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Filing supporting Brineura was supported by a tiny, single-arm study and had no advisory committee review, the latest sign of the US regulatory agency's willingness to speed orphan drugs for serious pediatric diseases.


Rapid development and FDA approval of BioMarin Pharmaceutical Inc.'s Brineura (cerliponase alfa) for a rare, life-threatening form of Batten disease afflicting children shows that despite some past controversy, the regulatory doors are still wide open for orphan drugs.


The company announced April 27 that the US FDA approved the drug for symptomatic pediatric patients who are at least three years of age and have late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), a type of Batten disease that is also known as tripeptidyl peptidase 1 (TPP1) deficiency. TPP1 is caused by mutations in the TPP1 gene. Brineura is an enzyme replacement therapy (ERT) administered into the brain via cerebrospinal fluid.


BioMarin's filing was supported by a single-arm study of 22 evaluable patients, with efficacy compared to a natural history cohort. In all but one patient taking the test drug, motor function did not decline, whereas typically half would be expected to decline based on historical controls.


CLN2 disease is associated with seizures and a delay in language development. The disease also causes movement disorders and is typically fatal by age six. It is ultra-rare, affecting only one in 200,000 people. In the US, about 20 children are born with CLN2 disease every year, and BioMarin's worldwide target population is between 1,200 and 1,600.


BioMarin priced the drug at $702,000 annually but said that it expects with discounts the yearly net price in the US will be about $486,000. (Also see "BioMarin Expects 30% Markdown For Orphan Pediatric Drug Brineura" - Scrip, 28 Apr, 2017.)


Brineura has also enjoyed a warm reception with European regulators. The Committee for Medicinal Products for Human Use recommended approval of the drug on April 21 and a final decision is expected in the second quarter. (Also see "BioMarin Could Launch Brineura Concurrently In US And Europe" - Scrip, 24 Apr, 2017.) Brineura was the first drug to use a revised EU process for accelerated assessment and it was recommended for full approval for patients of all ages. BioMarin said it is prepared to launch in Europe two weeks after approval; it expects to introduce the drug in the US in June.



‘Maximum Flexibility’ At FDA

The drug was developed and approved in just under three years and eight months, CEO Jean-Jacques Bienaime noted during an April 27 investor call. Approval "represents the commitment of the FDA in exercising maximum flexibility by considering the approval of a medicine to treat an ultra-rare disease based on one small clinical study," the exec said.


FDA noted in its approval letter that there had been no need to refer the filing for an advisory committee review.


"The statement speaks volumes to the collaboration we had with the agency throughout the review process in terms of the value of Brineura to children with CLN2 and the tremendous unmet medical need for treatment. We are pleased to experience how the FDA prioritizes innovative treatments for patients with rare and ultra-rare diseases and we are very appreciative of their support for BioMarin's mission," Henry Fuchs, president of worldwide research and development, said.



Good Times For Orphan Drugs

Approval of Brineura, along with clearance of Biogen Inc./Ionis Pharmaceuticals Inc.'s Spinraza for the ultra-rare condition spinal muscular atrophy in December, demonstrates FDA's willingness to exercise flexibility in approving drugs as long as sound data support the drug's benefit, Leerink Swann analyst Joseph Schwartz said in an April 27 note.


The Brineura approval, however, lacks much precedent even for orphan drugs in that development included a single Phase I/II study with 24 patients that demonstrated compelling evidence of efficacy, he said.


FDA has long shown a willingness to be highly flexible in the preapproval requirements and regulatory pathway for investigational drugs intended for very rare diseases. One external study showed that two-thirds of non-cancer orphan drug approvals used some agency flexibility in the requirements to prove effectiveness. (Also see "FDA Orphan Approval Flexibility Remains Steady As Pressure Increases" - Pink Sheet, 27 Oct, 2014.)


Like Brineura, orphan drugs that have capitalized on the agency’s regulatory flexibility often command a high price tag at launch. (See sidebar.)

