Sapropterin dihydrochloride, soluble tablet, 100 mg (equivalent to 77 mg of sapropterin), Kuvan® - November 2011
Page last updated: 16 March 2012
Public Summary Document
Product: Sapropterin dihydrochloride, soluble
tablet, 100 mg (equivalent to 77 mg of sapropterin),
Kuvan®
Sponsor: Merck Serono Australia Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To seek a Section 100 (Highly Specialised Drugs Program) Authority
Required listing for the initial and continuing treatment of:
1) hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU) in
patients who are sapropterin responsive and are:
a) 10 years of age or younger
b) 11 to 17 years of age
c) 18 years of age or older who meet certain criteria.
2) HPA due to PKU or tetrahydrobiopterin (BH4) in pregnant women,
who meet certain criteria and are sapropterin responsive
3) HPA due to BH4 deficiency in patients who are sapropterin
responsive
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Sapropterin was granted orphan drug status and TGA registered on 21 October 2010 for the indication:
- For the treatment of hyperphenylalaninaemia (HPA) in sapropterin-responsive adult and paediatric patients, with phenylketonuria (PKU) or tetrahydrobiopterin (BH4) deficiency.
4. Listing Requested and PBAC’s View
Section 100 (Highly Specialised Drugs
Program)
Authority Required
Treatment under the supervision of a paediatrician or metabolic
clinician of patients 10 years of age or younger, diagnosed with
hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU) with a
phenylalanine level > 350 μmol/L. Patients will be eligible
for a maximum of 1 script as initial therapy to enable their
response to treatment to be assessed. If adequate response is not
achieved within 1 month, the patient is no longer eligible for
PBS-subsidised treatment with sapropterin.
Authority Required
Continuing PBS-subsidised treatment, in paediatric patients
with hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU), who
have a ≥ 30 percent reduction in blood phenylalanine
levels.
Authority Required
Treatment under the supervision of a paediatrician or metabolic
clinician of patients 11 to 17 years inclusive, diagnosed with
hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU) with a
phenylalanine level > 400 μmol/L. Patients will be eligible
for a maximum of 1 script as initial therapy to enable their
response to treatment to be assessed. If adequate response is not
achieved within 1 month, the patient is no longer eligible for
PBS-subsidised treatment with sapropterin.
Authority Required
Continuing PBS-subsidised treatment, in paediatric patients with
hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU) who have
a ≥ 30 percent reduction in blood phenylalanine levels.
Authority Required
Treatment under the supervision of a metabolic clinician of
patients 18 years of age or older, diagnosed with
hyperphenylalaninaemia (HPA) due to phenylketonuria (PKU) with a
phenylalanine level > 600 μmol/L. Patients will be eligible
for a maximum of one script as initial therapy to enable their
response to treatment to be assessed. If adequate response is not
achieved within one month, the patient is no longer eligible for
PBS-subsidised treatment with sapropterin.
Authority Required
Continuing PBS-subsidised treatment, in adult patients with
hyperphenylalaninaemia (HPA), due to phenylketonuria (PKU), who
have a ≥30% reduction in blood phenylalanine levels.
Authority Required
Treatment under the supervision of a metabolic clinician of women,
diagnosed with hyperphenylalaninaemia (HPA), due to phenylketonuria
(PKU) or tetrahydrobiopterin (BH4), with phenylalanine level >
240 μmol/L, who are pregnant. Patients will be eligible for a
maximum of one script as initial therapy to enable their response
to treatment to be assessed. If adequate response is not achieved
within one month, the patient is no longer eligible for
PBS-subsidised treatment with sapropterin.
Authority Required
Continuing PBS-subsidised treatment, in pregnant patients with
hyperphenylalaninaemia (HPA), due to phenylketonuria (PKU) or
tetrahydrobiopterin (BH4), who respond to treatment.
Authority Required
Treatment under the supervision of a paediatrician or metabolic
clinician of patients diagnosed with hyperphenylalaninaemia (HPA)
due to tetrahydrobiopterin (BH4) deficiency.
Patients will be eligible for a maximum of one script as initial
therapy to enable their response to treatment to be assessed. If
adequate response is not achieved within one month, the patient is
no longer eligible for PBS-subsidised treatment with
sapropterin.
Authority Required
Continuing PBS-subsidised treatment, in patients with
hyperphenylalaninaemia (HPA) due to tetrahydrobiopterin (BH4)
deficiency, who respond to treatment.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Hyperphenylalaninaemia (HPA) is a chronic abnormal elevation in
blood levels of phenylalanine resulting from reduced activity of
the liver enzyme phenylalanine hydroxylase (PAH). Phenylketonuria
(PKU) and tetrahydrobiopterin (BH4) deficiency account for the
majority of cases of clinically significant HPA.
