Thursday, April 27, 2017

Cerliponase alfa for late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease

The US Food and Drug Administration (FDA) has approved cerliponase alfa (Brineura, BioMarin International Ltd) to treat symptomatic children aged 3 years and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a form of Batten disease.

CLN2 is a rare fatal lysosomal storage disorder characterized by a deficiency in enzyme tripeptidyl peptidase-1 (TPP1), which leads to a build-up of protein deposits in the cells, including nerve cells. This damages tissues and leads to progressive degeneration of the brain and retina. Most children with CLN2 lose their ability to walk and talk by the age of 6 years. Often children with CLN2 die between 8 and 12 years of age.

Cerliponase alfa is a recombinant form of TPP1 that replaces the missing enzyme.

Cerliponase alfa had orphan drug and breakthrough therapy designations and received priority review. It's the first drug approved by the FDA to slow loss of walking ability in children with CLN2.

"The FDA is committed to approving new and innovative therapies for patients with rare diseases, particularly where there are no approved treatment options," Julie Beitz, MD, director, Office of Drug Evaluation III in the FDA's Center for Drug Evaluation and Research, said in a statement. 

"Approving the first drug for the treatment of this form of Batten disease is an important advance for patients suffering with this condition."

Cerliponase alfa is administered into the cerebrospinal fluid (CSF) by infusion via an intraventricular access device. The recommended dose is 300 mg given once every other week, followed by an infusion of electrolytes. The complete treatment takes approximately 4.5 hours. Patients should receive antihistamines with or without antipyretics or corticosteroids 30 to 60 minutes before the start of the infusion, the FDA said.

The efficacy of cerliponase alfa was demonstrated in a nonrandomized, single-arm dose-escalation clinical study involving 22 symptomatic children with CLN2 disease and 42 untreated children with CLN2 disease from a natural history cohort.

After taking into account age, baseline walking ability, and genotype, patients treated with cerliponase alfa had fewer declines in walking ability compared with untreated patients, the FDA said.

The most common adverse reactions in patients treated with cerliponase alfa include fever, electrocardiogram (ECG) abnormalities (including bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma, headache, irritability, pleocytosis, device-related infection, feeling jittery, and low blood pressure.

Cerliponase alfa should not be administered if there are signs of acute intraventricular access device–related complications, such as leakage, device failure, or signs of device-related infection (eg, swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device).

If intraventricular access device complications do occur, clinicians should discontinue cerliponase alfa infusion and refer to the device manufacturer's labeling for further instructions, the FDA said.
Clinicians should also routinely test CSF samples to detect device infections. Cerliponase alfa should not be used in patients with ventriculoperitoneal shunts.

In addition, clinicians should monitor vital signs before the infusion starts, periodically during infusion, and after infusion, and they should perform ECG monitoring during infusion in patients with a history of bradycardia, conduction disorder, or structural heart disease, the FDA said.

Hypersensitivity reactions have been reported in cerliponase alfa–treated patients. Because of the potential for anaphylaxis, appropriate medical support should be readily available when the drug is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated, the FDA said.

The FDA will require the manufacturer to further evaluate the safety of cerliponase alfa in patients with CLN2 younger than age 2 years. In addition, a long-term safety study will assess cerliponase alfa–treated patients for a minimum of 10 years.

Earlier this month, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of cerliponase alfa for CLN2 disease.


  1. The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended approval for two orphan drugs given accelerated review that is designed to facilitate access to medicines meeting an unmet medical need.

    At its April meeting, CHMP recommended approval for cerliponase alfa (Brineura, BioMarin International Ltd) for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare, fatal neurodegenerative disorder in children…

    CLN2 is a lysosomal storage disorder characterized by a deficiency in enzyme tripeptidyl peptidase 1 (TPP1), which leads to a build-up of protein deposits in the cells, including nerve cells. This damages tissues and leads to progressive degeneration of the brain and retina. Most children with CLN2 lose their ability to walk and talk by the age of 6 years. Often children with CLN2 die between 8 and 12 years of age.

