Type of information: Patent infringement lawsuit
Product name: Kuvan®
Compound: sapropterin dihydrochloride
Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases
Action mechanism: enzyme co-factor. Kuvan® is the synthetic form of 6R-BH4, a naturally occurring co-factor that works in conjunction with the enzyme phenylalanine hydroxylase (PAH) to metabolize phenylalanine (Phe) into tyrosine. Clinical data show that Kuvan® produces significant reductions in blood Phe concentration in a large subset of patients.
European marketing authorization was granted for Kuvan® in 2008. Kuvan® was the first, and remains the only, medication in combination with dietary modifications in Europe designed to reduce the concentration of phenylalanine in the blood and in the brain in those patients who are responsive to Kuvan® to prevent the debilitating effects of PKU. Kuvan® is indicated in patients of all ages with tetrahydrobiopterin (BH4) deficiency, and in those aged 4 years and above with PKU (due phenylalanine hydroxylase enzyme deficiency) who are responsive to Kuvan. Currently, there is no licensed medication in Europe for the treatment of PKU in the 0–4 years age group. Kuvan® is marketed by Merck Serono outside the USA, Canada and Japan, by BioMarin in the USA and Canada, and under the name Biopten® by Asubio Pharma in Japan. In the USA and Europe, Kuvan® received orphan drug designation.
Company: BioMarin Pharmaceutical (USA - CA) Merck KGaA (Germany)
- • On July 20, 2015, Merck KGaA announced that the European Commission (EC) has authorized a change to the European marketing authorization for Kuvan® (sapropterin dihydrochloride), to allow its use in children with phenylketonuria (PKU) below 4 years of age who have been shown to be responsive to such treatment. The EC decision follows the positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) in May 2015, which was based on a review of data from SPARK*, a Phase IIIb clinical study. The EC decision is applicable to all 28 EU member states and the basis for corresponding decisions issued by Norway, Iceland and Liechtenstein.
Detailed 26-week data from the SPARK study were presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium in September 2014. Results showed that the addition of Kuvan to a phenylalanine-restricted diet significantly
increased phenylalanine tolerance by 30.5 mg/kg/day in children with PKU below 4 years of age and responsive to Kuvan, when compared with phenylalanine tolerance in children following a phenylalanine-restricted diet alone (p<0.001). In the group treated with phenylalanine-restricted diet plus Kuvan phenylalanine tolerance was increased from 37.1 mg/kg/day at baseline to 80.6 mg/kg/day after 26 weeks, and in the phenylalanine restricted diet alone from 35.8 mg/kg/day at baseline to 50.1 mg/kg/day after 26 weeks, respectively.
Following EC approval, the Summary of Product Characteristics (SmPC) will be updated to include details about the use of Kuvan in this younger population. It affects approximately 1/10,000 newborns in Europe.
- • On 21 May 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Kuvan®. The CHMP adopted an extension to an existing indication as follows: “Kuvan is indicated for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with phenylketonuria (PKU) who have been shown to be responsive to such treatment .”
• On September 24, 2014, BioMarin Pharmaceutical announced that a Paragraph IV Certification Notice Letter was submitted to the FDA in connection with an Abbreviated New Drug Application (ANDA) to the FDA for approval to market a generic version of Kuvan® (sapropterin dihydrochloride) Tablets, although it has not yet received notice of the certification. BioMarin has 8 patents listed in the FDA Orange Book with expiration dates between 2024 and 2026. BioMarin will evaluate the Paragraph IV certification when it receives the Notice Letter and intends to vigorously enforce its intellectual property rights. By statute, if BioMarin initiates a patent infringement lawsuit against the party submitting the letter within 45 days of receiving the notice letter, then the FDA would be automatically precluded from approving the ANDA for 30 months, or until a district court decision finding the patents invalid or not infringed, whichever occurs earlier. Once the lawsuit is filed, the 30 month stay period will begin as of the date BioMarin was notified of the filing.
Patents: • On April 13, 2017, BioMarin Pharmaceutical announced that it has entered into a settlement agreement with Par Pharmaceutical that resolves patent litigation in the United States (U.S.) related to Kuvan® (sapropterin dihydrochloride) 100mg oral tablets and powder for oral solution in 100mg packets. Under the terms of the settlement, BioMarin will grant Par a non-exclusive license to its patents related to Kuvan to allow Par to market a generic version of sapropterin dihydrochloride 100mg tablets and powder for oral solution in 100mg and 500 mg sachets in the U.S. for the indications approved for Kuvan beginning October 1, 2020 or earlier under certain circumstances. Additional details of the agreement remain confidential. BioMarin holds patents in Europe related to Kuvan that are valid until at least 2024.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
UE authorization: 2015-07-20
Favourable opinion UE: 2015-05-21
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: