Long-Term Safety and Efficacy of Pegvaliase in Japanese Adults With Phenylketonuria: Final Results of a Phase III Trial.

Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of phenylalanine hydroxylase, resulting in high blood phenylalanine (Phe) concentrations with potential for impaired neurocognition. Pegvaliase, a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe, is approved for use in adults with PKU and high blood Phe despite prior management. In the Phase 3 PRISM studies conducted in the United States, pegvaliase induction/titration/maintenance dosing led to clinically meaningful and statistically significant blood Phe reductions versus placebo, with a manageable safety profile. Here we report the primary endpoint, change in blood Phe levels from baseline to Week 52, and 2-year interim efficacy and safety results (to Week 144; data cut-off March 31, 2022) of an ongoing, open-label study in a Japanese PKU population (JapicCTI-194,642). Participants were 12 adults with PKU from Japan aged 18–70 years with blood Phe levels >600 μmol/L. In Part 1, participants received subcutaneous 2.5 mg pegvaliase once weekly for 4 weeks (induction), followed by titration up to 20 mg/day, then dose adjustment to a maximum 40 mg/day to achieve blood Phe efficacy (≤360 μmol/L); this maintenance dose was continued to Week 52. In Part 2, participants continued pegvaliase with dose adjustments up to a maximum 60 mg/day for up to 168 weeks. Among 11 participants evaluable for efficacy, mean (standard deviation) blood Phe concentration decreased from 1025.9 (172.7) μmol/L at baseline to 448.3 (458.8) μmol/L at Week 52 (mean 57.5% decrease). Up to Week 104, all 11 (100%) efficacy-evaluable participants achieved blood Phe levels ≤600 μmol/L, 9 (81.8%) achieved ≤360 μmol/L, and 8 (72.7%) achieved ≤120 μmol/L. All 12 participants reported ≥1 adverse event (AE), most commonly injection site erythema and injection site swelling (n = 10, 83.3% each). The pegvaliase exposure-adjusted AE rate was 23.5 per person-years overall, 41.2 per person-years during induction/titration, and 13.5 per person-years during maintenance. All participants developed pegvaliase-induced antibody responses. There were no AEs leading to discontinuation, no deaths, and no anaphylaxis events. Although interim, these results support the use of pegvaliase in Japanese adults with PKU with elevated blood Phe levels and are consistent with results from the Phase 3 PRISM studies.

Pegvaliase for the treatment of phenylketonuria: Results of the phase 2 dose-finding studies with long-term follow-up

Background: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. Methods: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. Results: A total of 1323 patients (age range:1–57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2–5 years: 84%; 6–12 years: 73%; 13–18 years: 85%; 19–30 years: 64%; 31–40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 μmol/L; 96 ± 24%) and mild PKU (365 ± 224 μmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 μmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6–12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13–18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31–40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 μmol/L; percentage within target 84 ± 39% vs. 406 ± 334 μmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 μmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 μmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 μmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 μmol/L, (70 ± 58%). Conclusions: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Evaluating change in diet with pegvaliase treatment in adults with phenylketonuria: Analysis of phase 3 clinical trial data

BackgroundIn phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. MethodsIn a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. ResultsPlasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. ConclusionThis study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. Take-home messageBlood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

The maternal phenylketonuria (PKU) syndrome is caused by high blood phenylalanine (Phe) levels during pregnancy, leading to a host of birth defects, especially microcephaly and congenital heart disease (CHD). For finding whether the maternal PKU syndrome could be prevented, an international collaborative study was organized to evaluate treatment with a Phe-restricted diet. Blood Phe levels, maternal weight gain, and nutrient intakes during pregnancy were evaluated as to their effect on the rate of microcephaly and CHD in the offspring. The study was a prospective, longitudinal effort aimed at lowering blood Phe during pregnancy. Women were enrolled at time of referral for pregnancy. Nutrient intake analysis, which serves as the basis for this report, was available from 251 pregnancies. Subjects were stratified by blood Phe control of < or =600 micromol/L by 8 weeks gestation or >600 micromol/L by 8 weeks gestation. Outcome of these pregnancies was correlated to blood Phe levels, weight gain, and nutrient intake. The study goal was to attain blood Phe levels of 120 to 360 micromol/L 3 months preconception; however, this goal was achieved by only a limited number of patients. Therefore, the data presented were based on blood Phe control < or =600 micromol/L or >600 micromol/L by 8 weeks of gestation. Blood Phe control of < or =600 micromol/L by 8 weeks of gestation was attained by 86 (34.3%) of the 251 women in this study, whereas the other 165 women had blood Phe control >600 micromol/L by 8 weeks of gestation. Of the 251 offspring, 166 were born with normal head circumference and 85 were born with microcephaly (<2 standard deviations below normal). Women with blood Phe >600 micromol/L at 8 weeks of gestation included 78 (92%) of the 85 infants with microcephaly compared with 8% in the group of women who had blood Phe levels < or =600 micromol/L. Weight gain during pregnancy was related to the rate of microcephaly. The highest occurrence of microcephaly (58%) was found in the pregnant women who gained <70% of recommended weight gain. Stepwise logistic regression analysis was used to determine factors associated with microcephaly. Significant factors included higher blood Phe levels when off diet, higher average Phe exposure during the pregnancy, low prepregnancy weight, poor weight gain during the pregnancy, and lower intake of protein and higher iron intake during the pregnancy. Infants with CHD were found only in the group of women who had blood Phe levels >600 micromol/L by 8 weeks of gestation. There was a higher rate of CHD in the offspring who were born to women who consumed <50% of the recommended intake of protein in the first trimester. The main source of protein for women with PKU is the medical food; therefore, when protein intake was low, vitamin and mineral intakes were also inadequate. The data indicate that blood Phe control and how soon it is attained during pregnancy with PKU is important. Normal pregnancy weight gain should be encouraged to reduce microcephaly. Adequate protein and vitamin intakes early in pregnancy may have a protective effect for the prevention of CHD, even if blood Phe is elevated. The rate of microcephaly and CHD may be reduced if nutrient intake is optimal while attempting to control blood Phe levels.

