FDA Should Fast-Track New Muscular Dystrophy Drug
The Food and Drug Administration may be about to screw up again on a very important Disease treatment, and in the opposite direction from the last time I criticized the agency. Instead of approving something that was worthless and that it knew was worthless, it may be delaying approval of a vital treatment for a horrible disease that has no real alternatives.
Not that it hasn't done stuff like this before.
For example, a company developed a drug to treat the devastating neuromuscular disease Duchenne muscular dystrophy, or DMD. The agency originally refused to "fast-track" the drug but later gave it accelerated approval in 2016 because it appeared (and, in subsequent research, appears) beneficial in a minority (about 14 percent) of patients with a certain mutation. The drug is eteplirsen, and its maker Sarepta Therapeutics.
Now, maybe, it's déjà vu all over again as the FDA is reportedly considering rejecting the company's request to fast-track what could be a vital new Gene therapy called SRP-9001, or, if you're a glutton for punishment, call it by the generic name of delandistrogene moxeparvovec. (Trolls in northern Sweden are tasked with coming up with these.)
What causes DMD are genetic mutations that interfere with making the protein dystrophin, essential for muscle health. SRP-9001 is made to deliver a gene encoding micro-dystrophin — a shortened, albeit functional, version of the protein — to muscle cells. As it stands, the FDA will meet on May 12 to issue a decision.
The FDA is now licking its wounds and probably wary of similar accusations arising.
DMD is the awful disease made famous by actor and comedian Jerry Lewis on his Muscular Dystrophy Association Labor Day Telethon, which he hosted for decades. About 10,000 to 12,000 Americans alone are believed to currently suffer from DMD. Those afflicted suffer a gradual weakening of the muscles, leading to difficulties with walking, standing, and other movements. Symptoms can range from mild to severe and may include muscle stiffness, frequent falls, difficulty climbing stairs, and trouble breathing. Death is not pleasant.
According to research, "patients born after 1990 have a median life expectancy of just 28.1 years."
DMD is not a good example of male privilege because the gene responsible for producing the protein dystrophin is located on the X chromosome. Females have two X chromosomes and so may have a "backup," so to speak. Males have but one.
I remember thinking as a child: If they just raised enough money at the telethon this year…
But, unfortunately, no effective DMD drugs were approved until after the telethons ended and just before Lewis' death, the first being Sarepta's eteplirsen.
Yes, we now walk around with super-computers-combined-awesome-cameras in our pocket, yet, almost six decades from that first telethon and over a decade since the last, we've made little progress against this awful killer.
But perhaps nobody is better positioned to achieve the dream than Sarepta. It's a Cambridge-based biopharmaceutical company that only researches degenerative muscular diseases, primarily DMD. Sarepta has three approved therapies, all for DMD. It may know this area better than anyone else, as it has, in its words, "over 40 programs in various stages of development across 3 technologies, RNA, gene therapy and gene editing."
Currently, there are five FDA-approved drugs for DMD. These can help slow the progression of the disease and improve muscle strength, but they don't address the underlying genetic cause of the disease.
If SRP-9001 succeeds, it will be in completely different league. It's a one-time treatment designed to deliver a functional copy of the missing or defective dystrophin gene to muscle cells. The current designation Sarepta seeks would allow it to be used on perhaps 5,000 people with DMD in the U.S. And could reach all estimated 10,000 to 12,000 Americans with expanded approvals. That would be the largest patient pool for any gene therapy developed to date.
Regarding other countries, the huge Swiss-based pharma company Roche has bet big on the therapy, paying Sarepta more than $1 billion in late 2019 for the non-U.S. Rights.
Despite some sensationalist coverage to the contrary, SRP-9001 does not confer benefits equivalent to those attributed to Lourdes or, to that matter, demonstrated in that scene in Forrest Gump when the boy's braces break off and he can suddenly fly like the wind. It cannot restore lost muscle, nor can it restore abilities that have been lost, such as walking. It's only been administered to young boys still able to walk. It's been theorized that younger dosing is more beneficial, but since all dosing in the formal clinical trials has been administered in those ages 4–7, there's no control group. Sarepta has dosed a group of patients who are 3 years old — individuals who are still gaining functional abilities — but it's early, the study is ongoing, and Sarepta has not yet released results.
What is accelerated approval?
In certain cases, the FDA may decide to fast-track a drug if it is intended to treat a serious or life-threatening condition, and there are no other treatments available. Fast-tracking can help speed up the approval process by allowing the drug to be reviewed more quickly and with fewer clinical trials.
Among the factors considered when making such a decision are:
SRP-9001 clearly qualifies for the first three. "Fatal" is pretty severe. Likewise for "slow and lingering."
