Staff Writer

The novel gene therapy AAVrh74.MHCK7.micro-Dystrophin demonstrated impressive early results in a small sample of 3 children with Duchenne muscular dystrophy (DMD), according to preliminary phase I/IIa results announced by Sarepta Therapeutics, the company developing the therapy.

In the study, all patients exhibited a robust expression of transduced microdystrophin, which was properly localized to the muscle sarcolemma. All post-treatment biopsies exhibited high levels of microdystrophin. Additionally, all 3 patients showed significant decreases of serum creatine kinase (CK) levels, with a nearly 100% reduction in the mean by day 60 (87% reduction).

“I have been waiting my entire 49-year career to find a therapy that dramatically reduces CK levels and creates significant levels of dystrophin,” principal investigator Jerry Mendell, MD, of Nationwide Children’s Hospital, said in a statement. “Although the data are early and preliminary, these results, if they persist and are confirmed in additional patients, will represent an unprecedented advancement in the treatment of DMD. I look forward to treating more patients in the clinical study to generate the data necessary to bring this therapy to patients with DMD, with the goal of dramatically changing the course of the disease.”

In the 3-patient data, the mean intensity of microdystrophin-positive fibers was 76.2%. The mean intensity of fibers was 74.5%. The mean microdystrophin, as measured by Western blot, was 38.2% compared with normal. Utilizing Sarepta’s method, which adjusts for fat and fibrotic tissue, the rate was 53.7% compared with normal. A mean of 1.6 vector copies per cell nucleus was found and was consistent with the microdystrophin expression levels observed.

No serious adverse events were noted in the study, and 2 patients who experienced elevated gamma-glutamyl transferase (GGT) corrected within a week and returned to baseline levels through increased steroid intake. Furthermore, during the first week of treatment, patients experienced transient nausea which correlated with increased steroid dosing.

“As a genetic medicine company, our goal is to work with the world’s leading clinicians and scientists to advance scientific discoveries to the clinic and, ultimately, to therapies that profoundly improve and extend the lives of those living with Duchenne muscular dystrophy and other rare, fatal diseases,” Doug Ingram, Sarepta’s president and chief executive officer, said in a statement.

AAVrh74.MHCK7.micro-Dystrophin vector consists of a rhesus monkey-derived AAV vector, which shows lower immunogenicity rates in existing early-stage clinical studies than expected with other AAV vectors. The MHCK7 cassette allows for AAVrh74 to effectively enter skeletal, diaphragm, and cardiac muscle preferentially via the blood, making it an ideal candidate for neuromuscular diseases.

“Since the discovery of the dystrophin gene in 1986, scientists, clinicians, patient advocates and the biotech ecosystem have tirelessly searched for ways to restore or replace dystrophin and rescue boys with DMD from the damage and early death," said Ingram. "Dr. Mendell’s results, if confirmed in additional patients, studies, measures and time points, represent a monumental leap forward in the direction of our goal.”

Several AAV vector-based therapies are currently in development for patients with DMD; however, some of these agents have been faced with safety obstacles. One such therapy, SGT-001, was placed on clinical hold by the FDA for safety concerns related to a reduction in red blood cell count and complement activation.

SGT-001 also utilizes AAV-mediated gene transfer; however, it is attached to a different promoter cassette known as CK8, which is different from the MHCK7 promoter used for AAVrh74.MHCK7.micro-Dystrophin.

Pfizer is also developing a third gene therapy utilizing AAV-mediated microdystrophin gene transfer for DMD. This agent, PF-06939926, was first administered to a patient in March 2018. Early data from this preliminary trial are anticipated in early 2019.

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A novel gene therapy has demonstrated impressive early results in a small sample of 3 children with Duchenne muscular dystrophy.

Gene Therapy Shows Robust Activity for Duchenne Muscular Dystrophy

An expanded access program (EAP) has been opened to allow patients with amyotrophic lateral sclerosis (ALS) to have access to BHV-0223, a sublingual formulation of riluzole, according to Biohaven Pharmaceutical, the company developing the new drug. Based on data released earlier this year, the company is preparing a new drug application (NDA), which they plan to submit in the coming months.