    Cerliponase alfa is a recombinant form of TPP1 that replaces the missing enzyme.

    The safety and efficacy of this agent were assessed in a single-arm, open-label phase 1/2 study involving 24 children 3 to 8 years old.

    "In the study, 20 of the 23 patients treated (and who could take part in the efficacy analyses) experienced either a slower than expected progression of the disease, a stabilization of the progression of the disease or some improvement in their motor and language abilities. This was considered a significant therapeutic effect," the EMA said in a news release.

    In an extension study, the slowdown in the progression of the disease was observed for more than 1 year and occurred even when the disease was already advanced.

    The most common side effects were fever, vomiting, hypersensitivity, seizures, and upper respiratory tract infections.

    The CHMP has asked the company to complete an ongoing study of cerliponase alfa that is part of the pediatric investigation plan to further assess its safety, efficacy, and tolerability, with a particular focus on children younger than age 2 years. The company will also monitor the long-term safety of the medicine through a patient registry.

    The product will be available as a solution for intracerebroventricular infusion (150 mg) and should be administered only by a trained healthcare professional knowledgeable in intracerebroventricular administration, the EMA said.

  2. Though it may not help their family, the VanHoutans are celebrating the Food and Drug Administration’s (FDA) recent approval of the first treatment for Batten disease, a rare, terminal genetic disorder that primarily affects children. The agency’s decision on Brineura, which is manufactured by Biomarin Pharmaceutical Inc, came on Thursday and will benefit patients diagnosed with CLN2, just one of the 14 variations of Batten disease.

    The VanHoutans, of Chicago, were introduced to the progressive disease in 2009, after their eldest child, Noah, was diagnosed with LINCL — another variation of the disease — at age 3. A year later, their then-toddler daughter Laine received her own diagnosis of CLN2.

    “[Doctors] said, ‘Take your children home and enjoy the time you had left with them,’” Tracy VanHoutan told ABC News. “That didn’t sit well with us, and we started looking at different avenues.”

    They founded Noah’s Hope and began working with the Batten Disease Support and Research Association to help raise money for research, ABC News reported. The VanHoutans are one of several families afflicted by Batten who helped fund the initial research that led to Brineura, according to the news outlet. The drug is meant to slow the progression of the disease, including the loss of walking ability in patients 3 years or older.

    Brineura’s passage evokes many emotions for the VanHoutans. Noah died in March 2016, weeks shy of his 12th birthday, and Laine’s diagnosis has progressed too far for her to benefit from treatment, doctors say. Laine's fraternal twin, Emily, does not have Batten disease.

    “Seeing all of that come to fruition in an approved product last Thursday — it was rewarding, and it was bittersweet,” VanHoutan told ABC News.

    Jennifer VanHoutan said her family is celebrating what the approval will mean for other children facing Batten disease.

    “Laine had a smile on her face all week,” she told ABC News.

  3. When doctors told Bekah and Danny Bowman that a neurodegenerative disease was robbing them of their then 5-year-old son Titus, they never imagined it would strike his little brother, 3-year-old Ely, too. But on June 26, 2015, just two months after Titus was diagnosed with Batten disease, the Bowmans were devastated all over again.

    "We experienced all of that extreme regression and loss and grieving over that, and then we got the diagnosis for Ely at the end of June,” Bekah, 33, told Fox News. “I was at my in-laws in Idaho, I got a phone call and stepped outside, and collapsed on the sidewalk. I had never been that emotionally broken before."...

    Titus and Ely have what scientists call late infantile Batten disease, also known as CLN2…

    Although he was immediately diagnosed with epilepsy, 14 months later, a genetic test revealed Titus had CLN2. Wang said CLN2 patients experience a rapid decline once seizures begin, and at one point Titus was experiencing up to 100 per day.

    “Right before [the first seizure], he was losing skills. He couldn’t name colors, shapes, letters of the alphabet. He was having a really hard time with that, and his eyesight was not doing well,” Bekah said. “He would fall with muscle spasms, and it got to the point where it was really scary and we didn’t know why.”