As noted, no other treatments are in the same league. That's probably why the FDA has just fast-tracked Biogen's ALS drug Qualsody, even though at best it will help about 2 percent of Lou Gehrig's disease sufferers. It also essentially failed in phase three, having missed its primary endpoint.
So far, the side-effects profile of SRP-9001 is quite good. In numerous instances, patients on the placebo had more side effects than those receiving the treatment. (That's actually pretty common.)
On factor number four, I would definitely like to see more. So would the FDA. So would Sarepta. But this is a balancing act, not one of those irritating CAPTCHAs where you get bonked if you don't check all the boxes with crosswalks or fire hydrants. Meanwhile, the FDA can insist on continuing tests.
This indeed appears to be a major sticking point with fast-tracking SRP-9001. The FDA requested further data on eteplirsen, but the confirmatory trial is still ongoing, as are two others that the agency fast-tracked.
But the FDA is also stumbling a bit in the dark with SRP-9001. No company has ever asked the agency to grant accelerated approval to a one-time gene therapy before, according to STAT. It notes (and actually depicts in photos) some great case reports but also says that the actual data have been mixed.
Also, I may have played a very small part in the FDA's reticence, having published two articles blasting the agency for fast-tracking an Alzheimer's drug from Biogen called Aduhelm. But that issue was really cut and dried. With Aduhelm, there truly was no "there there." In fact, the FDA assembled an advisory board of a dozen people, and none approved fast-tracking, in part because there existed zero evidence that it could delay, much less halt or reverse, cognitive decline. Rather, it relied on a "surrogate endpoint" that it had previously rejected for other Alzheimer's applications.
Here, Sarepta is also relying on surrogate endpoints, but there's nothing inherently wrong with such a measure so long as the surrogate represents the actual disease. With Aduhelm, Biogen relied on the theory that amyloid buildup in the brain causes the dementia, even as much recent research indicates that this is only associated. It's like presuming that opening umbrellas makes it rain.
It all stunk to high heaven, and two congressional committees later ripped the agency for being too chummy with Biogen. That said, the FDA is now licking its wounds and probably wary of similar accusations arising from moving too fast with any given drug. Ideally, pendulums that go too far to one side should settle in the middle. And, ultimately, they usually do. But in the short term, they often swing too far to the other side.
And although case reports with almost miraculous results have become a fixture at medical conferences, the actual data on the drug have been mixed, with what was deemed an outright stock-plummeting failure in January of 2021. The drug didn't appear to beat the placebo in a phase two clinical trial. Functional motor ability scores in the SRP-9001 arm were statistically no better than in the placebo group.
There's nothing else to offer these poor people.
Sometimes a company will throw in the towel at this point, but sometimes it keeps moving forward, if only because it's invested so much into the work already. And sometimes they keep going because they've identified a problem with the study in question — or think they have. This time it looks like the study quite possibly really was a problem.
Even with rodents, it's impossible to perfectly match the placebo group to that receiving the therapy. But this time the mismatch may have made all the difference. For example, if the placebo control arm is made up of patients who have less severe symptoms than the patients in the treatment arm, the treatment arm may appear less effective than it actually is because the placebo control arm is artificially inflating the response rate.
In mid–clinical trial results released in January, SRP-9001 did not show a statistically significant improvement over placebo in the primary endpoint, which was an assessment of patients' ability to walk. But patients who received SRP-9001 showed improvements in certain secondary endpoints, such as muscle function and respiratory performance. These improvements may be clinically meaningful for patients with DMD.
That's what the chief scientific officer at Sarepta, Louise Rodino-Klapac, Ph.D., says happened.
The researchers also found that at all time points in the study, the group that received the new treatment had slightly higher scores, albeit not statistically significant.
The study is not yet complete, and more information will be available once Sarepta receives data on all participants (scheduled for 2026), including those in the crossover group. Sarepta is also conducting a separate study using commercial materials. The results of the phase two study will inform the phase three study for the best chance of success.
Sarepta proceeding with its application is hardly radical. Applied Therapeutics has just announced that it will seek FDA approval despite its pediatric drug apparently faring no better in phase three testing than the placebo. It thinks it can make a good case that it actually did.
So, on balance, this would seem to indicate a fast track.
There's nothing else to offer these poor people. Recently I spent 10 weeks without use of a leg post-surgery, and that was horrible enough. The other limbs worked fine, and I knew the disability was temporary.