HPA is a rare, autosomal recessive condition which is detected
through the Newborn Screening program. The estimated prevalence of
HPA in Australia is approximately 2000 individuals. If left
untreated it can cause severe neurocognitive delay and mental
retardation, neuromotor disability and adverse pregnancy outcomes
for affected women. Current treatment of HPA in PKU is with a
strict, lifelong low phenylalanine diet achieved by controlled
dietary restriction of whole protein, with concomitant
administration of commercial phenylalanine-free protein
supplements. The majority of Australian patients with HPA due to
BH4 deficiency are treated with hospital-funded synthetic
BH4.
The submission proposed that in the treatment of PKU, sapropterin
would be an alternative therapy to current dietary management. In
BH4 deficiency, sapropterin would be an alternative therapy to
synthetic BH4.
6. Comparator
The submission nominated placebo (plus standard management:
phenylalanine (Phe)-restricted diet with Phe-free protein
supplements) as the comparator for sapropterin (added to standard
management) in patients with BH4 responsive PKU.
The PBAC did not accept that this was the appropriate
comparator,see Recommendation and Reasons.
The submission nominated prior treatment with sapropterin as the
comparator for patients with BH4 deficiency.
The PBAC accepted that this was the appropriate comparator,see Recommendation and Reasons.
7. Clinical Trials
For BH4 responsive PKU, the basis of the submission was two randomised placebo controlled fixed dose trials
(PKU-003, and PKU-006 Part 2), comparing treatment with sapropterin (in addition to
a Phe-restricted diet) with placebo (dietary control of Phe alone), in known responders
to sapropterin and tolerance to normal diet. Responders suitable for inclusion in
these trials were identified in two single arm open-label lead-in phase 2 studies
(PKU-001 and PKU-006 Part 1, respectively). Two extension studies (PKU-004 and PKU-008)
examined dose response and safety as supporting studies.
For BH4 deficiency, the basis of the submission was one small single arm phase 2 open-label study (PKU-007)
of patients switching from a non-registered formulation of BH4 to sapropterin or commencing
treatment with sapropterin, while maintaining pre-trial Phe dietary management. The
submission also presented one published open-label study (Kitagawa, 1990 (Japanese)),
11 published case series reports (Shintaku, 2009; Chien, 2001; Al Aqeel, 1991; Cabalska,
2002; Kao, 2004; Wang, 2006; Ye, 2002; Ye, 2007; Jaggi, 2008; Lee, 2006 and Liu, 2008)
and one post marketing report (2004) as supporting studies.
Details of the trials published at the time of submission are in the table below.
| Trial ID/First author | Protocol title/Publication title | Publication citation |
|---|---|---|
| PKU randomised controlled trials | ||
| PKU open-label studies | ||
| BH4 deficiency other published studies | ||
| PKU-003 | ||
| Levy et al. 2007. | Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. | Lancet 2007; 370:504-510. |
| PKU-006 | ||
| Trefz et al. 2009. | Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomised double-blind, placebo-controlled study. | Journal of Pediatrics 2009; 154:700-707. |
| PKU-001 | ||
| Burton et al. 2007. | The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-Tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. | Journal of Inherited Metabolic Diseases 2007; 30:700-707. |
| PKU-004 | ||
| Lee et al. 2008. | Safety and efficacy of 22 weeks of treatment with Sapropterin dihydrochloride in patients with phenylketonuria. | American Journal of Medical Genetics Part A 2008; 146A:2851-2859. |
| Al Aqeel 1991 | Biopterin-dependent hyperphenylalaninaemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase, | Neurology 1991; 41:730-737. |
| Cabalska 2002 | [Atypical phenylketonuria treatment effectiveness.] [Polish] | Med Wieku Rozwoj 2002; 6:193-202. |
| Chien 2009 | Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations. | Journal of Inherited Metabolic Diseases 2009; 24:815-823. |
| Jaggi 2008 | Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. | Molecular Genetics and Metabolism 2008; 93:295-305. |
| Kao 2004 | Subtle brain dysfunction in treated 6-pyruvoyl-tetrahydropterin synthase deficiency: relationship to motor tasks and neurophysiological tests. | Brain and Development 2004; 26:93-98. |
