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The U.S. Food and Drug Administration (FDA) has granted conditional approval to Biogen&#8217;s <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">tofersen</a>, now named Qalsody, for the treatment of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) associated with mutations in the SOD1 gene.
The decision, which marks the first conditional approval for ALS in the country, comes about eight months after the regulatory agency <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">accepted the application for review</a> under its accelerated approval pathway. That pathway allows the FDA to give conditional marketing authorization to medications based on early clinical trial data suggesting a likely benefit.
Qalsody&#8217;s clearance had been based on biomarker data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">Phase 1/2/3 VALOR clinical trial (NCT02623699)</a> and its <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a>. That data showed that the therapy led to <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">marked reductions</a> in blood levels of neurofilament light chain (NfL), a marker of nerve cell damage.
&#8220;The findings are reasonably likely to predict a clinical benefit in patients,&#8221; the FDA stated in a <a href="https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene">press release</a> announcing the approval, adding, &#8220;The observed reduction in NfL was consistent across all subgroups based on sex, disease duration since symptom onset, site of onset, and use of other medications for ALS treatment.&#8221;
&#8220;For more than a decade, Biogen has been steadfast in our commitment to pursuing treatments for ALS, and I want to thank the scientists as well as the entire ALS community who have all worked tirelessly to bring this first-of-its-kind treatment to people with SOD1-ALS,&#8221; said Christopher A. Viehbacher, president and CEO of Biogen, in an email to ALS News Today. &#8220;Today also marks a pivotal moment in ALS research as we gained, for the first time, consensus that neurofilament can be used as a surrogate marker reasonably likely to predict clinical benefit in SOD1-ALS. We believe this important scientific advancement will further accelerate innovative drug development for ALS.”
[recommended-reading id=80852]
<h3>Regulators in Europe now considering Qalsody application for EU</h3>
The members of the FDA&#8217;s Peripheral and Central Nervous System Drugs Advisory Committee last month <a href="https://alsnewstoday.com/news/panel-favors-tofersen-biomarker-data-mixed-on-efficacy-sod1-als/">were mixed</a> in their views on whether the available data provided substantial evidence that Qalsody is effective in people with SOD1-ALS.
However, the experts unanimously considered NfL levels a good surrogate marker of the drug&#8217;s effectiveness — which likely supported the early approval.
According to the FDA announcement, the therapy is now approved at a recommended dose of 100 mg. It&#8217;s given via an injection into the spinal canal, called an intrathecal injection, containing 15 mL of the solution. The first three doses are given two weeks apart, and maintenance doses are then administered monthly.
No information is yet available on Qalsody&#8217;s list price, or how soon it will be available.
A similar application for the medication&#8217;s approval is being reviewed by the European Medicines Agency.
Meanwhile, the treatment is available in 34 countries via early access programs, Biogen has said.
<a href="https://alsnewstoday.com/als-and-genetics/">Mutations in the SOD1 gene</a> 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. Such mutations result in a toxic form of the SOD1 protein that accumulates and forms clumps that damage nerve cells.
Administered via an intrathecal injection, Qalsody is designed to lower SOD1 levels and preserve nerve cell function. It does that by targeting SOD1’s messenger RNA (mRNA) — an intermediate molecule derived from DNA that guides protein production — for degradation.
By reducing the amount of SOD1 protein that is produced in cells, the therapy has the potential to slow disease progression and extend survival.