So, unless the FDA has access to material that nobody has been able to ferret out, the agency should allow fast-tracking. If nothing else, Sarepta's pipeline (and that of other companies) could seriously benefit from whatever SRP-9001 does outside of clinical trials. Gene therapy is the future for the treatment of not just genetically related diseases but others as well. For example, there has been work on not just adding extra anti-cancer p53 genes to those lacking them, which would be terrific by itself, but even adding extra copies to genetically normal people to make them more resistant to cancer.
As a sort of post-script, after I had essentially finished this article, I came across a Vimeo collection of before and after of little boys dosed with SRP-9001. You can't absolutely rule out the power of suggestion, because even kids that young (the oldest was 9) might be susceptible. When I was about 10, a doctor gave me huge "wart elimination" pills that completely worked. Only years later did I discover that, then as well as now, there's no such thing, except for genital warts — not my variety. But to see these kids running up stairs, in playgrounds, on bicycles — it was touching even to this cynical old SOB. I don't think that was all psychogenic.
I still remember going door to door to collect money for "Jerry's kids." And I think this is worth a try. Too bad the late great comedian won't be here to see it.
Michael Fumento ([email protected]) is an attorney and author and has been a science journalist for over 35 years. His work has appeared in the New York Times, the Washington Post, the Wall Street Journal, the Sunday Times, the Atlantic, and many other fora. He has no holdings in Sarepta and will not before this article appears.
READ MORE from Michael Fumento:
If AI 'Wants' to Destroy Us, It Can. But Why Would It?
Of Mice and Men: Bypassing Animals for Drug Testing Is a Good Move
Fusion Follies
Mendelian Genetics: Patterns Of Inheritance And Single-Gene Disorders
Autosomal recessive single-gene diseases occur only in individuals with two mutant alleles of the disease-associated gene. Remember, for any given gene, a person inherits one allele from his or her mother and one allele from his or her father. Therefore, individuals with an autosomal recessive single-gene disease inherit one mutant allele of the disease-associated gene from each of their parents. In pedigrees of families with multiple affected generations, autosomal recessive single-gene diseases often show a clear pattern in which the disease "skips" one or more generations.
Phenylketonuria (PKU) is a prominent example of a single-gene disease with an autosomal recessive inheritance pattern. PKU is associated with mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH); when a person has these mutations, he or she cannot properly manufacture PAH, so he or she is subsequently unable to break down the amino acid phenylalanine, which is an essential building block of dietary proteins. As a result, individuals with PKU accumulate high levels of phenylalanine in their urine and blood, and this buildup eventually causes mental retardation and behavioral abnormalities.
The PKU-associated enzyme deficiency was determined biochemically in the 1950s—long before the PAH-encoding gene was mapped to human chromosome 12 and cloned in 1983. Specifically, Dr. Willard Centerwall, whose child was mentally handicapped, developed the first diagnostic test for PKU in 1957. Called the "wet diaper" test, Centerwall's test involved adding a drop of ferric chloride to a wet diaper; if the diaper turned green, the infant was diagnosed with PKU. The wet diaper test was used to reliably test infants at eight weeks after birth; by this time, however, infants who were affected by PKU had already often suffered irreversible brain damage.
Thus, in 1960, Dr. Robert Guthrie, whose niece suffered from PKU and whose son was also mentally handicapped, established a more sensitive method for detecting elevated phenylalanine levels in blood, which permitted a diagnosis of PKU within three days after birth. Guthrie's test used bacteria that were unable to make their own phenylalanine as messengers to report high blood levels of phenylalanine in an infant's blood sample obtained via heel prick. With Guthrie's method, the phenylalanine-deficient bacteria were grown in media together with a paper disk spotted with a drop of the infant's blood. If the phenylalanine levels in the blood were high, the bacteria would grow robustly, and a diagnosis of PKU could be made. Through the ability to discover that their child had PKU at such an early age, parents became able to respond immediately by feeding their child a modified diet low in proteins and phenylalanine, thereby allowing more normal cognitive development. Guthrie's test continues to be used today, and the practice of obtaining an infant's blood sample via heel prick is now used in numerous additional diagnostic tests.
Several other human diseases, including cystic fibrosis, sickle-cell anemia, and oculocutaneous albinism, also exhibit an autosomal recessive inheritance pattern. Cystic fibrosis is associated with recessive mutations in the CFTR gene, whereas sickle-cell anemia is associated with recessive mutations in the beta hemoglobin (HBB) gene. Interestingly, although individuals homozygous for the mutant HBB gene suffer from sickle-cell anemia, heterozygous carriers are resistant to malaria. This fact explains the higher frequency of sickle-cell anemia in today's African Americans, who are descendants of a group that had an advantage against endemic malaria if they carried HBB mutations. Finally, oculocutaneous albinism is associated with autosomal recessive mutations in the OCA2 gene. This gene is involved in biosynthesis of the pigment melanin, which gives color to a person's hair, skin, and eyes.
X Chromosome: X Inactivation
Bacher, C. P., et al. Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nature Cell Biology 8, 293-299 (2006) doi:10.1038/ncb1365 (link to article)
Borsani, G., et al. Characterization of a murine gene expressed from the inactive X chromosome. Nature 351, 325–329 (1991) doi:10.1038/351325a0 (link to article)
Boumil, R. M., & Lee, J. T. Forty years of decoding the silence in X-chromosome inactivation. Human Molecular Genetics 10, 2225–2232 (2001)
Brockdorff, N., et al. Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351, 329–331 (1991) doi:10.1038/351329a0 (link to article)
———. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992)
Brown, C. J., et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349, 38–44 (1991) doi:10.1038/349038a0 (link to article)
———. The human XIST gene: Analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527-542 (1992)
Carrel, L., & Willard, H. F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404 (2005) doi:10.1038/nature03479 (link to article)
Clemson, C. M., et al. XIST RNA paints the inactive X chromosome at interphase: Evidence for a novel RNA involved in nuclear/chromosome structure. Journal of Cell Biology 132, 259–275 (1996)
Costa, F. F. Non-coding RNAs, epigenetics, and complexity. Gene 410, 9–17 (2008)
Duret, L., et al. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312, 1653–1655 (2006)
Graves, J. A. Sex chromosome specialization and degeneration in mammals. Cell 124, 901–914 (2006)
Ham, A. L., et al. Does genotype predict phenotype in Rett syndrome? Journal of Child Neurology 20, 768–778 (2005)
Hornecker, J. L., et al. Meiotic sex chromosome inactivation in the marsupial Monodelphis domestica. Genesis 45, 696–708 (2007)
Huynh, K. D., & Lee, J. T. X-chromosome inactivation: a hypothesis linking ontogeny and phylogeny. Nature Reviews Genetics 6, 410–418 (2005) doi:0.1038/nrg1604 (link to article)
Johnston, C. M., et al. Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genetics 4, e9 (2008)
Lee, J. T. Disruption of imprinted X inactivation by parent-of-origin effects at Tsix. Cell 103, 17–27 (2000)
Lee, J. T., & Lu, N. Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99, 47–57 (1999)
Lee, J. T., et al. Tsix, a gene antisense to Xist at the X-inactivation centre. Nature Genetics 21, 400–404 (1999) (link to article)
Liao, D. J., et al. Novel perspective: Focusing on the X chromosome in reproductive cancers. Cancer Investigation 21, 641–658 (2003)
Lucchesi, J. C., et al. Chromatin remodeling in dosage compensation. Annual Review of Genetics 39, 615–651 (2005)
Luikenhuis, S., et al. Antisense transcription through the Xist locus mediates Tsix function in embryonic stem cells. Molecular and Cellular Biology 21, 8512–8520 (2001)
Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961) doi:10.1038/190372a0 (link to article)
Marahrens, Y., et al. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes & Development 11, 156–166 (1997)
Martin, G. R., et al. X-chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro. Nature 271, 329–333 (1978) (link to article)
Namekawa, S. H., et al. Sex chromosome silencing in the marsupial male germ line. Proceedings of the National Academy of Sciences 104, 9730–9735 (2007)
Ogawa, Y., et al. Intersection of the RNA interference and X-inactivation pathways. Science 320, 1336–1341 (2008)
Okamoto, I., & Heard, E. The dynamics of imprinted X inactivation during preimplantation development in mice. Cytogenetic and Genome Research 113, 318–324 (2006)
Penny, G. D., et al. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996) doi:10.1038/379131a0 (link to article)
Rastan, S., & Robertson, E. X chromosome deletions in embryo-derived (EK) cell lines associated with lack of X chromosome inactivation. Journal of Embryology and Experimental Morphology 90, 379–388 (1985)
Sado, T., et al. Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128, 1275–1286 (2001)
Sleutels, F., & Barlow, D. P. The origins of genomic imprinting in mammals. Advances in Genetics 46, 11–163 (2002)
Stavropoulos, N., et al. A functional role for Tsix transcription in blocking Xist RNA accumulation but not in X-chromosome choice. Proceedings of the National Academy of Sciences 98, 10232–10237 (2001)
Wutz, A., & Jaenisch, R. A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Molecular Cell 5, 695–705 (2000)
Xu, N., et al. Transient homologous chromosome pairing marks the onset of X inactivation. Science 311, 1149–1152 (2006) doi:10.1126/science.1122984
———. Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein. Nature Genetics 39, 1390–1396 (2007) doi:10.1038/ng.2007.5 (link to article).
