FDA APPROVED
The first and only approved treatment to target a genetic cause of amyotrophic lateral sclerosis (ALS)1
QALSODY is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).
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Clinical pharmacology
Study 1 Part C (VALOR) pharmacodynamics
Biomarker analyses in the intent-to-treat (ITT) population
Total CSF SOD1, an indirect measure of target engagement, and plasma NfL, a blood-based biomarker of axonal injury and neurodegeneration, were
evaluated in patients with SOD1-ALS in VALOR.
Effect of QALSODY on total CSF SOD1 protein
VALOR ITT population Week 28 reduction in total CSF SOD1 protein (geometric mean ratio to baseline)1
Difference in geometric mean ratios for QALSODY to placebo: 34%
Effect of QALSODY on plasma NfL protein
VALOR ITT population Week 28 change in mean plasma NfL (geometric mean ratio to baseline)1
Difference in geometric mean ratios for QALSODY to placebo: 60%
Plasma NfL declined until approximately Day 113, after which the reductions were sustained. The reductions in phosphorylated neurofilament heavy chain were similar compared to reductions in NfL, as were reductions in CSF compared to plasma.
Cardiac electrophysiology
At the maximum approved recommended dosing regimen, QALSODY does not prolong the QTc interval to any clinically relevant extent.
CSF=cerebrospinal fluid.
Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).
Clinical studies
VALOR study design1
The efficacy and safety of QALSODY in adults with SOD1-ALS were evaluated in VALOR
- 28 weeks, randomized, double-blind, placebo controlled
- Adults aged 23 to 78 years diagnosed with weakness attributed to ALS and a SOD1 mutation confirmed by a central laboratory
- 108 participants randomized 2:1 to receive treatment with either QALSODY 100 mg or placebo for 24 weeks (3 loading doses followed by 5 maintenance doses)
- Concomitant riluzole and/or edaravone use was permitted for patients
- The prespecified primary analysis population (n = 60, modified intent to treat [mITT]) had a slow vital capacity (SVC) ≥ 65% of predicted value and met prognostic enrichment criteria for rapid disease progression, defined based on their pre-randomization ALS Functional Rating Scale–Revised (ALSFRS-R) decline slope and SOD1 mutation type
- The non-mITT population (n = 48) had a slow vital capacity (SVC) ≥ 50% of predicted value and did not meet the enrichment criteria for rapid disease progression
- At the end of VALOR, study participants had the option to enroll in the VALOR open-label extension study (OLE)
Baseline and disease characteristics in VALOR
Baseline disease characteristics in the ITT population (combined modified intent-to-treat [mITT] and non-mITT population) were generally similar in patients treated with QALSODY and patients who received placebo, with slightly shorter time from symptom onset and higher plasma NfL at baseline in the QALSODY group.1
*Concomitant riluzole and/or edaravone use was permitted for patients.
ALSFRS-R=Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised; NfL=neurofilament light; OLE=open-label extension.
Primary efficacy analysis in VALOR1
The primary efficacy analysis was the change from baseline to Week 28 in the ALSFRS-R total score in the mITT population
The mITT population (n=60):
- Analyzed using the joint rank test to account for mortality in conjunction with multiple imputation to account for missing data for withdrawals other than death
- Had an SVC ≥65% of predicted value
- Met prognostic enrichment criteria for rapid disease progression, defined based on their pre-randomization ALSFRS-R decline slope and SOD1 mutation type
- The non-mITT population (n = 48) had a slow vital capacity (SVC) ≥ 50% of predicted value and did not meet the enrichment criteria for rapid disease progression
Patients treated with QALSODY experienced less decline from baseline in the ALSFRS-R compared to placebo, but the results were not statistically significant (QALSODY-placebo adjusted mean difference [95% CI]: 1.2 [-3.2, 5.5]). Other clinical secondary outcomes also did not reach statistical significance.
Biomarker results in the ITT and mITT populations†
†Notes:
Note 1: N is the number of patients with baseline value.
Note 2: MI was used for missing data. Model included treatment, use of riluzole or edaravone, relevant baseline score and post-baseline values (natural log transformed data). Separate models for mITT and nonmITT were used and combined for ITT analyses.
Note 3: Adjusted geometric mean ratios to baseline, treatment differences in adjusted geometric mean ratios to baseline were obtained from the ANCOVA model for change from baseline including treatment as a fixed effect and adjusting for the following covariates: baseline disease duration since symptom onset, relevant baseline score, and use of riluzole or edaravone. The analysis was based on natural log transformed data.
Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).
Plasma NfL adjusted geometric mean ratio to baseline values in VALOR by study week for the ITT population
- At Week 28 in Study 1 Part C, mean plasma NfL was reduced 55% (geometric mean ratio to baseline) in the QALSODY-treated subjects, compared to a 12% increase with placebo in ITT population (difference in geometric mean ratios for QALSODY to placebo: 60%).
