subset of als patients find hope through newly approved medication
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new als drug could significantly slow disease progression in two per cent of patients.
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roughly 3,000 to 4,000 canadians are currently living with amyotrophic lateral sclerosis (als), and for the majority of them, better therapies are too far off to make a difference in their conditions. after diagnosis, people with als tend to lose their lives to the progressive disease within two to five years.
there are several subsets of als based on differing genetic mutations, and for one small subset of als patients that have sod1-als, hope is on the horizon. roughly two per cent of people with als have this mutation.
qalsody, the latest breakthrough medication for als patients, has recently been granted marketing authorization from health canada. this gives patients with sod1-als, a form of the disease driven by changes in the sod1 gene (roughly two per cent of patients), access to a highly effective drug.
als and current therapies
the current therapies available for als are designed to slow down the progression of the disease, but they’re not as effective as many would hope and work only mildly. life expectancy may increase by six months to a year using these current therapies, radicava and riluzole.
dr. lorne zinman, an als neurologist and clinical researcher at sunnybrook hospital’s als clinic, sees firsthand why the current therapies are nowhere near enough to help the als community.
“sadly, we have three to four deaths every week. this is a really bad disease,” he said.
people living with als have to contend with widespread issues in the body that start small but progress significantly throughout the two to five years they have the disease. someone may begin experiencing weakness in their legs or arms or be unable to do simple tasks such as clipping their nails or brushing their teeth.
as the disease worsens, people continue to lose faculty over their movements until they eventually become paralyzed and succumb to the disease.
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the driving factor of als isn’t the same for everyone with the disease. in some cases, people develop it sporadically, where no known cause is found. in others, genetic mutations are to blame, as is the case with sod1-als.
the most common genetic mutation, found in 25 to 40 per cent of familial als patients, is the c9orf72. regardless of the type of mutation or whether it is genetically or sporadically developed, the end result is the same for all patients with als.
since it’s a rare disease, diagnosing it can be challenging, and many people often wait one to one and a half years for a formal diagnosis.
“by the time they get to me, we rule out all the other causes, and once we’ve confirmed the diagnosis of als, we follow them in our multidisciplinary clinics,” said dr. zinman. “we get them on the two health canada-approved medications.”
the current therapies, radicava and riluzole, aren’t as effective as medical providers such as dr. zinman would like. however, they are the two main medications on the list for those living with als. in the past 20 years, they have also been the only two available—until qalsody.
tammy moore, the ceo of the als society of canada, notes that the new drug can do what the former two cannot, sparking hope for a small group of als patients.
“those two therapies really helped to look to slowing progression, but they’re not disease modifiers like the new one that is coming through, and so, there have been significant limitations in terms of their effectiveness in comparison,” she said.
dr. angela genge, neurologist and leader in the als clinical space, has worked with als patients and research for over three decades. she notes that not everyone with als takes the current therapies as well, making it even more essential to find more breakthroughs in the als therapy space.
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als society of canada (als canada)
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“not everyone is on both medications,” she said, later continuing, “for the first time, we are able to stop the progression of the disease in a group of patients (with qalsody).”
dr. zinman notes that specific criteria need to be met for people to be able to take the older available medications because their efficacy depends on it.
“as long as they’re early enough and they meet the inclusion criteria,” he said. “you have to have a strong lung function and not be too disabled.”
qalsody and sod1-als patients
qalsody is a high-level achievement for the als space and patients with sod1-als because of the lack of therapies available. however, the drug is not a cure, nor is it viable for everyone with als.
this is because of how it works in the body and the mechanisms behind the development of als in different people.
the sod1 gene creates code for the enzyme superoxide dismutase 1, a protein typically tasked with protecting cells from damage by cleaning up free radicals in the body. free radicals are unstable molecules that damage dna and cells.
when that genetic code given to the enzyme is faulty, these proteins do not clean up the damage but rather begin building up to dangerous levels and attacking brain cells in charge of motor skills.
this became a unique biomarker that can be used to assess disease progression in people with this specific type of als. when researchers identified this as a cause of als, they went to work on determining how to stop it from happening.
“the thinking was … let’s just specifically design a drug that can prevent the formation of this protein by blocking its mrna, and that’s what qalsody is,” said dr. zinman.
during the first round of clinical trials, which involved patients with als getting spinal tap procedures where a needle is placed directly into the cerebral spinal fluid once every two weeks, researchers discovered that there wasn’t much of a difference between the medication and placebo groups in terms of clinical signs.
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however, the build-up of proteins went down.
research continued, and during another round of testing, patients with sod1-als who got the drug early on in the disease showed a slower decline in their motor abilities than those who didn’t.
“what we have seen in this development program is that people who respond, not everyone responds, but people who respond to qalsody are not dying. their life expectancy has gone from two to five years to indefinite at this point,” said dr. genge.
the caveat is that patients who started the drug earlier in their disease progression had better outcomes. the level at which it is slowed depends on the patient, but as it stands, qalsody may have the potential to stop progression in some patients with als.
“i can’t give you an exact number because it’s still so fresh,” said dr. zinman. “but … it’s significantly slower, and it could be as much as you know, depending on the patient, 30, 40, 50 per cent, or even shut it down. so, that’s what’s really exciting about it.”
how qalsody has opened the door to future interventions
while the news of an effective, disease-modifying drug for als is welcomed in the als community, it doesn’t negate that only two per cent of those with the disease can potentially benefit from it. that said, this research and development can pave the way for treatments for those with other forms of als.
according to moore, it posits several questions about the future of als.
“it’s very exciting for that particular population of people to think that they may have an opportunity with that. but what it also then presents is, could that help us to understand the disease in other people prior to the symptom onsets? and if we get a better understanding of that disease, how can we apply it to other gene mutations?” said moore. “if we can better understand the disease, will we be able to be more effective at finding other targets for similar therapies?
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according to dr. zinman, the answer to those questions is yes, but only if they can figure out the exact mechanism of other forms of the disease.
“on one side of the coin, it’s extremely exciting because we have an intervention that can significantly slow disease progression. on the other side of the coin, it didn’t seem to work for the most common mutation because it doesn’t involve that protein,” he said. “it’s a different mechanism.”
while newer therapies for other forms of als are still being researched, as are the mechanisms that cause the disease, the latest discovery of qalsody and its interaction provides hope for other areas, including risk factors and diagnosis.
“this gives us another way to being able to look at people that have the gene mutation but don’t yet have als and what could cause that flip of that switch so that they end up having als,” said dr. genge.
dr. zinman also notes that the discovery of biomarkers is significant, stating, “we can use that biomarker to screen the most promising therapeutics and get to a more promising effective treatment faster.”
as of now, the breakthrough discovery of the biomarker and qalsody is simply a key to a locked door that als doctors and researchers have been knocking on for decades. while it doesn’t promise a cure or a viable treatment for everyone with als, it does provide hope.
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