Date: 2017-06-01

Type of information: Granting of a Market Authorisation in the EU

Product name: Brineura™ - BMN 190

Compound: cerliponase alfa

Therapeutic area: Rare diseases - Neurodegenerative diseases - Genetic diseases

Action mechanism:

  • enzyme replacement therapy. Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (rhTPP1). This enzyme replacement therapy is designed to restore TPP1 enzyme activity and break down the storage materials that cause neuronal ceroid lipofuscinosis type 2. In order to reach the cells of the brain and central nervous system, the treatment is delivered directly to the cerebrospinal fluid using BioMarin's patented technology.
  • In the absence of TPP1, lysosomal storage materials normally metabolized by this enzyme accumulate in many organs, particularly in the brain and retina. Buildup of these storage materials in the cells of the nervous system contribute to the progressive and relentless neurodegeneration which manifests as loss of cognitive, motor, and visual functions. Disease progression is rapid. The onset of symptoms is typically between ages two and four. Patients typically present initially with language delay and seizures, followed by movement disorders, motor deterioration, dementia, blindness and early death. During the later stages of the disease, feeding and tending to everyday needs become very difficult and death typically occurs between ten and 16 years of age.
  • Cerliponase alfa has been granted Orphan Drug Designation by the FDA and EMA and Breakthrough Therapy designation by the FDA.

Company: BioMarin Pharmaceutical (USA - CA)

Disease: late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), a form of Batten disease

Latest news:

