FDA Approves Zolgensma (onasemnogene abeparvovec-xioi) Gene Therapy to Treat Pediatric Patients with Spinal Muscular Atrophy

FDA Approves Zolgensma (onasemnogene abeparvovec-xioi) Gene Therapy to Treat Pediatric Patients with Spinal Muscular Atrophy

May 24, 2019 — The U.S. Food and Drug Administration today approved Zolgensma (onasemnogene abeparvovec-xioi), the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), the most severe form of SMA and a leading genetic cause of infant mortality.

“Today’s approval marks another milestone in the transformational power of gene and cell therapies to treat a wide range of diseases,” said Acting FDA Commissioner Ned Sharpless, M.D. “With each new approval, we see this exciting area of science continue to move beyond the concept phase into reality. The potential for gene therapy products to change the lives of those patients who may have faced a terminal condition, or worse, death, provides hope for the future. The FDA will continue to support the progress in this field by helping to expedite the development of products for unmet medical needs through the use of review pathways designed to advance innovative, safe and effective treatment options.”

SMA is a rare genetic disease caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the survival motor neuron (SMN) protein – a protein found throughout the body, which is critical for the maintenance and function of specialized nerve cells, called motor neurons. Motor neurons in the brain and spinal cord control muscle movement throughout the body. If there is not enough functional SMN protein, then the motor neurons die, leading to debilitating and often fatal muscle weakness. SMA caused by mutations in the SMN1 gene is generally classified into several subtypes, based on the age of onset and severity; infantile-onset SMA is the most severe and most common subtype. Children with this condition have problems holding their head up, swallowing and breathing. These symptoms may be present at birth or may present by the age of 6 months.

“Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival. This approval demonstrates the continued momentum of this promising new area of medicine and the FDA’s commitment to supporting and helping expedite the development of these products.”

Zolgensma is indicated for the treatment of children less than two years of age with SMA. The product is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. The vector delivers a fully functional copy of human SMN gene into the target motor neuron cells. A one-time intravenous administration of Zolgensma results in expression of the SMN protein in a child’s motor neurons, which improves muscle movement and function, and survival of a child with SMA. Dosing is determined based on the weight of the patient.

The safety and effectiveness of Zolgensma is based on an ongoing clinical trial and a completed clinical trial involving a total of 36 pediatric patients with infantile-onset SMA between the ages of approximately 2 weeks and 8 months at study entry. The primary evidence of effectiveness is based on results from the 21 patients treated with Zolgensma in the ongoing clinical trial. In this trial, there are 19 remaining patients, who range in age from 9.4 to 18.5 months; 13 of these 19 patients are at least 14 months of age. Compared to the natural history of patients with infantile-onset SMA, patients treated with Zolgensma also demonstrated significant improvement in their ability to reach developmental motor milestones (e.g., head control and the ability to sit without support).

The most common side effects of Zolgensma are elevated liver enzymes and vomiting. Zolgensma has a boxed warning that acute serious liver injury can occur. Patients with pre existing liver impairment may be at higher risk of experiencing serious liver injury. Clinical examination and laboratory tests to assess liver function should be completed prior to treatment with Zolgensma, and patients’ liver function should be monitored for at least three months after Zolgensma administration.

Certain vaccines are contraindicated for patients on a substantially immunosuppressive steroid dose. Therefore, caregivers should consult with their healthcare professional to determine if adjustments to the patient’s vaccination schedule are necessary to accommodate concomitant corticosteroid administration.

The FDA granted this application Fast Track, Breakthrough Therapy, and Priority Review designations. Zolgensma also received Orphan Drug designation, which provides incentives to encourage the development of drugs for rare diseases.

The FDA also awarded the manufacturer a rare pediatric disease priority review voucher, under a program intended to encourage the development of new drugs and biological products for the prevention and treatment of certain rare pediatric diseases.

The FDA granted the approval of Zolgensma to AveXis Inc.

Posted: May 2019

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Zolgensma (onasemnogene abeparvovec-xioi) FDA Approval History

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FDA Approves Broadened Indication for Xeomin (incobotulinumtoxinA) as First-Line Treatment for Blepharospasm (Involuntary Blinking) in Adult Patients

RALEIGH, N.C.  –  May 13,  2019  –  Merz Americas announced today that the U.S. Food and Drug Administration (FDA) has approved the supplemental Biologics License Application (sBLA) for Xeomin (incobotulinumtoxinA), broadening its indication to be a first-line treatment of blepharospasm (involuntary blinking) in adult patients.

“Merz is proud to offer a first-line treatment option for blepharospasm, a devastating condition that has no cure and affects up to 50,000 patients in the U.S.,”1 said Kevin O’Brien, Vice President and U.S. Head of Neurosciences, Merz. “This milestone, along with the July 2018 approval of Xeomin for the treatment of chronic sialorrhea (drooling) in adults, reinforces our commitment to providing comprehensive care for patients living with movement disorders.”

Blepharospasm causes muscles around the eyes to contract involuntarily. Patients suffering from blepharospasm can experience symptoms including excessive blinking, light sensitivity, dry eyes, eye irritation and watering eyes, and symptoms may worsen over time.1,2

The approval is based on a Phase 3, randomized, double-blind, placebo-controlled, multi-center trial in a total of 61 treatment-naïve patients who had a diagnosis of blepharospasm with a baseline Jankovic Rating Scale (JRS) Severity subscore ≥2.  JRS is the most commonly used clinical scale to measure severity and frequency of blepharospasm.Patients were defined as treatment-naïve if at least 12 months had passed since their last toxin treatment.

