MD Magazine® Staff

An original version of this article was published by sister publication 

The US Food and Drug Administration (FDA) has approved ubrogepant (Ubrelvy) for the acute treatment of 

 with or without aura in adults, making it the first-in-class oral calcitonin gene-related peptide (CGRP) antagonist for this indication.

The new drug application (NDA) from Allergan was supported by data from a pair of pivotal studies—ACHIEVE I and II&mdash;as well as 2 additional safety studies showing that both doses were effective, with patients reporting significant rates of pain freedom and freedom from most bothersome symptoms at 2 hours post-dose.

It is contraindicated for co-administration with strong CYP3A4 inhibitors.

Billy Dunn, MD, acting director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said the organization is pleased to approve a novel migraine treatment.

“Migraine is an often-disabling condition that affects an estimated 37 million people in the US,” Dunn said in a statement. “Ubrelvy represents an important new option for the acute treatment of migraine in adults, as it is the first drug in its class approved for this indication.”

ACHIEVE I was a multicenter, double-blind, placebo-controlled study (NCT02828020) that included 1672 patients with migraine, randomly assigned 1:1:1 to either a 50 mg ubrogepant (n = 556), 100 mg ubrogepant (n = 557), or placebo (n = 559). Ultimately, the modified intention-to-treat population included 1436 participants.

Among the 3 dose groups, 19.2% of patients in the 50 mg ubrogepant group (

 = .002, adjusted for multiplicity, for comparison with placebo), 21.2% of patients in the 100 mg ubrogepant group (

 <.0001) and 11.8% of patients in the placebo group experienced freedom from pain at 2 hours after the initial dose.

At 2 hours, 38.6%, 37.7% and 27.8% of patients in the 50 mg, 100 mg, and placebo groups had freedom from the most bothersome symptom respectively.

At 48 hours post initial dose in ACHIEVE I, 12.9% of participants (n = 185) reported an AE. Within 30 days of any dose, the number of patients who reported an AE rose to 26.3% (n = 378). Among patients treated with 100 mg, 28.7% reported an AE, most of the 3 groups.

The most common adverse events during the trial were nausea (n = 44), somnolence (n = 20), and dry mouth (n = 16). In total, 5 patients across the 3 groups experienced a serious adverse event, though none were recorded within 48 hours after the first dose.

C. David Nicholson, PhD, Chief Research and Development Officer, Allergan, said in a statement that the oral administration at 2 doses "allows for treatment flexibility and relief when a migraine attack occurs. As we continue to drive innovation in migraine treatment, we are very proud to offer patients another option, and we are confident that it will make a difference for those in need. At Allergan, we believe that migraine patients deserve access to all new medications for this debilitating disease."

ACHIEVE II showed that compared to placebo, treatment with the oral CGRP antagonist resulted in significant rates of pain freedom at 2 hours for both doses assessed (50 mg, 

 = .03) as well as significant rates of freedom from the most bothersome symptom with the higher dose (50 mg, 

 = .01). the phase 3 study included 1465 patients randomized to either ubrogepant 50 mg (n = 562), 25 mg (n = 561), or placebo (n = 563).

At 2 hours post-dose, pain-freedom was reported by 21.8% (101 of 464 patients; odds ratio [OR], 1.62 [95% CI, 1.14—2.29) of those in the 50-mg group, 20.7% (90 of 435; OR, 1.56 [95% CI, 1.09–2.22) in the 25-mg group, compared to only 14.3% (65 of 456) in the placebo group. The absolute difference between the 25-mg group and placebo was 6.4% (95% CI, 1.5–11.5) and between the 50-mg group and placebo was 7.5% (95% CI, 2.6–12.5).

Likewise, at 2 hours post-dose, the absence of the most bothersome symptoms—photophobia, phonophobia, and nausea&mdash;was reported by 38.9% (180 of 463; OR, 1.65 [95% CI, 1.25—2.20]) of the 50-mg group for an absolute difference from placebo of 11.5% (95% CI, 5.4–17.5). For the 25-mg group, absence of the symptom was reported by 34.1% (148 of 434; OR, 1.37 [95% CI, 1.02–1.83), for an absolute difference of 6.7% (95% CI, 0.6–12.7; 

The safety population of ACHIEVE II included 488 patients who took ≥1 dose of 50-mg ubrogepant, 478 who took ≥1 dose of 25-mg ubrogepant, and 499 who took ≥1 dose of placebo. In total, Treatment-emergent AEs were reported within 48 hours of the initial or optional second dose by 12.9% (63 of 488) of the 50-mg group, 9.2% (44 of 478) of the 25-mg group, and 10.2% (51 of 499) of the placebo group.

The most common adverse events within 2 days of any dose were nausea (50mg: 10 of 488 [2.0%]; 25mg: 12 of 478 [2.5%]; placebo: 10 of 499 [2.0%]) and dizziness (50mg: 7 of 488 [1.4%]; 25mg: 10 of 478 [2.1%]; placebo: 8 of 499 [1.6%]).

Articles

The oral CGRP antagonist becomes the first in its class approved for the indication.

FDA Approves Ubrogepant for Acute Migraine in Adults

An original version of this article was published on sister publication 

The US Food and Drug Administration (FDA) has approved lemborexant (Dayvigo) for the treatment of 

The Esai Pharmaceuticals small molecule orexin receptor antagonist will be made available in 5 mg and 10 mg doses.

Lemborexant's approval was based on data from a pair of pivotal phase 3 studies, SUNRISE 1 and SUNRISE 2, that assessed lemborexant versus placebo for 1 and 6 months.

SUNRISE 1 was a one-month, placebo- and active-controlled, double-blind study that included the first phase 3 head-to-head comparison versus zolpidem tartrate extended release, an active comparator, that evaluated the safety and efficacy of lemborexant in 1006 participants 55 years of age and older with insomnia. Lemborexant 5 mg and 10 mg demonstrated a statistically significant superiority over placebo on the primary end point, which was mean change in log-transformed latency to persistant sleep (LPS) from baseline to end of treatment. Treatment with the study drug also demonstrated statistically significant improvements in sleep efficiency and wake after sleep onset compared with placebo.

In SUNRISE 2, patients age 18 or older with insomnia were randomly assigned to lemborexant 5 mg, 10 mg, or placebo. Compared to placebo, the study drug was found to be statistically significantly superior on the primary end point, which was mean change from baseline to end of treatment at 6 months for log-transformed, patient-reported sleep onset latency. The study drug was also statistically superior to placebo on the secondary end points, including change from baseline to end of treatment on patient-reported sleep efficiency and wake after sleep onset. After 6 months of treatment, patients in the placebo group were re-randomized to either 5 mg or 10 mg lemborexant, while patients in the original treatment group maintained their therapy. 

Twelve-month results from SUNRISE 2 showed that sleep onset latency was lowered by almost 20 minutes for patients treated with both 5 mg and 10 mg of lemborexant, with maintained efficacy through months 6 and 12. In addition, subjective sleep efficiency at baseline was 65.3% (SD, 19.1) and 64.7% (SD, 17.9) for the 5 mg and 10 mg dose groups, respectively, with increases of 6.4% (95% CI, 5.1 to 7.6) and 7.3% (95% CI, 6.1 to 8.6) in both groups at 1 month. At 6 and 12 months, the 5- and 10-mg dose groups had respective increases of 11.1% and 12.6%, and 11.1% and 13.7%.

Subjective wake after sleep onset decreased 17.3 minutes (95% CI, -22.5 to -12.0) in the 5-mg group and 18.7 minutes (95% CI, -24.1 to 13.3) in the 10-mg group after 1 month, followed by decreases of 36.1 and 31.5 minutes, respectively, at 6 months. After 1 year, the 5-mg and 10-mg groups had subjective wake after sleep onset decreases of 42.9 and 43.8 minutes, respectively.

The most common adverse events reported in SUNRISE 1 and SUNRISE 2 was somnolence (10 mg, 10%; 5 mg, 7%; placebo, 1.0%). The most common adverse events leading to discontinuation of lemborexant were somnolence (10 mg, 1.0%; 5 mg, 0.7%; placebo, 0.4%) and nightmares (10 mg, 0.3%; 5 mg, 0.3%; and placebo, 0%).

In addition to effects on sleep onset latency, additional investigations found that treatment with lemborexant had no statistically significant or clinically relevant effects on next-morning driving performance.

Lynn Kramer, MD, chief clinical officer of Eisai's Neurology Business Group, expressed excitement to make a new therapy available for the millions of US insomnia patients.

"We believe the approval of Dayvigo is particularly exciting because it is the first FDA-approved medication to report safety data over a 12-month period along with sleep onset and sleep maintenance efficacy data over a six-month period in a pivotal clinical study," Kramer said in a statement.

The drug will be available early in 2020 following scheduling by the Drug Enforcement Administration.

The small molecule orexin receptor antagonist will be made available for the US market in 2 different doses, in 2020.

FDA Approves Lemborexant for Insomnia in Adults

The US Food and Drug Administration (FDA) has approved antisense oligonucleotide golodirsen injection (Vyondys 53) for the treatment of 

 with genetic mutations subject to skipping exon 43 of the dystrophin gene.

The injection therapy from Sarepta Therapeutics, previously known as SRP-4053, is anticipated to benefit the 8% of patients with DMD who also have this mutation. The approval was based on data from a clinical trial showing statistically significant increases in dystrophin production in skeletal muscle among treated patients.

Clinical findings were so significant for this outcome, in fact, that investigators indicated a benefit for patients with DMD who are amenable to exon 53 skipping. A post-marketing, placebo-controlled confirmatory trial (ESSENCE) is expected to be completed in 2024.

