QALSODY 100mg solution for injection medication leaflet

Qalsody 100 mg solution for injection

Each 15 ml vial contains 100 mg of tofersen.

Each ml contains 6.7 mg of tofersen.

Each 15 ml vial contains 52 mg of sodium.

For the full list of excipients, see section 6.1.

Solution for injection

Clear and colourless to slightly yellow solution with a pH of 6.7 to 7.7.

Qalsody is indicated for the treatment of adults with amyotrophic lateral sclerosis (ALS), associatedwith a mutation in the superoxide dismutase 1 (SOD1) gene.

Treatment with tofersen should only be initiated by a physician with experience in the management of

ALS.

Qalsody should be administered by, or under the direction of, healthcare professionals experienced inperforming lumbar punctures.

The recommended dose is 100 mg of tofersen per treatment.

Tofersen treatment should be initiated with 3 loading doses administered at 14-day intervals.

A maintenance dose should be administered once every 28 days thereafter.

Missed or delayed doses

If the second loading dose is delayed or missed, tofersen should be administered as soon as possible,and the third loading dose should be administered 14 days later.

If the third loading dose is delayed or missed, tofersen should be administered as soon as possible, andthe first maintenance dose should be administered 28 days later.

If a maintenance dose is delayed or missed, tofersen should be administered as soon as possible.

Subsequent maintenance doses should be administered every 28 days from the last dose.

The need for continuation of therapy should be reviewed regularly and considered on an individualbasis depending on the patient’s clinical presentation and response to the therapy.

Experience with the use of tofersen in the elderly is limited. However, from the clinical data available,the efficacy and safety of tofersen are expected to be similar to that of other age groups studied.

There is no evidence for special dose considerations based on age when tofersen is administered.

Tofersen has not been studied in patients with renal impairment.

Tofersen has not been studied in patients with hepatic impairment.

The safety and efficacy of Qalsody in paediatric patients below the age of 18 years has not beenestablished. No data are available.

Qalsody is for intrathecal use by lumbar puncture.

* It is recommended to ensure intrathecal access prior to removing the plastic cap from the vialand drawing up the tofersen dose.

* Just prior to administration, the plastic cap should be removed from the vial and a nonspinalanesthesia needle attached to the syringe for the purpose of withdrawing tofersen from thevial. The syringe needle is inserted into the vial through the center of the overseal to withdrawthe required dose of 15 ml (equivalent to 100 mg) from the vial.

- Qalsody must not be diluted.- External filters, including bacterial or particulate filters, are not required.

* It is recommended that approximately 10 ml of cerebrospinal spinal fluid (CSF) is removedusing a lumbar puncture needle prior to administration of tofersen.

* Tofersen is administered as an intrathecal bolus injection using a lumbar puncture needle over1 to 3 minutes.

Procedural preparation instruction:

* If indicated by the clinical condition of the patient, sedation can be considered.

* If indicated by the clinical condition of the patient, imaging to guide intrathecal administrationof tofersen can be considered.

* Prior to removing the vial’s cap on the aluminium overseal, readiness of the patient should beconfirmed. An unopened vial can be returned to the refrigerator; for total time permitted, seesection 6.3.

* Patients should be evaluated prior to and after intrathecal injection for the presence ofpotential conditions related to lumbar puncture to avoid serious procedural complications.

Following injection, standard post-lumbar-puncture care is recommended.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Lumbar puncture procedure

There is a risk of adverse reactions occurring as part of the lumbar puncture procedure (e.g. headache,back pain, post lumbar puncture syndrome, infection).

Myelitis and/or radiculitis

Serious cases of myelitis and radiculitis have been reported in patients treated with tofersen. Ifsymptoms consistent with these adverse reactions develop, diagnostic evaluation and treatment shouldbe initiated according to the standard of care.

Increased intracranial pressure and/or papilloedema

Serious cases of increased intracranial pressure and/or papilloedema have been reported in patientstreated with tofersen. If symptoms consistent with these adverse reactions develop, diagnosticevaluation and treatment should be initiated according to the standard of care.