In a bioequivalence study that is acting as the basis for the NDA, BHV-0223 achieved an area-under-the-curve of 90% and peak exposures of 113% compared with generic riluzole. The 90% confidence intervals for these numbers were within the limits to define bioequivalence in the study (80% to 125%).

"Recognizing that many ALS patients with dysphagia may be unable to take conventional riluzole tablets for reasons that include difficulty with swallowing, Biohaven is pleased to be able to offer patients living with ALS access to sublingual BHV-0223 via this expanded access program while we prepare to submit our NDA,” Vlad Coric, MD, CEO of Biohaven, said in a press release.

“For those patients with significant dysphagia, waiting for the approval of sublingual BHV-0223 may mean never getting the opportunity to take this drug and receive the benefits of riluzole, the only drug for ALS known to impact survival," said Coric. "We are happy to help address this pressing need within the FDA's EAP framework."

Riluzole was first approved by the FDA for patients with ALS in 1995. The efficacy for the approval of the agent was established in 2 controlled, randomized trials for patients with 

. Across both studies, there was an improvement in survival. However, despite this, measures of muscle strength and neurological function did not show a benefit. Similar findings are anticipated with the bioequivalent, sublingual BHV-0223 formulation of the drug.

In the bioequivalent study, BHV-0223 showed similar blood exposure levels as riluzole, but at a 20% reduced dose. In the study, BHV-0223 was given at 40 mg while ingested riluzole was administered as 50 mg tablets. Observational evidence suggested that the lower dose could result in lower drug exposure to the liver, causing a reduction in overall risk for liver enzyme abnormalities.

"We are very excited about favorable results from the current study establishing the bioequivalence of our innovative sublingually administered BHV-0223," Coric said when the results of the study were released. "Sublingual BHV-0223 is unique in that it is a Zydis orally dissolving tablet formulation, that is optimized to allow administration to patients with dysphagia and to provide therapeutic blood levels with a lower milligram dose for all patients suffering from ALS."

EAPs are regulated by the FDA to provide access to drugs in development, prior to regulatory approval for marketing, to eligible patients with serious or life-threatening diseases or conditions for which there are insufficient pharmacologic alternatives. In December 2016, BHV-0223 was granted orphan drug designation in ALS.

"It is great for the ALS community that Biohaven is taking advantage of the FDA's expanded access program," said Calaneet Balas, president and CEO of The ALS Association. "We believe this is the first instance of a company offering expanded access for widespread use in ALS. Such programs enable people with ALS and their doctors to consider the use of investigational drugs."

An expanded access program has been opened to allow patients with ALS access to BHV-0223, a sublingual formulation of riluzole, all while Biohaven Pharmaceutical prepares a new drug application for the drug.
 

BHV-0223 Expanded Access Program Opened for ALS, as FDA Application Is Prepared

The US Food and Drug Administration (FDA) has approved amantadine (Osmolex ER, Osmotica) extended-release tablets for the treatment of Parkinson disease (PD) and drug-induced extrapyramidal reactions in adults, often adversely caused by many common medications.

The tablet is a formulation of both the immediate and extended-release versions of amantadine, which utilizes Osmotica Pharmaceuticals’ patented Osmodex technology to provide a once-daily option for adults with PD and drug-induced involuntary movement conditions, such as tardive dyskinesia (TD).

The therapy will be available in 3 doses: 129 mg, 193 mg, and 258 mg. The maximum daily dose will be regulated at 322 mg. As the therapy is administered in the morning each day, patients will have flexibility in regimen setting among the trio of dosing options.

“The FDA’s approval of OSMOLEX ER provides a new treatment option for those patients suffering from Parkinson’s disease and adults who have extrapyramidal reactions, or movement disorders, that are caused by certain medicines,” Brian Markison, Chief Executive Officer of Osmotica, said.

 “We are eager to make OSMOLEX ER available to physicians and patients in the US.”

Previously, the FDA approved the therapy for antiviral and antiparkinsonian treatment. In 2017, a version of it was granted approval by the FDA to Adamas. In a trial that year, it displayed a dual benefit for the treatment of dyskinesia and motor symptoms in a population of 126 patients with PD who had developed levodopa-induced dyskinesia (LID), which occurs in more than 50% of patients treated with the common therapy for more than 4 years.