The NDA was supported by Study 4053-101, the first-in-human, multiple-dose, 2-part study that assessed golodirsen in 25 boys with confirmed deletions of dystrophin gene amenable to exon 53 skipping over a total of 144 weeks. The first part of the trial was randomized, placebo-controlled, and dose-titrated to assess safety, tolerability, and pharmacokinetics of 4 dose levels of SRP-4053; while part 2 was an open-label evaluation of golodirsen patients from part 1, along with newly enrolled participants with DMD with deletions amenable to exon 53 skipping, and an untreated group of participants with DMD with deletions not amenable to exon 53 skipping.

Escalating doses of golodirsen were tested against placebo to evaluate safety for the trial’s first 12 weeks. Participants then amendable to exon 53 skipping received weekly treatment infusions at 30 mg/kg. The efficacy of the therapy was measured against an untreated group of patients with Duchenne whose disease-causing mutation is not amenable to exon 53 skipping.

Results revealed statistically significant findings in favor of the therapy on all biological end points. Patients treated with golodirsen had significantly increased dystrophin production, from .095% at baseline to 1.019% at week 48 (range, 0.09—4.30), a significant mean change of .924% (

<.001). The data also confirmed that golodirsen effectively skipped exon 53, which enabled the production of functional dystrophin.

In August, the FDA issued a Complete Response Letter (CRL) to Sarepta following 

its new drug application (NDA) for the therapy

, to which Sarepta replied with a formal dispute resolution request.

The matters raised in the letter were “rapidly evaluated and resolved” according to Sarepta, and its appeal and re-submission were accepted for expeditious review.

The indication was monumental for both the therapeutic company and the DMD community, Doug Ingram, Sarepta president and chief executive officer, said in a statement.

 “VYONDYS 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation,” Ingram said in a statement. “Along with EXONDYS 51 (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the US.”

Billy Dunn, MD, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, added the FDA’s recognition of an urgent need for new therapies indicated for serious neurological disorders includes that of DMD.

“With today’s accelerated approval, patients with Duchenne—a rare and devastating disease&mdash;who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dunn said in a statement.

The approval comes 4 months following a Complete Response Letter was submitted and successfully disputed, to Sarepta Therapeutics.

FDA Approves Golodirsen Injection for DMD with Genetic Mutations

The US Food and Drug Administration has expanded the indication for Allergan’s Botox (onabotulinumtoxinA) as a treatment for lower limb spasticity in pediatric patients, excluding those with cerebral palsy (CP).

The injection was approved for pediatric upper limb spasticity earlier this year, and is also approved for treatment of both upper and lower limb spasticity in adults.

"Lower limb spasticity can impact many aspects of a child's life and have a drastic influence on their overall development and quality of life," David Nicholson, chief research and development officer, Allergan, said in a 

. "This milestone will continue to support and advance care for children and their caregivers who may be struggling with lower limb spasticity.”

The approval was based on findings from a phase 3 study in more than 300 patients aged 2-17 with lower limb spasticity.

The 12-week, double-blind, placebo-controlled study also included a 1-year open-label extension study. Notably, while trial participants had CP, the FDA-approved indication excludes lower limb spasticity caused by CP due to marketing exclusivity by another company.

The FDA approved a recommend dose per treatment session of 4-8 U/kg divided among affected lower limbs, with the total dose per treatment session not exceeding 8 U/kg or 300 U, whichever is lower.

When using onabotulinumtoxinA to treat both lower or upper limbs or upper and lower limbs in combination, patients should not exceed a total dose of 10 U/kg body weight or 340 U, whichever is lower, in a 3-month period.

Common adverse events include dry mouth, injection site pain or discomfort, tiredness, headache, neck pain, eye problems, including double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of your eyelids, dry eyes, and drooping eyebrows, and upper respiratory tract infection.

Findings of a sub-analysis were recently presented at the 2019 Child Neurology Society Annual Meeting in Charlotte, North Carolina, where investigators reported significant achievement in active and passive goals among patients with CP who were randomly assigned to receive treatment with onabotulinumtoxinA  4 U/kg, 8 U/kg, or placebo plus weekly standardized physiotherapy (PT) as part of the 12-week trial.

At baseline, 265 patients set active goals related to walking and moving, while 289 patients set passive goals related to symptoms of pain, spasm, or orthosis/brace wear. Investigators assessed patients using the Goal Attainment Scale (GAS), while a subset of 65 patients were assessed using the Edinburgh Visual Gait (EVG). 

Overall, improvements in GAS were significant for onabotulinumtoxinA plus PT versus placebo plus PT for both active and passive goals at weeks 8 and 12 for patients who received the 8 U/kg dose (

Patients who received the 4 U/kg dose plus PT saw significant improvements at week 8 (

Patients who received either the 4 U/kg or 8 U/kg doses plus PT demonstrated a dose dependent improvement in total EVG score as well as select individual items, including foot stance and swing, compared with placebo. Notably, the 8 U/kg group reached statistical significance versus placebo at week 8 (

 time the FDA has approved Botox for a therapeutic indication.

This article was originally published in 

The FDA approves Botox injections to treat pediatric patients with both upper and lower limb spasticity, unless it was caused by cerebral palsy.