Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism

Definitions

• TECHNICAL FIELD The invention relates to nitisinone (2-[2-nitro-4-(trifluoromethyl)benzoyl]-1 ,3- cyclohexanedione) for use in the treatment of alkaptonuria, wherein nitisinone is
• the invention also relates to a
• composition comprising nitisinone for use in the treatment of alkaptonuria, wherein nitisinone is administered in a dose of at least 4 mg per day.
• Alkaptonuria is an autosomal recessive disorder caused by a deficiency of the enzyme homogentisate 1 ,2-dioxygenase (HGD). It is a rare disease affecting approximately one in every 250,000 to 1 million people. Due to the absence of HGD, alkaptonuria patients are unable to fully metabolize the amino acid tyrosine, which results in high plasma (or serum) levels of homogentisic acid (HGA). Despite efficient and marked urinary excretion of much of the HGA formed in AKU patients, some of it is oxidized to a melanin-like polymeric pigment via benzoquinone acetic acid (BQA).
• BQA benzoquinone acetic acid
• This pigment polymer is deposited in connective tissues (particularly cartilage) in a process termed ochronosis. This leads to severe arthritis of the spine and synovial joints with an early onset. Until the late 20s or early 30s, there are few clinical features aside from dark urine. Thereafter, progressive arthritic pain begins, affecting the spine and all synovial joints. The high levels of HGA further cause damage to heart valves and lead to the formation of kidney stones, as well as prostate stones in men.
• Nitisinone (2-[2-nitro-4-(trifluoromethyl)benzoyl]-1 ,3-cyclohexanedione) is a competitive inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD). Under the brand name Orfadin ® , it is used in the treatment of hypertyrosinaemia type 1 (HT-1 ) where it acts by blocking the metabolic degradation of 4-hydroxyphenylpyruvate. Nitisinone thereby prevents the formation of HGA and the accumulation of the toxic intermediates maleylacetoacetate (MAA) and fumarylacetoacetate (FAA) in HT-1 patients (see scheme 1 ).
• MAA maleylacetoacetate
• FAA fumarylacetoacetate
• Nitisinone has also been investigated for the treatment of AKU in a long-term (36 months) clinical trial in a dose of 2 mg/day. Although the urinary excretion of nitisinone was reduced by about 95 % on average, compared to pre-treatment levels, the trial failed to show an effect on the primary efficacy variable, hip rotation (Introne et al., Mol. Genet. Metab. 201 1 , vol. 103, no. 4, p. 307-314).
• FIG. 1 shows a plot of the urinary excretion of HGA at baseline and at week 4 for all patients (including untreated controls).
• FIG. 2 shows a plot of u-HGA 24 ( ⁇ ) at week 4 for nitisinone-treated patients.
• FIG. 3 shows a plot of the daily average serum concentrations of tyrosine ( ⁇ " ⁇ / ⁇ _) at baseline and week 4 for nitisinone-treated patients.
• FIG. 4 shows a plot of the urinary excretion of HGA and serum concentrations of tyrosine at week 4 for all patients (including untreated controls).
• FIG. 5 shows a plot of the urinary excretion of HGA and serum concentrations of tyrosine at week 4 for nitisinone-treated patients.
• FIG. 6 shows the relationship between average daily serum tyrosine concentrations and urinary excretion of HGA for nitisinone-treated patients (1 -8 mg daily).
• nitisinone The inevitable consequence of treatment with nitisinone is the elevation of tyrosine levels. In the treatment of HT-1 , it is therefore recommended that a more restricted tyrosine and phenylalanine diet should be implemented to keep plasma tyrosine levels below 500 ⁇ " ⁇ / ⁇ _.
• tyrosine levels in untreated patients were approximately 60 ⁇ , whereas the 20 patients on nitisinone 2 mg daily had tyrosine levels of 332 - 1528 ⁇ , with an average of 800 ⁇ (Introne et al., supra). Stable but variably increased plasma tyrosine concentrations were seen by 3-4 weeks post-nitisinone. It is thus difficult to keep the tyrosine concentrations at or below an acceptable level without diet restrictions.
• serum tyrosine levels are kept as low as possible.
• serum tyrosine levels are normally between about 40 and 90 ⁇ " ⁇ / ⁇ _, and levels higher than 500 ⁇ " ⁇ / ⁇ _ should generally be avoided.
• serum tyrosine levels already are between 600 and 1000 ⁇ / ⁇ _.
• nitisinone at considerably higher doses than previously used in the treatment of alkaptonuria may suppress the formation of HGA to more than 99 %, while only marginally further increasing the tyrosine level in serum.
• the dose of nitisinone can be increased without an increased risk of for example tyrosine-related side-effects.
• the invention relates to nitisinone for use in the treatment of alkaptonuria, wherein nitisinone is administered in a dose of at least 4 mg per day.
• the daily dose of nitisinone as disclosed herein represents a fixed daily dose. This means that the dose is not adjusted based on e.g. body weight of the patient.
• a dose of at least 4 mg nitisinone per day thus represents the minimum level of a fixed daily amount of nitisinone administered to a patient.
• nitisinone is administered in a dose of at least 6 mg per day. In a more preferred embodiment, nitisinone is administered in a dose of at least 8 mg per day. In a yet more preferred embodiment, nitisinone is administered in a dose of at least 10 mg per day.
• nitisinone is administered in a dose of 8-12 mg per day. In a most preferred embodiment, nitisinone is administered in a dose of 10 mg per day.