Qalsody&#8217;s approval in the U.S. was based on data from a <a href="https://clinicaltrials.gov/ct2/show/NCT03764488?term=BIIB067&amp;draw=2&amp;rank=1">Phase 1 trial (NCT03764488)</a> in healthy volunteers, as well as on the findings from the VALOR trial and its open-label extension study in ALS patients.
The Phase 1/2 part of VALOR found that Qalsody, given in single and multiple ascending doses, <a href="https://alsnewstoday.com/news/tofersen-safe-appears-to-slow-disease-progression-in-sod1-als-patients-phase-1-2-trial-shows/">was generally well tolerated</a> and able to lower SOD1 and NfL levels in the cerebrospinal fluid, the liquid surrounding the brain and spinal cord.
Exploratory analyses also suggested the treatment could slow ALS progression, with patients given the now approved 100 mg dose experiencing slower declines in functional ability, lung function, and muscle strength over 12 weeks compared with those on a placebo. The benefits were particularly evident in patients with rapidly progressing disease.
[recommended-reading id=80302]
<h3>Additional studies of Qalsody already underway</h3>
VALOR&#8217;s Phase 3 portion was designed to confirm the drug&#8217;s benefits in a larger group of patients. It enrolled 108 participants who were randomly assigned to receive eight intrathecal injections of either 100 mg of Qalsody or a placebo over six months.
The main goal was to assess changes in functional disability — as measured with the ALS Functional Rating Scale Revised (ALSFRS-R) — among the 60 participants with rapidly progressing ALS after 28 weeks, or about seven months.
While <a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">that goal was not met</a>, researchers saw some trends toward slower lung function and muscle strength decline. Also, patients given Qalsody experienced marked drops in their SOD1 and NfL CSF levels.
After completing VALOR&#8217;s Phase 3 part, a total of 95 participants opted to join an open-label extension study, in which all are receiving Qalsody for up to seven years. That study is expected to conclude in June 2024.
One-year data spanning the Phase 3 trial and the extension study showed the treatment resulted in a significant and clinically meaningful slowing of ALS progression.
Compared with patients who were initially assigned a placebo and then switched to Qalsody in the extension study, those who were always on Qalsody for one year experienced a smaller decline in their ALSFRS-R scores — 6 vs. 9.5.
Significant differences between these groups also were observed for measures of lung function and muscle strength. The early-start group also experienced significant extensions in survival and in time to death or permanent ventilation.
Additional analyses demonstrated that reductions in blood NfL levels within the first four months of treatment <a href="https://alsnewstoday.com/news/tofersen-clinical-benefits-linked-nfl-levels-trial-data/">predicted slower reductions in ALSFRS-R scores</a> up to 6.5 months. Such early drops also were linked to slower declines in other measures of function and disease severity.
The findings led the FDA&#8217;s advisory committee to unanimously consider blood NfL levels as a good surrogate measure of Qalsody&#8217;s efficacy in ALS patients, which likely contributed to the FDA deeming the available biomarker data enough to support its accelerated approval.
An ongoing Phase 3 trial, called <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">ATLAS (NCT04856982)</a>, is now evaluating Qalsody&#8217;s clinical benefit in people with SOD1 mutations associated with rapidly progressing ALS. These participants have not yet experienced symptoms but show signs of neuronal damage as defined by elevated NfL levels.
A total of 150 adults are expected to enroll at <a href="https://clinicaltrials.gov/ct2/show/NCT04856982#contactlocation">nearly 30 sites worldwide</a>. They will be randomly assigned to receive either Qalsody (100 mg) or a placebo at the approved schedule — three intrathecal injections over the first month followed by monthly injections thereafter — for up to two years.
The main goal is to determine if the treatment can prevent patients from developing ALS symptoms. Top-line data are expected in 2026.

