In January 2011, the Canadian Expert Drug Advisory Committee (CEDAC) issued a Final Recommendation that Kuvan not be reimbursed.6 The key reason for the recommendation was that patient details were insufficient to identify a subpopulation for which SAP may provide a significant clinical benefit that is cost-effective. Although there was sufficient evidence that SAP lowers blood Phe levels in certain patients with PKU, the submission did not provide sufficient details of how to identify patients who would benefit in a cost-effective manner. A proposed “Kuvan Starter Program” was suitable only to screen patients to identify “responders,” but such response did not differentiate low response from clinically important response. In addition, starting and stopping rules, beyond the screening stage, that are linked to substantive benefit were needed. The Final CEDAC Recommendation was based on a review of Kuvan in November 2010 and a Request for Reconsideration in January 2011.6 A Request for Advice (RfA) was also made by the participating drug plans in October 2011, which did not result in any changes to the recommendation.7
In making its recommendation, CEDAC considered a systematic review of two double-blind, randomized controlled trials (RCTs) in patients with BH4-responsive PKU (PKU-003 and PKU-006), a critique of the manufacturer’s pharmacoeconomic evaluation, and patient input.6 For both RCTs, eligible patients were required to demonstrate a 30% or greater reduction in Phe blood levels following an eight-day challenge with SAP. PKU-003 enrolled 89 responder patients aged eight years and older who were not adherent to a Phe-restrictive diet who were treated with SAP 10 mg/kg/day or placebo over six weeks. PKU-006 (Part 2) enrolled 46 responder children aged four to 12 years who were adherent to a Phe-restricted diet who were treated with SAP 20 mg/kg/day or placebo over 10 weeks. The primary end point in PKU-003 was change in Phe blood level from baseline to week 6 and in PKU-006 was the Phe supplement tolerated at week 10 while maintaining Phe blood levels at less than 360 µmol/L. Results demonstrated that in PKU-003, SAP-treated patients experienced statistically significantly greater mean reductions in Phe blood levels compared with placebo at six weeks: —235.9 µmol/L versus +2.9 µmol/L, respectively. In addition, a statistically significantly greater proportion of SAP-treated patients, compared with placebo-treated patients, achieved blood Phe levels of 600 µmol/L or less (54% versus 23%) and blood Phe levels of 360 µmol/L or less (32% versus 2%). In PKU-006 (Part 2), the mean Phe supplement tolerated was 21 mg/kg per day for SAP compared with 2.9 mg/kg per day for placebo. In general, adverse events (AEs) were mild, with the most frequent AEs observed in SAP-treated patients including headache, upper respiratory tract infection, and cough.
The RfA that was made regarding the aforementioned recommendation sought to clarify the “Of Note” section of the CEDAC Final Recommendation for SAP, as the jurisdictions participating in the CADTH Common Drug Review (CDR) indicated that the statements “Starting and stopping rules...are needed. It would be advisable for the manufacturer to work with provinces to establish these requirements with respect to age, PKU classification, and specific benefits to be achieved that support the price of this product” conflicted with the “Do Not List” Recommendation and the usual role of CEDAC in providing coverage criteria recommendations. A reassessment of the clinical evidence (including new evidence available since the original CDR review), however, did not lead to a change in the recommendation. Specifically, the CDR RfA report concluded, “In the absence of evidence demonstrating benefit of sapropterin therapy on neurocognitive outcomes or diet liberalization, there is insufficient evidence to support specific starting and stopping rules for sapropterin treatment (beyond percentage reductions in blood Phe levels). There is no direct evidence to support the rules proposed by the manufacturer in response to the RfA, which are based on arbitrary percentage changes in blood Phe levels and dietary Phe tolerance, and unspecified improvements in neurocognitive or behavioural outcomes.” Despite this, several jurisdictions did subsequently proceed to develop criteria to allow access to SAP (e.g., see Appendix 8A for the criteria in Ontario), and these criteria are largely the subject of the manufacturer’s current resubmission.
2.1. Basis of Resubmission
According to the manufacturer, the rationale for filing a resubmission for Kuvan is the availability of new clinical evidence. Following the CEDAC recommendation, provincial reimbursement of Kuvan has occurred in Ontario (as of February 2013) and Saskatchewan (as of September 2013).12 The manufacturer states that listing criteria for reimbursement in these provinces were established with the aim of providing access and with the understanding that new data would be forthcoming that may affect knowledge about the effectiveness and appropriate use of SAP to treat patients with PKU.
The new clinical evidence submitted by the manufacturer includes the following studies:
PKU-016, which is a phase 3b, double-blind RCT comparing SAP and placebo on symptoms of attention-deficit/hyperactivity disorder (ADHD) and executive and global functioning in PKU patients who are responders to SAP (i.e., defined in this study as a ≥ 20% reduction in Phe blood levels after one month of SAP therapy).
9,10PKU-015, which is an ongoing, phase 3b, two-part, multi-centre, open-label, single-arm study to evaluate the safety of SAP and its effect on maintaining neurocognitive function, blood Phe levels, and growth in children aged zero to six years with PKU.
14The SPARK study, which is a phase 3b, multi-centre, open-label, RCT of the efficacy, safety, and population pharmacokinetics of SAP plus a Phe-restricted diet compared with a Phe-restricted diet alone in children with PKU who are younger than four years of age.
11The PKUDOS registry study is a phase 4 voluntary observational study designed to provide longitudinal safety and efficacy data for up to 15 years in patients with PKU who are (or have been) treated with SAP.
15
Both Study PKU-016 and the SPARK study met the selection criteria for inclusion in the systematic review of the resubmission. Study PKU-015 and the PKUDOS registry study are summarized in Appendix 6.
The price of Kuvan has not changed from the price considered in the original review (i.e., $33.00 per 100 mg tablet). A new pharmacoeconomic analysis was submitted utilizing new clinical data available from the PKU-016 study to determine the cost-effectiveness of SAP in conjunction with a Phe-restricted diet compared with diet alone for patients with PKU over a lifetime horizon.
It does not appear that reimbursement criteria for Kuvan were put forth in the previous submission. In the resubmission, the manufacturer has suggested reimbursement criteria for Kuvan (as detailed in section 1.3) that support providing an initial trial of Kuvan therapy to determine a patient’s response.12 The manufacturer has also stated that the existing provincial reimbursement criteria are not supported by the metabolic geneticist community in Ontario and have been a deterrent to physicians to trial patients on SAP, as no patients have met the criteria since their inception.12 The current provincial reimbursement criteria and a submission made directly to CADTH with proposed reimbursement criteria for SAP from a group of metabolic physician specialists from Ontario are included in Appendix 8.
