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Date: 2016-05-31

Type of information: Withdrawal of a market application in the EU

Product name: Kyndrisa® (drisapersen - PRO051/GSK2402968)

Compound: drisapersen - exon 51 specific phosphorothioate oligonucleotide

Therapeutic area: Genetic diseases - Neuromuscular diseases - Rare diseases

Action mechanism:

antisense oligonucleotide. This antisense oligonucleotide induces exon skipping of exon 51 in the DMD gene.

Company: Prosensa (The Netherlands) now BioMarin Pharmaceutical (USA - CA)

Disease:

Duchenne muscular dystrophy

Latest news:

* On May 31, 2016, BioMarin Pharmaceutical announced that it has withdrawn its Kyndrisa™ (drisapersen) Marketing Authorization Application (MAA) from the European Medicines Agency (EMA) following discussions at the May 2016 Committee for Medicinal Products for Human Use (CHMP) meeting. Those discussions clearly indicated that the CHMP intended to issue a negative opinion. Based on discussions at the CHMP meeting and the FDA Complete Response Letter in January, BioMarin intends to discontinue clinical and regulatory development of Kyndrisa® as well as the three other first-generation follow-on products, BMN 044, BMN 045 and BMN 053, currently in Phase 2 studies for distinct forms of Duchenne muscular dystrophy. Notwithstanding this outcome for Kyndrisa® in Europe, the Company continues to expect to achieve non-GAAP break-even or better in 2017.
BioMarin plans to work with physicians, patient groups, and regulatory authorities to develop a transition plan for those patients currently being treated with Kyndrisa®, BMN 044, BMN 045 and BMN 053. The Company will continue to explore the development of next generation oligonucleotides for the treatment of Duchenne muscular dystrophy.

* 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.

* On January 14, 2016, BioMarin Pharmaceutical announced that the FDA issued a Complete Response letter to the Company's New Drug Application (NDA) for Kyndrisa® (drisapersen) for the treatment of Duchenne muscular dystrophy (Duchenne) amenable to exon 51 skipping. The FDA issues Complete Response letters to indicate that the review cycle for an application is complete and that the application is not ready for approval in its present form. FDA has concluded that the standard of substantial evidence of effectiveness has not been met. BioMarin is reviewing the Complete Response Letter and will work with the FDA to determine the appropriate next steps regarding this application. The ongoing Kyndrisa® extension studies will continue, as will the ongoing clinical trials for other exon-skipping oligonucleotides, BMN 044, BMN 045 and BMN 053, while BioMarin is exploring next steps for this application. Patients currently receiving Kyndrisa®, BMN 044, BMN 045 and BMN 053 will remain on therapy.

* On October 15, 2015, BioMarin Pharmaceutical announced that the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA will review the New Drug Application (NDA) for drisapersen. The FDA is currently reviewing drisapersen for the treatment of patients with Duchenne muscular dystrophy amenable to exon 51 skipping. The advisory committee will review drisapersen data included in a new drug application (NDA) during a meeting on November 24, 2015. The Prescription Drug User Fee Act (PDUFA) action date for completion of FDA review of the drisapersen NDA is December 27, 2015. The FDA has granted drisapersen Priority Review status, which is designated to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. The FDA has also granted drisapersen Orphan and Fast Track status, as well as Breakthrough Therapy designation.

* On June 8, 2015, BioMarin Pharmaceutical announced the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for drisapersen for the treatment of the largest subset of Duchenne muscular dystrophy (DMD) amenable to single exon skipping. Drisapersen induces the skipping of dystrophin exon 51, potentially providing a therapeutic benefit to DMD patients for whom skipping of exon 51 restores the proper dystrophin reading frame, corresponding to approximately 13% of DMD patients. The drisapersen clinical dataset includes data from more than 300 patients in three randomized, placebo-controlled, efficacy trials and two ongoing long-term extension studies, in which some boys have been treated for approximately 3.4 years.

* On April 27, 2015, BioMarin Pharmaceutical announced completion of the rolling submission of a New Drug Application (NDA) to the FDA for drisapersen, an investigational exon-skipping drug candidate for the treatment of Duchenne muscular dystrophy. The company intends to also submit an application for registration in the European Union in summer 2015.  Drisapersen has been granted Orphan and Fast Track status, as well as Breakthrough Therapy designation by the FDA (See below). Last January BioMarin Pharmaceutical has completed the initial offering period for the tender offer for all of the outstanding ordinary shares of Prosensa.

