Pegvaliase for the treatment of hyperphenylalaninaemia in adults with phenylketonuria first line

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1 May 2016 Horizon Scanning Research & Intelligence Centre Pegvaliase for the treatment of hyperphenylalaninaemia in adults with phenylketonuria first line LAY SUMMARY This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Phenylketonuria (PKU) is an inherited disorder of protein metabolism that causes a problem with the phenylalanine hydroxylase enzyme. This enzyme is responsible for breaking down the amino acid phenylalanine, a chemical in protein from food, so that in PKU the amount of phenylalanine in the blood increases. Hyperphenylalaninaemia is when the levels of phenylalanine in the blood are too high. If untreated, hyperphenylalaninaemia can cause damage to the brain which can cause severe mental disability, seizures and tremors. In addition, it may lead to psychological, social and behavioural problems, and lead to depression, anxiety, phobias and low self-esteem. Pegvaliase is a new drug which is injected into the skin daily to treat hyperphenylalaninaemia in adult patients with PKU. PKU is currently treated by adopting a protein restricted diet and taking dietary supplements, pegvaliase could potentially allow patients to relax these dietary restrictions. NIHR HSRIC ID: 5020 This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Phenylketonuria (PKU): hyperphenylalaninaemia; adults first line; adjunct to the PKU diet a. TECHNOLOGY DESCRIPTION Pegvaliase (BMN 165; PEG PAL; pegylated phenylalanine ammonia lyase; ravpal-peg) is a pegylated recombinant phenylalanine ammonia lyase intended for the treatment of hyperphenylalaninaemia in adults with PKU. Pegvaliase is self-administered by subcutaneous (SC) injection for an induction period (4 weeks) at a fixed dose of 2.5 mg/week. This is followed by a titration period (week 5 up to week 32) where pegvaliase is administered by SC injection at increasing doses up to 20mg or 40mg/day. A maintenance regimen is then used in order to safely achieve the target phenylalanine level for the individual patient, this is administered for a further 4 weeks b. Pegvaliase does not currently have Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, pegvaliase will offer an additional treatment option for adult PKU patients with hyperphenylalaninaemia b. Expert opinion suggests that there is a great desire amongst patients and families for a treatment which allows relaxation of the PKU diet a. DEVELOPER BioMarin Europe Limited. AVAILABILITY, LAUNCH OR MARKETING Pegvaliase is in phase III clinical trials. PATIENT GROUP BACKGROUND PKU is a rare inherited disorder of protein metabolism, where there is a deficiency in the enzyme phenylalanine hydroxylase (PAH). PAH catalyses the conversion of the amino acid phenylalanine to tyrosine. PAH deficiency prevents normal metabolism of phenylalanine, causing it to accumulate in the blood. PKU is an autosomal recessive disorder; most forms are caused by mutations in the PAH gene on chromosome 12q All babies born in the UK are routinely screened for high phenylalanine levels in the first week of life 1. High levels of phenylalanine can damage the brain which, if not recognised and managed can cause severe mental disability, reduced IQ, seizures and tremors, impaired a Expert personal opinion. b Company provided information. 2

