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Tofersen

Tofersen, marketed as Qalsody, is an antisense oligonucleotide administered intrathecally for the treatment of amyotrophic lateral sclerosis (ALS) in adults harboring a mutation in the superoxide dismutase 1 (SOD1) gene, which accounts for approximately 2% of ALS cases.^[1]^[2] Developed collaboratively by Biogen and Ionis Pharmaceuticals, it targets SOD1 mRNA to reduce aberrant SOD1 protein production implicated in motor neuron degeneration.^[3]^[4] The U.S. Food and Drug Administration granted accelerated approval to tofersen on April 25, 2023, based on phase 3 trial data demonstrating significant reductions in cerebrospinal fluid SOD1 protein and plasma neurofilament light chain (NfL) levels—a biomarker of neuronal damage—compared to placebo, though direct clinical benefits on disease progression remain under confirmatory study.^[1]^[5]^[3] Administered via lumbar puncture every four weeks following loading doses, it represents the first therapy specifically addressing a genetic etiology of ALS, marking a precision medicine advance for this subset of patients.^[6]^[2] Early real-world and extension trial evidence suggests tofersen may stabilize function and further lower NfL in SOD1-ALS patients, but its long-term efficacy and safety profile, including risks like headache, procedural pain, and potential falls, require ongoing validation through required post-approval studies.^[7]^[8]^[2] As the only approved genetic-targeted ALS treatment, tofersen underscores the potential of RNA-based therapies yet highlights challenges in translating biomarker surrogates to unambiguous clinical outcomes in neurodegenerative diseases.^[4]^[9]

Pharmacology

Mechanism of action

Tofersen is a synthetic antisense oligonucleotide (ASO) composed of 18 nucleotides designed to hybridize with the messenger RNA (mRNA) transcribed from the superoxide dismutase 1 (SOD1) gene.^[3] Upon intrathecal administration, tofersen binds specifically to SOD1 mRNA via Watson-Crick base pairing, forming a DNA-RNA duplex that recruits RNase H1 enzyme.^[10] This enzymatic cleavage degrades the target mRNA, preventing its translation into SOD1 protein and thereby reducing both wild-type and mutant SOD1 protein levels in cerebrospinal fluid (CSF).^[2] The mechanism exploits the RNase H-dependent pathway, a hallmark of second-generation ASOs like tofersen, which incorporate phosphorothioate backbones and 2'-O-methoxyethyl modifications for enhanced stability, binding affinity, and resistance to nucleases.^[11] In SOD1-mutated amyotrophic lateral sclerosis (ALS), where mutant SOD1 protein aggregates contribute to motor neuron degeneration, this targeted mRNA knockdown lowers toxic protein accumulation without altering the underlying genetic mutation.^[12] Preclinical studies in transgenic SOD1 mouse models demonstrated up to 80% reduction in SOD1 mRNA and protein in spinal cord tissue following repeated dosing.^[11] Clinical trials confirmed the mechanism's pharmacodynamic effect, with SOD1 protein concentrations in CSF decreasing dose-dependently—up to 37% at the highest dose (100 mg) after six loading doses—correlating with reduced neurofilament light chain (NfL) levels as a biomarker of neurodegeneration.^[3] Unlike small-molecule inhibitors, tofersen's nucleic acid-based approach provides allele-nonspecific suppression, effective against the over 200 known SOD1 mutations linked to familial ALS, though it does not distinguish between mutant and wild-type transcripts.^[13] This reduction in SOD1 expression is posited to mitigate downstream oxidative stress and proteotoxic pathways, though direct causal links to clinical benefits remain under investigation.^[14]

Pharmacokinetics and administration

Tofersen is administered intrathecally by direct injection into the cerebrospinal fluid (CSF) via lumbar puncture, a procedure performed by healthcare professionals experienced in spinal injections.^[15] The recommended regimen consists of an initial loading phase with three 100 mg (15 mL) doses given at 14-day intervals, followed by maintenance dosing of 100 mg every 28 days.^[15] Prior to injection, 10 mL of CSF is withdrawn, and the drug is delivered as a bolus over 1 to 3 minutes without dilution; vials should be warmed to room temperature, inspected for particulate matter or discoloration, and used within 4 hours of opening, with any unused portion discarded.^[15] Pharmacokinetically, intrathecal administration enables tofersen distribution from the CSF throughout central nervous system (CNS) tissues, with maximum CSF trough concentrations achieved by the third loading dose and median plasma T_max of 2 to 6 hours post-dose; no accumulation occurs with monthly maintenance dosing after loading.^[15] Distribution extends to CNS tissues, as evidenced by autopsy findings in treated patients.^[15] Metabolism occurs via 3'- and 5'-exonuclease-mediated hydrolysis into shorter oligonucleotides and nucleotides, with no involvement as a substrate, inhibitor, or inducer of cytochrome P450 enzymes.^[15] The effective half-life in CSF is approximately 4 weeks, though the primary elimination route remains uncharacterized; no clinical pharmacokinetic studies have evaluated impacts from renal or hepatic impairment, and tofersen is not expected to require dose adjustments based on sex, race, age, or body weight.^[15]^[2]