* On October 10, 2014, Prosensa announced that it has commenced the submission process for a New Drug Application (NDA) regulatory filing to the FDA for its lead exon-skipping drug candidate, drisapersen, for treating Duchenne muscular dystrophy. The drug received "Fast Track status" from the FDA, making it eligible for a rolling review of an NDA and was also granted "Breakthrough Therapy Designation" in June 2013 (See below). Prosensa expects the rolling submission to be completed before the end of the year. The company is also on track to submitting a marketing authorization application for conditional approval with the EMA in early 2015.

* On June 3, 2014, Prosensa announced that the FDA has outlined a regulatory path forward, under an accelerated approval pathway, for drisapersen, the Company's lead program for the potential treatment of Duchenne Muscular Dystrophy. In addition, the company has been interacting with the European Medicines Agency (EMA) and based on these interactions intends to file in Europe as well. Following the positive feedback from the FDA, Prosensa has confirmed that it will pursue a New Drug Application (NDA) filing for drisapersen with the FDA, under an accelerated approval pathway based on existing data. The company plans to submit a file later this year and will commit to the initiation of two confirmatory post-approval studies. The FDA has outlined the following approaches for confirmatory trials, which the Company is urged to initiate both as soon as possible, as quoted from the guidance letter:

1. "A historically-controlled trial might be acceptable to confirm clinical benefit following accelerated approval. We note that a historically-controlled study is likely to provide interpretable evidence of efficacy only if the beneficial effect of drisapersen is large, by clearly showing that performance is better in drisapersen-treated subjects than could be reasonably expected, based on knowledge of the natural history of the disease. The effect size would have to be sufficient to overcome the uncertainty inherent in historically controlled trials, and motivational factors that can affect the results.

2. A randomized, placebo-controlled trial of another exon-skipping drug with a similar mechanism of action, directed at a different exon (e.g., PRO044 or PRO045), with demonstration of a correlation between dystrophin protein production and definitive clinical benefit on 6-minute walk or another measure, could provide confirmatory evidence of drisapersen's clinical benefit if approval were based on a surrogate endpoint."

In conjunction with commencing confirmatory post-approval studies of drisapersen, Prosensa will continue with its plans to re-dose an initial cohort of boys in the third quarter of 2014 who have previously participated in clinical studies with drisapersen. Based on the guidance, one option is to enroll a number of previously treated patients in these confirmatory studies. Moreover, Prosensa's natural history study, which has enrolled 250 patients, can serve as a historical control.

* On June 27, 2013, GSK has announced that it has received verbal notification that its investigational compound drisapersen (GSK2402968/PRO051) has been granted Breakthrough Therapy designation by the FDA for the potential treatment of patients with Duchenne Muscular Dystrophy. The Breakthrough Therapy designation is one of several programmes created by the FDA to expedite the development and review of drugs for serious or life-threatening conditions and was enacted in 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). GSK’s clinical development plan evaluates the effect of drisapersen in ambulant (Phases II and III) and non-ambulant boys (Phase I) with DMD who have dystrophin gene mutations amenable to an exon 51 skip. Up to 13% of boys with DMD have dystrophin gene mutations/deletions amenable to an exon 51 skip.  The Breakthrough Therapy designation was based on results from the Phase II Study (DMD114117), presented in April at Cold Spring Harbor.  GSK is developing drisapersen under an exclusive, worldwide license from the Dutch company, Prosensa Holding.

* In October 2009, Prosensa partnered with GSK for the development of PRO051/GSK2402968. A Phase III study (DMD114044) started early 2011 and is currently recruiting patients. Several other studies are on-going, such as a Phase II study comparing two doses (DMD114876) , a Phase II dose regimen study (DMD114117) , a safety and PK study in non-ambulatory DMD boys (DMD114118) and an open-label study for patients that have previously participated in the 114044 or 114117 study. 

* On 27 February 2009, orphan designation (EU/3/08/599) was granted by the European Commission to Prosensa for exon 51 specific phosphorothioate oligonucleotide for the treatment of Duchenne muscular dystrophy . The sponsorship was transferred to GSK in June 2010.

 

Patents:

Submission of marketing authorization application USA : 2015-04-27

Submission of marketing authorization application UE: 2015-06-08

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE: 2016-05-31

US authorization:

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA:

Orphan status UE: 2009-02-27/june 2010

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes