FDA Grants Orphan Drug Designation to PPL-002 for the Treatment of Danon Disease

The FDA granted orphan drug designation to PPL-002 (Papillon Therapeutics, Inc) for the treatment of Danon disease. PPL-002 is an experimental, gene-modified CD34+ hematopoietic stem and progenitor cell therapy, expressing LAMP2 protein.¹

Image Credit: C Davids/peopleimages.com - stock.adobe.com

“We are grateful that the FDA has granted orphan drug designation to PPL-002, which marks the second designation for Papillon's pipeline,” Carter Cliff, CEO of Papillon Therapeutics, said in a news release. "We believe our therapeutic approach has the potential to treat multiple symptoms and address the unmet treatment needs of patients and their families. This designation reinforces our dedication to advancing therapies for people living with Danon disease and other rare, debilitating conditions."¹

The drug has shown improvement in disease phenotype for the affected tissues in preclinical trials. PPL-002 also targets multiple organ symptoms, potentially modifying and reversing disease progression, according to the news release.¹

Danon disease is a rare genetic disorder that is X-linked and manifests with cardiomyopathy, skeletal myopathy, and intellectual disability. There are over 160 mutations that are identified in the LAMP2 gene, making the disease not well understood. More research is needed to improve both diagnosis and treatment of Danon disease.^2,3

For those with the disease, DNA instruction is needed for the body to create the LAMP2 protein, playing a role in lysosomes function and autophagy. Without the protein the lysosomes cannot break down molecules and compounding, causing a build-up of debris and triggering cardiomyopathy, muscle weakness, intellectual disabilities, eye disease, and liver function. Danon disease must be confirmed with a genetic test, according to the Danon Foundation.³

According to a report in the National Library of Medicine, males show signs of muscle weakness and possibly delayed motor skills at younger ages. Additionally, males present more often with hypertrophic cardiomyopathy (90%), and females could manifest equally with either hypertrophic or dilated cardiomyopathy. Furthermore, women also manifest with symptoms during middle adulthood, typically with heart disease symptoms. Skeletal myopathy and intellectual disabilities may not be present in females.²

Currently, there are no established guidelines for treatment or management of Danon disease. It is suggested that a thorough cardiac workup is provided for newly diagnosed patients, including electrocardiogram, echocardiography, serum brain natriuretic peptide levels, and 24-Holter monitoring. Implantable cardioverter-defibrillator or cardiac ablation could be necessary for some patients. Further, it is suggested that early consideration of cardiac transplant should be given, especially for young males with rapid progression of hypertrophic cardiomyopathy and at risk for sudden cardiac death.²

Physical therapy is also utilized to preserve muscle strength and flexibility as is a comprehensive neuropsychological exam for neurocognitive issues. The report suggest that due to limited life expectancy, extensive counseling should be provided for the patient and family. A strong interprofessional health care team is the recommended approach, including a physician, in order to have the best treatment plan for the patient. If approved, PPL-002 would be the first pharmaceutical option for patients with Danon disease.²

REFERENCES

1. Papillon Therapeutics Receives Orphan Drug Designation from the U.S. Food and Drug Administration for PPL-002 for the Treatment of Danon Disease. News release. Papillon Therapeutics. October 1, 2024. Accessed October 2, 2024. https://www.businesswire.com/news/home/20241001469618/en/Papillon-Therapeutics-Receives-Orphan-Drug-Designation-from-the-U.S.-Food-and-Drug-Administration-for-PPL-002-for-the-Treatment-of-Danon-Disease

2. D'Souza RS, Law L. Danon Disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Updated July 24, 2023. Accessed October 2, 2024. https://www.ncbi.nlm.nih.gov/books/NBK545211/

3. Danon Foundation. Understanding Danon. Updated 2024. Accessed October 2, 2024. https://www.danonfoundation.org/understanding-danon