BackgroundPhenylalanine hydroxylase (PAH) deficiency is one of 31 targeted inherited metabolic diseases (IMD) for the Canadian Inherited Metabolic Diseases Research Network (CIMDRN). Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. However, clinical evidence demonstrates that subtle suboptimal neurocognitive outcomes are present in the early and continuously diet-treated population with PAH deficiency. This may be attributed to variation in blood phenylalanine levels to outside treatment range and this, in turn, is possibly due to a combination of factors; disease severity, dietary noncompliance and differences in practice related to the management of PAH deficiency. One of CIMDRN’s goals is to understand current practices in the diagnosis and management of PAH deficiency in the pediatric population, from the perspective of both health care providers and patients/families.ObjectivesWe investigated Canadian metabolic dietitians’ perspectives on the nutritional management of children with PAH deficiency, awareness of recently published North American treatment and nutritional guidelines in relation to PAH deficiency, and nutritional care practices within and outside these guidelines.MethodsWe invited 33 dietitians to participate in a survey, to ascertain their use of recently published guidelines and their practices in relation to the nutritional care of pediatric patients with PAH deficiency.ResultsWe received 19 responses (59% response rate). All participants reported awareness of published guidelines for managing PAH deficiency. To classify disease severity, 89% of dietitians reported using pre-treatment blood phenylalanine (Phe) levels, alone or in combination with other factors. 74% of dietitians reported using blood Phe levels ≥360 μmol/L (6 mg/dL) as the criterion for initiating a Phe-restricted diet. All respondents considered 120-360 μmol/L (2–6 mg/dL) as the optimal treatment range for blood Phe in children 0–9 years old, but there was less agreement on blood Phe targets for older children. Most dietitians reported similar approaches to diet assessment and counseling: monitoring growth trends, use of 3 day diet records for intake analysis, individualization of diet goals, counseling patients to count grams of dietary natural protein or milligrams of dietary Phe, and monitoring blood Phe, tyrosine and ferritin.ConclusionWhile Canadian dietitians’ practices in managing pediatric PAH deficiency are generally aligned with those of the American College of Medical Genetics and Genomics (ACMG), and with the associated treatment and nutritional guidelines from Genetic Metabolic Dietitians International (GMDI), variation in many aspects of care reflects ongoing uncertainty and a need for robust evidence.

Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria

Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program

IntroductionPegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. MethodsPRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo. ResultsThe pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 μM (504.6) in the group assigned to the 20 mg/day placebo group (n = 14), 508.2 μM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 μM (520.3) in those assigned to continue pegvaliase treatment (n = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 μM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 μM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 μM (−68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group (P < 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). ConclusionMean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.

Sapropterin dihydrochloride use in pregnant women with phenylketonuria: An interim report of the PKU MOMS sub-registry

Phenylketonuria (PKU) is a rare metabolic disorder characterized by impaired conversion of phenylalanine (Phe) to tyrosine. If left untreated, the resultant accumulation of excess blood Phe can cause physiological, neurological, and intellectual disabilities. The National PKU Alliance (NPKUA) conducted a survey of its membership to assess current health status and interest in new treatments for PKU. Of the 625 survey respondents, less than half (46.7%) reported blood Phe within (120–360μmol/L) — the range recommended by the American College of Medical Genetics and Genomics (ACMG). The survey results also showed that younger (≤18years) individuals were about 3-times as successful in keeping their blood Phe concentrations within the recommended clinical range compared with adults. Blood Phe over 360μmol/L was reported in one-quarter (25.5%) of ≤18year old individuals and almost two-thirds (61.5%) of adults. A little more than half (51.7%) of respondents reported having difficulty in managing their PKU, including the maintenance of a Phe-restricted diet. Individuals with PKU desire new treatments that would allow them to increase their intake of natural protein, discontinue or reduce their intake of medical foods (medical formula and foods modified to be low in protein), improve their mental health (including a reduction in depression and anxiety), and a reduction of their blood Phe concentrations. Respondents preferred oral administration of any newly developed therapies and, in general, disliked therapeutic injections. Injections at home were preferred over injections at a clinic. Payers, government agencies, clinicians, and industry partners should consider patient input when developing and approving new therapies and treatments for PKU.

BackgroundPhenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. MethodsTwo Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. ResultsOf 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. ConclusionResults from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.

Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria

PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi-center, three-period crossover, open-label, active controlled, all-comers study