Special Report: 2021 Neurology Drug & Device Approvals

Aducanumab (Aduhelm; Biogen, Cambridge, MA and Eisai, Woodcliff Lake, NJ)

Approved: June 7, 2021 (accelerated, conditional approval)

Indication: treatment of Alzheimer disease in individuals with characteristics matching the population studied in clinical trials.

Available as: 170 mg/1.7 mL (100 mg/mL) solution or 300 mg/3 mL (100 mg/mL) solution in single-dose vials

Approval was based on data from the EMERGE (NCT02484547), ENGAGE (NCT02477800), and PRIME (NCT01677572) studies, which showed aducanumab provided dose- and time-dependent reductions in Aβ in the brains of people with confirmed Aβ at baseline who had mild cognitive impairment or dementia due to Alzheimer disease. Clinical use recommendations suggest that aducanumab should be used only in people who match those inclusion criteria.

In the EMERGE clinical trial, aducanumab also reduced the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score by 22% for participants given the higher of 2 doses of aducanumab after 78 weeks of treatment (n=547) compared with those given placebo (n=548) (P=.01). Statistically significant improvement was also seen on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; P=.01), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% vs placebo; P=.001). However, improvements seen in other cognitive measures in EMERGE or ENGAGE did not reach statistical significance.

Treatment should be titatrated with a recommended maintenance dosage of 10 mg/kg administered as a 1-hour infusion every 4 weeks. Brain MRI is required before initiation and during treatment to monitor for amyloid-related imaging abnormalities (ARIA), which may be asymptomatic and can cause microbleeds in the brain.

EMG-Based Adjunctive Seizure Monitor (Speac; Brain Sentinel, San Antonio, TX)

Cleared: February 6, 2021

Indication: adjunctive seizure monitoring of adults in the home or long-term care facilities during periods of rest

Available as: device with surface EMG cutaneous electrode that attaches to belly of biceps muscle

This small prescription device continously monitors and records surface EMG activity for rapid identification of generalized tonic-clonic seizures in conjunction with other seizure monitoring. The device sends alarms to care partners and clinicians and also records the EMG data for later review by the clinician. Because specific EMG patterns that occur during tonic-clonic flexion are detected and differentiated from other movements, the device is more sensitive and specific for identifying generalized seizures than other seizure monitors.

Brivaracetam (Briviact; UCB, Atlanta, GA)

Approved: August 27, 2021

Expanded indication: adjunctive treatment of partial-onset seizures in people over age 1 month

Available as: tablets (10 mg, 25 mg, 50 mg, 75 mg, and 100 mg; oral solution (10 mg/mL); intravenous 50 mg/5 mL single-dose vial

Already approved for people age 16 years or more, the indication for brivaracetam as monotherapy or adjunctive therapyto treat partial-onset seizures was expanded to include people age 1 month to 4 years for oral formulations and age 1 month to 16 years for intravenous formulations. These expanded indications make all forms of brivaracetam available for treatment of partial-onset seizures in people age 1 month or more whether an oral route of administration is available or not.

In an open label follow-up pediatric study, an estimated 71.4% and 64.3% of participants, age 1 month to 17 years, with partial-onset seizures (n=168), remained on treatment with brivaracetam at 1 and 2 years, respectively.

The recommended pediatric dose is weight-based.

Lacosamide (Vimpat, UCB, Atlanta, GA)

Approved: October 14, 2021

Expanded indication: adunctive treatment of primary generalized tonic-clonic seizures in people over age 1 month

Available as: tablets (50 mg, 100 mg, 150 mg, 200 mg), single-dose vial (200 mg/20 mL) for intravenous use, oral solution (10 mg/mL)

The Food and Drug Administration (FDA) has approved lacosamide (Vimpat; UCB, Atlanta, GA) as adjunctive therapy for primary generalized tonic-clonic seizures (PGTCS) in children age 4 years or more and lacosamide injection for intravenous use. Results from a phase 3 study (NCT02477839) show lacosamide was generally tolerated in children with idiopathic generalized epilepsy (IGE) and PGTCS. Adjunctive treatment with lacosamide lowered the risk of developing a second PGTCS during the 24-week treatment period, with risk reduction of 45% (P=.001) and a significantly higher rate of freedom from PGTCS during the treatment period compared with placebo (31.3% vs 17.2%, P=.011).

