Among other items in the bill, The Council for 21st Century Cures is established to accelerate the discovery, development, and delivery of innovative cures, treatments, and preventive measures. The priority review voucher program for rare pediatric diseases is revised and extended.
And of important significance to the approval of eteplirsen, this bill amends the Federal Food, Drug, and Cosmetic Act to revise the drug approval process, including by: (1) allowing patient experience data to be considered in the risk-benefit assessment of a new drug. HR6. On to the Senate and the President!
The USPO recently granted two more patents to Sarepta:
1.Oligonucleotide analogues targeting human LMNA. This patent is intended to cure Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disease that causes young children to prematurely and rapidly age; and
2. Antisense modulation of nuclear hormone receptors. This patent is intended to treat inflammatory diseases without the usual, and sometimes serious side effects like diabetes, osteoporosis and glaucoma caused by glucocorticoids, the current standard of care.
From the New England Journal of Medicine: After only 12 weeks of PRO051, "new dystrophin
expression was observed between approximately 60% and 100% of muscle fibers in
10 of the 12 patients, as measured on post-treatment biopsy, which increased in a
dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the
12-week extension phase, there was a mean (±SD) improvement of 35.2±28.7 m (from the baseline of 384±121 m) on the 6-minute walk test."
is scheduled to complete in April 2016. Enrolling 67-72 children, ages 5 and up for 48 weeks at 13 sites in the US and Canada. All but 5 sites are actively enrolling. Efficacy is not a primary endpoint - only safety (incidents of adverse events), especially heart and lung, but also including lab tests studying hematology, biochemistry, and urinalysis parameters. Secondary outcome measurements for efficacy. Offering intermittent dosing of 6mg/kg for those kids that can't tolerate continuous dosing. No minimum duration, as the company probably expects children to drop out because of adverse events. Clinical trial dot gov website last updated March 5, 2015.
Posted Today by the USPO. Wilton, et al are the inventors, though Sarepta and Murdoch University (in Washington State) are the joint applicants.
Pompe Disease is caused by a missing enzyme that would normally break down glycogen (a sugar). When glycogen is not broken down, it accumulates in the heart, liver, nervous system and muscles, eventually causing respiratory failure and death. Sarepta's drug would splice RNA (exon 2) that contains the coding needed to produce the enzyme that will break down the glycogen. Sarepta's work in the Pompe disease area has been highlighted in its recent presentations, though it is not specifically listed as a development program on Sarepta's Pipeline webpage. Expect it soon.
Correction: Murdoch, WA (where Murdoch University is located) is not in Washington state. WA is Western Australia (which makes more sense if Wilton is an inventor).
This new trial, treating both exons 45 and 53, is labeled as a Phase 3 trial. There will be 99 enrollees: 33 needing exon 45 skipped, 33 needing exon 53 skipped, and then 33 amenable to exon 45 or 53 skipping but receiving placebos (I wonder why not against natural history like our other trials). Duration, 48 weeks. Trial site locations not yet listed.
Bionerd, any safety/adverse events reports on GS/PPMO? Is this a drug that will require lifetime treatment like eteplirsen? Thanks.
Fact is, if eteplirsen is used to treat ANY other deletion, the treatment will harm the child by disrupting production of dystrophin at an otherwise healthy site on the gene.
jrrt, that summary of the upcoming Sarepta presentation at WMS is a little disturbing. What that tells me is that the FDA may back away from Sarepta's push for platform approval because, at least in the case of the exon 45 analog, there appears to be some toxicity, though "minimal", in nonhuman primates at near human dose levels. An abundantly cautious FDA may pause, even if the toxicity is described as "non-adverse and reversible".
I don't think that "cure" is out of the question at all. I foresee a time when eteplirsen and its follow-on DMD treatments are administered prenatally so that dystrophin is produced before the child is born and actually prevents the disease from becoming symptomatic. Dreams can become reality and I think Sarepta is very close to a cure.
PDUFA date for Drisapersen is December 27th, 2015;
Marketing Authorization for Drispersen application validated in EU by EMA June 15th, 2015, with committee opinion by first half 2016, and Decision by third quarter 2016;
Extension studies for Drisapersen continue in US and Europe in two studies;
New global extension study (IV administration) to being Q3;
Young patient and non-ambulate patient studies of Drisapersen to begin later this year and in 2016;
Exon 44 extension study in Europe initiated Dec. 2014, expected to complete Dec. 2016;
Exon 45 phase 1/2 European study ongoing, data emerging and being evaluated;
Exon 53 phase 1/2 Eurpean study ongoing, data emerging and being evaluated;
Natural History study enrollment complete. Data similar to other natural history studies.
immed - Sarepta has not received a voucher, only a designation for eteplirsen as a Rare Pediatric Disease now eligible for a voucher if eteplirsen is approved for use as a drug by the FDA. While I believe that will happen in a few months, it hasn't happened yet.
Actually, its the 4045 dose titration study on non-ambulatory or almost non-ambulatory boys. 12 weeks, 12 boys, 3 sites. I'm hoping that the 4053 dose titration study is not needed by the FDA because of available data from the 4053 dose-titration/efficacy European study that began last winter.
Berg, is there any evidence at all that drisapersen makes a functional dystrophin gene in enough quantity to be effective? I'm not aware of any. Simply skipping an exon will not treat duchenne if not enough functional dystrophin is created from the exon skipping. You ask if drisapersen is not efficacious because of its toxicity. The answer is yes. It's toxicity limits its dose, and therefore its efficacy, in boys with duchenne. Not enough drug equals not enough exon-skipping to do the job. It's that simple.
The trial was for six weeks, and was an open-label study. Xuriden (uridine triacetate), is the first FDA-approved treatment for patients with hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disorder, which has been reported in approximately 20 patients worldwide. The manufacturer of Xuriden also was granted a rare pediatric disease priority review voucher.
Approval granted last week. The trial only lasted 6 weeks and was on children aged 3-19 years old. There were no side effects. Well, there we go. The FDA just shot down the primary short thesis against approval of eteplirsen. Size doesn't matter.
Found this on the FDA website:
"Methodology for Quantification of Dystrophin using Widefield Fluorescence Microscope: Assessment of Percent of Dystrophin Positive Muscle Fiber Population".
Nice slide presentation on dystrophin production and method of quantification of dystrophin in eteplirsen Phase IIb trial:
from Zarife Sahenk, MD, PhD - Professor of Neurology and Pediatrics,The Ohio State University Center for Gene therapy, Director, Clinical and Experimental Neuromuscular Pathology, The Research Institute at Nationwide Children’s Hospital.
Each trial participant had 3 biopsies during 48 week trial, with 24 images of dystrophin positive fibers for each biopsy (total of 72 images per trial participant) - 864 images analyzed from trial participants. [Even though the study was unblinded after 24 weeks, the acquisition and analysis of muscle biopsy remained blinded through 48 weeks].
Several conclusions derived from the blinded, automated, bias-controlled acquisition and analysis of biopsy samples, not the least of which was this: "Using this methodology in the Eteplirsen study, the percent
positive muscle fibers correlated with the clinical efficacy".
This conclusion may give the FDA a basis for finding with reasonable confidence that dystrophin-positive fiber counts predict clinical outcomes (6MWT performance) in DMD patients, a pivotal element in granting accelerated approval of eteplirsen.
Another important note. The slideshow was posted to the FDA website on May 8, 2015, just 10 days before Sarepta announced the FDA go ahead to submit an NDA. Coincidence?
Here's the latest statement from the FDA (from its October press release), of which I am aware, regarding an AdCom for eteplirsen:
"FDA also plans to present the NDA for eteplirsen to a public advisory committee meeting before making a decision on approval. This will afford FDA the ability to gain advice from outside experts and interested stakeholders on the adequacy of the data to support approval, including the possibility of “accelerated approval” – a mechanism to approve drugs in particular situations prior to the availability of definitive evidence of effectiveness."