Indications and medical use

Targeted patient population

Tofersen is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults with a confirmed mutation in the superoxide dismutase 1 (SOD1) gene.^[1]^[16] This targets a rare genetic subtype of ALS, SOD1-ALS, which accounts for approximately 2% of all ALS cases and typically follows an autosomal dominant inheritance pattern.^[17] Pathogenic SOD1 variants lead to toxic gain-of-function in the mutant superoxide dismutase 1 protein, contributing to motor neuron degeneration.^[2] Eligibility requires genetic confirmation of a SOD1 mutation via validated testing prior to treatment initiation, as the therapy's mechanism relies on antisense oligonucleotide binding to mutant SOD1 mRNA to reduce protein production.^[16]^[10] The U.S. Food and Drug Administration (FDA) approved tofersen under an accelerated pathway on April 25, 2023, for adults with symptomatic ALS and SOD1 mutations, relying on surrogate endpoints such as reductions in cerebrospinal fluid SOD1 protein and plasma neurofilament light chain levels rather than direct clinical improvement.^[1] In the United States, this population is estimated at around 330 individuals, reflecting the low prevalence of SOD1-ALS.^[17] While the approved indication focuses on adults with established ALS diagnosis, ongoing research, including the phase 3 ATLAS trial, evaluates tofersen in presymptomatic SOD1 mutation carriers to determine if early intervention can delay or prevent disease onset.^[5] No specific subgroups based on age within adulthood, mutation type, or disease stage beyond confirmed ALS are delineated in the labeling, though clinical data from trials included patients across varying disease durations.^[18]

Dosing and delivery method

Tofersen is administered intrathecally via lumbar puncture as a bolus injection over 1 to 3 minutes.^[19]^[20] Prior to injection, approximately 10 mL of cerebrospinal fluid (CSF) is removed to facilitate administration and reduce pressure.^[20] The procedure must be performed by healthcare professionals experienced in intrathecal injections, with patients monitored for at least 3 hours post-administration for potential adverse effects such as headache or back pain.^[19]^[2] The recommended dosage is 100 mg (15 mL) per administration for adults with SOD1-mutated amyotrophic lateral sclerosis (ALS).^[19]^[21] Treatment initiation involves three loading doses given at 14-day intervals to achieve therapeutic levels in the central nervous system.^[19]^[21] This is followed by maintenance doses administered once every 28 days.^[19]^[21] No dosage adjustments are specified based on body weight, age, or renal/hepatic impairment, though the drug is not recommended during pregnancy due to limited data.^[19] If a maintenance dose is missed, it should be administered as soon as possible, with the subsequent dose scheduled 28 days later; loading doses should not be repeated if interrupted.^[19]^[22] Tofersen is supplied as a preservative-free solution in single-dose vials, which must be used immediately after withdrawal from the vial and protected from light.^[19] Unused portions should be discarded, and the solution should not be diluted or mixed with other medications.^[19]

Clinical development

Preclinical and early-phase studies

Preclinical studies of tofersen, an antisense oligonucleotide designed to induce RNase H-mediated degradation of SOD1 mRNA, demonstrated dose-dependent reductions in SOD1 mRNA and protein levels in vitro and in vivo. In transgenic rodent models expressing mutant SOD1, such as SOD1^G93A mice and rats, intrathecal administration of next-generation SOD1-targeted ASOs, including prototypes leading to tofersen, reduced SOD1 protein concentrations in the central nervous system, prolonged median survival by over 50 days in rats (from approximately 130 days to more than 180 days), and improved motor performance as measured by grip strength and rotarod tests.^[23] These effects were attributed to decreased toxic SOD1 aggregate formation and neuroinflammation in spinal cord tissue. In nonhuman primates, similar ASOs lowered SOD1 protein levels in cerebrospinal fluid (CSF) without significant off-target effects.^[11] The phase 1/2 clinical trial (NCT02623699), conducted from 2015 to 2019 and involving 50 adults with ALS and confirmed SOD1 mutations, assessed safety, pharmacokinetics (PK), and pharmacodynamics (PD) through single- and multiple-ascending intrathecal doses. In the multiple-dose escalation cohort (n=28 tofersen, n=10 placebo), doses of 20 mg, 40 mg, 60 mg, and 100 mg administered every 4 weeks for three doses resulted in dose-dependent reductions in CSF SOD1 concentrations from baseline, with the 100 mg group showing a mean 36% decrease at day 85 versus 3% in placebo (difference: -33%, 95% CI -47 to -16).^[11] Peak plasma and CSF drug concentrations increased with dose, with limited systemic exposure and a half-life supporting monthly dosing.^[11] Tofersen was generally well-tolerated in the trial, with no dose-limiting toxicities observed. The most common adverse events were procedure-related, including headache (42% in tofersen vs. 30% placebo), post-lumbar puncture syndrome (34% vs. 20%), and procedural pain (42% vs. 20%); serious adverse events occurred in 21% of tofersen participants versus 10% placebo, primarily respiratory infections unrelated to the drug. Three deaths occurred (two in tofersen, one placebo), attributed to ALS progression rather than treatment. Transient elevations in CSF white blood cells (pleocytosis in 11% tofersen) and protein (13%) were noted but resolved without intervention.^[11] These findings supported advancement to phase 3, confirming target engagement while highlighting the need for monitoring injection-site reactions.^[24]