52-week interim VALOR OLE analysis
After completion of Study 1, patients had the option to enroll in an OLE study. At an interim analysis at 52 weeks, reductions in NfL were seen in patients previously receiving placebo who initiated QALSODY in the OLE study, similar to the reductions seen in patients treated with QALSODY in Study 1.
Earlier initiation of QALSODY compared to placebo/delayed initiation of QALSODY was associated with trends for reduction in decline on ALSFRS-R, SVC percent-predicted, and hand-held dynamometry (HHD) megascore that were not statistically significant.
Through all open-label follow-up at the time of the interim analysis, earlier initiation of QALSODY was also associated with a trend towards reduction of the risk of death or permanent ventilation, although it was not statistically significant.
These exploratory analyses should be interpreted with caution given the limitations of data collected outside of a controlled study, which may be subject to confounding.
Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).
Safety
Warnings and Precautions1
Myelitis and/or Radiculitis
- Serious adverse reactions of myelitis and radiculitis have been reported in patients treated with QALSODY
- Six patients treated with QALSODY experienced myelitis or radiculitis in the clinical studies
- Two patients discontinued treatment with QALSODY and required symptomatic management with full resolution of symptoms
- In the remaining 4 patients, symptoms resolved without discontinuation of QALSODY
- If symptoms consistent with myelitis or radiculitis develop, diagnostic workup and treatment should be initiated according to the standard of care
- Management may require interruption or discontinuation of QALSODY
Papilledema and Elevated Intracranial Pressure
- Serious adverse reactions of papilledema and elevated intracranial pressure have been reported in patients treated with QALSODY
- Four patients developed elevated intracranial pressure and/or papilledema
- All patients received treatemnt with standard of care with resolution of symptoms, and no events led to discontinuation of QALSODY
- If symptoms consistent with papilledema or elevated intracranial pressure develop, diagnostic workup and treatment should be initiated according to the standard of care
Aseptic Meningitis
- Serious adverse reactions of aseptic meningitis (also called chemical meningitis or drug-induced aseptic meningitis) have ben reported in patients treated with QALSODY
- One patient experienced a serious adverse reaction of chemical meningitis, which led to discontinuation of QALSODY
- One patient experienced a serious adverse reaction of aseptic meningitis, which did not lead to discontinuation of QALSODY
- In addition, nonserious adverse drug reactions of CSF white blood cell increased, and CSF protein increased have also been reported with QALSODY
- If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care
Adverse reactions in VALOR1
The safety of QALSODY was evaluated in 147 patients with SOD1-ALS. The median patient exposure was 119.4 weeks (range from 4 to 212 weeks). QALSODY was evaluated in the placebo-controlled VALOR and in the OLE. The mean age at entry in VALOR was 49.8 years (range from 23 to 78 years).
The most common adverse reactions (≥ 10% of patients treated with QALSODY and greater than placebo) were pain, fatigue, arthralgia, CSF white blood cell increased, and myalgia.
Less Common Adverse Reactions
Serious adverse reactions of myelitis and radiculitis; papilledema and elevated intracranial pressure; and aseptic meningitis have occurred in patients treated with QALSODY.
In the long-term extension study, nonserious adverse reactions of pyrexia have occurred with repeat administration of QALSODY.
*Pain includes preferred terms of pain, back pain, and pain in extremity.
†CSF white blood cell increased includes preferred terms of CSF white blood cell increased and pleocytosis.
Dosing and administration
After an initial dosing period, QALSODY is administered
every 28 days1
QALSODY should be administered intrathecally using a lumbar puncture by healthcare professionals experienced in performing lumbar punctures.1
Missed second dose1:
If the second loading dose is missed, administer QALSODY as soon as possible, and give the third loading dose 14 days later.
Missed third dose1:
If the third loading dose is missed, administer QALSODY as soon as possible, and give the next dose 28 days later.
Missed maintenance dose1:
If a maintenance dose is missed, administer QALSODY as soon as possible, and give the next dose 28 days later.
Preparation and administration instructions
Use aseptic technique when preparing and administering QALSODY intrathecally. Prepare and administer QALSODY according to the following steps:
Preparation
Vial preparation instructions
- Allow refrigerated QALSODY to warm to room temperature (25°C/77°F) prior to administration, without using external heat sources
- Inspect the solution in the QALSODY vial prior to administration. Do not administer if particles are observed or the liquid in the vial is not clear and colorless to slightly yellow
- Do not shake the vial
Procedural preparation instructions
- If indicated by the clinical condition of the patient, consider sedation
- If indicated by the clinical condition of the patient, consider imaging to guide intrathecal administration of QALSODY
- Prior to removing the vial’s cap on the aluminum overseal, confirm readiness of the patient. An unopened QALSODY vial can be returned to the refrigerator
- Evaluate patients prior to and after intrathecal injection for the presence of potential conditions related to lumbar puncture, to avoid serious procedural complications
Administration1
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Storage and handling
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