medications or daily routines.
HCM symptoms include:
Lexeo's Gene Therapy Shows Promising Phase 1/2 Results For Friedreich's Ataxia Cardiomyopathy
The results are from eight patients with 6-12 months of follow up data and show reductions in left ventricular mass, thickening of the heart wall and myocardial injury as a result of the treatment.
The therapy, LX2006, is being tested by the company, but also by Weill Cornell medical school in New York and the trial is ongoing. As of July 15, 13 patients have been treated with the therapy across two trials. Next steps include testing a higher dose of the therapy.
"We are very encouraged by these data and the potential of LX2006 to treat FA cardiomyopathy, a devastating and fatal condition with no currently approved therapies," said Eric Adler, Chief Medical Officer and Head of Research, at Lexeo in a press statement.
"Based on the favorable safety profile and clinical benefits observed to date, we are excited to explore expedited clinical development of LX2006, including potential for accelerated approval of this possibly life-saving treatment."
As well as a positive impact on cardiac symptoms, no significant side effects were seen in patients given the therapy and no participants discontinued the trial.
Focus on rare disease
Lexeo is focused on developing gene therapies for rare genetic cardiac and neurological conditions, including for people with APOE4-linked Alzheimer's disease.
Friedreich's ataxia is inherited in an autosomal recessive manner and is caused by mutations in a gene that encodes the protein frataxin (FXN) on chromosome 9. People with this disease produce less frataxin than normal and this causes degeneration of nerve tissue that leads to difficulty walking, loss of coordination and impaired speech.
Symptoms of this condition can start as early as 5 years of age and are usually present by the age of 20. Although it is a rare condition, it is one of the most common inherited ataxias and impacts between 1 in 20,000 and 1 in 50,000 people of Caucasian descent, in whom it is most common.
Many people with Friedreich's ataxia also develop cardiomyopathy, where the heart struggles to pump blood to the body, mostly caused by abnormal thickening of the heart wall in people with this condition. Life span varies in people with Friedreich's ataxia but cause of death is related to cardiomyopathy in up to 80% of people with the disease.
LX2006 is an adeno-associated viral vector therapy designed to restore the function of FXN and increase levels of the protein in people with Friedreich's ataxia to treat symptoms of cardiomyopathy.
The first therapy, omaveloxolone, to treat the condition was approved by the US FDA last year and the EMA earlier this year. However, it is not specifically focused on cardiac symptoms of the condition, which Lexeo hopes to target, and is focused on treating neurological symptoms of the condition.
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