The randomized, double-blind, placebo-controlled trial tested a 274-mg dose of amantadine in patients with PD who experienced at least 1 hour of troublesome dyskinesia each day. After daily nighttime administration of the therapy for 12 weeks, patients in the intervention arm (n = 63) experienced Unified Dyskinesia Rating Scale (UDRS) total score decrease of -15.9 (standard error [SE], 1.6) from baseline. In comparison, patients treated with placebo (n = 58) in that same timeframe saw a decrease of -8 (SE, 1.6) for a treatment difference of 7.9 (95% CI, -12.5 to -3.3; 

The mean OFF time for patients on amantadine was decreased by -0.6 (SE, 0.3) hour, while placebo patients experienced an increase of 0.3 (SE, 0.3) hours (difference, -.09 hours; 95% CI, -1.6 to -0.2; 

The most common adverse events (AEs) experienced by patients were visual hallucinations, peripheral edema, and dizziness. In 13 (20.6%) patients treated with amantadine treatment was discontinued due to AEs, in comparison with 4 (6.9%) patients on placebo.

The therapy has been contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m

. It also protected by a trio of formulation patents with protection extending through March 2030, with additional patent applications pending, according to Osmotica.

Markison noted that Osmotica is currently finalizing its plans for commercialization of the therapy. “We believe that the approved indications and compelling value proposition will be important factors in physician adoption and marketing of OSMOLEX ER,” he added.

1. FDA Approves Osmotica Pharmaceutical’s Once-Daily OSMOLEX ER™ (amantadine) extended-release tablets for the treatment of Parkinson’s Disease and Drug-Induced Extrapyramidal Reactions in Adults [press release]. Bridgewater, NJ: Osmotica; February 19, 2018. osmotica.com/PDF/Osmotica_Release_2_19_18_FINAL.pdf. Accessed February 19, 2018.

2. Pahwa R, Tanner CM, Hauser RA, et. al. ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study). 

The once-daily therapy will be available in 3 doses&mdash;129 mg, 193 mg, and 258 mg&mdash;giving patients flexibility in regimen setting among the options.

FDA Green Lights Amantadine Extended-Release Tablets for Parkinson Disease

The treatment landscape for patients with amyotrophic lateral sclerosis (ALS) is evolving rapidly, with promising therapies in late-stage development and a recent FDA approval for edaravone (Radicava) in May 2017. Prior to these developments, there had been just 1 drug approved by the FDA in 22 years.

In the 137-patient study that was the basis for approval of edaravone, there was a LS mean change of -5.01 from baseline for ALSFRS-R scores with the neuroprotective drug compared with a change of -7.50 for placebo, for a 2.49-point difference. This represented a 33% improvement in ALSFRS-R with edaravone versus placebo.

“For people with ALS and their families, having a new therapy which slows the decline of physical ability is incredibly significant,” Jonathan S. Katz, MD, ALS Clinic Director, Forbes Norris MDA/ALS Research and Treatment Center at California Pacific Medical Center, said when edaravone was approved. “The approval of Radicava brings us into a new era of treatment by evolving how we manage this complex disease. This is an uplifting milestone for the ALS community especially since it’s been so long since we had anything new.”

The last agent to gain approval prior to edaravone was riluzole (Rilutek), which is now being combined with other agents in clinical trials. At the 2017 American Neurological Association meeting, findings were presented for the tyrosine kinase inhibitor masitinib in combination with riluzole for patient with ALS. Moreover, on the same day, the first patient was enrolled in a phase III study exploring a novel cellular therapy.

Following on promising phase II results, BrainStorm Cell Therapeutics initiated a phase III study for their NurOwn mesenchymal stem cell platform. The study is enrolling approximately 200 patients with rapidly progressing ALS. These patients with a more aggressive disease course are ostensibly more difficult to treat.

