Nitisinone

Uses

Nitisinone is used to treat hereditary tyrosinemia type 1, in combination with restriction of tyrosine in the diet.

Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition. I It is marketed under the brand name Orfadin.

It has been demonstrated that treatment with nitisinone can reduce urinary levels of homogentisic acid in alkaptonuria patients by 95%. A series of clinical trials run by DevelopAKUre to determine whether nitisinone is effective at treating the ochronosis suffered by patients with alkaptonuria are ongoing. If the trials are successful, DevelopAKUre will try to get nitisinone licensed for use by alkaptonuria patients.

Mechanism of action

The mechanism of action of nitisinone involves reversibile inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD),. This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys. This causes the symptoms of Tyrosinemia type 1 experienced by untreated patients.

Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty so can't break down homogentisic acid (HGA). Alkaptonuria patients treated with nitisinone produce far less HGA than those not treated (95% less in the urine), because nitisinone inhibits HPPD meaning HGA doesn't form in the first place. Clinical trials are ongoing to test whether nitisinone could prevent the ochronosis experienced by older alkaptonuria patients.

Adverse effects

Nitisinone has several negative side effects; these include but are not limited to: bloated abdomen, dark urine, abdominal pain, feeling of tiredness or weakness, headache, light-colored stools, loss of appetite, weight loss, vomiting, and yellow-colored eyes or skin.

Research

Nitisinone is being studied as a treatment for alkaptonuria.

Research at the National Institutes of Health (NIH) has demonstrated that nitisinone can reduce urinary levels of HGA by up to 95% in patients with alkaptonuria. The primary parameter of the NIH trial was range of hip motion, for which the results were inconclusive.

Research done using alkaptonuric mice has shown that mice treated with nitisinone experience no ochronosis in knee joint cartilage. In contrast, all of the mice in the untreated control group developed ochronotic knee joints.

The efficacy of Nitisinone is now being studied in a series international clinical trials called DevelopAKUre. The studies will recruit alkaptonuria patients in Europe. A larger number of patients will be recruited in these trials than in the previous NIH trial. The trials are funded by the European Commission.

Nitisinone has been shown to increase skin and eye pigmentation in mice, and has been suggested as a possible treatment for oculocutaneous albinism.

History

Nitisinone was discovered as part of a program to develop a class of herbicides called HPPD inhibitors. It is a member of the benzoylcyclohexane-1,3-dione family of herbicides, which are chemically derived from a natural phytotoxin obtained from the Australian bottlebrush plant, Callistemon citrinus. HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine. In plants, preventing this process leads to destruction of chlorophyll and the death of the plant. In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats and humans.

In Type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is mutated and doesn't work, leading to very harmful products building up in the body. Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making herbicides in the class of HPPD inhibitors hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials attempted with one of their compounds, nitisinone, were conducted and were successful, leading to nitisinone being brought to market as an orphan drug Swedish Orphan International, which was later acquired by Swedish Orphan Biovitrum (Sobi).

Sobi is now a part of the DevelopAKUre consortium. They are responsible for drug supply and regulatory support in the ongoing clinical trials that will test the efficiacy of nitisinone as a treatment for alkaptonuria. It is hoped that if the trials are successful, nitisinone could also be licensed for treatment of alkaptonuria.

Generic versions

There is no generic version of Orfadin in G7 countries. Prior to the market authorization of MDK-Nitisinone in Canada, the only Nitisinone product available globally was Orfadin. Until recently, Nitisinone was not approved in Canada where it was distributed for over 20 years via a Health Canada Special Access Program. In September 2016, MendeliKABS was granted approval of a Priority New Drug Submission (PNDS) by Health Canada for a bioequivalent generic version of Orfadin capsules (MDK-Nitisinone). In November 2016 Cycle Pharma was also granted approval of a PNDS by Health Canada for Nitisinone tablets that are bioequivalent to Orfadin capsules. SOBI was granted approval of a PNDS in December 2016.