Marco Meglio

The FDA has accepted the biologics license application (BLA) for avalglucosidase alfa (Sanofi) for long-term enzyme replacement therapy for the treatment of patients with Pompe disease. A prescription drug user fee act (PDUFA) date has been set for May 18, 2021.

Avalglucosidase alfa has received FDA breakthrough therapy and fast track designations for the treatment of people with Pompe disease. The basis for the BLA originates from positive data from both the phase 3 COMET trial (NCT02782741) and the phase 2 mini-COMET trial (NCT03019406), which showed improvements over standard of care.

The investigational enzyme replacement therapy was designed to improve the delivery of acid alpha-glucosidase (GAA) enzyme to muscle cells, in which patients with Pompe disease are deficient. It has approximately a 15-fold increase in mannose-6-phosphate (M6P) content, compared to standard of care alglucosidase alfa, and aims to help improve cellular enzyme uptake and enhance glycogen clearance in target tissues. Sanofi noted that the M6P receptor plays a key role in the transport of GAA.

"The hallmarks of Pompe disease are the relentless and debilitating deterioration of the muscles, which causes decreased respiratory function and mobility,” Karin Knobe, MD, PhD, head of development for rare diseases and rare blood disorders, Sanofi, said in a statement. “Avalglucosidase alfa is specifically designed to deliver more GAA enzyme into the lysosomes of the muscle cells. We have been greatly encouraged by positive clinical trial results in patients with late-onset and infantile-onset Pompe disease.”

READ MORE: Centralizing Neuromuscular Disease Data With the MDA MOVR Database

Data from the double-blind, global comparator-controlled COMET trial showed that 

avalglucosidase alfa met the primary end point

 of the study in demonstrating non-inferiority in improving respiratory function compared to the standard of care with alglucosidase alfa (Lumizyme; Sanofi) in patients with late-onset Pompe disease.

Those treated with the drug showed a 2.43-point greater improvement (95% CI, –0.13 to 4.99) in percent-predicted forced vital capacity (FVC) compared to the standard of care (

 = .0074). All told, those in the avalglucosidase alfa group reported a percent predicted FVC of 2.89 (standard deviation [SD], 0.88) compared to the reported 0.46 (SD, 0.93) with the standard of care group.

The agent, while achieving statistical significance for the primary end point, did not achieve statistical superiority (

= .0626). Due to the hierarchy of the study protocol, Sanofi noted that the formal statistical testing for all secondary end points was not conducted. Although, a key secondary end point measuring mobility was the 6-minute walk test (6MWT), and those treated with avalglucosidase alfa walked 30.01 m farther (95% CI, 1.33–58.69; distance, 32.21 m [SD, 9.93]) than the standard of care group (distance, 2.19 m [SD, 10.40]).

Also assessed were the percent-predicted Maximum Inspiratory Pressure and Maximum Expiratory Pressure. Those in the avalglucosidase alfa group reported percentages of -0.29 (SD, 3.84) and 2.39 (SD, 4.00), respectively, compared to -2.87 (SD, 4.04) and 5.00 (SD, 4.20) with standard of care. Those totaled differences of 2.58 (95% CI, -8.54 to 13.71) for Maximum Inspiratory Pressure and -2.61 (95% CI, -14.22 to 9.00) for Maximum Expiratory Pressure.

Mini-COMET is an ongoing, phase 2, open-label, ascending-dose, 3-cohort study of avalglucosidase alfa in 22 patients under 18 years of age with infantile-onset Pompe disease, who were previously treated with avalglucosidase alfa and showed incomplete treatment response in pre-specified clinical outcomes.

Presented at the WORLDSymposium in February 2020, results showed that treatment with avalglucosidase alfa was well-tolerated at 20mg/kg and 40mg/kg dose every 2 weeks at the 6-month period. The most common adverse events (AEs) reported were all mild to moderate in nature, including vomiting and pyrexia (6 patients each), upper respiratory tract infections (5 patients), and cough and rash (4 patients each). There were no serious or severe treatment-related AEs, including no AEs that resulted in permanent discontinuation or death.

1. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed November 19, 2020. 

http://www.news.sanofi.us/2020-11-18-FDA-grants-priority-review-for-avalglucosidase-alfa-a-potential-new-therapy-for-Pompe-disease

2. Sanofi’s investigational enzyme replacement therapy shows clinically meaningful improvement in critical manifestations of late-onset Pompe disease. News release. Sanofi. June 16, 2020. Accessed November 19, 2020. https://www.sanofi.com/en/media-room/press-releases/2020/2020-06-16-14-00-00

3. Avalglucosidase alfa showed positive exploratory efficacy and was well-tolerated in phase 2 trials in Pompe disease. News release. February 10, 2020. Accessed November 19, 2020. https://www.sanofigenzyme.com/en/about-us/newsroom/2020/2020-02-10-04-45-00

Articles

Evidence from 2 clinical trials were the basis of the biologics license application, with an FDA decision expected to be made by May 18, 2021.

FDA Accepts BLA for Avalglucosidase Alfa for Pompe Disease

 partnered with the Dravet Syndrome Foundation, Lennox-Gastaut Syndrome Foundation, and the Tuberous Sclerosis Alliance for a chat on Twitter to discuss and raise awareness towards epilepsy, a disorder with many variations that affects nearly 3.5 million people each year.

Topics of the night included barriers in epilepsy care, recommended resources for patients with epilepsy and their caregivers, improving education on managing a patient’s daily activities, and how family members and siblings can help better understand an epileptic condition.

There was also an increased effort to discuss the role that advocacy organizations play within the community. That being said, all 3 of the previously mentioned co-hosts are leading advocacy groups whose drive to create change and raise awareness helped fuel the tweet chat idea.

Throughout the night, participants chimed in with responses while co-hosts of the chat provided helpful links and resources to the overall community.

When discussing the ways that we can better educate people on seizure first aid and how to handle a critical situation, Wendy Fry, director of Family and Caregiver Engagement, Dravet Syndrome Foundation, stressed the role schools can play in assisting this change.

The importance of advocacy organizations and the benefits they bring to patients with epilepsy was echoed through multiple tweets, including this thread from the TS Alliance. Embedded below, the TS Alliance provided a multitude of links and resources they offer patients with tuberous sclerosis complex.

Patients with epilepsy often face a number of barriers that can impede on their quality of life, including finding an expert suited for their needs. The Dravet Syndrome Foundation laid out the multi-step process when trying to find a doctor or institution that specializes in their rare disease.

 has been committed to contributing socially and raising awareness to neurological disorders and the impact they have on their communities. Stay on the lookout for future events and tweet chats that highlight these issues.

An overview of the NeurologyLive tweet chat honoring National Epilepsy Awareness Month, featuring highlighted contributions from the medical community.

Tweet Chat Highlights: Epilepsy Awareness Month

Sodium oxybate (SO), a first-line treatment of type 1 narcolepsy (NT1), has the ability to improve nocturnal rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) in patients with NT1, according to a newly published study.

The study evaluated 19 children and adolescents with NT1 (mean age, 12.5 [±2.7] years; mean disease duration, 3.4 [±1.6] years) who underwent 3 months of stable treatment with SO. RSWA, automatically computed by means of the validated REM sleep atonia index (RAI) was significantly improved (

 <.05) in patients who received the drug compared to baseline.

Study author Giuseppe Plazzi, MD, director, Sleep Laboratory, Department of Neurological Sciences, University of Bologna, and colleagues noted that the treatment “remarkably” reduced complex movements during REM sleep. They wrote that the improvements on RBD and RSWA point to a direct role of the drug in modulating motor control.

"In our cohort, the significant increase of RAI implies that the decrease of motor episodes during REM sleep cannot be only ascribed to the reduction of the amount of REM sleep and the increase of deep sleep, but reflects a direct effect of SO in improving and stabilizing muscle atonia during REM sleep,” Antelmi et al concluded.

READ MORE: Digital Cognitive Behavioral Therapy Proves Cost-Effective for Insomnia

Compared to baseline, children who received the drug improved in clinical complaints, as well as showed a decrease of the Epworth Sleepiness Scale (ESS) score (14.4 [±9.01] vs 3.25 [±4.87]; 

The treatment also had an effect on the different distribution of sleep stages. Compared to baseline, there was a decrease of the percentage of non-REM (NREM) sleep stage 1 (14.2 [±9.01] vs 3.25 [±4.87]; 

 <.0005) and of REM sleep (23.1 [±7] vs 13.1 [±6.45]; 

 <.0001), and an increase of NREM sleep stage 3 (11.1 [±10.13] vs 53.9 [±17.96]; 

Patients within the study underwent neurological investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. In order to properly rate RBD episodes, v-PSG was independently analyzed by 2 sleep experts. The v-PSG included at least 3 electroencephalography (EEG) channels (frontal, central, and occipital leads, referred to the contralateral mastoid), bilateral electrooculogram, submentalis and anterior tibialis electromyography, respiratory parameters, and electrocardiogram.

