Merck KGaA announced that its division Merck Serono has submitted an application to the European Medicines Agency (EMEA) for the marketing authorization (MA) of Sapropterin (INN: Sapropterin dihydrochloride, formerly known as Phenoptin) as an oral treatment for significant hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency.
Sapropterin had previously received Orphan Medicinal Product designation for the treatment of HPA from both the EMEA and the Food and Drug Administration (FDA).
"The filing for Sapropterin is an important milestone for patients with phenylketonuria or BH4 deficiency. These are serious, debilitating diseases for which there is currently no drug approved in Europe. This submission underscores Merck Serono's commitment to address unmet medical needs," said Roberto Gradnik, Head, Operations for Europe, Merck Serono.
PKU and BH4 deficiency are caused by genetic defects in the metabolism of the amino acid phenylalanine, resulting in hyperphenylalaninemia, i.e. abnormally high levels of phenylalanine in the blood.
Hyperphenylalaninemia can cause serious brain damage in infants and young children, and neurological impairment in older patients. There are at least 50,000 people diagnosed with hyperphenylalaninemia due to PKU or BH4 deficiency in the developed world. However, there is no approved drug for the treatment of this condition in Europe. The only alternative for PKU patients to manage their disease is a diet highly restricted in phenylalanine.
Data from two international, double-blind, randomised, placebo-controlled Phase III clinical trials in patients with hyperphenylalaninemia due to PKU show that treatment with Sapropterin reduces blood phenylalanine levels and may reduce the need to limit phenylalanine in patients' diet. The most frequently reported potential undesirable effects were headache, runny nose, diarrhoea, vomiting, sore throat, cough, abdominal pain, stuffy nose, and low levels of phenylalanine in the blood. These adverse events were generally mild to moderate and transient.
Sapropterin is being developed in partnership with BioMarin Pharmaceutical Inc. Under the terms of the agreement with BioMarin, Merck Serono has exclusive rights to market Sapropterin in all territories outside the United States and Japan. BioMarin has exclusive rights to market Sapropterin in the United States.
Sapropterin (INN: Sapropterin dihydrochloride, formerly Phenoptin) is an oral therapeutic for the treatment of hyperphenylalaninemia (HPA) due to phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency. Sapropterin is the synthetic form of 6R-BH4, a naturally occurring enzyme cofactor that works in conjunction with the enzyme phenylalanine hydroxylase (PAH) to metabolize phenylalanine (Phe). Clinical data suggest that Sapropterin produces significant reductions in blood Phe levels in the subset of patients who are BH4-responsive. BioMarin and Merck Serono estimate that Sapropterin could be a potential treatment option for approximately 30-50 per cent of the estimated 50,000 patients in the developed world who have been diagnosed with HPA, due to PKU or BH4 deficiency.
Sapropterin received Orphan Medicinal Product designation to treat HPA from both the FDA and the EMEA. If Sapropterin becomes the first drug therapy approved for the treatment of HPA, Sapropterin would receive seven years of market exclusivity in the United States and ten years in the European Union for this indication. Additionally, the FDA has granted Sapropterin Fast Track designation, which is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.
Disorders of phenylalanine (Phe) metabolism can lead to abnormal elevations of blood Phe levels, also called hyperphenylalaninemia (HPA). Two inborn errors of metabolism, phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency, account for the majority of cases of HPA.
PKU, a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is required for the metabolism of phenylalanine (Phe), an essential amino acid found in all protein-containing foods. The only treatment currently available for PKU patients is a highly restrictive and expensive medical food diet that most patients fail to adhere to the extent needed for achieving adequate control of blood Phe levels.
BH4 deficiency is a very rare inborn error of metabolism, and is estimated to account for 1-2 per cent of cases of HPA. BH4 deficiency is an autosomal recessive genetic condition and can result from deficiencies of any of the five different enzymes involved in BH4 synthesis and regeneration. BH4 is a necessary co-factor for PAH. Therefore, BH4 deficiency impairs PAH activity leading to a biochemical situation similar to PKU, with HPA resulting from deficient conversion of Phe to tyrosine. In addition, since BH4 is also a necessary co-factor for both tyrosine hydroxylase and tryptophan hydroxylase, BH4 deficiency causes deficiencies in the downstream neurotransmitter products of these amino acids including catecholamines and serotonin. Dietary limitation of whole protein or Phe intake is often not necessary with BH4 treatment. However, since BH4 does not cross the blood brain barrier, concomitant therapy with neurotransmitter precursors, i. e. levodopa and 5-hydroxytryptophan, may be necessary to boost central nervous system substrate levels for catecholamine and serotonin synthesis, respectively.
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