What are "Orphan Drugs"?

What are "Orphan Drugs"?

Orphan products are drugs, biologics, or other therapeutics that treat diseases that affect fewer than 200,000 people in the United States.

What is the Orphan Drug Act of 1983?

The U.S. Orphan Drug Act (1983) gives incentives to pharmaceutical companies to develop drugs, biologics, or other therapeutics that will treat diseases that affect fewer than 200,000 people in the United States. The orphan drug law offers tax breaks and a seven-year exclusivity on product sales to induce companies to undertake the development and manufacturing of such product, which otherwise might not be profitable because of the small potential market. (Of the 5,000 diseases covered under the act, 47% affect fewer than 25,000 people.) The law has led to the introduction of over 200 valuable new products for the treatment of rare diseases.



Hereditary Tyrosinemia Type I FAQ's

• What is it? • Hereditary Tyrosinemia Type I
• General Questions • Technical Questions
• Administration & Dosage • Side Effects



What is Hereditary Tyrosinemia Type I?

Hereditary Tyrosinemia Type I is a rare genetic metabolic disorder characterized by lack of a liver enzyme called fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down a nutrient found in everyone's diet, tyrosine, leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with Hereditary Tyrosinemia Type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Hereditary Tyrosinemia Type I may progress to more serious complications such as severe liver disease. Hereditary Tyrosinemia type one is inherited as an autosomal recessive trait. Unless the patient receives a liver transplant or the drug Orfadin TM, the patient could die within the first year of life.

GENERAL (questions 1-10)

1. What is the indication?

Orfadin® capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1

2. Contraindications?

None Known

3. Any Drug Interactions?

No drug-drug interaction studies have been conducted with nitisinone

4. What is the chemical designation for Orfadin® (nitisinone)?

2-(2-nitro-4-trifluoromethylbenzoyl) cyclohexane-1,3-dione

or

C 14 H 10 F 3 NO 5

5. How does Orfadin® work?
Nitisinone is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme upstream of FAH in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites Succinylacetone and Succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation of 5-Aminolevulinate, a neurotoxin responsible for the porphyric crisis characteristic of HT-1.


6. How were the clinical trials done?

An open-label study conducted by 96 investigators at 87 hospitals in 25 countries.

7. How quickly does Orfadin® work?

The median time to normalization was 0.3 months for the excretion of succinylacetone in urine and for porphobilinogen synthase (PBG) activity of erythrocytes. Plasma concentrations of succinylacetone normalized in a median time of 3.9 months


8. How does Orfadin® affect the overall survival of HT-1 patients?

Patients presenting with HT-1 under 2 months of age and treated with dietary restrictions alone had 2 and 4-year survival probabilities of 29% and 29%, respectively; HOWEVER- patients presenting with HT-1 under 2 months of age and treated with dietary restriction and nitisinone had 2 and 4-year survival probabilities of 88% and 88%, respectively in the study patients.

Additionally;
Patients historically presenting with HT-1 under 6 months of age and treated with dietary restriction alone had 2 and 4-year survival probabilities of 74% and 60%, respectively; HOWEVER- patients presenting with HT-1 under 6 months of age and treated with dietary restriction and ORFADIN® had 2 and 4 year survival probabilities of 94% and 94% respectively in the study patients.

9. What are the effects of Orfadin® treatment on the incidence of liver transplantation and death due to liver failure?

The long-term prognosis of patients treated with nitisinone wth regard to hepatic function is not yet known and long term studies are being conducted in Sweden.

The results of this clinical study suggest a market reduction (>75%) in the risk of early onset liver failure that characterizes the natural history of HT-1

10. How should Orfadin® be stored?

Store refrigerated, 2-8°C or 36-46°F


ADMINISTRATION AND DOSAGE (questions 11-18)

11. How is it dosed?

(Treatment should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1) The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1mg/kg/day divided for morning and evening administration.

12. Can it be taken with food?

Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal

13. How can it be given to infants and children too small to swallow a capsule?
For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use

14. What kind of diet should I prescribe for the child?

A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine

15. How and when do you adjust (titrate) the dosage?

Treatment should lead to normalized porphyrin metabolism. Succinylacetone should not be detectable in urine or plasma.

If the biochemical parameters (except plasma succinylacetone) are not normalized within one month… the dose should be increased to 1.5 mg/kg/day. For plasma succinylacetone, it may take up to three months before the level is normalized after the start of nitisinone treatment.

16. What is the maximum recommended dose for all patients?

2 mg/kg/day

17. Are strict dietary restrictions enough?

Dietary restrictions of tyrosine and phenylalanine may improve liver and kidney function but does not prevent the progression of the disease.

18. Why is there a concern about patient taking Orfadin® needing to follow a strict dietary regimen?

Since nitisinone inhibits catabolism of tyrosine, use of this drug can result in elevated plasma levels of this amino acid. Treatment with nitisinone therefore, requires restriction of the dietary intake of tyrosine and phenylalanine to prevent the toxicity associated with elevated plasma levels of tyrosine


HEREDITARY TYROSINEMIA TYPE I (questions 19-23)


19. What are the clinical symptoms of hereditary tyrosinemia type 1?

• Progressive liver failure
• Increased risk of hepatocellular carcinoma
• Coagulopathy
• Painful neurologic crisis
• Renal tubule dysfunction resulting in rickets


20. What are the three types of hereditary tyrosinemia type 1?

Acute, subacute and chronic:

Most patients exhibit symptoms before 6 months of age with the acute form of the disease.

In the subacute form children present with symptoms between 6 and 12 months

Chronic form patients do not exhibit symptoms until after one year of age. These patients have a more gradual progression to liver failure but are at increased risk of developing hepatocellular carcinoma.

21. Who (or which form is) at risk for the painful porphyria-like neurologic crises?

Patients with all forms of the disease are at risk of painful porphyria-like neurologic crises, which occur in 5-20% of patients per year as apart of the natural history of the disorder

22. What is the upside of liver transplantation in HT-1 patient?

Liver transplant can correct most of the metabolic effects of the disorder except for the renal tubular dysfunction, which may be due to local production of toxic metabolites in the kidney

23. What is the downside of liver transplantation in HT-1 patient?

• availability
• cost
• a 5-25% retransplantation rate
• onerous drug regimen

TECHNICAL (questions 24-29)

24. Have pharmacokinetics/ drug metabolism studies been done in children?

No pharmacokinetics studies of nitisinone have been conducted in children or in HT-1 patients.

25. Are there concerns about using nitisinone in special populations?

The effects on the pharmacokinetics of nitisinone have not been studied in the following special populations:

• Geriatric: No studies/ no patients

• Gender: Not studied

• Race: Not studied

• Renal Insufficiency: Not studied

• Hepatic Dysfunction: Not studied


26. What is porphobilinogen synthase (PBG)?-

Porphobilinogen synthase (PBG) is one of the 8 requisite enzymes of heme biosynthesis. Abnormally elevated porphyrin levels and their precursors including PBG results in a group of disorders known as porphyrias. Deficiencies in PBG result in porphyria-like neurologic symptoms.

Porphobilinogen synthase is formed in the heme biosynthesis pathway by the conversion of aminolevulinic acid (ALA) into PBG. Succinylacetoacetone is a potent inhibitor of ALA thus a resulting in a deficiency of PBG.

27. How does Orfadin® affect porphyrin metabolism?

Porphyric crisis was observed in 0.3% cases per year. This compares to the incidence of 5-20% cases per year expected as part of the natural history of the disorder

28. What were the effects of Orfadin® on renal function?

At the one year visit, both urine excretion of amino acids and serum concentration of phosphate were within the reference range in studied patients

29. What is the significance of serum alpha-fetoprotein concentrations?

Increased alpha-fetoprotein may be a sign of inadequate treatment or may be indicative of hepatic malignancy.