| Kitagawa 1990 | Clinical results of using apropterin hydrochloride (R-tetrahydrobiopterin) for atypical hyperphenylalaninaemia. | Japanese Journal of Pediatric Medicine 1990; 22:1737-1750. |
| Lee 2006 | Long-term follow-up of Chinese patients who received delayed treatment for 6-pyruvoyl-tetrahydropterin synthase deficiency. | Molecular Genetics and Metabolism 2006; 86:128-134. |
| Liu 2008 | Long-term follow-up of Taiwanese Chinese patients treated early for 6-pyruvoyltetrahydropterin synthase deficiency. | Archives of Neurology 2008; 65:387-392. |
| Shintaku 2009 | Longitudinal follow-up of tetrahydrobiopterin (BH4) therapy in patients with BH4 deficiency in Japan. | Molecular Genetics and Metabolism 2009; 98:9 (abstract 128). |
| Wang 2006 | [Study on tetrahydrobiopterin deficiency in Northern Chinese population.] [Chinese] | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006; 23:275-279. |
| Ye 2002 | Screening for tetrahydrobiopterin deficiency among hyperphenylalaninaemia patients in Southern China. | Chinese Medical Journal 2002; 115:217-221. |
| Ye 2007 | [Diagnosis, treatment and long-term following up of 223 patients with hyperphenylalaninemia detected by neonatal screening programs.] [Chinese] | Zhonghua Yu Fang Yi Xue Za Zhi 2007; 41:189-192. |
Abbreviations: BH4 = tetrahydrobiopterin.
8. Results of Trials
PKU: Lead-in studies PKU-001 and PKU-006 Part 1
The proportion of responders to sapropterin on day 8 of treatment, from Trial PKU-001
and PKU-006 part 1, are summarised in the table below by baseline blood Phe level
subgroups.
Proportion of responders at 8 days of treatment (≥ 30% reduction in Phe)
| Trial ID | Baseline Phe | Responders n | N | Proportion responders (95% CI) |
|---|---|---|---|---|
| PKU-001 | <600μmol/L a | 31 | 57 | 54% (41, 68) |
| ≥600μmol/L | 65 | 428 | 15% (12, 19) | |
| All | 96 | 485 | 20% (16, 23) | |
| PKU-006 Part 1 | All | 50 | 90 | 56% (45, 66) |
Abbreviations: PKU = phenylketonuria; Phe = phenylalanine.
a Entry criteria required a blood Phe level ≥450μmol/L.
In Trial PKU-001, the rate of response to sapropterin was higher in patients with
low baseline blood Phe levels < 600 μmol/L (54%) compared to patients with blood Phe
levels ≥ 600 μmol/L (15%). This was consistent with Trial PKU-006 Part 1, which reported
a response rate of 56% for patients with blood Phe levels ≤ 480 µmol/L at baseline,
i.e. the rate of response to sapropterin appears to be higher in patients controlled
on a Phe-restricted diet compared to patients who are uncontrolled. Trial PKU-006
used a higher dose of sapropterin compared to Trial PKU-001 (20 mg/kg/day and 10 mg/kg/day
respectively).
PKU: Reduction in blood Phe levels in Trial PKU-003, PKU-006 part 2 and PKU-004
In trial PKU-003, all participants who received at least one post baseline dose were
included in the analysis. For subjects who were missing their Week 6 blood Phe measurement,
the LOCF was used to impute complete data for the analysis. The analysis of the primary
endpoint included approximately 98% of participants.
Trial PKU-003 reported that patients treated with sapropterin (10 mg/kg/day) and a
Phe-restricted diet had a statistically significantly larger reduction in blood Phe
levels over 6 weeks compared to patients on Phe-restricted diet alone, with a mean
difference of -245 (95% CI: -350, -141; p < 0.001). Mean blood Phe levels fell to
606.9 μmol/L (± 377.0) in patients treated with sapropterin.
In Trial PKU-006 part 2, the mean change from baseline to endpoint was not the primary
endpoint, as the overall objective was to determine patients’ tolerance to Phe supplementation.
Therefore, Phe levels beyond week 3 are not indicative of a reduction as a result
of sapropterin treatment. The results for the mean change from baseline to 3 weeks
in PKU-006 part 2 are summarised in the table below as after this time Phe supplementation
commenced.
Mean change from baseline at 3 weeks in blood Phe in PKU-006 Part 2
| Analysis | SAP | Pbo | Mean difference SAP - Pbo (95% CI) | ||
|---|---|---|---|---|---|
| n | Mean (SD) | n | Mean (SD) | ||
| Week 3 | 33 | -148.5 (134.2) | 12 | -96.6 (243.6) | -51.9 (-197.1, 93.3) |
Abbreviations: PKU = phenylketonuria; Phe = phenylalanine; SD = standard deviation.