• nitisinone In order to limit the risk of side effects, the dose of nitisinone should not exceed 15 mg per day. It can be estimated by extrapolation that such a dose should be sufficient to decrease u- HGA by about 99.9 % in a majority of patients.
• nitisinone is administered in a dose of at least 4 and up to 15 mg per day.
• nitisinone is administered in a dose of at least 6 and up to 15 mg per day.
• nitisinone is administered in a dose of at least 8 and up to 15 mg per day.
• nitisinone is administered in a dose of at least 10 and up to 15 mg per day.
• the invention also relates to the use of nitisinone in the manufacture of a medicament for the treatment of alkaptonuria, wherein the nitisinone is administered in the doses described above.
• the invention also relates to a method of treating alkaptonuria, comprising
• nitisinone administered to a patient in need of such treatment in the doses described above.
• the invention relates to nitisinone for use in the treatment of alkaptonuria as disclosed herein, wherein nitisinone is administered as a pharmaceutical composition which comprises nitisinone in admixture with one or more pharmaceutically acceptable excipients.
• the invention relates to a pharmaceutical composition
• nitisinone for use in the treatment of alkaptonuria, wherein nitisinone is administered in a dose of at least 4 mg per day.
• nitisinone is administered in a dose of at least 6 mg per day.
• nitisinone is administered in a dose of at least 8 mg per day.
• nitisinone is administered in a dose of 8-12 mg per day, such as 10 mg per day.
• nitisinone is administered in a dose of at least 4 and up to 15 mg per day.
• nitisinone is administered in a dose of at least 6 and up to 15 mg per day. In yet another embodiment, nitisinone is administered in a dose of at least 8 and up to 15 mg per day. In yet another embodiment, nitisinone is administered in a dose of at least 10 and up to 15 mg per day.
• the pharmaceutical composition comprising nitisinone may additionally comprise one or more pharmaceutically acceptable excipients.
• the daily dose of nitisinone may be a single dose that is administered once a day, or may be divided into two or more smaller doses that are administered several times a day.
• the frequency of administration can remain constant or be variable during the duration of the treatment.
• nitisinone is administered once daily as a single dose.
• nitisinone is administered orally.
• Nitisinone can be administered in a composition comprising a therapeutically effective amount of the active ingredient, in admixture with one or more pharmaceutically acceptable excipients.
• a composition comprising nitisinone can be formulated as, e.g., capsules, tablets, solutions and oral dispersions.
• a suitable liquid pharmaceutical composition for oral administration is disclosed in WO 2012/177214. Said liquid pharmaceutical composition comprises a suspension of an effective amount of micronized nitisinone and citric acid buffer having a pH in the range of 2.5 to 3 .5, preferably pH 3.0.
• a randomized, open-label, parallel-group dose-response study with a no-treatment control group was performed. Patients with AKU were randomized to receive either 1 mg, 2 mg, 4 mg or 8 mg nitisinone once daily (oral administration) or no treatment (control). Forty patients were randomized, equally distributed amongst the five groups (8 patients per group). Patients
• Uncontrolled hypertension blood pressure greater than 180 mmHg systolic or greater than 95 mmHg diastolic.
• Nitisinone was administered as an oral suspension containing 4 mg/mL. The following dose volumes were administered once daily, in the morning: 1 mg 0.25 ml_
• Each dose was given to a group of 8 patients, and there was an untreated control group also consisting of 8 patients.
• Urinary excretion of HGA over a 24-hour period was assessed at weeks 0, 2 and 4. Urine was collected into 2.5-L bottles containing 30 mL of 5N H 2 S0 4 . The exact length of the collection interval and the volume of the collected urine were recorded. The concentration of HGA in the urine was measured by liquid chromatography tandem mass spectrometry (LCMSMS). The 24-hour excretion of HGA was calculated by multiplying the concentration with the volume of the collected urine, and correcting for any deviation from a 24-hour collection period. (There were no reports of missed samples within the collection interval.)
• LCMSMS chromatography tandem mass spectrometry
• Figure 3 shows the daily average serum concentrations of tyrosine ( ⁇ " ⁇ / ⁇ _) at baseline and week 4 for all doses. It can be seen that the inter-individual variability in s-Tyr is of the same magnitude for all doses.

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• 2015
  • 2015-04-29 AU AU2015254669A patent/AU2015254669A1/en not_active Abandoned
  • 2015-04-29 SG SG11201608957VA patent/SG11201608957VA/en unknown
  • 2015-04-29 WO PCT/EP2015/059352 patent/WO2015165972A1/en not_active Ceased
  • 2015-04-29 TN TN2016000479A patent/TN2016000479A1/en unknown
  • 2015-04-29 BR BR112016024756A patent/BR112016024756A2/pt not_active IP Right Cessation
  • 2015-04-29 JP JP2016564948A patent/JP2017514820A/ja active Pending
  • 2015-04-29 MA MA039918A patent/MA39918A/fr unknown
  • 2015-04-29 CA CA2947062A patent/CA2947062A1/en not_active Abandoned
  • 2015-04-29 US US15/307,622 patent/US20170049716A1/en not_active Abandoned
  • 2015-04-29 EP EP15722113.6A patent/EP3137066A1/en not_active Withdrawn
• 2016
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