SIDE EFFECTS (questions 30-35)

30. Are there Warnings for use of Orfadin®?

High Plasma Tyrosine Levels
Inadequate restriction of tyrosine and phenylalanine intake can result in elevations of plasma tyrosine. Plasma tyrosine levels should be kept below 500 μmol/L in order to avoid toxic effects. Toxic effects of elevate plasma tyrosine include:

Eyes
• corneal ulcers
• corneal opacities
• keratitis
• conjunctivitis
• eye pain
• photophobia

Skin
• painful hyperkeratotic plaques on the soles and palms

Nervous System
• various degrees of mental retardation
• developmental delay

Transient Thrombocytopenia and Leucopenia
3% of patients treated were observed to develop transient thrombocytopenia and leucopenia, while 1.5% developed both. Decreasing the dose, stopping treatment for observation were employed on various patients –all of whom normalized their platelet and white blood counts and continued on Orfadin®.

Platelet and white blood counts should be monitored regularly during treatment with Orfadin®


31. Are there Precautions for use of Orfadin®?

Ophthalmologic Care
• Slit-lamp examination of the eyes should be performed before initiation of nitisinone treatment
• Patients that become symptomatic need re-examination and measurement of plasma tyrosine concentration
• More restricted diet should be implemented if the plasma tyrosine level is above 500 μmol/L
• Nitisinone dosage should not be adjusted in order to lower the plasma tyrosine concentration, since HT-1 metaoblic defect may result in deterioration of the patient’s clinical condition

Risks of Porphyric Crises, Liver Failure and Hepatic Neoplasms
Patients were observed to suffer these afflictions during a median time of 22 months the clinical study as follows:

• Liver transplantation 13%
• Liver failure 7%
• Malignant hepatic neoplasms 5%
• Benign hepatic neoplasms 3%
• Porphyria 0.5%

Regular liver monitoring by imaging and laboratory tests including serum alpha-fetoprotein concentration is recommended

32. What about overdosage?

Accidental ingestion will result in elevated tyrosine levels, however, there is no information available on a specific treatment. Patients should be monitored for adverse events.

33. Are there any Drug/ Laboratory Test Interactions?

None Known

34. How about Carcinogenesis?

According to the Package Insert:
“Studies in animals have not been performed to evaluate the carcinogenic potential of nitisinone. Nitisinone was not mutagenic in the Ames test. In a single dose-group study in rats given 100 mg/kg/day (12 times the recommended clinical dose based on relative body surface area), reduced litter size, decreased pup weight at birth, and decreased survival of pups after birth was demonstrated.”

35. What were the adverse reactions observed during the study?

1% or Greater:

Liver and Biliary System-hepatic neoplasm 8%, liver failure 7%

Visual System- conjunctivitis 2%, corneal opacity 2%, keratitis 2%, photophobia 2%, blephraritis 1%, eye pain 1% and cataracts 1%

Hemic and Lymphatic- thrombocytopenia 3%, leucopenia 3%, porphyria 1%, epistaxis 1%

Skin and Appendages-pruritis 1%, exfoliative dermatitis 1%, dry skin 1%, maculopapular rash 1%, alopecia 1%

Less than 1%:

Death

Nervous System- seizures, brain tumor, encephalopathy, headache, hyperkinesia

Cardiovascular-cyanosis

Digestive System- abdominal pain, diarrhea, enanthema, gastritis, gastroenteritis, gastrointestinal hemorrhage, melena, tooth discoloration

Liver and Biliary System-elevated hepatic enzymes, hepatic function disorder, liver enlargement

Metabolic and Nutritional-dehydration, hypoglycemia, thirst

Resistance Mechanism Disorders- Infection, septicemia, otitis

Respiratory-bronchitis, respiratory insufficiency

Musculoskeletal-pathologic fracture

Female Reproductive- amenorrhea

Psychiatric- nervousness, somnolence