Phase 3 VALOR trial

The VALOR trial was a multicenter, double-blind, randomized, placebo-controlled phase 3 study evaluating the efficacy, safety, and tolerability of tofersen in adults with amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations.^[3] Conducted from March 2019 to July 2021, it randomized 108 symptomatic patients with confirmed SOD1 mutations in a 2:1 ratio to receive intrathecal tofersen (100 mg; n=72) or placebo (n=36), with treatment administered via lumbar puncture: loading doses at weeks 0 and 2, followed by doses every 4 weeks through week 24, and assessments up to week 28.^[3] ^[24] Inclusion required disease duration of less than 3 years from symptom onset and screening ALS Functional Rating Scale-Revised (ALSFRS-R) score of 36 or higher (out of 48, with higher scores indicating better function).^[3] A prespecified faster-progression subgroup (n=60; 39 tofersen, 21 placebo) was defined by baseline ALSFRS-R slope of -1.67 points or worse per month in the prior year.^[3] ^[25] The primary endpoint was the change in total ALSFRS-R score from baseline to week 28, analyzed using a joint rank test accounting for death in the modified intention-to-treat population.^[3] Tofersen did not meet this endpoint, with a least-squares mean change of -6.98 points in the tofersen group versus -8.14 in placebo (difference of 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P=0.97).^[3] ^[25] Key secondary clinical endpoints, including forced vital capacity (FVC) and hand-held dynamometry (HHD) for muscle strength, also showed no statistically significant differences, though numerical trends favored tofersen in the faster-progression subgroup (e.g., FVC difference of 7.9% predicted; HHD difference of 0.02).^[25] Tofersen demonstrated significant biomarker reductions: cerebrospinal fluid (CSF) SOD1 protein concentration decreased by a geometric mean ratio of 0.62 (95% CI, 0.49-0.78) relative to placebo, equating to a 38% reduction in the faster-progression subgroup; plasma neurofilament light chain (NfL) levels, a marker of neuroaxonal injury, fell by a ratio of 0.33 (95% CI, 0.25-0.45), or 67% in the faster-progression group.^[3] ^[25] These pharmacodynamic effects were consistent with prior phase 1/2 data and supported the drug's mechanism of reducing mutant SOD1 production.^[3] Safety data from VALOR indicated that adverse events were primarily procedure-related, including post-lumbar puncture headache (50.0% tofersen vs. 47.2% placebo) and back pain (29.2% vs. 25.0%).^[3] Serious neurologic adverse events occurred in 7% of tofersen recipients, such as myelitis or hydrocephalus, compared to none in placebo, though overall discontinuation rates were low (2.8% tofersen vs. 2.8% placebo).^[3] An open-label extension (OLE) enrolled 95 participants (88% of VALOR completers), allowing delayed-start placebo patients to receive tofersen.^[3] Integrated analyses at week 52 showed slower functional decline in early-start tofersen recipients (ALSFRS-R change of -6.0) versus delayed-start (-9.5; difference 3.5 points; 95% CI, 0.4-6.7), alongside sustained biomarker reductions and trends in respiratory and muscle strength measures favoring earlier treatment.^[3] ^[25] These OLE findings, despite limitations like lack of concurrent placebo control, informed regulatory considerations for SOD1-ALS.^[3] Topline results were announced on October 17, 2021, with full publication in the New England Journal of Medicine on September 21, 2022.^[25] ^[3]

Real-world and post-approval data

In the period following FDA accelerated approval on April 25, 2023, real-world data on tofersen have been limited to small-scale cohort studies and expanded access programs, reflecting its targeted use in rare SOD1-mutated ALS cases. A multicenter 12-month cohort from the German early access program, involving adults with confirmed SOD1-ALS treated with intrathecal tofersen (100 mg every 4 weeks after loading doses), demonstrated significant reductions in serum neurofilament light chain (NfL) levels (median relative change -42% at 6 months) and cerebrospinal fluid phosphorylated neurofilament heavy chain (pNfH) (median -35%), alongside stabilization or modest improvements in ALS Functional Rating Scale-Revised (ALSFRS-R) scores in some participants, with no evidence of persistent neurologic symptoms.^[26]^[27] Data from the ALS Network of German-speaking countries, analyzing real-world outcomes up to January 2025, reported sustained disease stabilization in SOD1-ALS patients on tofersen, with preservation of pulmonary function and muscle strength metrics over 12-18 months, and indications of functional recovery in a subset, though cohort sizes remained small (n<50) and lacked randomized controls.^[8]^[28] These findings align with biomarker trends but highlight variability due to heterogeneous baseline disease stages and mutation types. Additional post-approval observations from expanded access (initiated July 2021, continuing post-approval) and interim reports noted consistent NfL declines (up to 60% in responsive patients) but elevated neuroinflammatory markers in cerebrospinal fluid, suggesting potential immune activation without clear clinical correlation to progression.^[29] No large-scale post-marketing surveillance data have been published as of October 2025, with ongoing confirmatory trials (e.g., VALOR open-label extension) required for full approval; early real-world evidence supports biomarker surrogates but awaits validation against long-term survival endpoints.^[30]^[31]

