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Developmental biology - Progeria|
Free treatment for children with Progeria
Lonafarnib inhibits farnesyltransferase, an enzyme that facilitates the production ofprogerin. As a farnesyltransferase inhibitor (FTI), lonafarnib helps prevent cellular damage caused by the mutant protein. However, Lonafarnib is not currently approved for use outside of clinical trials.
Since 2007, PRF has funded four clinical trials to study lonafarnib’s effect on Progeria ± treating children from more than 30 countries. PRF Medical Director Leslie Gordon MD PhD, along with her research teams at Boston Children’s Hospital and Brown University, recently published results of a study of lonafarnib in Progeria in The Journal of the American Medical Association (JAMA). The study reported that treatment with lonafarnib alone compared against no treatment was associated with a significantly lower mortality rate (3.7% vs. 33.3%) after a median of 2.2 years of follow up (see JAMA citations below).
“This progress is due in large part to the courage and strength of children with Progeria and their families who participated in the lonafarnib clinical trials,” explains Dr. Gordon. “More than a decade of intensive investigation has enabled PRF to strike this partnership with Eiger and move towards potential FDA review and approval. Reaching this tremendous milestone gives us even more optimism that we will discover additional treatments that complement the lonafarnib therapy and keep us moving forward towards more effective treatments and the cure.” As the parents of Sam Berns, who died in 2014 at the age of 17, with Progeria, Dr. Gordon and her husband, Scott Berns, MD MPH co-founded PRF in 1999 with Gordon’s sister Audrey Gordon, Esq.
Merck, known as MSD outside of the United States and Canada, previously provided lonafarnib free of charge for use in PRF-sponsored clinical trials. Following a transfer of manufacturing technology from Merck in 2015, Eiger began to provide lonafarnib at no cost for use in ongoing clinical trials funded by PRF. Eiger has since expanded its licensing agreement with Merck to include rights to develop lonafarnib for the treatment of Progeria and will be responsible for regulatory execution, commercialization and distribution activities across the licensed and approved indications in the future.
PRF has granted Eiger a non-exclusive, world-wide license to all PRF intellectual property, know-how and clinical data generatedby PRF to prepare and file a new drug application (NDA) for Progeria. Eiger also intends to establish an expanded access program that would enable access to lonafarnib for children with Progeria.“Continued patient access to lonafarnib was the fundamental motivation for this agreement with PRF,” explains David Cory, President and CEO of Eiger. “Eiger will provide lonafarnib for ongoing clinical trials and expanded access in Progeria and work together with PRF to seek regulatory guidance on a pathway toward regulatory approval of lonafarnib for use in children with Progeria.”
• In 2003 the PRF Genetics Consortium discovered the Progeria gene, a collaboration led by Dr. Francis Collins, then Director of the National Human Genome Research Institute, and currently Director of the National Institutes of Health (NIH).
• Today, PRF continues to be the only organization in the world solely dedicated to finding treatments and the cure for Progeria and its aging-related conditions, including heart disease.
• The organization takes Progeria children out of the medical background where they had been for more than 100 years and puts them and Progeria at the forefront of scientific efforts.
• For more information and to donate to PRF, please visit www.progeriaresearch.org.
Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment.
Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS.
Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date >=1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018.
Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications.
Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients.
Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04).
Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.
JAMA reference: Gordon et. al., Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome, JAMA, April 24, 2018 Volume 319, Number 16 and accompanying editorial..
Authors: Leslie B. Gordon MD PhD; Heather Shappell PhD; Joe Massaro PhD; Ralph B. D’Agostino Sr PhD; Joan Brazier MS; Susan E. Campbell MA; Monica E. Kleinman MD; Mark W. Kieran MD PhD.
About Eiger BioPharmaceuticals, Inc.: Eiger BioPharmaceuticals (NASDAQ: EIGR) is a clinical-stage biopharmaceutical company focused on the development and commercialization of targeted therapies for rare diseases. Eiger is committed to translational innovation and the development of well-characterized drugs acting on newly identified or novel targets. Eiger’s mission is to systematically reduce the time and cost of the drug development process to more rapidly deliver important medicines to patients with rare diseases. Eiger’s lead program evaluating lonafarnib in Hepatitis Delta Virus (HDV) infection is moving into Phase 3 with a single, pivotal trial planned to initiate by the end of the year. For additional information about Eiger and its clinical programs, please visit www.eigerbio.com.
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The Progeria Research Foundation (PRF) was founded in 1999 by Leslie B. Gordon MD PhD, Sam's mother and Scott Berns, MD MPH, Sam's father in 1999 along with Gordon’s sister Audrey Gordon, Esq. in response to the complete lack of attention to, and progress being made in Progeria research. Their original mission: to discover the cause, treatments and cure for Progeria. Be sure to view Sam's TED talk: Sam Berns