In early studies exploring the treatment using various dosing strategies, there was a 50% improvement in ALSFRS-R progression from baseline. In a phase II study, 40% of patients treated with NurOwn achieved at least a 50% improvement in ALSFRS-R slope at 12 weeks’ post-treatment compared with 17% with placebo.

Ralph Kern, MD, chief operating officer and chief medical officer of BrainStorm Cell Therapeutics, told 

 that patients with ALS who experience faster deterioration have a particular need for innovative treatment. "This is a very important group of patients who currently, even with the 2 approved therapies right now, really don’t have their needs met,” he said.

The NurOwn treatment involves autologous harvesting of the patient’s bone marrow-derived mesenchymal stem cells, propagating them ex vivo and inducing them to secrete neurotrophic factors (NTF). These MSC-NTF cells are then transplanted into the patient intrathecally by standard lumbar puncture, where it is expected that neurons and glial cells will take up the neurotrophic factors secreted by the transplanted cells.

A principal investigator of the phase III study, Robert Miller, MD, director of the Forbes Norris MDA/ALS Research and Treatment Center at California Pacific Medical Center (CPMC) in San Francisco, California, said in a statement, “NurOwn cells have the important advantage of being autologous, so patients do not need to be immunosuppressed. In addition, the production process is relatively straightforward, and the harvesting and delivery of cells is much less invasive than other stem cell systems that have been tested in the clinic.”

Kern elaborated on the production process, noting 2 significant advances have been made over the course of development. “The changes in the process over the [past] 10 years have been primarily around the practical aspects of cryopreserving the cells, to make it easier to maintain the cells and then allow them to be used at a later date,” he said.

In addition, there has been a substantial reduction of the cycle time from harvesting the bone marrow—derived MSC to making the treatment available. “We’ve been able to shorten the time, for example, from thawing the cells that are cryopreserved to being available for injection to 7 days, which is an incredible technological achievement and important for making this a treatment for repeated dosing,” Kern said.

Patients in the trial will be randomized to receive 3 intrathecal administrations of the autologous MSC-NTF cells or placebo at bimonthly intervals. The course of illness will be evaluated with the ALSFRS-R 28 weeks after the first treatment. Biomarkers will also be tracked, including cell-secreted NTF, inflammatory factors, and cytokines in the cerebrospinal fluid and serum.

Recent phase III findings for the combination of masitinib and riluzole have shown some promise for patients with ALS, offering hope after 2 decades of failure. “The overwhelming majority of human clinical trials in ALS have failed to demonstrate clinical efficacy,” study author Angela Genge, MD, director of the Clinical Research Unit, and ALS Clinic at Montreal Neurological Institute and Hospital in Quebec, Canada, said. “There remains a persistent and urgent unmet medical need in ALS."

In the double-blind trial, 394 patients in 34 sites in 9 countries were randomized to receive 48 weeks of treatment with riluzole in combination with placebo or with masitinib in either a 4.5-mg/kg or 3.0-mg/kg daily dose.

Patients receiving 4.5 mg/kg/day of masitinib with riluzole demonstrated a 27% slower deterioration in ALSFRS-R—rated symptoms at 48 weeks than did those receiving placebo with riluzole. In secondary efficacy measures, this group showed a 29% slower deterioration in quality of life as measured on the ALSAQ-40, and a 22% slower deterioration in respiratory function.

In the measure of survival-to-event endpoint, marked by a deterioration in ALSFRS-R of 9 points from baseline or death, patients receiving masitinib 4.5 mg/kg/day had a significant 25% delay in disease progression (20 months vs 16 months with placebo).

“Masitinib simultaneously targets microglia, macrophage, and mast cell activity in both the central and peripheral nervous system,” Genge said. “The positive benefit—risk balance of study AB10015 signals that masitinib provides a significant new therapeutic option in an ALS population.”

Two more novel therapies are quickly following the first approval in 2 decades for ALS. 

Staff Writer

Articles

Gene Therapy Shows Robust Activity for Duchenne Muscular Dystrophy

BHV-0223 Expanded Access Program Opened for ALS, as FDA Application Is Prepared

FDA Green Lights Amantadine Extended-Release Tablets for Parkinson Disease

After Long Wait, Several Novel Therapies Are on the Horizon for ALS