3 executive function, psychological and behavioural issues, social difficulties and epilepsy 2,3. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment 1. However, since the introduction of newborn screening programmes and early dietary intervention, severe mental retardation associated with untreated classical PAH deficiency can be prevented 1,4. Over time, subtle intellectual and neuropsychiatric issues may manifest even with treatment 4. Common reported conditions in adult patients with PKU include: depression, anxiety disorders, phobias and low self-esteem 2. Current management of PKU involves meticulous management of the diet. For a significant number of patients the restrictions of the diet impact greatly on their day to day life c. It can be a burden for parents and carers to administer and supervise, particularly as children become older and more independent c. As the child grows and they become more independent, the social impact increases due to the limitations on lifestyle. Being on a medical diet creates differences at school and college, occasionally leading to bullying, which young patients find difficult to manage c. The planning and organisation that goes into food can preclude spontaneous enjoyment of meals, holidays and family occasions, and can increase the risk of eating disordered behaviour c. In some cases the difficulties result in reduced adherence to dietary treatment with higher phenylalanine levels, and this can negatively impact on cognition and mood long-term c. Current recommendations are that individuals with PKU continue this diet lifelong although many adults with PKU struggle to adhere strictly to this recommendation, and some opt to discontinue the PKU diet completely c. Reported difficulties in adult patients include impairment of executive function and anxiety c. Other individuals with variable/poor adherence have developed problems secondary to nutritional, e.g. vitamin B12, deficiencies c. Some individuals with PKU find the supplements and low protein foods unpalatable c. The supplements used in the PKU diet are strong tasting c. An alternative to the liquid supplement involves taking over 100 tablets a day d. Regular home blood monitoring of phenylalanine levels can also be a major burden of the disorder c. Monitoring of blood phenylalanine levels is made difficult by the delay in receiving results, and it is suggested that this can currently take approximately 2-3 days d. This is of particular concern as phenylalanine blood levels are elevated during illness d. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to the following Department of Health policy areas: NHS England. 2013/14 NHS Standard Contract for Paediatric Neurosciences: Neurology. E09/S/b. NHS England. July Clinical Commissioning Policy: The use of sapropterin in children with phenylketonuria. E06/P/a. CLINICAL NEED and BURDEN OF DISEASE The incidence of positive screening tests for PKU was 1 in 10,998 live births in , with an overall incidence of 1 in 8,600 from Not all screen positives will prove to c Expert personal opinion. d Patient group personal communication. 3

4 have PKU, but according to expert opinion, the vast majority do e. Carriage frequency of dysfunctional alleles is about 1 in The population likely to be eligible to receive pegvaliase could not easily be estimated from routine available published sources. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance No relevant guidance. Other Guidance The National Society for Phenylketonuria. Management of Phenylketonuria American College of Medical Genetics and Genomics. Phenylalanine hydroxylase deficiency: diagnosis and management guideline CURRENT TREATMENT OPTIONS PKU can be successfully treated by strict compliance with a low-protein diet and dietary supplements, such as low protein medical foods, amino acid, vitamin and mineral supplements (provided on prescription) 1. Dietary supplements contain essential nutrients and amino acids that are absent in a low-protein diet. This treatment is very effective and with good control of phenylalanine levels, the majority of individuals with PKU would be expected to achieve a normal IQ, allowing them to access education, employment and relationships independently. As the PKU diet is started immediately upon diagnosis in the neonatal period, for many individuals they grow up with this diet, are used to it, and incorporate it well into daily life. However, data suggests that blood phenylalanine concentration cannot always be maintained below the recommend value. In children younger than age 4 years, almost 30% of blood phenylalanine concentrations were greater than the recommended maximum value, but in year olds, this proportion rises to 80%, despite older children and adolescents being on a more relaxed diet 8. EFFICACY and SAFETY Trial NCT , , Prism301; pegvaliase; phase III. Sponsor BioMarin Pharmaceutical NCT , , Prism302; pegvaliase vs placebo; phase III. BioMarin Pharmaceutical NCT , , Prism303; pegvaliase; phase III extension. BioMarin Pharmaceutical Status Complete but unpublished. Ongoing. Ongoing. Source of information Trial registry 9 ; manufacturer. Trial registry 10 ; manufacturer 11. Trial registry 12 ; manufacturer. Location USA. USA. USA. e Expert personal opinion. 4