Efficacy evidence

Biomarker reductions

In the phase 3 VALOR trial, tofersen treatment resulted in a 29% reduction from baseline in cerebrospinal fluid (CSF) superoxide dismutase 1 (SOD1) protein concentrations at week 28 (geometric mean ratio to baseline: 0.71; 95% CI, 0.62–0.83), compared to a 16% increase in the placebo group (geometric mean ratio: 1.16; 95% CI, 0.96–1.40), yielding a between-group geometric mean ratio of 0.62 (95% CI, 0.49–0.78).^[3] In the prespecified faster-progressing subgroup (defined by baseline ALSFRS-R total score decline ≥2 points over the prior year), the reduction was more pronounced at 40% versus 19% with placebo (geometric mean ratio: 0.74; 95% CI, 0.63–0.88).^[3] These changes reflect target engagement, as SOD1 protein serves as a direct pharmacodynamic biomarker for antisense oligonucleotide inhibition of SOD1 mRNA expression.^[3] Plasma neurofilament light chain (NfL), a biomarker of neuroaxonal injury and neurodegeneration, also declined substantially with tofersen. At week 28 in VALOR, plasma NfL levels decreased by 60% from baseline in the tofersen group (geometric mean ratio: 0.40), versus a 20% increase with placebo (geometric mean ratio: 1.20), for a between-group geometric mean ratio of 0.33 (95% CI, 0.25–0.45).^[3] Reductions in plasma NfL were evident as early as weeks 12–16 (approximately 50% from baseline) and persisted through the open-label extension phase.^[3]^[25] Real-world evidence corroborates these findings, with serum NfL reductions observed in SOD1-ALS patients treated outside clinical trials, including a robust decrease maintained over follow-up periods of up to 12 months in small cohorts.^[32]^[26] Such biomarker effects supported the U.S. Food and Drug Administration's accelerated approval of tofersen in April 2023, designating plasma NfL as a surrogate endpoint reasonably likely to predict clinical benefit, pending verification in confirmatory trials.^[33]

Clinical and functional outcomes

In the phase 3 VALOR trial, tofersen failed to meet the primary efficacy endpoint of a significant difference in the change from baseline to week 28 in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score among patients in the faster-progression subgroup, with a least-squares mean decline of -6.98 points in the tofersen group versus -8.14 points in the placebo group (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P=0.97).^[3] Subgroup analyses by baseline neurofilament light chain levels showed no significant differences in clinical endpoints.^[3] Exploratory analyses at 52 weeks, comparing early-start (tofersen from baseline) to delayed-start cohorts (placebo followed by tofersen), indicated less functional decline with early treatment, with ALSFRS-R changes of -6.0 points versus -9.5 points (difference, 3.5 points; 95% CI, 0.4 to 6.7).^[3] Secondary functional endpoints supported potential benefits of earlier initiation, including a between-group difference of 9.2 percentage points in percent predicted slow vital capacity (95% CI, 1.7 to 16.6) and 0.28 in handheld dynamometry total score (95% CI, 0.05 to 0.52), both favoring tofersen.^[3] These findings suggest a possible delay in progression with prompt treatment, though confirmatory data from ongoing extensions remain pending. Post-approval real-world evidence has shown functional stabilization in SOD1-ALS patients. In a 12-month multicenter cohort from the German early access program (n=30), the median ALSFRS-R total score declined from 38.0 (interquartile range [IQR], 32.0-42.0) to 35.0 (IQR, 29.0-42.0), yielding a median progression rate of 0.92 points per month—slower than rates observed in historical SOD1-ALS cohorts without targeted therapy.^[26] A separate real-world analysis (mean treatment duration 18.4 months) reported a mean ALSFRS-R change of +1.1 points (standard deviation [SD], 0.7), reflecting stabilization or slight gain alongside an estimated 52% reduction in expected progression rate; muscle strength improved in most patients (mean handheld dynamometry change +11.2%), and mobility metrics advanced in over two-thirds.^[34] These outcomes align with biomarker reductions but require larger, controlled studies to establish causality amid variable natural disease trajectories in SOD1-ALS.^[30]

Safety and adverse effects

Common side effects

In clinical trials, including the phase 3 VALOR study and its open-label extension, the most frequently reported adverse reactions to tofersen were pain (including back pain, procedural pain, and pain in extremities), fatigue, arthralgia, myalgia, and increased cerebrospinal fluid white blood cell count.^[1]^[3] These events occurred at higher rates in tofersen-treated patients compared to placebo, though many were attributed to the intrathecal administration procedure via lumbar puncture, which is required for delivery.^[3]^[35] Adverse reactions were predominantly mild to moderate in severity, with lumbar puncture-related events such as headache, back pain, and procedural pain being common across both treatment arms but more pronounced in those receiving active drug.^[3] In the VALOR trial, headache, falls, and extremity pain were also noted among the top events in tofersen recipients during the 12-month period encompassing the trial and extension.^[35] Post-approval prescribing information from the FDA and EMA similarly highlights pain in various sites (back, arms, legs, muscles, or joints), tiredness, and elevated CSF leukocytes as affecting more than 10% of patients.^[1]^[36] Real-world data from early access programs align with trial findings, reporting similar profiles dominated by injection-site and musculoskeletal complaints without evidence of new common effects emerging.^[7] Monitoring for these effects is recommended, particularly given the drug's antisense oligonucleotide mechanism, which can influence local inflammation in the central nervous system.^[37]