Thrombocytopenia and coagulation abnormalities

Thrombocytopenia and coagulation abnormalities, including acute severe thrombocytopenia, havebeen observed after administration of subcutaneously or intravenously administered antisenseoligonucleotides. If clinically indicated, platelet and coagulation laboratory testing is recommendedprior to administration of tofersen.

Renal toxicity

Renal toxicity has been observed after administration of subcutaneously and intravenouslyadministered antisense oligonucleotides. If clinically indicated, urine protein testing (preferably usinga first morning urine specimen) is recommended. For persistent elevated urinary protein, furtherevaluation should be considered.

This medicinal product contains 52 mg sodium in each 15 ml, equivalent to 3% of the WHOrecommended maximum daily dietary intake of 2 g sodium for an adult.

This medicinal product contains potassium, less than 1 mmol (39 mg) per 15 ml dose, i.e., essentially‘potassium-free’.

No interaction studies have been performed.

The co-administration of other intrathecal medicinal products with tofersen has not been evaluated andthe safety of these combinations is not known.

Tofersen is not an inducer or inhibitor of CYP450-mediated oxidative metabolism; therefore, it shouldnot interfere with other medicinal products that interact with these metabolic pathways.

There are no data from the use of tofersen in pregnant women. Studies in animals in which tofersen isnot pharmacologically active do not indicate direct or indirect harmful effects with respect toreproductive toxicity (see section 5.3).

Tofersen is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

There are no data on the use of tofersen during breast-feeding in humans. Available pharmacodynamicdata in animals have shown excretion of tofersen in milk (see section 5.3). A risk to thenewborn/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tofersentherapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for thewoman.

There are no data available on the potential effects on fertility in humans. Toxicity studies in animalshave indicated that tofersen would not appear to have harmful effects on male or female fertility (seesection 5.3).

Tofersen has minor influence on the ability to drive and use machines. Patients who develop visualdisturbance under tofersen should be cautioned to avoid driving or operating machinery.

The serious adverse reactions in tofersen-treated participants were myelitis (2.7%), increaseintracranial pressure and/or papilloedema (2.7%), radiculitis (1.4%) and aseptic meningitis (1.4%).

The most common adverse reactions reported in tofersen-treated participants were pain (66%),arthralgia (34%), fatigue (28.6%), CSF white blood cell increased (26.5%), CSF protein increased(26.5%), myalgia (19%) and pyrexia (18.4%).

The adverse reactions are listed by system organ class and frequency using the following convention:

Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1 000 to <1/100); Rare(≥1/10 000 to <1/1 000); Very Rare (<1/10 000); not known (cannot be estimated from the availabledata).

Table 1: Adverse reactions with Qalsody-treated participants in Study 101 and Study 102

System Organ Class (SOC) Adverse reaction Frequency

Nervous system disorders CSF white blood cell increased* Very common

CSF protein increased Very common

Papilloedema‡ Common

Neuralgia Common

Aseptic meningitis†† Common

Radiculitis† Common

Myelitis§ Common

Musculoskeletal and Arthralgia Very commonconnective tissue disorders Myalgia Very common

Musculoskeletal stiffness Common

General disorders and Pain‡‡ Very commonadministration site conditions Fatigue Very common

Pyrexia Very common

* CSF white blood cell increased includes preferred terms of CSF white blood cell increased and pleocytosis.† Radiculitis includes preferred terms of radiculopathy and lumbar radiculopathy.‡ Papilloedema includes preferred terms of papilloedema and intracranial pressure increased. See discussion in Description ofselected adverse reactions (ARs).§ Myelitis includes preferred terms of myelitis, myelitis transverse, and neurosarcoidosis. See discussion in Description ofselected adverse reactions.†† Aseptic meningitis includes preferred terms of meningitis chemical and meningitis aseptic. See discussion in Descriptionof selected adverse reactions.‡‡ Pain includes preferred terms of pain, back pain, and pain in extremity.

