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Health Canada is now reviewing <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) as a potential treatment for people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who carry mutations in the SOD1 gene, according to the therapy&#8217;s developer <a href="https://www.biogen.com/">Biogen</a>.
The Canadian regulatory authority agreed to review Biogen&#8217;s application for the therapy&#8217;s approval, with its decision expected in early 2025, according to a <a href="https://www.newswire.ca/news-releases/health-canada-accepts-for-review-new-drug-submission-for-tofersen-for-treatment-of-rare-genetic-form-of-als-806869519.html">company press release</a>.
If approved, Qalsody will become the first and only therapy approved in Canada to target a genetic cause of ALS. Qalsody already is <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">approved in the U.S.</a> and has been <a href="https://alsnewstoday.com/news/committee-favors-eu-approval-qalsody-1st-treatment-sod1-als/">recommended for approval</a> in the European Union to treat ALS-SOD1 patients.
The application &#8220;represents a critical milestone for the Canadian ALS community and those suffering from this ultra-rare genetic form of the disease that robs them of time with loved ones,&#8221;said Eric Tse, vice president and general manager of Biogen Canada.
&#8220;For over a decade, Biogen has been committed to advancing ALS research to provide a deeper understanding of this devastating disease. We are passionate about doing what we can to make a difference and are deeply committed to the rare disease community,&#8221; Tse added.
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<h3>Request for approval based on data from VALOR trial</h3>
Mutations in the SOD1 gene are found in as many as 20% of people with <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> and in up to 2% of <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> cases. These mutations lead to the production of an abnormal SOD1 protein, which tends to accumulate and form toxic clumps inside nerve cells, causing damage.
Qalsody belongs to a class of therapies called antisense oligonucleotides, or ASOs. Such therapies prevent the production of disease-causing proteins by interfering with their messenger RNA (mRNA) — an intermediate molecule derived from DNA that&#8217;s used as a template for protein production.
The drug is designed to bind to SOD1&#8217;s mRNA and target it for degradation, preventing the cell&#8217;s protein-making machinery from reading this template to produce the protein. This causes a marked reduction in SOD1 levels, which is expected to slow disease progression and extend survival.
The treatment is administered via intrathecal injection, or an injection into the spinal canal. In the U.S., it&#8217;s given as three initial three doses 14 days apart, followed by maintenance doses every 28 days.
Qalsody&#8217;s submission to Health Canada was based on data from Part 3 of the <a href="https://clinicaltrials.gov/study/NCT02623699">VALOR trial (NCT02623699)</a>, which enrolled 108 adults with ALS and a confirmed SOD1 mutation. It aimed to assess the safety and efficacy of Qalsody versus a placebo.
Participants were randomly assigned to receive eight intrathecal injections of either 100 mg of Qalsody or a placebo over six months.
The trial&#8217;s main goal was to assess changes in functional disability, as measured with the ALS Functional Rating Scale-Revised (ALSFRS-R), in a group of 60 patients with fast-progressing disease after about seven months.
That goal <a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">was not met</a>, but there were some indications that Qalsody slowed the decline in measures of lung function and muscle strength. Also, the treatment <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">significantly reduced</a> spinal fluid levels of SOD1 and blood levels of neurofilament light chain (NfL), a marker of nerve cell degeneration, both of which increased in the placebo group.
After completing the trial, 95 participants joined an <a href="https://clinicaltrials.gov/study/NCT03070119">open-label extension study (NCT03070119)</a>, in which all are receiving Qalsody for up to seven years. That study is expected to be concluded in June.
After one year, data from the Phase 3 study and its extension showed that patients who were always on Qalsody experienced a smaller drop in their ALSFRS-R scores relative to those who were initially assigned to the placebo and then switched to the treatment in the extension study. That decline averaged six points for those always treated versus 9.5 points for patients who switched from the placebo.
The early-start group also showed significant extensions in survival and in time to death or permanent ventilation.
A Phase 3 trial called <a href="https://clinicaltrials.gov/study/NCT04856982">ATLAS (NCT04856982)</a>, launched in 2021, is now testing whether Qalsody can delay the onset of disease symptoms in individuals with a SOD1 mutation who already show signs of neuronal damage —  specifically, who have elevated blood levels of NfL — but are asymptomatic.
The trial, slated to run through 2027, is expected to involve about 150 patients who receive the treatment or a placebo for up to two years. Top-line data also is anticipated in 2027.