    Titus was diagnosed in April 2015, and by the end of May, he couldn’t talk, walk or eat by mouth. He died September 17, 2016, when he was 6 years old…

    Even though Ely wasn’t showing symptoms as severe as his brother’s when he received his diagnosis, the confirmation was no less devastating for the Bowmans. What’s different for Ely, though, is a clinical trial sponsored by BioMarin Pharmaceutical that came too late for his brother.

    “They developed a manmade version of the TPP enzyme that the boys are missing,” Wang said. “I got ahold of BioMarin and told the Bowmans, ‘I’m going to do everything I can to make sure I can get this to your boys.’”

    Once a patient is enrolled in the trial, doctors perform surgery to insert a reservoir device into the patient’s brain that will directly inject the medication into the brain’s ventricles. The enzymes are injected during a four-hour process every two weeks in a hospital where the treatment is offered. Though the FDA has yet to approve the treatment, it is only option available to patients like Ely…

    Thus far, the treatment has shown promise in holding the disease at bay, which buys researchers and families more time to find a cure. Some of the patients have even shown improvement in motor skills that had begun to regress. Titus’ disease was too far advanced for enrollment, but Ely was accepted into the early-access program and his first week of treatment was in October 2016.

    Since then, Bekah and Ely have boarded a plane every 10 days to travel from their Irvine, California, home to the Nationwide Children’s Hospital in Columbus, Ohio, which is the only center in the United States that offers the treatment. A GoFundMe page has helped them cover travel-related costs, and Bekah regularly blogs to help cope and connect with other Batten disease families.

  4. Batten disease came to the attention of the Naperville community when three local moms — Casey McCormick, Bianca Morin and Whitney Robbins — raised $400,000 to fight a rare disease afflicting the daughters of a childhood friend.

    n a matter of months, the group pulled together a fundraiser to benefit the foundation created by former Naperville resident Kristen Kaiser Gray and her husband, Hollywood film producer Gordon Gray, on behalf of their daughters, Charlotte and Gwenyth Gray.(see ,

    Although Brineura cannot help Charlotte and Gwenyth (they have a different form known as CLN6), Kaiser Gray said the news is "extremely exciting" for the Batten community.

    "Families have been waiting for something," she said. "It just opens doors to the possibilities."

    Kaiser Gray said Dr. Emily de los Reyes, attending pediatric neurologist at Nationwide Children's Hospital in Ohio and principal investigator for the Brineura studies, also established the protocols for the gene therapy program that Charlotte and Gwenyth have been receiving for the past year.

    Thursday was both happy and sad for Downers Grove residents Tracy and Jennifer VanHoutan, parents of two children affected by CLN2 — Laine, 11, whose condition is too far along for Brineura to benefit, and Noah, who died last year at age 11.

    Their Hope for Noah foundation created in 2009 helped fund the research that led to the clinical trials needed to bring the drug for FDA approval.

  5. BrineuraTM, an enzyme replacement therapy approved by the U.S. Food and Drug Administration (FDA) in April, is the Gieselmann family's only hope for slowing the progression of 5-year-old Elle's Batten disease — a diagnosis that leads to progressive loss of motor and cognitive functions and seizures.

    Batten disease claimed the life of Elle's older sister, Milla, last year. Until the drug's recent FDA approval for neuronal ceroid lipofuscinosis (CLN type 2) Batten disease, Elle participated in its clinical trial at Nationwide Children's Hospital in Columbus, Ohio. The Gieselmanns, who live in Memphis, are relieved Elle can now receive BrineuraTM- administered twice a month close to home.

    "Being able to stay home will not only help Elle and her recovery from infusions, but it is a game changer for our family as we continue fighting through each day," said Elle's dad, Frazer.

    Le Bonheur is committed to helping families who face a rare, devastating diagnosis find hope, says Neuroscience Institute Co-director James Wheless, MD.

    from Brain Waves LeBonheur Children's Hospital Winter 2017