Lumbar puncture procedure

Adverse reactions associated with the administration of tofersen by lumbar puncture have beenobserved. The adverse reactions commonly associated with lumbar puncture are headache, back pain,post lumbar puncture syndrome, infection. The incidence and severity of these events were consistentwith events expected to occur with lumbar puncture.

Myelitis and/or radiculitis

In the clinical studies, 4 participants receiving tofersen 100 mg reported serious reactions of myelitis(2.7%). The number of tofersen doses received before the onset of myelitis ranged from 5 to 15 doses.

Two participants were symptomatic and 2 participants were asymptomatic. All 4 participants hadabnormal magnetic resonance imaging (MRI) findings related to the event. Two participantsdiscontinued treatment, and the event resolved. In the remaining 2 participants, the event did not leadto discontinuation of treatment (see section 4.4).

Two participants receiving tofersen 100 mg reported serious reactions of radiculitis (1.4%). Thenumber of tofersen doses received before the onset of radiculitis ranged from 1 to 24 doses. Bothreactions were symptomatic. One participant had abnormal MRI findings related to the event and oneparticipant had a normal MRI. No participants discontinued treatment, and the reactions resolved withsequelae in one and without sequalae in the second participant (see section 4.4).

Increased intracranial pressure and/or papilloedema

Four participants receiving tofersen 100 mg reported serious reactions of increased intracranialpressure and/or papilloedema (2.7%). The number of tofersen doses received before the onset ofincreased intracranial pressure and/or papilloedema ranged from 7 to 18 doses. All 4 reactions ofincreased intracranial pressure and/or papilloedema were symptomatic. Four participants had an MRIwith no findings pertinent to the event. One reaction finally led to permanent discontinuation oftofersen, one reaction led to interruption of tofersen treatment. All reactions were manageable withstandard of care (see section 4.4).

Aseptic or chemical meningitis

Two participants receiving tofersen 100 mg reported serious reactions of aseptic or chemicalmeningitis (1.4%). The number of tofersen doses received before the onset of aseptic or chemicalmeningitis ranged from 5 to 7 doses. Both reactions of aseptic or chemical meningitis weresymptomatic. One participant had an MRI with no findings pertinent to the event. One participantdiscontinued tofersen, and the other participant did not.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose associated with tofersen were reported in clinical studies.

In the event of an overdose, supportive medical care should be provided including consulting with ahealthcare professional and close observation of the clinical status of the patient.

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX22

SOD1-ALS is a primarily autosomal-dominant disorder affecting approximately 2% of the ALSpopulation. Mutations in the SOD1 gene lead to accumulation of a toxic form of SOD1 protein. Over200 unique SOD1 mutations associated with ALS have been identified with a median disease durationof approximately 2.3 years.

The human SOD1 gene encodes an abundant dimeric enzyme, copper/zinc superoxide dismutase(Cu/ZnSOD or SOD1), which catalyses the transmutation of superoxide (O -2 ) into oxygen (O2) andhydrogen peroxide (H2O2). In SOD1-ALS patients, mutations in the SOD1 gene lead to accumulationof a toxic form of SOD1 protein, resulting in axonal injury and neurodegeneration.

Tofersen is an antisense oligonucleotide (ASO) that is complementary to a portion of the 3′untranslated region (3′UTR) of the mRNA for human SOD1 and binds to the mRNA by Watson-Crickbase pairing (hybridisation). This hybridisation of tofersen to the cognate mRNA results in RNase-H-mediated degradation of the mRNA for SOD1, which reduces the amount of SOD1 protein synthesis.

Total CSF SOD1 protein

Total CSF SOD1 was measured in Studies 101 Part C (VALOR) and 102 as an indirect measure oftarget engagement.

At Week 28 in Study 101 Part C, a reduction in total CSF SOD1 protein of 35% (geometric mean ratioto baseline) in the tofersen-treated group versus a 2% decrease from baseline in the correspondingplacebo participants in the ITT population was observed (difference in geometric mean ratios fortofersen to placebo: 34% (95% CI: 23%, 43%). Total CSF SOD1 declined until approximately Day 56,after which the reductions were sustained over time.

