Qalsody

QALSODY is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (

[see Clinical Studies (

14 CLINICAL STUDIES

The efficacy of QALSODY was assessed in a 28-week randomized, double-blind, placebocontrolled clinical study in patients 23 to 78 years of age with weakness attributable to ALS and a SOD1 mutation confirmed by a central laboratory (Study 1 Part C, NCT02623699). One hundred eight (108) patients were randomized 2:1 to receive treatment with either QALSODY 100 mg (n = 72) or placebo (n = 36) 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.

Baseline disease characteristics in the overall intent-to-treat (ITT) population (combined 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. At baseline, 62% of patients were taking riluzole, and 8% of patients were taking edaravone. Mean baseline ALSFRS-R score was 36.9 (5.9) in the QALSODY treatment group and 37.3 (5.8) in the placebo group. Median time from symptom onset was 11.4 months in the QALSODY treatment group and 14.6 months in the placebo group.

The primary efficacy analysis was the change from baseline to Week 28 in the ALSFRS-R total score in the mITT population, analyzed using the joint rank test to account for mortality in conjunction with multiple imputation (MI) to account for missing data for withdrawals other than death. 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.

Secondary endpoints of change from baseline at Week 28 in plasma NfL and CSF SOD1 protein were nominally statistically significant (see Table 2). NfL reduction was consistently observed for all subgroups based on sex, disease duration since symptom onset, site of onset, and riluzole/edaravone use.

Table 2: Biomarker Results of QALSODY in Study 1 Part C at Week 28

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 postbaseline 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 and corresponding 95% CIs and nominal p-values 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.
Biomarker Endpoints	QALSODY	Placebo
Plasma NfL
ITT population	N=72	N=36
Adjusted geometric mean ratio to baseline	0.45	1.12
QALSODY to placebo difference in geometric mean ratio (95% CI)	0.40 (0.33, 0.49)
Nominal p-value (ANCOVA+MI)	<0.0001
mITT population	N=39	N=21
Adjusted geometric mean ratio to baseline	0.40	1.20
QALSODY to placebo difference in geometric mean ratio (95% CI)	0.33 (0.25, 0.45)
Nominal p-value (ANCOVA+MI)	<0.0001
CSF SOD1 Protein
ITT population	N=72	N=36
Adjusted geometric mean ratio to baseline	0.65	0.98
QALSODY to placebo difference in geometric mean ratio (95% CI) Nominal p-value (ANCOVA+MI)	0.66 (0.57, 0.77) <0.0001
mITT population	N=39	N=21
Adjusted geometric mean ratio to baseline	0.71	1.16
QALSODY to placebo difference in geometric mean ratio (95% CI)	0.62 (0.49, 0.78)
Nominal p-value (ANCOVA+MI)	<0.0001

Figure 2: Plasma NfL Adjusted Geometric Mean Ratio to Baseline Values in Study 1 Part C by Study Week for the ITT Population

After completion of Study 1, patients had the option to enroll in an open-label extension study. At an interim analysis at 52 weeks, reductions in NfL were seen in patients previously receiving placebo who initiated QALSODY in the open-label extension 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.

Figure 2

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QALSODY is administered intrathecally (

• Recommended dose: 100 milligrams (15 mL) per administration
• Initiate QALSODY treatment with 3 loading doses administered at 14day intervals. A maintenance dose should be administered once every 28 days thereafter.

• Allow to warm to room temperature prior to administration
• Administer within 4 hours of removal from vial
• Prior to administration, remove approximately 10 mL of cerebrospinal fluid
• Administer as an intrathecal bolus injection over 1 to 3 minutes

Injection: 100 mg/15 mL (6.7 mg/mL) as a clear and colorless to slightly yellow solution in a single-dose vial.

There are no adequate data on developmental risks associated with the use of QALSODY in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

• Myelitis and/ or Radiculitis:
  Serious events of myelitis and radiculitis have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to the standard of care. (
  5.1. 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 events of papilledema and elevated intracranial pressure have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to standard of care. (
  5.2. 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 treatment 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 events of aseptic meningitis have been reported. Monitor for symptoms; diagnostic workup and treatment should be initiated according to standard of care. (
  5.3. Aseptic Meningitis

  Serious adverse reactions of aseptic meningitis (also called chemical meningitis or drug-induced aseptic meningitis) have been 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

  [see Adverse Reactions ].

  If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care.
  )