The primary efficacy endpoint was the change from baseline in JRS Severity subscore determined at week 6 after the Xeomin injection. The 50 unit treatment group demonstrated statistically significant improvement compared to placebo, with a difference of -1.2 (p=0.0004). The safety findings were similar to previous studies and in line with the known safety profile of Xeomin.

Xeomin was first approved by the FDA in 2010 for the treatment of blepharospasm (previously treated with onabotulinumtoxinA) and cervical dystonia in adult patients and later in 2015 for upper limb spasticity in adult patients. Most recently, Xeomin was approved by the FDA in July 2018 to treat chronic sialorrhea (excessive drooling) in adult patients.

  1. 1.     “Benign Essential Blepharospasm.” National Institutes of Health, USA.gov, 28 Aug. 2018, ghr.nlm.nih.gov/condition/benign-essential-blepharospasm#statistics. Last accessed May, 10 2019.
  2. 2.     Tsui JKC. Blepharospasm and hemifacial spasm. In: Brin MF, Comella C, Jankovic J, eds. Dystonia: Etiology, Clinical Features, and Treatment. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:151-157.

Source: Merz Americas

Posted: May 2019

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Xeomin (incobotulinumtoxinA) FDA Approval History

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FDA Approves Ruzurgi (amifampridine) for Children with Lambert-Eaton Myasthenic Syndrome

FDA Approves Ruzurgi (amifampridine) for Children with Lambert-Eaton Myasthenic Syndrome

May 06, 2019 — The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 years to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. LEMS can occur at any age. The prevalence of LEMS specifically in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide.

Use of Ruzurgi in patients 6 to less than 17 years of age is supported by evidence from adequate and well-controlled studies of the drug in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients and safety data from pediatric patients 6 to less than 17 years of age.

The effectiveness of Ruzurgi for the treatment of LEMS was established by a randomized, double-blind, placebo-controlled withdrawal study of 32 adult patients in which patients were taking Ruzurgi for at least three months prior to entering the study. The study compared patients continuing on Ruzurgi to patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients that continued on Ruzurgi experienced less impairment than those on placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness that evaluated the feeling of weakening or strengthening. The scores indicated greater perceived weakening in the patients switched to placebo.

The most common side effects experienced by pediatric and adult patients taking Ruzurgi were burning or prickling sensation (paresthesia), abdominal pain, indigestion, dizziness and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Patients should inform their health care professional immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Fast Track designations. Ruzurgi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Ruzurgi to Jacobus Pharmaceutical Company, Inc.

Posted: May 2019

Ruzurgi (amifampridine) FDA Approval History

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FDA Approves Dengvaxia (dengue vaccine) for the Prevention of Dengue Disease in Endemic Regions

FDA Approves Dengvaxia (dengue vaccine) for the Prevention of Dengue Disease in Endemic Regions

May 01, 2019 — The U.S. Food and Drug Administration announced today the approval of Dengvaxia, the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands.

“Dengue disease is the most common mosquito-borne viral disease in the world and global incidence has increased in recent decades,” said Anna Abram, FDA deputy commissioner for policy, legislation, and international affairs. “The FDA is committed to working proactively with our partners at the U.S. Centers for Disease Control and Prevention, as well as international partners, including the World Health Organization, to combat public health threats, including through facilitating the development and availability of medical products to address emerging infectious diseases. While there is no cure for dengue disease, today’s approval is an important step toward helping to reduce the impact of this virus in endemic regions of the United States.”

The CDC estimates more than one-third of the world’s population is living in areas at risk for infection by dengue virus which causes dengue fever, a leading cause of illness among people living in the tropics and subtropics. The first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu or another viral infection. A subsequent infection can lead to severe dengue, including dengue hemorrhagic fever (DHF), a more severe form of the disease that can be fatal. Symptoms may include stomach pain, persistent vomiting, bleeding, confusion and difficulty breathing. Approximately 95 percent of all severe/hospitalized cases of dengue are associated with second dengue virus infection. Because there are no specific drugs approved for the treatment of dengue disease, care is limited to the management of symptoms.

Each year, an estimated 400 million dengue virus infections occur globally according to the CDC. Of these, approximately 500,000 cases develop into DHF, which contributes to about 20,000 deaths, primarily among children. Although dengue cases are rare in the continental U.S., the disease is regularly found in American Samoa, Puerto Rico, Guam, the U.S. Virgin Islands, as well as Latin America, Southeast Asia and the Pacific islands.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease, which may lead to hospitalization or even death,” said Peter Marks, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “As the second infection with dengue is often much more severe than the first, the FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease.”

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region. The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease. Dengvaxia has already been approved in 19 countries and the European Union.

The most commonly reported side effects by those who received Dengvaxia were headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever. The frequency of side effects was similar across Dengvaxia and placebo recipients and tended to decrease after each subsequent dose of the vaccine.

Dengvaxia is not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown. This is because in people who have not been infected with dengue virus, Dengvaxia appears to act like a first dengue infection – without actually infecting the person with wild-type dengue virus – such that a subsequent infection can result in severe dengue disease.Therefore, health care professionals should evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus. This can be assessed through a medical record of a previous laboratory-confirmed dengue infection or through serological testing (tests using blood samples from the patient) prior to vaccination.

Dengvaxia is a live, attenuated vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.

The FDA granted this application Priority Review and a Tropical Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of certain tropical diseases. The approval was granted to Sanofi Pasteur.

Source: FDA

Posted: May 2019

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Dengvaxia (dengue vaccine) FDA Approval History

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