NEW YORK (Reuters Health) – Treatment with lonafarnib, a farnesyltransferase inhibitor, is associated with significantly reduced mortality in children with Hutchinson-Gilford progeria syndrome (HGPS), according to an observational study.
“These results are a major breakthrough for clinical investigation in progeria, because this is the first support we have for a single medication influencing the lifespans of the children with progeria,” said Dr. Leslie B. Gordon from Hasbro Children’s Hospital, Warren Alpert Medical School of Brown University, in Providence, Rhode Island.
“This, along with supporting data that we have previously published showing lonafarnib’s influence on the cardiovascular system and skeletal systems, is extremely encouraging, because we now know that we can push this disease towards health,” she told Reuters Health by email.
There are no drugs approved for the treatment of HGPS, which usually results in death from heart failure at a mean age of 15.
In the current study, reported in the April 24 issue of JAMA, Dr. Gordon and colleagues assessed the association between lonafarnib monotherapy and mortality, compared with no treatment, in 195 untreated patients and 63 patients treated with lonafarnib in two clinical trials – one completed, and one ongoing.
In the completed phase 2 trial, the mortality rate after 2.2 years of follow-up was significantly lower in the lonafarnib group (1/27, 3.7%) than in the matched untreated group (9/27, 33.3%), an 88% reduction. In this earlier trial, lonafarnib was well-tolerated and associated with improvements in some features of HGPS.
In the ongoing treatment trial, there have been three deaths (8.3%) among 36 patients in the lonafarnib group and eight deaths (22.2%) among 36 patients in the matched untreated group, a difference that falls short of statistical significance.
The combined mortality rate is significantly lower in the lonafarnib groups (4/63, 6.3%) than in the matched untreated groups (17/63, 27.0%; P=0.04).
Most deaths in both groups were due to heart failure (75% of lonafarnib-treated patients and 80% of matched untreated patients).
“Lonafarnib is a treatment and not a cure,” Dr. Gordon said. “These findings inspire us to find additional treatments and the cure for children with this fatal disease. These findings, along with the supporting data, inspire us to move towards FDA approval of lonafarnib for progeria.”
“The Progeria Research Foundation is working tirelessly to fund new scientific breakthroughs, because the research funded today will lead to better treatments and the cure for children with progeria in the future,” she said. “For these children and families, every day counts. We have a stronger sense of urgency than ever before.”
Dr. Fuki Marie Hisama from the University of Washington School of Medicine in Seattle, who co-authored a linked editorial, told Reuters Health by email, “Treatment with lonafarnib appears to be the first effective treatment for a fatal, genetic premature-aging disease of children. Previous studies found the drug is well-tolerated; side effects were mainly gastrointestinal, mild, and improved with time.”
“The discovery of the gene causing HGPS enabled remarkable progress in only fifteen years,” she said. “HGPS is a model for other rare diseases in the power of the partnership of families, physicians, and scientists who have been brought together through the work of the Progeria Research Foundation.”
Dr. Maria Eriksson from Karolinska Institutet, in Huddinge, Sweden, who recently reviewed emerging candidate treatments for HGPS, told Reuters Health by email, “There are no available treatments for this devastating disease, even though trials are ongoing. Many attempts have been pursued both in vitro and in vivo in mice models, during the last 1.5 decades since the genetic mechanism was identified. This study provides additional evidence for the benefits of farnesyltransferase inhibitors (FTIs).”
“It is hard to value the effect of the drug in such a small sample set when you have so many other variables that can affect the final outcome, that is, mortality,” said Dr. Eriksson, who was not involved in the research. “The improvement from clinical trials in patients using FTIs have previously been associated with improved cardiovascular benefit, but these results have previously not been associated with a lower mortality.”
Dr. Nicolas Levy from Aix Marseille Universite, Marseilles, France, who has researched various aspects of progeria and its treatment, also urged caution when considering the new findings.
Still, he told Reuters Health by email, “These results probably represent a step towards identifying treatments that could influence disease progression.”
Dr. Levy, who also was not involved in the study, added, “They also provide a methodological approach that could be helpful in assessing future treatments for rare and ultra-rare diseases for which placebo-controlled clinical trials are unethical and efficacy results must be compared with historical controls.”
Dr. Gordon is the parent of a child who participated in the study.
Schering-Plough/Merck provided the medication used in the two trials.
SOURCE: https://bit.ly/2HK7CEK and https://bit.ly/2FfkA8p
JAMA 2018.
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