Plasma neurofilament light chain (NfL) biomarker

Plasma neurofilament light chain (NfL) was measured in Studies 101 Part C (VALOR) and 102 as amarker of axonal injury and neurodegeneration.

At Week 28 in Study 101 Part C, mean plasma NfL was reduced 55% (geometric mean ratio tobaseline) in the tofersen-treated participants (ITT), compared to a 12% increase with placebo(difference in geometric mean ratios for tofersen to placebo: 60% (95% CI: 51%, 67%)). Plasma NfLlevels declined until approximately Day 113, after which the reductions were sustained over time. Thereductions in CSF NfL were consistent compared to those observed in plasma.

Figure 1: Study 101 Part C: plasma NfL adjusted geometric mean ratio to baseline valuesby study week for the ITT population

Abbreviations: NfL = neurofilament light chain; ANCOVA = analysis of covariance; MI = multiple imputation; LS = leastsquare.

Note 1: Baseline is defined as day 1 value prior to the clinical study drug. If day 1 value is missing, the non-missing value(including screening visit) closest to and prior to the first dose will be used as the baseline value.

Note 2: Values below limit of quantitation (BLQ) are set to half of lower limit of quantitation (LLOQ, 4.9 pg/mL) incalculations. Multiple imputation is used for missing data.

Note 3: The ITT analysis is based on ANCOVA model with natural log transformed data. The model includes covariatesfor the corresponding baseline value i.e. log value, baseline disease duration since symptom onset, and use ofriluzole or edaravone.

Note 4: The table at the bottom presents the number of participants with observed non-missing data at each visit.

ECG measurements and the values for the tofersen 100 mg group (n = 41) were similar to placebogroup (n = 34) in Study 101 Part C. The incidence of abnormalities in ECG measurements was higherin the tofersen group compared to the placebo group, with 8 participants (11.3%) displaying amaximum increase from baseline in Fridericia formula (QTcF) > 30 to 60 ms in the tofersen groupcompared to 2 participants (5.6%) in the placebo group. The clinical significance of this imbalance isnot known. No participants in the tofersen or placebo group displayed an increase from baseline in

QTcF > 60 ms, and no participants displayed maximum postbaseline QTcF > 480 ms.

Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact on efficacyor safety was observed. However, data are still limited.

The efficacy of tofersen was assessed in a 28-week randomised, double-blind, placebo-controlledclinical study (Study 101, Part C) in participants aged 23 to 78 years with weakness attributable to

ALS and a SOD1 mutation confirmed by central laboratory. One hundred eight (108) participantswere randomised 2:1 to receive treatment with either tofersen 100 mg or placebo for 24 weeks(3 loading doses followed by 5 maintenance doses). Forty-two (42) unique SOD1 mutations wereevaluated, with the most common being p.Ile114Thr (n = 20), p.Ala5Val (n = 17), p.Gly94Cys (n = 6),and p.His47Arg (n = 5). Concomitant riluzole and/or edaravone use was permitted for participantswho were on a stable dose for at least 30 or 60 days prior to study baseline, respectively.

Baseline disease characteristics in the overall intent to treat (ITT) population were generally similar inthe tofersen-treated participants (n=72) and placebo participants (n=36), with a baseline ALS

Functional Rating Scale-Revised (ALSFRS-R) total score of 36.9 (SD: 5.9) in the tofersen group and37.3 (SD: 5.81) in the placebo group. The tofersen group had a shorter median time from symptomonset (11.4 months; range: 1.7, 145.7) as compared to the placebo group (14.6 months; range: 2.4,103.2), and a higher median baseline plasma NfL level (78.5 pg/mL; range 5 to 329) as compared tothe placebo group (64.6 pg/mL; range: 8 to 370).