Perhaps the most high-profile, and controversial, example of regulatory flexibility in the orphan setting is the September 2016 accelerated approval of Sarepta Therapeutics Inc.’s Exondys 51 (eteplirsen) for Duchenne muscular dystrophy.


The NDA was based on a 12-patient, historically controlled, Phase I/II study that FDA officials described as flawed. However, Center for Drug Evaluation and Research Director Janet Woodcock made the approval decision following Sarepta’s submission late in the review of interim muscle biopsy data from 13 patients in an ongoing, Phase III trial that showed a small but statistically significant increase in dystrophin levels.


Although review staff believed substantial evidence of efficacy was lacking, Woodcock overruled their objections and said the approval represented FDA’s greatest flexibility possible while remaining within its statutory framework. (Also see "Accelerated Approval After Eteplirsen: A Lowered Bar Or A Unique Event?" - Pink Sheet, 20 Sep, 2016.)


Biogen and Ionis provided a far more robust data package – both in patient numbers and efficacy – for Spinraza (nusinersen), a treatment for the ultra-rare condition of spinal muscular atrophy treatment, in an NDA submitted just days after the eteplirsen approval.


At FDA’s suggestion, the companies conducted an interim analysis for 82 of the 121 patients in the placebo-controlled, Phase III trial, and the results paved the way for FDA’s full approval in December after a review lasting just three months. (Also see "Biogen Spinraza Approval: The Perfect Antidote To Sarepta Headlines?" - Pink Sheet, 6 Jan, 2017.)


FDA’s Feb. 9 approval of Marathon Pharmaceuticals LLC's corticosteroid Emflaza for Duchenne muscular dystrophy (DMD) also required a considerable degree of flexibility on the agency’s part given challenges with the clinical data.


The application was based on a randomized, placebo-controlled trial of 196 patients, with an Italian study in 29 children submitted as supporting evidence. However, both studies were conducted more than 20 years before the NDA’s submission, and the age of the efficacy studies and missing documentation made for a challenging review. (Also see "Before Price Controversy, Emflaza Got Easy US Nod With Old But Good Enough Data" - Pink Sheet, 31 Mar, 2017.)

Postmarket Trials Could Expand Use

To date, Brineura has been studied in patients ages three years and older, which made FDA hesitant to approve the drug beyond this population – although the European recommendation is for all ages.


It's relatively uncommon for patients to present with symptoms before the age of three, Fuchs said, and FDA is keen to see safety data before labeling the drug for that use.


Postmarketing commitments in the US and anticipated in the EU include a single global study covering the entire pediatric age range of 0-18 years, with a requirement to study short-term safety in a certain number of children under the age of two years.


BioMarin is also committed to developing a registry to monitor safety and efficacy in both regions, Fuchs said.


"We would hope that data collected in the ongoing study of younger children would eventually support a label expansion to all patients in the US," he said.


In Europe, the absence of data for younger pediatric patients was mitigated by the impression that the benefit of treatment would be enough to outweigh concern about whether they could tolerate the dose administration, the exec said.


"So, it's a good indication of [how] scientists can see the same data two different ways, and the US chose to label the product according to how it was studied in a literal sense. We obviously have the opportunity to revisit this once further data are obtained," Fuchs said.


Adverse events for Brineura included two infections caused by the intraventricular access devices used to administer the medicine into the cerebrospinal fluid.


As another postmarketing requirement, the company is required to conduct a safety study that is at least 10 years long to evaluate hypersensitivity reactions, serious cardiovascular events and serious device-related complications.


"In addition, this study will evaluate the effects of serious adverse events on patient performance on the CLN2 motor and language clinical scales," the approval letter states.


FDA has also asked the company as part of the confirmatory trial in younger patients to perform a "root-cause analysis on any device-related complications and/or failures including, but not limited to, an analysis of the material integrity of the intraventricular access device reservoir."

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