Patients in Trial PKU-006 (20 mg/kg/day) achieved smaller reductions in blood Phe
levels compared to patients in Trial PKU-003. Sample sizes were small and confidence
intervals for the placebo and sapropterin (phenoptin) treated patients were wide and
overlapping suggesting high inter-patient variability. The reductions were not statistically
significantly different from reductions achieved in patients on a Phe-restricted diet
alone at 3 weeks.
The treatment effect reported in the fixed dose phase of PKU-004 (10 mg/kg/day) was
reasonably constant from 12 to 22 weeks. Blood Phe levels measured at 3, 6, 9, 12,
15, 18, 21, 24, 27, and 30 months of treatment and at termination in the long term
safety study PKU-008 (3 years) were not presented, but the submission noted that blood
Phe levels remained below 600 μmol/L in most patients achieving these levels in the
placebo controlled trials, and were sustained within levels consistent with local
clinical site recommendations for blood Phe control.
PKU: Tolerance of dietary Phe in Trial PKU-006 Part 2
Patients treated with sapropterin were able to tolerate statistically significantly
larger amounts of dietary Phe (20.9 mg/kg/day) compared to patients on a Phe-restricted
diet alone (2.9 mg/kg/day). There was considerable variability of Phe tolerance, and
14 of 33 patients treated with sapropterin required reductions in dietary Phe supplement
due to blood Phe levels exceeding 360 μmol/L, at one or more visits.
While the data suggested that in some patients initially well controlled on Phe-restricted
diets, the addition of sapropterin may increase tolerance of dietary Phe while maintaining
blood Phe at ≤ 360 μmol/L; this was based on tolerance periods as short as 2 weeks.
BH4 deficiency: PKU-007
In Trial PKU-007 patients with abnormalities of BH4 biosynthesis maintained blood
Phe levels of < 360 µmol/L at all time points. Patients with abnormalities of BH4
recycling showed mixed results, with only 1 of three patients maintaining blood Phe
levels at < 360 µmol/L at the end of the study period. In the published case series
and post marketing reports there appeared to be some evidence of patients with BH4
deficiency responding well to BH4 supplements, but it was unclear whether reductions
in blood Phe observed in the studies resulted in a clinically important improvement
in patient development and function, particularly in patients with recycling related
BH4 deficiency.
For PBAC’s comments on these results, see Recommendation and Reasons.
Patients treated with sapropterin most frequently reported pharyngolaryngeal pain,
headache, vomiting, and abdominal pain. No seizures or neurological deficits were
reported. More adverse events were reported in patients taking the higher dose of
sapropterin in
Trial PKU-006 (20 mg/kg/day) compared to the lower dose use in Trial PKU-003 (10 mg/kg/day).
Generally, the extended assessment of comparative harms was consistent with the safety
profiles of the randomised controlled trials and extension studies.
9. Clinical Claim
The submission described sapropterin (plus standard management) as
superior in terms of comparative effectiveness and equivalent in
terms of comparative safety over placebo (plus standard
management).
Based on trial PKU-003, the PBAC considered that although there
were statistically significant larger reductions in mean blood Phe
levels in patients treated with sapropterin compared to patients on
a Phe-restricted diet alone after 6 weeks of treatment, blood Phe
was not generally reduced to acceptable levels. It is uncertain if
the blood Phe levels reported represent a clinically important
difference in terms of irreversible or reversible neurological and
behavioural sequelae or would be sustained over the long
term.
The PBAC noted that overall, the extent of clinical benefit gained
by adding sapropterin treatment to diet in a patient already
controlled by diet is uncertain, and probably likely to be
small.
10. Economic Analysis
The submission presented a cost utility analysis based on the
randomised controlled trials.
Sapropterin treatment was compared to the Phe-free diet using three
alternative levels of compliance to dietary restrictions and
Phe-free protein supplements:
- 100% compliance (Phe-restricted diet);
- 50% compliance (relaxed diet/‘real-life’ scenario); and
- 0% compliance (uncontrolled)
The utility values used in the model were sourced from an
independent study commissioned by the sponsor.
The submission used the relaxed diet as the comparator in the base
case as this was considered to be reflective of ‘real
life’ compliance with diet restrictions and supplements
(based on selected case studies in the literature). The incremental
cost per QALY gained was between $105,000 – $200,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost to the PBS was estimated by the submission
to be between $10 – $30 million in Year 5 including patients
up to 40 years only and between $30 - $60 million in Year 5
including patients aged 40 and over.