The primary efficacy endpoint was the change from baseline to Week 28 in the ALSFRS-R total score

The results numerically favoured tofersen, but were not statistically significant (ITT population:tofersen-placebo adjusted mean difference [95% CI]: 1.4 [-1.3, 4.1]). Numerically larger differenceswere observed between tofersen and placebo over 28 weeks in patients with baseline NfL valuesabove median [mean difference (95% CI) 3.9, (-1.0;8.9)] compared to patients with baseline NfLvalues below median [0.6, (-1.3,4.2)]. Secondary clinical outcomes also did not reach statisticalsignificance.

The European Medicines Agency has waived the obligation to submit the results of studies withtofersen in all subsets of the paediatric population in ALS (see section 4.2 for information onpaediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct. The European Medicines Agency will review any new information which may becomeavailable every year and this SmPC will be updated as necessary.

The single and multidose pharmacokinetics of tofersen, administered via intrathecal injection, werecharacterised in plasma and CSF of adult ALS participants with a SOD1 mutation and in autopsytissue from deceased clinical study participants (n=3).

The maximum CSF trough concentration occurred at the third dose, which was the last dose of theloading period. There was little to no accumulation with monthly dosing after the loading phase; theaccumulation ratio appears to be less than 2-fold. Tofersen is rapidly transferred from CSF into thesystemic circulation, with a median time to maximum concentration (Tmax) plasma values ranged from2 to 6 hours post intrathecal (IT) administration. There was no accumulation in plasma exposuremeasures (Cmax and AUC) after monthly maintenance dosing.

Tofersen administered intrathecally was extensively distributed within the CNS, achieving therapeuticlevels in the target spinal cord tissues. The median plasma AUC at 100 mg (Study 101 Part C data)after first dose was 13973.1 ng/mL*h; median maximum plasma concentration (Cmax) was824.3 ng/mL, which occurred at between 4-6 hours post dose. The median plasma volume ofdistribution was estimated at 50.9L (119% CV) in study 101 and 102; and was 40.67 L (130% CV) inthe 100 mg dose group. Pharmacokinetic (PK) analysis demonstrates that intrathecally administeredtofersen is widely distributed into central nervous system (CNS) tissues and is rapidly transferred from

CSF to the systemic circulation.

Plasma Protein Binding

Tofersen is highly bound to human plasma proteins (≥ 98% bound) at clinically relevant or higherplasma concentrations (0.1 and 3 µg/ml), which limits glomerular filtration and reduces urinaryexcretion of the active substance. The likelihood of drug-drug interactions due to competition withplasma protein binding is very low.

Tofersen is metabolised through exonuclease (3'- and 5')-mediated hydrolysis and is not a substratefor, or inhibitor or inducer of CYP450 enzymes.

The primary route of elimination is expected via urinary excretion of unchanged tofersen and itsmetabolites. Although CNS tissue half-life cannot be measured in humans, the mean terminalelimination half-life was measured in the CNS tissue of cynomolgus monkeys and found to be 31 to40 days. The median plasma clearance was estimated at 8.32 L/hr (60.6% CV) in study 101 and 102;and was 5.73L/hr 60% CV) at 100 mg dose.

In CSF, the pharmacokinetics of tofersen administered IT increase less than dose proportional for doseranging from 20 mg to 100 mg.

In plasma, the pharmacokinetics of tofersen administered IT increase more than dose proportional fordose ranging from 20 mg to 100 mg.

The presence of anti-drug antibodies (ADAs) appeared to decrease plasma clearance by 28.0%.

Characteristics in specific patient populations

Of the 166 patients who received tofersen in clinical studies, a total of 22 patients were 65 years of ageand older, including 2 patients 75 years of age and older. No overall differences in clinical PK wereobserved between these patients, but data are limited.

The pharmacokinetics of tofersen in patients with renal impairment has not been studied.

The pharmacokinetics of tofersen in patients with hepatic impairment has not been studied.

Carcinogenicity studies with tofersen have not been performed.

Tofersen demonstrated no evidence of mutagenicity based on nonclinical genotoxicity studies (in vitro

Ames bacterial mutagenicity, in vitro chromosome aberration, and in vivo mouse micronucleusassays).