Health Canada now reviewing Qalsody as treatment for SOD1-ALS

The recent conditional approval of <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) for adults with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who carry mutations in the SOD1 gene is a major cause for celebration, according to the <a href="https://www.mda.org/">Muscular Dystrophy Association</a> (MDA).
The therapy <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">earned accelerated approval</a> from the U.S. Food and Drug Administration (FDA) last week, making it the first to target a genetic cause of the disease to be approved.
The organization funded early research toward developing Qalsody for SOD1-associated ALS, which is estimated to affect about 330 people in the U.S. Its approval gives people with this rare form of the disease a new &#8220;treatment option,&#8221; according to the MDA.
“The approval of Qalsody is a turning point in therapy development for ALS as it represents the first therapy to target a genetic cause of the disease,” Sharon Hesterlee, PhD, chief research officer at MDA, said in a <a href="https://www.globenewswire.com/news-release/2023/04/25/2654417/0/en/Muscular-Dystrophy-Association-Celebrates-FDA-Approval-of-Biogen-s-Qalsody-for-Treatment-of-SOD1-ALS.html">press release from the organization</a>. &#8220;It’s gratifying to see a strategy that we and other organizations funded substantially in earlier stages maturing into a real solution for people living with this genetic form of ALS. It represents the fulfillment of the promise of effective genetic medicines for ALS patients and their families.&#8221;
Qalsody is expected to  be available to healthcare providers in the U.S. in the coming days, although its availability may vary as providers learn about it and adopt its use in their individual clinics, Biogen, the therapy&#8217;s developer, said in a <a href="https://investors.biogen.com/news-releases/news-release-details/fda-grants-accelerated-approval-qalsodytm-tofersen-sod1-als">press release announcing</a> the approval.
The company has launched a patient support services program, which can be accessed on the <a href="https://www.qalsody.com/">therapy&#8217;s website</a>. The program supports patients as part of their treatment, providing financial and insurance assistance, as well as education about the therapy.
“Since SOD1 mutations were first identified as a cause of ALS 30 years ago, the familial ALS community has been searching for genetically targeted treatments. Qalsody offers families who have lost generation after generation in the prime of their life to this devastating disease a therapy targeting the underlying cause of SOD1-ALS,&#8221; said Jean Swidler, chair of Genetic ALS &amp; FTD: End the Legacy.
Mutations in the SOD1 gene lead to the production of a toxic form of the SOD1 protein that forms clumps and causes nerve cell damage.
Qalsody is designed to lower SOD1 levels by targeting SOD1&#8216;s messenger RNA (mRNA) — an intermediate molecule needed for protein production — and marking it for degradation. Reducing the protein&#8217;s production should slow disease progression.
The therapy is approved at a dose of 100 mg via intrathecal injection — into the spinal canal — once a month following two initial loading doses.
[recommended-reading id=73945]
<h3>What led to Qalsody&#8217;s approval?</h3>
About eight months ago, the FDA <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">agreed to review</a> Qalsody under its accelerated approval pathway, which lets it give conditional approval to a treatment based on early clinical trial data that indicates it&#8217;s safe and likely efficacious.
The FDA&#8217;s decision was based largely on biomarker data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">Phase 1/2/3 VALOR clinical trial (NCT02623699)</a> and its ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a> that showed significant <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">reductions in blood levels of neurofilament light chain</a> (NfL), a biomarker of nerve cell damage.
The Phase 3 data indicated Qalsody <a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">failed to slow functional declines</a> for patients, however, but additional data spanning the trial and the extension phase showed <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">slower disease progression</a> for those who&#8217;d been using it longer. Moreover, early reductions in blood NfL levels were predictive of <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/#:~:text=predicted%20slower%20reductions%20in%20ALSFRS%2DR%20scores">slower functional declines</a>.
An FDA advisory committee last month <a href="https://alsnewstoday.com/news/panel-favors-tofersen-biomarker-data-mixed-on-efficacy-sod1-als/">unanimously agreed</a> these NfL level reductions were likely able to predict the treatment&#8217;s clinical efficacy, which may have supported the FDA&#8217;s ultimate approval.
Qalsody is now the first ALS therapy to be approved based on biomarker data.
“We’re excited to celebrate this milestone which brings the very first targeted treatment option to the SOD1-ALS community. This approval shows the FDA acting flexibly and progressively by using the accelerated approval pathway, innovative trial designs, and listening to the patient community to determine this treatment is safe and effective,&#8221; said Paul Melmeyer, vice president of public policy and advocacy at the MDA.
<h3>Continued Qalsody approval hinges on additional data</h3>
Qalsody&#8217;s continued approval may be contingent on additional data that supports its efficacy. Data from the ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">Phase 3 ATLAS (NCT04856982)</a> trial are expected to fulfill that requirement.
ATLAS is <a href="https://clinicaltrials.gov/ct2/show/NCT04856982#contacts">recruiting</a> about 150 adults with SOD1 mutations associated with rapidly progressing ALS. Eligible participants will not yet have symptoms, but will show signs of nerve cell damage, reflected by high NfL levels.
Participants will be randomly assigned to receive either Qalsody (100 mg) or a placebo at the approved dosing schedule for up to two years, with the main goal being to determine whether the treatment can prevent symptoms from emerging.
Top-line data are expected in 2026. More confirmatory trials may be needed if the findings aren&#8217;t positive.
While Qalsody&#8217;s approval covers adults with SOD1-ALS, Sunny Brous, founder of SunnyStrong and an ALS patient, said the approval benefits all ALS patients.
“Any win for a subgroup of ALS is a win for the entire community,&#8221; Brous said. &#8220;We are all thankful for steps towards a cure.”

