BRIEF SUMMARY-

TOFRSEN -(Apr 2023)

Indication- To treat amphotrophic lateral sclerosid in adults who have a Sodi Gene                                 

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

ADR-  most common adverse reactions (= 10% of patients treated , were pain, fatigue, arthralgia, cerebrospinal fluid white blood cell increased, and myalgia.

CI- None 

WARNINGS-  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.

Pat Inform- Inform patients and caregivers that the drug  could cause myelitis and radiculitis. Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with these adverse reactions develop

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 14

Name-        OSLSODY

Acive  Ingredient -  Tolfersen

 Pharmacological clssificiation-      To treat amphotrophic lateral sclerosid in adults who have a Sodi Gene                                                                                                                                                                                                                                                                                                                          

    Date of Approval-         4/25/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-                                                   These highlights do not include all the information needed to use QALSODY ™ safely and effectively.                                                                                                                 See full prescribing information for QALSODY. QALSODY (tofersen) injection, for intrathecal use.

Initial U.S. Approval: 2023

 INDICATIONS AND USAGE-                                         

QALSODY is an antisense oligonucleotide 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 observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

ADVERSE REACTIONS-

 The most common adverse reactions (= 10% of patients treated with QALSODY and greater than placebo) were pain, fatigue, arthralgia, cerebrospinal fluid white blood cell increased, and myalgia.

CONTRAINDICATIONS-

None 

WARNINGS AND PRECAUTIONS-

• 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.

 • 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.

 • 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.

DOSAGE AND ADMINISTRATION-                                                                           

 QALSODY is administered intrathecally.

 Dosing Information.                                                                                                             • Recommended dose: 100 milligrams (15 mL) per administration

• Initiate QALSODY treatment with 3 loading doses administered at 14- day intervals. A maintenance dose should be administered once every 28 days thereafter. Preparation and Administration Instructions

 • 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

PATIENT COUNSELING INFORMATION-

Myelitis and/or Radiculitis-                                                                                            Inform patients and caregivers that QALSODY could cause myelitis and radiculitis. Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with these adverse reactions develop..

Papilledema and Elevated Intracranial Pressure-                                                         Inform patients and caregivers that QALSODY could cause papilledema and elevated intracranial pressure.

Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with these adverse reactions develop..

Aseptic Meningitis-                                                                                                             Inform patients and caregivers that QALSODY could cause aseptic meningitis. Instruct patients and caregivers to contact their healthcare provider if symptoms consistent with meningitis develop .

Manufactured by: Biogen MA Inc. Cambridge, MA 02142 QALSODY is a trademark of Biogen MA Inc. © Biogen Inc.

CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                           Tofersen is an antisense oligonucleotide that causes degradation of SOD1 mRNA through binding to SOD1 mRNA, which results in a reduction of SOD1 protein synthesis.

2. Pharmacodynamics-                                                                                              Effect of Tofersen on Total CSF SOD1 Protein Total CSF SOD1, an indirect measure of target engagement, was evaluated in Study 1 Part C in SOD1-ALS patients..

Effect of Tofersen on Neurofilament Proteins Plasma NfL, a blood-based biomarker of axonal injury and neurodegeneration, was evaluated in Study 1 Part C in SOD1-ALS patients.

3. Pharmacokinetics-                                                                                               Absorption -Intrathecal administration of QALSODY into the CSF allows tofersen to be distributed from the CSF to central nervous system tissues.

Distribution-                                                                                                                  Autopsy tissue from patients treated with tofersen (n=3) showed that tofersen administered intrathecally was distributed within the central nervous system tissues.

Elimination-                                                                                                      Metabolism- Tofersen is expected to be metabolized through exonuclease (3'- and 5')-mediated hydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes.

Excretion- The primary route of elimination has not been characterized. The effective half-life in CSF is estimated to be 4 weeks.

Drug Interaction Studies-                                                                                                 No clinical drug interaction studies have been performed.

In vitro, QALSODY is not a substrate or inhibitor/inducer of major CYP enzymes or a substrate or inhibitor of major transporters.

Specific Populations-                                                                                                         Effect of sex, race, age, and body weight on tofersen exposure in plasma was not clinically significant. The effect of these factors on tofersen exposure in CSF is unknown.

Patients with Renal or Hepatic Impairment-                                                                      No clinical studies have been conducted to evaluate the pharmacokinetics of tofersen in patients with renal or hepatic impairment. Tofersen is not expected to undergo metabolism by hepatic enzymes.

Immunogenicity-                                                                                                             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.

USE IN SPECIFIC POPULATIONS

1. Pregnancy 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.

2 Lactation 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.

3. Pediatric Use-                                                                                                         Safety and effectiveness in pediatric patients have not been established.

4.Geriatric Use-                                                                                                                  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 

.