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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.”
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<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

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.
[recommended-reading id=82361]
&#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.

FDA panel votes in favor of tofersen biomarker data

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: Tofersen

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

FDA panel votes in favor of tofersen biomarker data

FDA Seeks Input on Tofersen’s Approval for ALS