Antelmi and colleagues noted, “this study offers class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in NT1 children, because of the absence of a control group.”

The investigators also noted that future studies are needed to confirm the findings in adults with NT1 and in patients with idiopathic RBD (iRBD).

In 2002, the original formulation of SO was approved as a central nervous system (CNS) depressant, marketed as Xyrem, to treat symptoms of narcolepsy in adults. The drug was only available through a risk evaluation and mitigation strategy (REMS) program mandated by the FDA. Additionally, it was approved with a black box warning because of its ability to potentially cause depression, seizures, coma, or death, especially in combination with other CNS depressants.

In January 2017, the FDA approved the first generic version of sodium oxybate oral solution, for the treatment of both cataplexy and excessive daytime sleepiness in narcolepsy in adult patients. The treatment’s label was also expanded in October 2018, to include an indication to treat cataplexy or excessive daytime sleepiness in patients with narcolepsy ages 7 and older.

1. Antelmi E, Filardi M, Pizza F, et al. REM sleep behavior disorder in children with type 1 narcolepsy treated with sodium oxybate. 

. Published online November 11, 2020. doi: 10.1212/WNL.0000000000011157

2. Xyrem (sodium oxybate) information. FDA.gov. 

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/xyrem-sodium-oxybate-information

. Updated January 1, 2017. Accessed November 18, 2020.

3. Jazz Pharmaceuticals announces FDA approval of Xyrem (sodium oxybate) for the treatment of cataplexy or excessive daytime sleepiness in pediatric narcolepsy patients. News release. Jazz Pharmaceuticals. October 29, 2018. Accessed November 18, 2020. 

https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-fda-approval-of-xyrem-sodium-oxybate-for-the-treatment-of-cataplexy-or-excessive-daytime-sleepiness-in-pediatric-narcolepsy-patients-300739288.html

The GABAergic mechanism of sodium oxybate was able to increase simple movements in non-rapid eye movement sleep.

Sodium Oxybate Improves Nocturnal RBD and REM Sleep Without Atonia in Narcolepsy

After consulting with the FDA, Eisai recently announced that it has initiated the phase 3 MOMENTUM1 clinical study (Study 304; NCT04572243), which will evaluate lorcaserin in patients with Dravet syndrome (DS).

 Lorcaserin, a selective serotonin 5-HT2C receptor agonist, will be used as an adjunctive treatment in both the phase 3 trial as well as an open-label extension.

The drug was originally FDA-approved under the name Belviq, a weight-loss medication which was voluntarily withdrawn from the market in February 2020 after data from a cardiovascular safety study, CAMELLIA-TIMI 61, showed an increased occurrence of cancer in patients taking the drug.

 Despite not being indicated for DS, the drug was being used off-label treatment in this patient population at the time.

As part of our NeuroVoices series, we sat down with Michael Irazarry, PhD, vice president, Clinical Research, Eisai, to discuss details of the recently initiated MOMENTUM trials and why lorcaserin’s selectivity makes it a good match for the pathology seen in patients with DS.

: What are the parameters of the MOMENTUM1 trial? How did you conclude which end points to use?

 The MOMENTUM trial is designed similarly to a standard epilepsy trial. Patients with Dravet syndrome have a range of types of epileptic seizures, but we’re going to focus on the convulsive seizures. Those are the tonic-clonic or clonic seizures that have the greatest impact on the increased risk of sudden death in epilepsy. The primary end point of these studies is the percent reduction in convulsive seizures, while the 50% responder rate acts as a secondary end point. It is a randomized, double-blind, controlled trial that includes patients with a diagnosis of Dravet syndrome greater than or equal to 2 years of age. To help improve the detectability of treatment effect, they have to have greater than or equal to 4 seizures per month or 4 seizures in the screening period. Based on that, they are randomized to either placebo or lorcaserin. The lorcaserin dose is weight-based, so the greater the weight, the greater the dose. There are 3 dosing categories in the trial and there’s an opportunity for investigators to do 1 dose increase within the weight category as well. [Patients are] followed for 14 weeks and will use seizure diaries as a way to assess the whole range of seizures that are experienced, with convulsive seizures serving as the primary outcome. After the completion of the study, they have the opportunity to enroll into an expanded access program which allows them to get continuous dosing of lorcaserin. Following the FDA withdrawal, we set up this program for these patients who were on the drug and would have lost access to it.