Serious neurologic risks

In clinical trials of tofersen, including the phase 3 VALOR study, serious neurologic adverse events occurred in approximately 7% of recipients, compared to none in placebo groups.^[3] These events encompassed myelitis, radiculitis (including lumbar radiculopathy), aseptic or chemical meningitis, papilledema, and increased intracranial pressure, often attributed to the drug's intrathecal administration via lumbar puncture.^[38] ^[39] No such events were reported in sham-treated controls, highlighting a potential causal link to tofersen exposure rather than underlying ALS progression.^[40] Myelitis and radiculitis presented as inflammatory responses in the spinal cord or nerve roots, with symptoms including back pain, sensory disturbances, and motor weakness, typically emerging shortly after dosing.^[41] In the VALOR trial, myelitis affected about 2% of treated participants, resolving with corticosteroids in most cases without permanent sequelae.^[35] Aseptic meningitis, a known class effect of antisense oligonucleotides like nusinersen, manifested with headache, fever, and meningismus, but tofersen's profile included additional radicular involvement not commonly seen with comparators.^[40] Papilledema and elevated intracranial pressure, observed in 4 patients across trials (none in placebo), prompted monitoring with fundoscopy and, in some instances, acetazolamide treatment; importantly, no evidence of hydrocephalus was found on imaging, distinguishing these from unrelated pediatric syndromes.^[41] ^[39] These events did not lead to treatment discontinuation in reported cases, though real-world data from early access programs noted similar serious adverse events, including autoimmune myelitis and intracranial hypertension, underscoring the need for vigilant neurologic surveillance post-administration.^[26] Overall incidence remained low relative to procedure-related risks like post-lumbar puncture headache, but the events' specificity to active treatment warrants informed consent emphasizing potential inflammatory mechanisms tied to oligonucleotide delivery into cerebrospinal fluid.^[38]

Regulatory approvals

FDA accelerated approval pathway

The U.S. Food and Drug Administration (FDA) granted accelerated approval to tofersen (marketed as Qalsody) on April 25, 2023, for adults with amyotrophic lateral sclerosis (ALS) harboring a mutation in the SOD1 gene, representing the first therapy approved specifically targeting this genetic form of the disease.^[1]^[4] This pathway, established under the FDA's 1992 regulations for serious conditions with unmet needs, permits approval based on surrogate endpoints reasonably likely to predict clinical benefit, rather than definitive improvements in survival or function, provided post-approval confirmatory trials verify efficacy.^[18] Approval relied on reductions in plasma neurofilament light chain (NfL), a biomarker of axonal degeneration and neurodegeneration, observed in phase 1b open-label extension studies where tofersen-treated patients showed greater NfL declines (up to 60% from baseline) versus external controls or historical data.^[5]^[33] The FDA qualified plasma NfL as such a surrogate, citing its correlation with ALS progression rates in natural history studies, though acknowledging limitations in fully establishing it as predictive of long-term clinical outcomes without prospective validation.^[39]^[42] The new drug application (NDA), submitted by Biogen and accepted by the FDA on July 27, 2022, received priority review, with an initial Prescription Drug User Fee Act (PDUFA) target action date of January 25, 2023, later extended by three months to accommodate additional data review.^[43] On March 22, 2023, a peripheral and central nervous system drugs advisory committee unanimously endorsed tofersen's favorable risk-benefit profile (16-0 vote) and the suitability of NfL as a surrogate for accelerated approval in this rare, rapidly progressive subset of ALS patients (affecting ~2% of cases).^[44]^[45] As a condition of approval, Biogen must complete confirmatory studies, including the phase 3 VALOR trial (NCT02625508) and its open-label extension, to demonstrate clinical benefits such as slowed functional decline on the ALS Functional Rating Scale-Revised (ALSFRS-R) or prolonged survival; failure to confirm could prompt withdrawal.^[18]^[46] Tofersen's intrathecal administration (100 mg every 4 weeks after loading doses) targets SOD1 mRNA reduction in motor neurons, aligning with the pathway's emphasis on molecularly precise interventions for unmet needs despite incomplete phase 3 clinical endpoint data at approval.^[17]