The recommended pediatric dose is weight-based.

Remote Electric Neurostimulator (Nerivio; Theranica Bio-Electronics, Netanya, Israel)

Cleared: January 25, 2021

Expanded indication: acute migraine treatment in people age 12 to18 years

Available as: wearable prescription device with 12 doses delivered to the home

In a clinical trial in adolescents who treated migraine attacks with the device, 71% had pain relief within 2 hours, and for 90% of these individuals, pain did not return for at least 24 hours. Improved function after 2 hours was reported by 60% of participants, and 35% of those who had pain relief reported complete pain relief after 2 hours.

The device is worn on either arm and turned on as early as possible after a migraine attack starts, and no later than 60 minutes afterward. Once turned on, the device delivers remote electric stimulation for 45 minutes and the intensity of stimulation can be controlled by the patient.

Rimegepant (Nurtec; Biohaven, New Haven, CT)

Approved: May 27, 2021

Expanded indication: preventive treatment of episodic migraine

Available as: orally disintegrating tablet (75 mg)

Rimegepant was approved for the expanded indication of preventive treatment of episodic migraine in addition to the prior approval for acute migraine treatment. This makes rimegepant the first drug approved to treat acute migraine attacks and help prevent future migraine attacks.

The FDA approval of rimegepant was based on the data from a double-blind randomized placebo-controlled phase 3 clinical trial with an open-label extension. The study demonstrated rimegepant was superior to placebo, decreasing monthly migraine days by 4.3 days/month after 3 months. Approximately half of participants treated with rimegepant had a 50% or more reduction in the number of moderate-to-severe migraine days per month.

Pain relief lasts up to 48 hours after a single 75 mg dose. Taken every other day, rimegepant reduces the number of monthly migraine days. Rimegepant can also be taken up to once daily or as needed to treat attacks when they do occur.

Spinal Cord Stimulator (Senza System, Nevro, Redwood City, CA)

Cleared: July 16, 2021

Expanded indication: chronic intractable unilateral or bilateral pain in lower limbs from diabetic neuropathy

Available as: surgically implantable device

This implanted spinal cord stimulator (Senza System; Nevro, Redwood City, CA) was approved for treatment of chronic pain associated with painful diabetic neuropathy in addition to prior approvals for intractable pain of failed back surgery syndrome, or intractable back or leg pain. In a clinical study, after 6 months of treatment, 79% of those treated with neurostimulation plus conventional management experienced had at least a 50% reduction in pain with no worsening of neurologic symptoms. Of those treated with conventional management alone, only 5% had a 50% pain reduction (P<.001). The mean pain reduction in people who had neurostimulation added to treatment was 79%.

Dihydroergotamine (Trudhesa; Impel Neuropharma, Seattle, WA)

Approved: September 2, 2021

Indication: acute migraine treatment

Available as: metered 0.725 mg nasal spray

This is a new formulation of dihydroergotamine (DHE) that delivers a dose to the upper nasal cavity for rapid bioavailability. In the pivotal phase 3 STOP 301 study (NCT03557333) more than 5,650 migraine attacks were treated over 24 or 52 weeks. Exploratory patient-reported efficacy data reported 66.3% of participants experienced pain relief, 38% of participants reported pain freedom, and 52% had freedom from their most bothersome migraine symptom (MBS) at 2 hours. In 85% of reported migraine attacks, participants did not use rescue medication. Pain relief occured as early as 15 minutes after treatment for 16.3% of participants and pain relief was not dependent on how early in a migraine attack a dose was used.