Qalsody’s conditional OK for genetic cause of ALS hailed as new ‘option’

Changes in neurofilament light chain (NfL) levels — a biomarker of nerve cell damage — were deemed by an advisory committee reasonably likely to predict clinical efficacy from <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">tofersen</a> in people with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by SOD1 gene mutations.
The unanimous vote from the Peripheral and Central Nervous System Drugs Advisory Committee, part of the U.S. Food and Drug Administration (FDA), indicates that NfL levels alone may be considered as a good surrogate marker of the experimental therapy&#8217;s effectiveness.
However, the committee narrowly voted &#8220;no&#8221; when asked if currently available data gives substantial evidence that tofersen is effective in SOD1-ALS patients.
The FDA will consider these recommendations from the committee&#8217;s March 22 meeting in its <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">ongoing review of tofersen</a>, with a decision <a href="https://alsnewstoday.com/news/decision-delayed-proposed-als-therapy-tofersen-until-april-2023/">expected by April 25</a>. The agency usually aligns with the decisions of its expert committees, but is not obligated to do so.
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&#8220;We thank the FDA for convening this important discussion,&#8221; Priya Singhal, MD, executive vice president and head of development, and interim head of research and global safety and regulatory sciences at <a href="https://www.biogen.com/">Biogen</a>, said in a <a href="https://investors.biogen.com/news-releases/news-release-details/biogen-provides-update-fda-advisory-committee-meeting-tofersen">press release</a>.
Biogen is developing tofersen after licensing the therapy from prior developer Ionis Pharmaceuticals.
&#8220;We are encouraged by the outcome of today&#8217;s advisory committee meeting,&#8221; C. Frank Bennett, PhD, executive vice president and chief scientific officer at <a href="https://www.ionispharma.com/">Ionis</a>, said in a <a href="https://www.prnewswire.com/news-releases/ionis-accounces-fda-advisory-committee-voted-unanimously-for-a-potential-accelerated-approval-of-tofersen-for-sod1-als-301779437.html">press release</a> from the company. &#8220;If approved, tofersen would be the first medicine targeting a known cause of familial ALS.&#8221;
Mutations in the <a href="https://alsnewstoday.com/als-and-genetics/">SOD1 gene</a> are found in up to 20% of people with <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a>, and up to 2% of <a href="https://alsnewstoday.com/forms-of-als/sporadic-als/">sporadic ALS</a> cases. These mutations lead to the production of an abnormal version of the SOD1 protein that forms clumps in nerve cells, which are thought to be toxic and drive disease progression.
Tofersen is an RNA-based therapy designed to disrupt the production of the SOD1 protein, thereby reducing the formation of these toxic protein clumps. It&#8217;s administered via an injection into the spinal canal, called an intrathecal injection.
<h3>VALOR clinical trial</h3>
Biogen&#8217;s <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">application for accelerated approval</a> of tofersen is supported by data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">Phase 1/2/3 clinical trial VALOR (NCT02623699)</a>. The Phase 1 and 2 portions of the study provided <a href="https://alsnewstoday.com/news/tofersen-safe-appears-to-slow-disease-progression-in-sod1-als-patients-phase-1-2-trial-shows/">proof-of-concept</a> that tofersen could lower SOD1 protein levels as designed, and also indicated the treatment was generally well tolerated.
In the Phase 3 part of VALOR, 108 adults with ALS were assigned randomly to receive eight injections of tofersen (100 mg) or a placebo over the course of 28 weeks, or about six months. The study&#8217;s main goal was to assess the impact of treatment on disease progression, as measured by the ALS Functional Rating Scale Revised (ALSFRS-R).