5 Design Randomised. Randomised, placebocontrolled. Participants n=300; aged yrs; n=250 (planned); pts who PKU with blood have completed a prior phenylalanine pegvaliase study (PAL-003 concentration >600µmol/L or ); after Part 1 of at screening or average the study pts with blood blood phenylalanine phenylalanine concentration of >600 concentration reduction µmol/l over the past 6 20% from baseline levels months. in study are eligible for participation in Part 2; pts unable to achieve the 20% blood phenylalanine reduction are eligible for participation in Part 4. Schedule Follow-up Primary outcomes Randomised to pegvaliase 20mg/day; or pegvaliase 40mg/day; both as selfadministered SC injections. Both arms receive a dose of 2.5mg/wk for 4 wks (induction period) followed by a titration period (wk 5 up to wk 42) in which increased doses (20mg/day or 40mg/day) are administered. A maintenance dose period of at least 2 weeks follows where the pt receives either pegvaliase 20mg/day or 40mg/day. Active treatment for up to 36 wks. Safety and tolerability (assessment of vital signs, physical examination, electrocardiograms (ECGs), adverse effects (AEs), concomitant medications and laboratory In Part 1 (up to 13 wks), pts receive pegvaliase SC at the same dosage as allocated in their previous study. In Part 2 (8 wks) pts are randomised to either continue their Part 1 pegvaliase dose (20mg/day or 40mg/day) or receive matching placebo for 8 wks. In Part 3 (6 wks), subjects who completed and received pegvaliase in Part 2 will continue to receive open-label pegvaliase at Part 2 dosage. Subjects will temporarily halt dosing in wk 6 before entering Part 4. All other subjects will be enrolled in Part 4. Part 4 (up to 190 wks) is an open-label extension period. Pts on a dose of 20mg/day in part 2 will continue with this dose in wk 1 and increase to 40mg/day at wk 2. All other pts will be treated at a dose of 40mg/day unless AEs previously prevented dosing at 20 or 40mg/day. Active treatment for up to 217 wks. Change in blood phenylalanine concentration from Part 2 baseline to Part 2 wk 8. Non-randomised, uncontrolled. n= 100 (planned); aged yrs; pts in Part 1 of study and meet criteria for Part 2 of ; pts who are concurrently administered study drug (pegvaliase and/or placebo) in Part 2 of study Patients receive pegvaliase 20mg/day SC; or pegvaliase 40mg/day SC; or placebo SC as allocated in Part 2 of study Changes in executive function (measured by Cambridge Neuropsychological Test Automated Battery [CANTAB]). 5

6 tests f ). Secondary outcomes Blood phenylalanine concentration; percentage of daily recommended intake for age of natural protein intake; dietary protein intake; Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) score (investigator rated inattentive subscale score, total score, and hyperactivity/impulsivity subscale score); Profile of Mood States (POMS) scores (observer rated and subject rated); pharmacokinetics. Change from Part 2 baseline to Part 2 wk 8 in cognitive and mood symptoms: ADHD Rating Scale-IV (ADHD-RS IV); PKU-specific POMS; PKU POMS total mood disturbance score. AEs; pharmacokinetics; protein intake reported in diet diary. Key results Not reported. The pegvaliase group maintained mean blood phenylalanine levels at 527.2μmol/L compared to baseline of 503.9μmol/L,; placebo group blood levels increased to μmol/L compared to baseline of 536.0μmol/L. 62% improvement in blood phenylalanine compared to placebo. Adverse effects (AEs) Expected reporting date Not reported. The company have not stated an expected reporting date. No pts discontinued study drug due to AEs and pegvaliase was generally well tolerated compared to placebo. Pegvaliase treated patients had more hypersensitivity AEs (39%) than the placebo group (14%). For pegvaliase vs placebo, respectively, the most frequent AEs were: arthralgia (14% vs 10%), headache (12% vs 24%), and fatigue (11% vs 10%). Study completion date reported as November Study completion date reported as April Trial NCT , ; pegvaliase; phase II. Sponsor BioMarin Pharmaceutical Status Complete but unpublished. NCT , PAL-002; pegvaliase; phase II. BioMarin Pharmaceutical Complete but unpublished. NCT , PAL-003; pegvaliase; phase II. BioMarin Pharmaceutical Ongoing. f Chemistry, haematology, and urinalysis tests. 6