The recommended dose is 1 spray of 0.725 mg into each nostril, which may be repeated after 1 hour for up to 2 doses every 24 hours or 3 doses within 7 days.

Atogepant (Qulipty; Abbvie, Chicago, IL)

Approved: September 28, 2021

Indication: preventive treatment of episodic migraine

Available as: Tablets (10 mg, 30 mg, 60 mg)

The approval was based on data from the pivotal phase 3 multicenter randomized double-blind placebo-controlled parallel-group ADVANCE trial (NCT03777059) in which atogepant treatment demonstrated statistically significant reductions in mean monthly migraine days compared with placebo.

Individuals treated with 60 mg of atogepant had a 4.2-day reduction in monthly migraine days (MMD) from baseline of 7.8. Approximately twice as many people who took atogepant compared with placebo had 50% to 100% reduction in migraine (56%-61% vs 29%; P<.001).

Amantadine (Gocovri; Adamas Pharma, Emeryville, CA)

Approved: February 1, 2021

Expanded indication: adjunctive treatment to levodopa for OFF episodes of Parkinson disease

Available as: capsules (68.5 mg, 137 mg)

Amantadine was granted the indication for adjunctive treatment to levodopa for OFF episodes in Parkinson disease (PD) in addition to the prior approval for dyskinesia in PD.

In clinical trials, amantadine improved ON time by 3.4 hours/day vs placebo, owing to both reduced OFF time and increased ON time without dyskinesia. Amantadine also demonstrated significant improvements in daily activities and provided more continuous ON time without interruptions from OFF and dyskinesia episodes.

Taken at bedtime, the recommended dose is 274 mg/day, titrated from 137 mg after 1 week.

Deep Brain Stimulator (Vercise, Boston Scientific, Marlborough, MA)

Cleared: October 21, 2021

Expanded indication: medication-refractory tremor from essential tremor or Parkinson disease (PD) causing disability

Available as: implantable device

A new indication was approved for neuromodulation of the ventral intermediate nucleus of the thalamus to treat medication-refractory essential tremor or tremor in PD. This is in addition to prior approvals for bilateral neuromodulation of the globus pallidus internus or subthalamic nucleus to treat medication-refractory motor symptoms of PD.

Focused Ultrasound (Exablate; Insightec, Miami, FL)

Cleared: October 29, 2021

Expanded indication: unilateral noninvasive pallidotomy for advanced Parkinson disease with medication-refractory motor complications in adults over age 30

Available as: introperative device

Focused ultrasound was approved for treatment of drug-refractory PD with mobility, rigidity, or dyskinesia by noninvasively ablating the globus pallidus (GPi) Prior approvals include medication-refractory essential tremor and tremor-dominant PD. There are 37 medical centers in the US providing focused ultrasound treatment.

Ponesimod (Zeposia; Celgene, Summit, NJ)

Approved: March 18, 2021

Indication: relapsing forms of multiple sclerosis (MS) in adults

Available as: tablets (2, 3, 4, 5, 6, 7, 8, 9, 10, or 20 mg)

Ponesimod is approved for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (CIS), relapsing-remitting MD (RRMS), and active secondary progressive MS (aSPMS). In a randomized double-blind head-to-head phase 3 clinical trial (NCT02425644), 71% of participants treated with ponesimod had no confirmed relapses vs 61% of those treated with an active comparator.

Ponesimod treatment also reduced occurrence of new gadolinium-enhancing (GdE) T1 lesions and the number of new or enlarging T2 lesions by 59% and 56%, respectively and prevented 3-month disability worsening for 90% of participants.

Ponesimode is an oral medication, taken once daily at a recommended dose of 20 mg/day after titration over a 2-week period using a starter pack.

Casimersen (Amondys 45; Sarepta, Cambridge, MA)

Approved: February 25, 2021

Indication: treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping

Available as: single-use vial (100 mg/2 mL) for infusion

Casimersen is an antisense oligonucleotide is an antisense oligonucleotide that blocks exon 45 of the dystrophin messenger RNA (mRNA) so that an functional exogenous dystrophin protein is produced. Approximately 8% of individuals with DMD have a mutation that is amenable to exon 45 skipping.