  • • On June 1, 2017, the European Commission has granted marketing authorization for Brineura™ (cerliponase alfa), the first treatment approved in the European Union for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency. The dosing administration includes all ages from birth. The Brineura™ Marketing Authorization Application (MAA) was based on an open-label, dose-escalation study for Brineura™ in 24 patients with CLN2 disease between 3 and 8 years of age, as well as an open-label extension study. The primary objectives were to evaluate the safety and tolerability of intracerebroventricular-administered Brineura™ and to evaluate effectiveness using a CLN2 disease-specific rating scale score in comparison with natural history data after 48 and 72 weeks of treatment.
  • The clinical study has shown that at 48 weeks, 87 percent or 20 of the 23 children who completed the trial did not decline in motor and language score. In the study, the mean rate of decline in patients treated with Brineura at 300 mg. every other week was 0.40 points per 48 weeks. When compared to the expected rate of decline based on the natural history, the study results are statistically significant (p<0.0001). The observed treatment effect was considered clinically meaningful in light of the natural history of untreated CLN2 disease. In the ongoing study as of June 3, 2016, the rate of decline in patients treated with Brineura™ compared to the natural history control group (N=42 patients) continues to show durability of the treatment effect.
  • In the clinical study, intraventricular access device-related infections were observed in two patients. In each case, antibiotics were administered, the intraventricular access device was replaced and the patient continued on Brineura treatment.  Hypersensitivity reactions have been reported in 14 (58%) Brineura treated patients during the clinical studies. The most common adverse reactions are convulsions, pyrexia, decreased cerebrospinal fluid (CSF) protein, ECG abnormalities, vomiting, upper respiratory tract infection, hypersensitivity, irritability, increased CSF protein, headache, needle issue and CSF pleocytosis.
  • • On April 27, 2017, the FDA approved Brineura™ (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura® is expected to be available in the United States by early June, and BioMarin will begin promotion of Brineura® immediately. Brineura® is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). Brineura® must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura® in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura® infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion. The efficacy of Brineura® was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least 3 years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, Brineura®-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.
  • The safety of Brineura® was evaluated in 24 patients with CLN2 disease aged 3 to 8 years who received at least one dose of Brineura® in clinical studies. The safety and effectiveness of Brineura® have not been established in patients less than 3 years of age.
  • The most common adverse reactions in patients treated with Brineura® include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure.
  • Brineura® should not be administered to patients if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, health care providers should discontinue infusion of Brineura and refer to the device manufacturer’s labeling for further instructions. Additionally, health care providers should routinely test patient CSF samples to detect device infections. Brineura® should also not be used in patients with ventriculoperitoneal shunts (medical devices that relieve pressure on the brain caused by fluid accumulation).
  • The FDA will require the Brineura® manufacturer to further evaluate the safety of Brineura® in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura® treated CLN2 patients for a minimum of 10 years.
  • The FDA granted this application Priority Review and Breakthrough Therapy designations. Brineura® also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
  • The sponsor is also receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the tenth rare pediatric disease priority review voucher issued by the FDA since the program began.
  • • On April 21, 2017, the European Medicines Agency (EMA) has recommended granting a marketing authorisation in the European Union for Brineura® (cerliponase alfa) for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease. There are currently no medicines approved for treatment of CLN2 disease. Current options only treat the symptoms of the disease. The safety and efficacy of Brineura® were assessed in a single-arm, open-label phase I/II study involving 24 children aged between three and eight years and an extension of this study which evaluated the long-term effects of the medicine. The study also compared the improvement of motor and language functions in children treated with Brineura with information from natural history studies that observe how the disease develops in untreated children over time.
  • 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 stabilisation of the progression of the disease or some improvement in their motor and language abilities. This was considered a significant therapeutic effect.
  • In the extension study, the slowdown in the progression of the disease was observed for more than one year and occurred even when the disease was already advanced. The most frequent adverse events were fever, vomiting, hypersensitivity, seizures and upper respiratory tract infections.
  • As CLN2 is a very rare disease, the Committee for Medicinal Products for Human Use (CHMP) agreed that it is not possible to provide comprehensive data on the efficacy and safety under normal conditions of use. Therefore the Committee recommended granting a marketing authorisation under exceptional circumstances and requested the applicant to complete an ongoing study that is part of the paediatric investigation plan to further evaluate the safety, efficacy and tolerability of Brineura®, with a particular focus on children younger than two. The company will also monitor the long term safety of the medicine through a patient registry.
  • • On September 15, 2016, BioMarin Pharmaceutical announced that the European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) for Brineura™ (cerliponase alfa) to treat children with CLN2 disease, a form of Batten disease. Validation of the MAA confirms that the submission is accepted and starts the formal review process by the EMA's Committee for Human Medicinal Products (CHMP). Earlier this year, the CHMP accepted BioMarin's request for accelerated assessment of the MAA on the grounds that Brineura™ is of major public health interest with the potential to have a major impact on medical practice for CLN2 patients in Europe. Accelerated assessment has the potential to shorten the EMA's review procedure. However, applications which are initially granted accelerated assessment frequently revert to standard assessment timelines. Assuming a positive opinion from the CHMP and standard assessment timing, a decision from the European Commission is anticipated by the third quarter of 2017.
  • BioMarin has implemented an early access (compassionate use) program as planned to provide experimental drug for additional CLN2 patients prior to obtaining marketing approval. The program is limited in scope and number of participants, and is being conducted under a protocol. The program initially is being conducted at centers that have participated in the cerliponase alfa study. The program began in August 2016 in Hamburg (Germany) and Columbus (USA).
  • • On September 6, 2016, BioMarin Pharmaceutical announced a program update for cerliponase alfa to treat children with CLN2 disease, a form of Batten disease. After 81 weeks, patients treated with cerliponase alfa continue to have motor-language (ML) scores representing substantial attenuation of disease progression compared to natural history.  These data are consistent with the data at 48 weeks submitted with the original Biologics License Application (BLA), and demonstrate durable and consistent treatment response.  During their initial review of the BLA, the FDA requested an updated efficacy data cut from the ongoing extension study, which the company provided.  The FDA designated this submission as a major amendment to the application, thus extending the PDUFA action date by three months to April 27, 2017.
  • The additional data continue to show that the Hamburg Motor + Language CLN2 scores1 of a majority of treated patients are stable.  Natural history of the disease shows an average of 2.1 points of decline over 48 weeks and an expected 3 points of decline over 81 weeks.2  Updated analysis of the estimated rate of decline including approximately 8 months of additional data continues to show substantial attenuation of disease progression with cerliponase alfa treatment. The mean (95% Confidence Interval) rate of decline of the Motor Language score in points per 48 weeks for the Intent to Treat (ITT) population (n = 23) as of 03 June 2016 was 0.32 (0.13, 0.52) (p < 0.0001 compared to a 2-point decline derived from available natural history), which was based on 81 weeks of treatment.  This rate is improved from the corresponding rate of decline reported in the original BLA of 0.48 (0.16, 0.81), which was based on 48 weeks of treatment.
  • The primary analysis, agreed to with FDA, is a responder analysis where patients with decline in CLN2 score (<2 points over 48 weeks) are defined as responders.  The response rate at 81 weeks (< 2 point decline in CLN2 score) remained 87%, as reported in the original BLA.
  • Consistent with previous data cuts, cerliponase alfa administered via intracerebroventricular infusion every 14 days was well tolerated, and no patients discontinued treatment due to adverse events (AEs).  Most AEs were Grade 1 or 2, and the majority are consistent with severe, chronic neurologic disease in pediatric patients.  The most common events associated with treatment included:  pyrexia, hypersensitivity, seizure, epilepsy, vomiting and headache.  No new safety signals were observed.
  • • On July 27, 2016, the FDA accepted for review the submission of a Biologics License Application (BLA) for cerliponase alfa. The Prescription Drug User Fee Act (PDUFA) goal date for a decision is April 27, 2017. The FDA granted cerliponase alfa Priority Review status, which is designated to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. Cerliponase alfa was previously granted Orphan Drug Designation and Breakthrough Therapy Designation by the FDA.
  • • On May 3, 2016, BioMarin Pharmaceutical announced that the European Medicines Agency (EMA) has granted BioMarin's request for accelerated assessment for the planned cerliponase alfa Marketing Authorization Application. The company expects to submit the cerliponase alfa MAA to the EMA and the Biologics License Application to the FDA) by mid-year. If the cerliponase alfa MAA is accepted by the EMA, then an opinion from the Committee for Medicinal Products for Human Use (CHMP) is anticipated in the first quarter of 2017, and, if positive, a decision from the European Commission could be received in the first half of 2017. In the U.S., BioMarin is seeking to shorten the regulatory review time by requesting Priority Review. Priority Review status is designated by the FDA to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. The FDA will evaluate this request following submission of the planned Biologics License Application (BLA).
  • • On 5-6 February 2013, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for recombinant human tripeptidyl-peptidase 1 for treatment of neuronal ceroid lipofuscinosis type 2.


Submission of marketing authorization application USA : 2016-09-15

Submission of marketing authorization application UE: 2016-07-15

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2017-04-27

UE authorization: 2017-06-01

Favourable opinion UE: 2017-04-21

Favourable opinion USA:

Orphan status USA: 2013-04-01

Orphan status UE: 2013-03-14

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

  • • On November 27, 2017, BioMarin Pharmaceutical announced that it has entered into a definitive agreement to sell the Rare Pediatric Disease Priority Review Voucher (PRV) it obtained in April of this year for a lump sum payment of $125,000,000. BioMarin was awarded the voucher when it received approval of Brineura® for patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2). The transaction remains subject to customary closing conditions, including anti-trust review. BioMarin will direct the proceeds from this voucher sale towards additional investment in its pipeline of products to treat rare and ultra-rare diseases.

Is general: Yes