7 Source of Trial registry 13. Trial registry 14. Trial registry 15. information Location USA. USA. USA. Design Randomised. Non-randomised, uncontrolled. Non-randomised, uncontrolled. Participants n=24; aged yrs; PKU with blood phenylalanine concentration of 600µmol/L at screening, average blood phenylalanine concentration of 600µmol/L over past 6 months. n=40; aged yrs; blood phenylalanine concentration 600μmol/L at screening (average 600μmol/L over the previous 3 yrs). n=50 (planned); aged yrs; pts who have completed participation in previous pegvaliase studies. Schedule Randomised to pegvaliase 4-8 wks induction at 2.5mg, followed by titration ( 4 wks) to find efficacious dose, followed by daily maintenance at that dose, all administered SC from 1-5 times per wk (2.5mg-375mg); or 8mg single bolus dose, followed by minimum 3-wk break, then titration ( 4 wks) to maintenance dose, all administered SC from 1-5 times per wk (2.5mg-375mg). Follow-up Active treatment for 24 weeks. Follow-up not reported. Primary outcomes Secondary outcomes Expected reporting date Phenylalanine plasma levels. Safety assessments (assessment of injection sites, vital signs and AEs.); safety tests g at baseline and at completion of the study; immunogenicity. No quality of life measurement included in trial outcomes. The company have not stated an expected reporting date. Pts receive pegvaliase SC at dose of 0.001, 0.003, 0.01, 0.03, or 0.1mg/kg on day 1; doses were increased progressively up to 0.1mg/kg. Treatment period and follow-up not reported. Blood phenylalanine concentrations AEs and clinically significant changes in vital signs and laboratory test results; antibody response; pharmacokinetics. No quality of life measurement included in trial outcomes. The company have not stated an expected reporting date. Pts receive pegvaliase SC at dose of 0.001, 0.003, 0.01, 0.03, or 0.1mg/kg on day 1; doses were increased progressively but did not exceed the upper limit of 5.0mg/kg per wk or 375mg/wk. Active treatment 392 wks. Follow-up not reported. Blood phenylalanine concentrations (3 days postdose). AEs and clinically significant changes in vital signs; antibody response; pharmacokinetics; safety based on clinically significant changes in laboratory test results. No quality of life measurement included in trial outcomes. Study completion date reported as August g Chemistry, haematology and urinalysis monthly clinical laboratory tests. Physical examination every other month, along with pregnancy test, ECG and chest x-ray. Patients assessed for AEs every time they are seen by clinical personnel. 7

8 ESTIMATED COST and IMPACT COST The cost of pegvaliase is not yet known. IMPACT SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: due to dietary treatment patients are expected to have a normal life span so pegvaliase will not impact survival or mortality h. Reduced symptoms or disability: pegvaliase may allow patients to follow a less strict version of the diet h. This will be of particular importance for those who struggle with the PKU diet. Reducing the dietary restriction on how much, and what, can be included in the diet will have a positive psychosocial impact as well as a positive impact on neurocognitive outcomes h. If there is improved compliance and better control of phenylalanine levels patients will have better quality of life and outcome in terms of anxiety, better job performance, relationships etc h. No impact identified Physical adverse effects from the current dietary treatment for PKU (assuming good metabolic control is achieved) are minimal and mainly centre around palatability and gastrointestinal (in)tolerance h. Pegvaliase has a greater side effect profile with arthralgia, injection site reactions and rash reported. It remains to be seen how well patients would tolerate these adverse effects long-term h. Impact on Health and Social Care Services Increased use of existing services: potential increase in number of adult patients receiving active treatment h. Decreased use of existing services. Potential increase in lab monitoring requirements h. Re-organisation of existing services: the current metabolic centres that already take care of these patients will be involved h. The pegvaliase treatment would be expected to have a similar resource need as current treatment; but with more emphasis on the role of the nurse specialist rather than the dietitian and dietetic assistant h. Need for new services h Expert personal opinion. 8