In the ESSENCE trial (NCT02500381), participants who received casimersen had a significantly greater increase in dystrophin protein levels over 48 weeks of treatment compared with placebo. A clinical benefit of the treatment (eg, improved motor function) has not been established. In making the decision to approve casimersen, the FDA considered the potential risks associated with casimersen, the life-threatening and debilitating nature of the disease, and the lack of available therapy.

The recommended dose is 30 mg/kg/week as intravenous (IV) infusion over 35 to 60 minutes.

Avalglucosidase alfa (Nexviazyme; Sanofi, Bridgewater, NJ)

Approved: August 6, 2021

Indication: Late-onset Pompe disease in persons age 1 year or more

Available as: powder (100 mg in single-use vial) for reconstituion and infusion

Avalglucosidase alfa (avalGA) is a lysosomal glycogen-specific enzyme replaces alpha-glucosidase (GAA), which is deficient in late-onset Pompe disease (LOPD). Treatment of people with LOPD with avalGA improved respiratory function and timed walking distance as well as the previously approved alglucosidase alfa (alGA)(Lumizyme, Sanofi).

In the COMET study (NCT03019406), participants treated with avalGA had a 2.9±0.9 point improvement in forced vital capacity (FVC) percent-predicted at week 49. This improvement was not statistically different from that seen with alGA meeting the measurement of noninferiority (P=.0074; 95% CI, -0.13, 4.99). Participants treated with avalGA walked 32.2±9.9 meters farther at week 49 than at baseline.

Compared with alGA, avalGA has a 15-fold greater effect on enhancing glycogen clearance, the pathogenic step in LOPD.

Efgartigimod (Vyvgart; Argenyx, Cambridge, MA)

Approved: December 17, 2021

Indication: Generalized myasthenia gravis in adults who harbor antibodies to the acetylcholine receptor (antiAChR)

Available as: single-dose vial (20 mg/mL in 20 mL) for dilution and intravenous infusion

Efgartigimod is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing IgG recycling to reduce overall levels of IgG, including antiAChR antibodies.

In the phase 3 ADAPT trial (NCT03669588), 68% (44/65) of individuals with antiACHR+ gMG had a 2-point reduction on the Myasthenia Gravis-Activities of Daily Living (MG-ADL) sclae for 4 consecutive weeks after a first cycle of efgartigimod compared with 30% (19/64; P<.0001) of those who received placebo. On the Quantitative Myasthenia Gravis (QMG) scale, of muscle strength, 63% of those who received efgartigimod responded to treatment with a 3-point or more reduction for 4 or more consecutive weeks. Only 14% of those who received placebo had improved muscle strength (P<.0001).

The recommended dose is a weekly infusion over 1 hour of 10 mg/kg for 4 weeks. Subsequent treatment cycles every 50 days can be given if clinically warranted.

Mixed Salts Oxybate (Xywav; Jazz Pharmaceuticals, Philadelphia, PA)

Approved: August 21, 2021

Indication: idiopathic hypersomnia in adults

Available as: 0.5 g/mL total salts (equivalent to 0.413 g/mL of oxybate)

Mixed salts oxybate is the first treatment approved for idiopathic hypersomnia. Approval was based on a results from a phase 3 trial (NCT03533114) in which statistically significant and clinically meaningful differences compared with placebo were seen on the Epworth Sleepiness Scale score (P<.001) and the secondary endpoints of Patient Global Impression of Change (P<.001) and the Idiopathic Hypersomnia Severity Scale (P<.001).

Recommended dose is 4.5 g/night titrated from 1.5 g/night with 1.5 g increases each week to a maximum of 9 g/night, if given twice nightly. For once nightly dosing, titrate from 3 g/night up to a 6 g/night dose, with increases of 1.5 g/week.