FDA approves tofersen, now Qalsody, as treatment for SOD1-ALS

The U.S. Food and Drug Administration (FDA) has announced an advisory committee meeting seeking advice on whether to approve <a href="https://www.biogen.com/">Biogen</a>&#8216;s investigational therapy <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">tofersen</a> for the treatment of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by SOD1 gene mutations.
The public meeting, to be <a href="https://www.federalregister.gov/documents/2023/01/24/2023-01216/peripheral-and-central-nervous-system-drugs-advisory-committee-notice-of-meeting-establishment-of-a">held online March 22</a>, by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, will determine whether tofersen can be approved based on the strength of biomarker data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">VALOR Phase 1/2/3 trial (NCT02623699)</a>.
The FDA <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">began reviewing the treatment</a> in June under its accelerated approval pathway, which allows a therapy to receive conditional approval based on early clinical data suggesting it likely is effective.
A decision initially was expected by Jan. 25, but the submission of additional data requested by the agency was <a href="https://alsnewstoday.com/news/decision-delayed-proposed-als-therapy-tofersen-until-april-2023/">deemed a major amendment to the application</a>, extending the review time by three months. The FDA’s new decision date now is April 25.
[recommended-reading id=80279]
<a href="https://alsnewstoday.com/als-and-genetics/">SOD1 gene mutations</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. Such mutations produce a toxic form of the SOD1 enzyme that builds up to harmful levels and is prone to forming clumps in nerve cells, disrupting their function.
Tofersen, administered by intrathecal injection (into the spinal canal), is an RNA-based therapy designed to reduce toxic SOD1 protein and preserve cell function. It does so by binding to SOD1 mRNA molecules, which are produced from the gene and used as a template for protein production, and targeting them for degradation.
The experimental therapy was investigated in the VALOR trial, which was conducted in three parts. Its Phase 1/2 portion found that tofersen, given in single and multiple ascending doses, is generally well-tolerated and able to lower SOD1 levels in the cerebrospinal fluid (CSF, the liquid that surrounds the brain and spinal cord).
The randomized Phase 3 part was designed to assess the safety and efficacy of tofersen in 108 patients, 60 of whom had rapidly progressing disease. Participants were assigned randomly to take tofersen or a placebo, given in eight intrathecal injections over six months.
<h3>Mixed results</h3>
This part <a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">failed to meet its primary goal</a> of showing that tofersen could significantly slow disease progression in fast-progressing ALS patients. However, the therapy did lead to a sustained decrease in toxic SOD1 protein and neurofilament light chain (NfL), a marker of nerve cell damage, compared with a placebo.
A total of 95 participants who completed VALOR&#8217;s Phase 3 portion chose to join an <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a>, where all receive tofersen for up to seven years.
Data spanning the placebo-controlled part and the open-label extension suggested that long-term treatment with tofersen <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">can slow ALS progression</a> in a significant and clinically meaningful manner.
After one year, patients who started on tofersen in the Phase 3 part experienced a six-point decline in their ALS Functional Rating Scale-Revised (ALSFRS-R) scores, compared with a decline of 9.5 points among those who were first given a placebo and started on tofersen six months later. Significant differences in early starters versus late starters also were observed in measures of lung function and muscle strength.
<div class="code-block code-block-6">Additional analyses suggested that early declines in NfL after treatment may <a href="https://alsnewstoday.com/news/tofersen-clinical-benefits-linked-nfl-levels-trial-data/">predict a slower disease progression over time</a>.</div>
The FDA advisory committee meeting will determine whether tofersen’s approval can rest solely on changes in NfL biomarker levels as an indicator of disease progression. Presentations by Biogen and others will be viewed, captioned, and recorded via an online platform.
Tofersen also is <a href="https://alsnewstoday.com/news/tofersen-to-treat-sod1-als-under-review-for-european-union/">under review</a> in the European Union.
Meanwhile, Biogen continues to evaluate tofersen in the ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">Phase 3 ATLAS study (NCT04856982)</a> in up to 150 people with SOD1 mutations. Eligible participants are those who show elevated NfL levels, indicating nerve damage, but have not yet developed ALS symptoms.
The trial will measure how many participants will develop symptoms of ALS after one year of tofersen versus a placebo. Along with safety, the study will assess disease progression, NfL levels, lung function, and survival.

Tag: Biogen

FDA approves tofersen, now Qalsody, as treatment for SOD1-ALS

FDA Seeks Input on Tofersen’s Approval for ALS