EMA and international status

The European Medicines Agency (EMA) recommended conditional marketing authorization for Qalsody (tofersen) on February 23, 2024, for adults with amyotrophic lateral sclerosis (ALS) harboring a superoxide dismutase 1 (SOD1) gene mutation, based on reductions in neurofilament light chain levels as a surrogate biomarker under exceptional circumstances due to the rarity and severity of the condition.^[36] The European Commission granted this authorization on May 29, 2024, valid across the European Union, marking the first approved therapy targeting genetic ALS in the region and reflecting the EMA's recognition of unmet need despite limited confirmatory clinical data.^[47] Internationally, tofersen received accelerated approval from the U.S. Food and Drug Administration (FDA) on April 25, 2023, for SOD1-mutated ALS, relying on the same biomarker endpoint with requirements for post-approval verification of clinical benefit.^[1] In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) approved it on July 22, 2025, as the first treatment for SOD1-related motor neuron disease, administered via intrathecal injection.^[48] Health Canada issued conditional marketing authorization on March 3, 2025, aligning with similar pathways emphasizing surrogate outcomes in this orphan indication.^[49] Biogen has indicated ongoing submissions to additional regulatory authorities outside these jurisdictions, though no further approvals were reported as of late 2025.^[50]

Controversies and criticisms

Approval despite unmet clinical endpoints

The phase 3 VALOR trial of tofersen, which enrolled 137 participants with SOD1-mutated ALS, failed to meet its primary endpoint of a significant difference in the change from baseline to week 28 in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), a validated measure of disease progression including motor function, breathing, and communication.^[3] In the faster-progressing subgroup (defined by baseline ALSFRS-R slope ≤ -1.67 points per month), the least-squares mean difference was -0.12 points favoring tofersen (95% CI, -2.14 to 1.89; P=0.90), indicating no statistically significant slowing of functional decline.^[3] Secondary endpoints, such as forced vital capacity and ALSFRS-R scores in the overall population, also showed no significant benefits at the primary analysis time point.^[25] Despite these results, the U.S. Food and Drug Administration (FDA) approved tofersen (Qalsody) on April 25, 2023, under the accelerated approval pathway, relying on reductions in plasma neurofilament light chain (NfL) levels as a surrogate biomarker of neurodegeneration rather than direct clinical outcomes.^[1] Tofersen-treated patients exhibited a mean NfL decrease of 55% from baseline to week 28 in the faster-progressing subgroup, compared to a 7% increase in the placebo group, with the FDA deeming this surrogate "reasonably likely" to predict clinical benefit based on mechanistic rationale and supportive data from open-label extensions showing trends toward slower progression.^[9]^[3] This marked the first ALS approval using NfL as a surrogate, following precedent with other antisense oligonucleotides approved on biomarkers despite limited clinical evidence.^[51] Prior to approval, an FDA advisory committee voted 6-0 against tofersen's effectiveness for ALS in a March 22, 2023, meeting, citing insufficient evidence that NfL reductions translated to meaningful clinical improvements, particularly given the unmet endpoints and small SOD1-ALS population (about 2% of ALS cases).^[52]^[39] The FDA overrode this vote, invoking accelerated approval for unmet needs in rare, fatal diseases, but required Biogen to conduct confirmatory trials, such as the ongoing open-label extension of VALOR, to verify clinical benefit or face withdrawal.^[1] Critics, including some neurologists, have questioned the surrogate's predictive validity, noting that prior ALS trials with biomarker signals failed to show durable functional gains, potentially risking false hope and resource allocation without proven survival or quality-of-life extensions.^[51]

Scientific and ethical debates

The scientific debate surrounding tofersen primarily revolves around the reliability of neurofilament light chain (NfL) reductions as a surrogate endpoint for clinical efficacy in superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS). In the phase 3 VALOR trial, tofersen significantly lowered cerebrospinal fluid SOD1 protein levels and plasma NfL concentrations compared to placebo over 28 weeks, yet it failed to demonstrate a statistically significant improvement in the primary endpoint of disease progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R).^[3] Proponents argue that NfL, a marker of neuroaxonal damage correlating with ALS progression rates, provides mechanistic evidence of target engagement and potential disease modification, justifying accelerated approval in a rare, fatal condition affecting only about 2% of ALS cases.^[9] Critics, including some FDA advisory committee members who voted 6-4 against overall effectiveness, contend that surrogate biomarkers have not been validated to predict functional outcomes in SOD1-ALS, raising risks of approving therapies with unproven patient benefits, as evidenced by the absence of ALSFRS-R differences even in faster-progressing subgroups.^[52] Emerging real-world data from small cohorts show variable slowing of progression, but lack randomized controls to resolve whether biomarker changes translate to meaningful survival or quality-of-life gains.^[26] Ethically, tofersen's development highlighted tensions between rapid access for terminally ill patients and the need for rigorous evidence generation. Biogen initially denied compassionate use of tofersen outside clinical trials to preserve phase 3 blinding and data integrity, drawing criticism for withholding a potentially beneficial therapy from SOD1-ALS patients amid ALS's median survival of 2-5 years, which prompted advocacy for "Right to Try" expansions and patient-centric trial designs.^[53] This stance was defended as necessary to avoid unblinding risks that could invalidate results and delay broader approval, but it fueled debates on equity, as placebo-assigned participants faced ethical dilemmas in forgoing treatment during unblinding delays.^[54] Post-approval, ethical scrutiny persists regarding informed consent, given the drug's reliance on invasive intrathecal administration and reports of serious neurologic events like papilledema (occurring in up to 4.8% of trial participants), balanced against uncertain long-term efficacy in a genetically defined subset where confirmatory trials remain ongoing.^[40] These issues underscore broader concerns in orphan drug development, where accelerated pathways may incentivize surrogate-based approvals but challenge physicians to weigh hope against evidence gaps in counseling patients.^[55]