<a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">Top-line results</a> from VALOR showed it failed to meet that goal; changes in ALSFRS-R scores were not significantly different between patients given tofersen or a placebo.
However, newer data from an <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a>, in which 95 patients from VALOR are being treated with tofersen for up to seven years, indicated that <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">disease progression was slower</a> among patients given tofersen in the initial study, compared with those who got placebo for six months in the original trial.
Data from VALOR and its extension study also indicated that treatment with tofersen markedly reduced levels of NfL, a structural protein in nerve fibers. When nerve cells are injured or die, NfL gets released into bodily fluids, so it often is used as a marker of nerve damage.
Analyses from VALOR suggested that tofersen-treated patients with a sharper NfL reduction in the first months after initiating treatment tended to experience <a href="https://alsnewstoday.com/news/tofersen-clinical-benefits-linked-nfl-levels-trial-data/">slower disease progression</a>.
In its meeting, the FDA voted unanimously &#8220;yes&#8221; in answer to the question, &#8220;Is the available evidence sufficient to conclude that a reduction in plasma neurofilament light chain (NfL) concentration in tofersen-treated patients is reasonably likely to predict clinical benefit of tofersen for treatment of patients with SOD1-ALS?&#8221;
<h3> Seeking accelerated approval</h3>
Biogen is seeking approval of tofersen under the FDA&#8217;s accelerated approval pathway, which allows the agency to give conditional marketing authorization for therapies where early biomarker data suggest a likely benefit. Developers of therapies given accelerated approval are mandated to conduct additional testing to confirm a clinical benefit.
According to Biogen and Ionis, the unanimous vote from the committee likely favors accelerated approval.
&#8220;After hearing the moving experiences of the ALS community and reviewing the totality of data, the Committee voted that reductions of neurofilament are reasonably likely to predict clinical benefit of tofersen,&#8221; Singhal said. &#8220;If approved, tofersen would potentially represent a major advance for people living with SOD1-ALS.&#8221;
Considering NfL as a good surrogate biomarker of efficacy may have implications beyond ALS, as NfL is a common marker of nerve damage and is elevated in numerous neurological disorders. However, it still remains to be seen whether the FDA itself will deem the NfL data sufficient to support an accelerated approval.
<h3>The second question</h3>
The committee was mixed, however, in its vote on the question, &#8220;Does the clinical data from the placebo-controlled study and available long-term extension study results, with additional supporting results from the effects on relevant biomarkers (i.e., changes in plasma NfL concentration and/or reductions in SOD1), provide substantial evidence of the effectiveness of tofersen in the treatment of patients with SOD1-ALS?&#8221;
In answer, five committee members voted no, three voted yes, and one abstained. This represents a narrow vote against a traditional approval of tofersen at this time, according to the therapy&#8217;s developers.
Biogen is running a <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">Phase 3 trial, ATLAS (NCT04856982)</a>, to learn more about the efficacy of tofersen. The study is testing tofersen against placebo in people who have SOD1 mutations and elevated NfL levels, but have not yet developed any <a href="https://alsnewstoday.com/als-symptoms/">symptoms of ALS</a>. The study is <a href="https://clinicaltrials.gov/ct2/show/NCT04856982#contactlocation">recruiting participants</a> at locations worldwide.
&#8220;We are grateful to all the people with SOD1-ALS who participated in our tofersen studies, and their caregivers, families, study investigators and the entire community, without whom this scientific progress could not have been made,&#8221; Singhal said.

Tag: SOD1-ALS

Health Canada now reviewing Qalsody as treatment for SOD1-ALS

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