12. Recommendation and Reasons
The PBAC noted the advice of the Highly Specialised Drugs Working
Party, which supported listing sapropterin as a HSD under Section
100, and suggested consideration of listing adult treatment with
sapropterin under Section 85.
The PBAC agreed that the appropriate comparator for patients with
BH4 deficiency is prior treatment with sapropterin. However, the
PBAC did not accept that placebo (plus standard management with a
phenylalanine (Phe)-restricted diet in combination with Phe-free
protein supplements) was the appropriate comparator for patients
with HPA due to PKU. The PBAC considered the appropriate comparator
for this patient population was standard management with a
Phe-restricted diet in combination with Phe-free protein
supplements as the same therapeutic outcome (reduction in blood Phe
levels) is also achieved by adherence to a Phe-restricted diet in
combination with Phe-free protein supplements. The PBAC considered
it was likely that patients taking sapropterin would relax their
dietary restrictions and in some patients sapropterin would
completely replace standard management.
The uncertainty around the comparator was compounded by
inconsistency in the submission regarding use of sapropterin to
replace or be used as an adjunct to diet. Although placebo as
add-on to standard management including Phe-restricted diet and
Phe-free protein supplements was nominated as the main clinical
comparator, the economic model and utilities assumed sapropterin
replaces a Phe-restricted diet with Phe-free protein supplements in
all patients.
The PBAC noted the trend for a higher response rate to treatment
with sapropterin in patients who had low baseline blood Phe levels,
although it was acknowledged that this may be in part due to
selection bias as those patients may be more motivated and
compliant with a restrictive diet. There were no data to suggest
whether treatment with sapropterin allows meaningful changes in
dietary restrictions for some patients over the long term, or in
patients uncontrolled using a Phe-restricted diet. The PBAC noted
there was inconsistency between the clinical trials presented,
which excluded pregnant women, children under the age of 4 years
and patients with BH4 deficiency, and the proposed populations for
whom listing was sought.
The PBAC was unclear whether the proposed restrictions for
treatment of HPA with PKU, which are split by age group with
different qualifying Phe levels, were clinically appropriate and
how they would relate to clinical practice. The Committee also
considered that the continuation rules would be impractical with
patients swapping between the different age groups, the
considerable variability in Phe levels, the uncertain clinical
relevance of a 30% reduction in baseline levels and the lack of
apparent treatment related variability in Phe levels. The PBAC
noted the sponsor’s suggestion in its Pre-Sub-Committee
Response that it may be appropriate to limit reimbursement to
patients less than 18 years of age. However, the TGA registered
indication is for both adults and paediatric patients.
The PBAC noted the utility assigned to uncontrolled adults (0.20)
was lower than that for uncontrolled children (0.37) and given the
far more serious health implications in children considered this to
be implausible. Uncertainty is also associated with the utilities
derived for the health states included in the model given that the
EQ-5D instrument was not developed for use in children, and the
utilities derived describe the health of the parents of the
children in several instances, rather than the health state of the
children. Improvement in quality of life (QoL) for patients treated
with sapropterin compared to diet alone appears to be attributable
solely to relaxation of the diet. Given the uncertainty around the
extent to which a relaxation of diet would be realised in clinical
practice, the PBAC did not consider claiming this benefit in the
model to be appropriate.
The PBAC considered that the utilisation estimate and the estimated
financial implications associated with listing sapropterin were
both uncertain and may be substantially underestimated. Both
estimates inappropriately exclude patients over the age of 40 years
and do not account for patients continuing PBS treatment with
sapropterin via grandfathering which is inconsistent with the
requested listing.
The PBAC noted there were inconsistencies identifying the
appropriate age of the population for treatment with sapropterin
between the proposed listing (all ages), the economic model (0-18
years) and the financial estimates (0-40 years). The PBAC also
agreed with the issues in relation to the economic modelling as
identified by the ESC.
The PBAC considered that in the context of the uncertainties raised
above, the base case (uncontrolled diet) incremental cost per QALY
in the range of $75,000 – $105,000 was high and uncertain.
Sensitivity analyses show that the model is sensitive to the age at
which patients cease taking sapropterin and the utilities used in
the model.
The PBAC therefore rejected the application to list sapropterin on
the PBS because of uncertainty around the clinical place in therapy
and high and uncertain cost effectiveness.
The PBAC acknowledged and noted the consumer comments on this
item.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Merck Serono Australia is disappointed with the recommendation and will continue to work with the PBAC to ensure access to this valuable therapy for patients with this rare and serious condition.