Access barriers and overhyping risks

Tofersen's access is restricted to adults with amyotrophic lateral sclerosis (ALS) confirmed to harbor a superoxide dismutase 1 (SOD1) gene mutation, representing approximately 2% of all ALS cases, necessitating prior genetic testing for eligibility.^[56]^[2] This limitation excludes the vast majority of ALS patients without SOD1 mutations, creating an inherent barrier despite expanded access programs aimed at broadening availability to all SOD1-ALS variants.^[57] Administration requires monthly intrathecal injections via lumbar puncture, a procedure that demands specialized neurology or interventional radiology facilities equipped for central nervous system delivery, as tofersen does not cross the blood-brain barrier effectively.^[2]^[6] These injections involve an experienced multidisciplinary team to manage preparation, infusion over 1-3 minutes, and post-procedure monitoring for adverse effects such as headache or back pain, with operational challenges including limited site resources and procedural familiarity further hindering widespread adoption.^[58]^[59] The drug's pricing exacerbates access issues, with each 100 mg/15 mL vial costing $14,230, translating to an annual expense exceeding $100,000 given the loading regimen of three doses in the first month followed by monthly maintenance.^[60]^[61] High costs, combined with variable insurance coverage and procurement logistics, pose financial and logistical burdens, particularly in resource-constrained settings.^[62] Risks of overhyping stem from tofersen's accelerated FDA approval relying on surrogate endpoints like reductions in neurofilament light chain (NfL) and SOD1 protein levels—biomarkers of neurodegeneration—despite the phase 3 VALOR trial failing to meet its primary endpoint of significant improvement in ALS Functional Rating Scale-Revised (ALSFRS-R) scores at 28 weeks compared to placebo.^[9]^[63]^[64] This disconnect raises concerns that promotional emphasis on biomarker data may foster undue optimism about clinical benefits, such as halting disease progression, which remain unproven in definitive trials.^[65] FDA advisory committee members voted against affirming tofersen's effectiveness on clinical grounds, highlighting skepticism over extrapolating surrogate reductions to meaningful patient outcomes.^[52] Such hype could lead to unintended harms, including false hope among eligible patients facing rapid disease decline, diversion of resources from broader ALS research, and ethical dilemmas in prioritizing unverified therapies amid ALS's dismal prognosis.^[66] Critics argue that approvals based on incomplete evidence, while providing early access, risk amplifying commercial narratives over rigorous validation, potentially eroding trust if confirmatory trials—required under accelerated approval—fail to substantiate benefits.^[65]^[9]

Commercial and economic aspects

Pricing and cost-effectiveness

Tofersen, marketed as Qalsody by Biogen, has a wholesale acquisition cost (WAC) of $14,230 per 100 mg vial, administered via intrathecal injection.^[67]^[60] The recommended regimen includes three loading doses of 100 mg every 14 days, followed by maintenance doses of 100 mg every 28 days.^[68] This results in approximately 14 doses in the first year, yielding an estimated annual cost of under $200,000, with subsequent years requiring about 13 doses at roughly $185,000.^[60]^[69] Biogen offers copay assistance programs that reduce out-of-pocket expenses to less than $50 per month for the majority of eligible commercially insured patients in the United States.^[70] Cost-effectiveness evaluations have raised concerns due to the drug's high price relative to clinical benefits observed in SOD1-ALS patients, a subgroup comprising about 2% of ALS cases and fewer than 500 eligible patients annually in the US. A Nordic health technology assessment by joint bodies in Denmark, Finland, Iceland, Norway, and Sweden used a Markov model to compare tofersen plus standard of care (riluzole) against standard of care alone, estimating an incremental cost-effectiveness ratio (ICER) of 11.5–29.5 million Norwegian kroner (NOK) per quality-adjusted life year (QALY) gained (approximately $1–3 million USD/QALY, assuming 1 USD ≈ 10.5 NOK).^[71] This analysis projected incremental costs exceeding 10 million NOK per patient and QALY gains of 0.20–1.6, depending on assumptions like progression hazard ratios (0.61–0.69) and utility values derived from trial data; sensitivity analyses confirmed the high ICER even under optimistic scenarios, such as including backward disease transitions or alternative staging systems.^[71] The assessors concluded that tofersen is not cost-effective at current pricing, citing uncertainties in long-term survival benefits and limited real-world data.^[71] These findings align with broader critiques of ALS therapies' economics, where similar drugs like Relyvrio cost $158,000 annually despite modest efficacy, but tofersen's targeted mechanism in a rare genetic subset does not offset the expense in modeled outcomes.^[72] Independent analyses, such as Canada's interim reimbursement review, project even higher first-year costs (CAD $425,560) under confidential pricing, underscoring access barriers in public systems without substantial QALY improvements.^[73] Biogen's base-case modeling claims a lower ICER of about 4.5 million NOK/QALY, but this relies on manufacturer-submitted data with potentially optimistic assumptions on treatment persistence and effect sizes, which HTA bodies deemed overly favorable.^[71] Overall, while patient assistance mitigates individual burdens, systemic cost-effectiveness remains unfavorable based on available evidence.

