BioMarin Pharmaceutical, a global biotechnology company, has announced that the US. Food and Drug Administration (FDA) approved Brineura (cerliponase alfa) to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency. Brineura is the first treatment approved to treat children with CLN2 disease, a form of Batten disease.

CLN2 disease is an ultra-rare, rapidly progressive fatal brain condition, which affects less than one in one million U.S. residents, many of whom are undiagnosed. Every year approximately 20 children are born in the US. with CLN2 disease.  These affected children completely lose the ability to walk and talk around 6 years of age. During the later stages of the disease, feeding and tending to everyday needs become very difficult with death often occurring between 8 and 12 years of age.

In clinical trials, Brineura, an enzyme replacement therapy, was shown to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with CLN2 disease. It is the first enzyme replacement therapy to be directly administered to the brain, treating the underlying cause of the condition by replacing the deficient TPP1 enzyme. Using an established technique most often used in oncology intraventricular administration the therapy is delivered directly into fluid surrounding the brain, known as the cerebrospinal fluid.

To support the community of families with children with neurologic disorders, BioMarin in partnership with a commercial lab is offering a no cost genetic testing program called 'Behind the Seizure' to support early testing for children who experience seizures. In addition, BioMarin is investing in tools and resources to educate physicians on CLN2 disease in order to help them diagnose patients with this disease earlier and prevent them from being misdiagnosed during critical years when therapy could help slow the loss of ambulation.

In addition, BioMarin RareConnections, a resource available to patients and families, provides a variety of personalized support services at no cost to patients, including education on CLN2 disease and Brineura, and coordination of additional services, such as information about financial assistance programs.

"We thank the FDA for recognizing Brineura's potential to alter the course of CLN2 disease and its urgency in delivering this treatment to children as quickly and safely as possible. Brineura was approved in under four years from starting the first clinical trial to today, a significant achievement for a condition that progresses so rapidly," said Jean-Jacques Bienaimé, chairman and chief executive officer of BioMarin. "Treating children with CLN2 disease requires an extraordinary amount of collaboration between families, hospitals, advocates and physicians. We are grateful for the partnership of all those involved and look forward to continuing to work together to make Brineura accessible to children who may benefit."

"CNL2 is a devastating diagnosis that robs families of life with their children much too young," said Emily de Los Reyes, M.D, attending pediatric neurologist at Nationwide Children's Hospital and principal investigator for Brineura studies. "Recent announcement gives my patients and their families hope."

"The approval of Brineura is an extraordinary medical breakthrough for the CLN2 Batten community who have been waiting for this moment for more than a century when the condition was first described," said Margie Frazier, PhD, LISW-S, executive director of Batten Disease Support and Research Association. "We appreciate BioMarin's commitment and partnership to the CLN2 Batten community and investing the resources needed to bring this pivotal treatment to families."

With this approval, the FDA also issued a Rare Pediatric Disease Priority Review Voucher, which confers priority review to a subsequent drug application that would not otherwise qualify for priority review. The rare pediatric disease review voucher program is designed to encourage development of new drugs and biologics for the prevention or treatment of rare pediatric diseases.

Brineura is expected to be available in the United States by early June, and BioMarin will begin promotion of Brineura immediately.

Last week, the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), adopted a positive opinion for the company's Marketing Authorization Application (MAA) for Brineura to treat children with Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease, a form of Batten disease, which is also known as tripeptidyl peptidase 1 (TPP1) deficiency. The CHMP's recommendation is now referred to the European Commission (EC), which is expected to render its final decision by the second quarter of 2017.

Clinical Trial Results

The approval was supported by safety and efficacy data assessed over 96 weeks in a non-randomized, single-arm dose escalation clinical study of patients with CLN2 disease. Brineura treated patients were compared to untreated patients from a natural history cohort.

Patients were assessed for decline in the motor domain of the CLN2 Clinical Rating Scale. The scale measures performance of mobility with normal function being a score of 3 and no function being a score of 0. Decline was defined as having a sustained 2-point decline or an unreversed score of 0 in the motor domain of the CLN2 Clinical Rating Scale.

Twenty-four patients aged 3-8 years were enrolled in the clinical study. One patient withdrew after week 1 due to inability to continue with study procedures; 23 patients were treated with Brineura every other week for 48 weeks and continued treatment during the extension.

Results from the 96-week analysis demonstrated the odds of Brineura-treated patients not having a decline were 13 times the odds of natural history cohort patients not having a decline (Odds Ratio (95% Confidence Interval): 13.1 (1.2, 146.9)).

Of the 22 patients treated with Brineura and evaluated for efficacy at week 96, 21 (95%) did not decline, and only the patient who terminated early was deemed to have a decline in the motor domain of the CLN2 Clinical Rating Scale. In comparison, 50% of patients in an independent natural history cohort demonstrated progressive decline in motor function. Two Brineura treated patients with a maximum score were excluded from the analyses, they maintained that score throughout the study period.

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. Hypotension was reported in 2 (8%) patients, which occurred during or up to 8 hours after Brineura infusion. Patients did not require alteration in treatment and reactions resolved spontaneously or after IV fluid administration.

Hypersensitivity reactions have been reported in 11 (46%) Brineura treated patients during the clinical studies. The most common adverse reactions (=8%) are pyrexia, ECG abnormalities, decreased cerebrospinal fluid (CSF) protein, vomiting, seizures, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension.