QALSODY Solution for injection Ref.[107302] Active ingredients: Tofersen

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.

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.

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

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Myelitis and/or Radiculitis [see Warnings and Precautions (5.1)]
• Papilledema and Elevated Intracranial Pressure [see Warnings and Precautions (5.2)]
• Aseptic Meningitis [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of QALSODY cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.

The safety of QALSODY 100 mg 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 Study 1 and in the open label extension Study 2. In Study 1 Part C, approximately 43% were female; 57% were male; 64% were White and 8% were Asian. The mean age at entry in Study 1 Part C 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. Table 1 shows the common adverse reactions that occurred in at least 5% of patients treated with QALSODY and at a 5% or higher frequency than placebo.

Table 1. Adverse Drug Reactions That Occurred in At Least 5% of Patients Treated with QALSODY and at >5% Higher Frequency Than Placebo:

^‡‡ 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.

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 [see Warnings and Precautions (5.1, 5.2, 5.3)].

In the long-term extension study, nonserious adverse reactions of pyrexia have occurred with repeat administration of QALSODY.

As with all therapeutic oligonucleotides, there is a potential for immunogenicity.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tofersen with the incidence of antibodies to other products may be misleading.

The immunogenic response to QALSODY was evaluated in 166 patients with post-baseline plasma samples for anti-drug antibodies (ADAs). Overall, 97 QALSODY-treated patients (58.4%) developed treatment-emergent ADAs, of which 14 were transient and 83 were persistent. The presence of anti-drug antibodies (ADA) appeared to decrease plasma tofersen clearance by 32%. Effects of ADA on CSF tofersen clearance is unknown. No discernible effects of ADAs on total SOD1 protein reduction or plasma NfL reduction have been observed. No discernible effects of ADAs on safety (incidence of AEs including hypersensitivity, anaphylactic reaction, and angioedema) have been observed. Medical review of individual cases of serious neurological events also showed no association with ADA status.

Risk Summary

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.

Data

Animal Data

Subcutaneous administration of tofersen (0, 3, 10, 30 mg/kg) every other day to pregnant mice during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposure at the highest dose tested (30 mg/kg) was approximately 4 times that in humans at the recommended human dose (RHD) of 100 mg.

Subcutaneous administration of tofersen (0, 3, 10, 30 mg/kg) every other day to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. Plasma exposure at the highest dose tested (30 mg/kg) was approximately 20 times that in humans at the RHD.

Subcutaneous administration of tofersen (0, 3, 10, or 30 mg/kg) every other day to male and female mice prior to and during mating and continuing in females throughout organogenesis resulted in no adverse effects on pre- or postnatal development. Plasma exposures at the highest dose tested (30 mg/kg) were approximately 4 times that in humans at the RHD.

Risk Summary

There are no data on the presence of tofersen or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Tofersen was detected in the milk of lactating mice following subcutaneous administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QALSODY and any potential adverse effects on the breastfed infant from QALSODY or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

A total of 13.5% (22/162) patients were 65 years of age and older and 1.2% (2/162) patients were 75 years of age and older at initiation of treatment in clinical studies for ALS in patients who have a mutation in the superoxide dismutase 1 (SOD1) gene [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these patients and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. There is no evidence for special dosage considerations based on age when QALSODY is administered.