9 Training would need to be given to parents/patients on the administration of the pegvaliase injection this would not be expected to be complex but would require nurse specialist time i. Other None identified Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs Other Reduced drug treatment costs Other reduction in costs None identified Other Issues Clinical uncertainty or other research question identified: unclear place in treatment as trials in adults, (of which approximately half may be off diet anyway due to patient choice i ) while management starts from newborn screening i. Research needs to explore if first line is the most suitable place in treatment i. The main patient group adhering to strict diet is the paediatric population i ; research is needed into the use of this treatment (including adverse events and tolerance of regular SC injections) in children and adolescents given that the greatest demand for use of pegvaliase is likely to come from parents and carers of children and adolescents with PKU i. None identified Research is required on the levels of phenylalanine in the blood after treatment with pegvaliase and whether this drug is given alone or in combination with the restricted diet i. Future research should focus on symptoms and how this treatment may affect symptoms j. Trials should closely monitor the diet of the participants in order to record any changes in dietary restriction j. Research should consider the impact on quality of life (perhaps using the phenylketonuria quality of life (PKU-QOL) questionnaires) i,16, the impact on common conditions reported in adult patients such as depression and anxiety, and the long term impact on cognitive/psychological outcomes. A key area for research is the potential use of pegvaliase in PKU mothers during pregnancy (known as maternal PKU) i,j. Kuvan (sapropterin) is used off-label in maternal PKU patients i,j. Research is needed into whether pegvaliase can be used in this way j. i Expert personal opinion. j Patient group personal communication. 9

10 REFERENCES 1 Williams RA, Mamotte CDS and Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clinical Biochemistry Review 2008; 29(1): NHS Choices. Phenylketonuria. Accessed 13 April Hagedorn TS, van Berkel P, Hammerschmidt G et al. Requirement for a minimum standard of care for phenylketonuria: the patient s perspective. Orphanet Journal of Rare Disease 2013; 8(191). 4 Vockley J, Andersson HC, Antshel KM et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genetics in Medicine 2014;16(2): Public Health England. Data Collection and Performance Analysis Report: Newborn blood spot screening in the UK 2014/15. London: PHE; March Patient.info. Phenylketonuria. Accessed 6 April The National Society for Phenylketonuria. Management of Phenylketonuria. NSPKU; Lancashire. July Walter JH, White FJ, Hall SK et al. How practical are recommendations for dietary control in phenylketonuria? The Lancet 2002;360(9326): ClinicalTrials.gov. A phase 3, open-label, randomized, multi-center study to assess the safety & tolerability of an induction, titration, and maintenance dose regimen of BMN 165 self administered by adults with PKU not previously treated with BMN Accessed 6 April ClinicalTrials.gov. A four-part, phase 3, randomized, double-blind, placebo- controlled, four-arm, discontinuation study to evaluate the efficacy and safety of subcutaneous injections of BMN 165 self-administered by adults with phenylketonuria (PKU). Accessed 6 April Biomarin Pharmaceutical BioMarin Phase 3 Study of Pegvaliase for Phenylketonuria (PKU) Meets Primary Endpoint of Blood Phenylalanine (Phe) Reduction (p<0.0001). 21 March investors.bmrn.com/releasedetail.cfm?releaseid= Accessed 17 May ClinicalTrials.gov. A Phase 3 Substudy to Evaluate Executive Function in Adults With Phenylketonuria Who Are Participating in the Phase 3 Study, Accessed 6 April ClinicalTrials.gov. A phase II, multi-center, open-label, dose-finding study to evaluate safety, efficacy and tolerability of subcutaneously (sc) administered ravpal-peg in patients with PKU for 24 weeks. Accessed 6 April ClinicalTrials.gov. Phase 2, open-label dose-finding study to evaluate the safety, efficacy, and tolerability of multiple subcutaneous (SC) doses of ravpal-peg in subjects with PKU. Accessed 6 April ClinicalTrials.gov. Long-term Extension of a Phase 2, Open-Label Dose-Finding Study to Evaluate the Safety, Efficacy, and Tolerability of Multiple Subcutaneous Doses of ravpal-peg in Subjects With PKU. Accessed 6 April Regnault A, Burlina A, Cunningham A et al. Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients and parents quality of life: the phenylketonuria quality of life (PKU-QOL) questionnaires. Orphanet Journal of Rare Diseases 2015;10:59. 10