What makes lorcaserin unique as a selective serotonin 5-HT2C receptor agonist?

One reason we selected Dravet syndrome was because of the understanding of the network dysfunction and the potential role of targeting the 5-HT2C receptor. In Dravet syndrome, over 80% of cases are caused by a sodium channel mutation. That sodium channel particularly impacts GABA inhibitory interneurons. Those neurons can suppress firing and it is thought that when that inhibition is released, it increases the susceptibility to seizures. Well, those GABA interneurons are ergic in their dendritic portion, and contain 5-HT2 receptors, in a nutshell. By stimulating those, we can increase the inhabitation, or the release of disinhibition, and suppress seizures. The main mechanism is increasing the activity of those GABAergic inner neurons that have these specific receptors. Because its specific to 5-HT2C, it won’t have some of the safety liabilities that other drugs who target the serotonergic system that have valvular safety issues, have. Notably, fenfluramine also activates the 5-HT2C receptor, but also activates the 5-HT2B receptor. We do hope that our selectivity can help differentiate either in terms of clinical effect or in safety.

How did this drug become so sought after for patients with DS? What has previously been observed in this population?

We hadn’t originally been developing lorcaserin for Dravet. It had been approved for a managed weight loss medication. As part of the approval, there was a post-marketing commitment that required a large cardiovascular safety study. In that study, which featured 12,000 people over 4 years, there was no cardiovascular liability. However, that study showed a numerical imbalance in malignancies, which was around 7.1% in placebo and 7.7% in lorcaserin.

Even though the regulators didn’t find evidence of causality for that, they thought that the benefit:risk for weight loss wasn’t justified, and thus recommended to stop the marketing. Soon after we did that, Eisai and the FDA received numerous requests from patients and physicians in advocacy groups. At the time, lorcaserin was being used to treat Dravet syndrome and other refractory epilepsies. As I mentioned, we set up the expanded access program and then looked into more detail in terms of the evidence around that mechanism. There was some basic scientific evidence describing the role of 5HT2C receptors on GABAergic interneurons.

Additionally, there was a zebrafish model of Dravet syndrome that tested multiple antiepileptic drugs. This was a couple of years ago, but lorcaserin came out as one of the most effective. There were then 2 publications of lorcaserin use in the clinic for both Dravet and refractory epilepsy. It was an open-label trial, but the investigators felt as though there was enough efficacy of lorcaserin. That nonclinical evidence about the networks, nonclinical model of zebrafish, and the case histories from physicians treating patients with epilepsy all impressed us and the FDA as well. In consultation with the FDA, we designed the expanded access program and the clinical trial.

Our intention would be to seek approval after this study. The way we’ve designed it, we’re looking for a large treatment effect. Our expectation is to see the study demonstrate efficacy. In terms of safety, we have a large safety database from the weight loss programs, as well as from a pediatric weight loss study that was ongoing before we withdrew the treatment. We believe the safety is well understood, and the key question will be the efficacy that’s demonstrated.

Eisai initiates phase 3 MOMENTUM 1 clinical trial (study 304) of lorcaserin in Dravet syndrome. News release. Eisai. September 30, 2020. Accessed November 17, 2020. 

https://www.biospace.com/article/releases/eisai-initiates-phase-3-momentum-1-clinical-trial-study-304-of-lorcaserin-in-dravet-syndrome/

2. FDA requests the withdrawal of the weight-loss drug Belviq, Belviq XR (lorcaserin) from the market. News release. FDA. February 13, 2020. Accessed November 17, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-withdrawal-weight-loss-drug-belviq-belviq-xr-lorcaserin-market 


The vice president of Clinical Research at Eisai provides updates on the MOMENTUM trials which will examine lorcaserin as a potential treatment for patients with Dravet syndrome.

Marco Meglio

Articles

FDA Accepts BLA for Avalglucosidase Alfa for Pompe Disease

Tweet Chat Highlights: Epilepsy Awareness Month

Sodium Oxybate Improves Nocturnal RBD and REM Sleep Without Atonia in Narcolepsy

NeuroVoices: Michael Irazarry, PhD, on Lorcaserin for Dravet Syndrome