Mechanism Of Action
CYSTADANE acts as a methyl group donor in the remethylation of homocysteine to methionine
in patients with homocystinuria. Betaine occurs naturally in the body. It is a metabolite of
choline and is present in small amounts in foods such as beets, spinach, cereals, and seafood.
CYSTADANE was observed to lower plasma homocysteine concentrations in three types of
homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect. Patients have
taken CYSTADANE for many years without evidence of tolerance. There has been no
demonstrated correlation between Betaine concentrations and homocysteine concentrations.
In CBS-deficient patients, large increases in methionine concentrations over baseline have been
observed. CYSTADANE has also been demonstrated to increase low plasma methionine and
S-adenosylmethionine (SAM) concentrations in patients with MTHFR deficiency and cbl defect.
Pharmacokinetic studies of CYSTADANE are not available. Plasma betaine concentrations
following administration of CYSTADANE have not been measured in patients and have not
been correlated to homocysteine concentrations.
CYSTADANE was studied in a double-blind, placebo-controlled, crossover study in 6 patients
(3 males and 3 females) with CBS deficiency, ages 7 to 32 years at enrollment. CYSTADANE
was administered at a dosage of 3 grams twice daily, for 12 months. Plasma homocystine
concentrations were significantly reduced (p<0.01) compared to placebo. Plasma methionine
concentrations were variable and not significantly different compared to placebo.
CYSTADANE has also been evaluated in observational studies without concurrent controls in
patients with homocystinuria due to CBS deficiency, MTHFR deficiency, or cbl defect. A review
of 16 case studies and the randomized controlled trial previously described was also conducted,
and the data available for each study were summarized; however, no formal statistical analyses
were performed. The studies included a total of 78 male and female patients with homocystinuria
who were treated with CYSTADANE. This included 48 patients with CBS deficiency, 13 with
MTHFR deficiency, and 11 with cbl defect, ranging in age from 24 days to 53 years. The
majority of patients (n=48) received 6 gm/day, 3 patients received less than 6 gm/day,
12 patients received doses from 6 to 15 gm/day, and 5 patients received doses over 15 gm/day.
Most patients were treated for more than 3 months (n=57) and 30 patients were treated for 1 year
or longer (range 1 month to 11 years). Homocystine is formed nonenzymatically from
two molecules of homocysteine, and both have been used to evaluate the effect of
CYSTADANE in patients with homocystinuria. Plasma homocystine or homocysteine
concentrations were reported numerically for 62 patients, and 61 of these patients showed
decreases with CYSTADANE treatment. Homocystine decreased by 83 to 88% regardless of the
pre-treatment concentration, and homocysteine decreased by 71to 83%, regardless of the pretreatment
concentration. Clinical improvement, such as improvement in seizures, or behavioral
and cognitive functioning, was reported by the treating physicians in about three-fourths of
patients. Many of these patients were also taking other therapies such as vitamin B6
(pyridoxine), vitamin B12 (cobalamin), and folate with variable biochemical responses. In most
cases, adding CYSTADANE resulted in a further reduction of either homocystine or