Manufacturing and supply issues

Tofersen is produced as a synthetic 20-mer antisense oligonucleotide via a seven-step solid-phase synthesis process for the active substance at a single manufacturing site, followed by compounding, filtration, and aseptic filling for the finished 100 mg/15 mL intrathecal solution at another dedicated site.^[74] Quality controls encompass specifications for appearance, pH, concentration, identity, purity, endotoxins, bioburden, osmolality, and sterility, aligned with ICH guidelines; process validation through performance qualification batches from 13 active substance lots and four finished product lots confirms batch-to-batch consistency and control of impurities, including organic, inorganic, residual solvents, and degradation products monitored by LC-UV-MS, with no elemental impurities or nitrosamines detected.^[74] No major manufacturing challenges or production failures have been disclosed in regulatory filings or public records.^[74] Stability data support a 24-month retest period for the active substance at 5±3°C and a 30-month shelf life for the finished product at 2-8°C, with allowances for temporary excursions up to 14 days at ≤30°C or limited room-temperature exposure.^[74] Supply chain requirements mandate refrigeration at 2-8°C with light protection during transport and storage; thermal cycling studies verify that short-term temperature deviations do not compromise product quality.^[74] Isolated dispensing errors arose in the expanded access program due to internal warehouse labeling discrepancies, unrelated to product packaging or similarity with other drugs, and were resolved without necessitating modifications to distribution protocols.^[74] No supply shortages or capacity constraints for tofersen have been reported as of October 2025.^[75]

Development history

Discovery and partnerships

Tofersen, known during development as IONIS-SOD1_Rx and BIIB067, was discovered by Ionis Pharmaceuticals, Inc., leveraging their proprietary antisense oligonucleotide technology to target and reduce superoxide dismutase 1 (SOD1) protein production in patients with SOD1-mutated amyotrophic lateral sclerosis (ALS).^[5]^[4] Ionis and Biogen had established a collaborative framework for neurological disease therapies prior to advancing tofersen, with Biogen exercising its option on December 6, 2018, to secure a worldwide, exclusive, royalty-bearing license for its development and commercialization from Ionis.^[76] This agreement positioned Biogen to lead clinical trials, including the pivotal Phase 3 VALOR study, while Ionis received upfront payments, milestone-based compensation, and royalties on net sales.^[4]^[76] No additional partnerships beyond the Ionis-Biogen alliance have been reported for tofersen's core development, though the drug's progression relied on Ionis's foundational expertise in RNA-targeted therapies.^[4]

Key milestones and timeline

Development of tofersen originated from Ionis Pharmaceuticals' antisense oligonucleotide platform, building on NIH-funded discoveries linking SOD1 gene mutations to familial ALS as early as 1993.^[77] The phase 1-2 clinical trial (NCT02623699), evaluating safety, tolerability, and pharmacokinetics in patients with SOD1-ALS, began enrolling participants in January 2016 across sites in the United States, Europe, and Canada.^[11] Results from this trial, published in 2020, demonstrated dose-dependent reductions in SOD1 protein levels in cerebrospinal fluid by up to 37% at the highest dose.^[11] In 2018, Biogen entered a collaborative development and license agreement with Ionis to advance tofersen, assuming primary responsibility for global development and commercialization.^[5] The phase 3 VALOR trial (NCT03070119) initiated dosing of the first patient in March 2019, randomizing 137 SOD1-ALS patients to receive intrathecal tofersen or placebo over 24 weeks, followed by an open-label extension.^[78] Topline results from VALOR, announced on October 17, 2021, showed no statistically significant difference in the primary endpoint of change in disease severity (measured by ALS Functional Rating Scale-Revised) at week 28, but indicated reductions in neurofilament light chain levels and trends toward slower functional decline.^[25] Biogen submitted the new drug application (NDA) to the FDA, which accepted it on July 26, 2022, granting priority review with a target action date initially set for January 2023.^[17] The European Medicines Agency (EMA) accepted the marketing authorisation application in December 2022.^[79] On March 22, 2023, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously (16-0) in favor of accelerated approval based on biomarker evidence of SOD1 reduction and neurofilament light chain lowering as surrogate endpoints reasonably likely to predict clinical benefit.^[80] The FDA granted accelerated approval for tofersen (branded Qalsody) on April 25, 2023, for adults with SOD1-ALS confirmed by genetic testing, requiring verification of clinical benefit in confirmatory trials like ATLAS (NCT04856982).^[5] The European Commission approved Qalsody on May 29, 2024, under exceptional circumstances for SOD1-ALS patients, reflecting the unmet need despite reliance on similar biomarker data.^[36] Confirmatory studies remain ongoing, with ATLAS enrollment surpassing 50% as of April 2023 and an estimated primary completion in 2026.^[4]

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