Reproductive toxicology studies were conducted using subcutaneous administration of tofersen inmice and rabbits. In a mice fertility and embryo-fetal development study, male mice in the high dosegroup of 30 mg/kg (> 50 times the human exposure [AUC] following 100 mg tofersen) had minimal tomild seminiferous tubular degeneration, seminiferous tubule dilatation, spermatid retention, apoptosisof epithelial cells, increased cellular debris in the testes, and hypospermia in the epididymis. However,there were no tofersen-related adverse effects on mating and fertility or sperm parameters. In femalemice, there was no tofersen-related mortality or early delivery and there were no effects on mating orfertility. No tofersen-related adverse effects on embryo-foetal development were observed in mice andrabbits (at exposures more than 40-times the human exposure at MRHD). In a perinatal/postnatalreproduction study in mice, there were no adverse effects on the F0 females or on the growth anddevelopment of the F1 pups at the highest dose evaluated (30 mg/kg). Tofersen was detected in mousemilk samples from all tofersen-dosed animals. Tofersen is not pharmacologically active in mice andrabbits, which limits the validity of these studies, as harmful effects associated with SOD1 down-regulation cannot be evaluated therein.

Microscopic evaluation of reproductive tissues from both males and females in the 13-week and 39-week non-human primate (NHP) toxicology studies in which tofersen is pharmacologically activerevealed no effects on the reproductive tissues.

In a repeat-dose toxicology study (9 months), intrathecal administration of tofersen to adultcynomolgus monkeys was generally well-tolerated. The exception was a female in the high dose group(35 mg; equivalent to 350 mg per IT injection in humans) that had behaviour described as musclecramping, head/neck dorsiflexion, and opisthotonos-like-back-arching posture after IT dosing.

Electroencephalogram (EEG) indicated the absence of seizure. The no observed adverse effect levels(NOAELs) in the repeat-dose chronic toxicology studies were 150 mg/kg subcutaneous administrationin the mouse and 12 mg intrathecal administration in the 9-month nonhuman primate. Using thenonhuman primate as the most sensitive species, a dose of 12 mg converts to the human equivalentdose (HED) of 120 mg (based on the monkey-to-human CSF volume scaling). The safety margin (1.2-fold) for the IT doses in monkeys to IT doses in humans is based on the converted HED withconsideration of volume difference in CSF (approximately 10-fold between human and monkeys).

Therefore, no toxicity effects were seen at dose levels equivalent to 120 mg in humans.

Disodium phosphate

Potassium chloride

Calcium chloride dihydrate

Magnesium chloride hexahydrate

Sodium chloride

Sodium dihydrogen phosphate dihydrate

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

42 months

Temporary storage conditions

The vial of Qalsody in its original carton can be stored for up to 14 days at room temperature (storebelow 30°C).

Unopened vials of Qalsody can be removed from and returned to the refrigerator, if necessary.

Unopened vials can be removed from the original carton for not more than 6 hours per day at roomtemperature for a maximum of 6 days.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For temporary storage conditions of unopened vials of the medicinal product, see section 6.3.

20 ml clear Type I glass vial with chlorobutyl rubber stopper and an aluminium overseal with flip-offplastic button.

Qalsody is available in a pack of 1 vial.

Aseptic technique must be used when preparing and administering tofersen intrathecally.

For single use only.

Vial preparation instructions:

* The refrigerated vial should be allowed to warm to room temperature (25°C) prior toadministration without external heat source.

* The vial should not be shaken.

* Qalsody contains no preservatives. Once drawn into the syringe, the solution should beadministered immediately (within 4 hours since removal from refrigeration) at roomtemperature; otherwise, it must be discarded.

* The solution should be visually inspected prior to removal of the solution from the vial. Thesolution should be essentially free of visible particles. Only clear and colourless to slightlyyellow solution should be administered. If not, the vial must not be used.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/23/1783/001

Date of first authorisation: 29 May 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu