Long-term comparative effectiveness of pegvaliase versus medical nutrition therapy with and without sapropterin in adults with phenylketonuria.

Phenylketonuria is characterized by intellectual disability and behavioral, psychiatric, and movement disorders resulting from phenylalanine (Phe) accumulation. Standard-of-care treatment involves a Phe-restricted diet plus medical nutrition therapy (MNT), with or without sapropterin dihydrochloride, to reduce blood Phe levels. Pegvaliase is an injectable enzyme substitution treatment approved for adult patients with blood Phe >600 µmol/L despite ongoing management. A previous comparative effectiveness analysis using data from the Phase 3 PRISM trials of pegvaliase (NCT01819727 and NCT01889862) and the Phenylketonuria Demographics, Outcomes and Safety Registry (PKUDOS; NCT00778206) suggested that pegvaliase was more effective at lowering mean blood Phe levels than sapropterin + MNT or MNT alone at 1 and 2 years of treatment. The current work augments and complements the previous analysis by including additional follow-up from the completed studies, robust methods reflecting careful consideration of issues with the distribution of Phe, and alternative methods for adjustment that are important for control of potential confounding in comparative effectiveness. Median blood Phe levels were lower, and median intact protein intakes were higher, in the pegvaliase group (n = 183) than in the sapropterin + MNT (n = 82) and MNT (n = 67) groups at Years 1, 2, and 3. In the pegvaliase group, median blood Phe levels decreased from baseline (1244 µmol/L) to Year 1 (535 µmol/L), Year 2 (142 µmol/L), and Year 3 (167 µmol/L). In the sapropterin + MNT group, median blood Phe levels decreased from baseline (900 µmol/L) to Year 1 (588 µmol/L) and Year 2 (592 µmol/L), and increased at Year 3 (660 µmol/L). In the MNT group, median blood Phe levels decreased slightly from baseline (984 µmol/L) to Year 1 (939 µmol/L) and Year 2 (941 µmol/L), and exceeded baseline levels at Year 3 (1157 µmol/L). The model-estimated proportions of participants achieving blood Phe ≤600 µmol/L were 41%, 100%, and 100% in the pegvaliase group at Years 1, 2, and 3, respectively, compared with 55%, 58%, and 38% in the sapropterin + MNT group and 5%, 16%, and 0% in the MNT group. The estimated proportions of participants achieving more stringent blood Phe targets of ≤360 µmol/L and ≤120 µmol/L were also higher in the pegvaliase group than in the other groups at Years 2 and 3. Overall, our results indicate that, compared with standard therapy, pegvaliase induces a substantial, progressive, and sustained decrease in blood Phe levels - to a much greater extent than sapropterin + MNT or MNT alone - which is expected to improve long-term outcomes in patients with phenylketonuria.

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

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165-304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 µmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 µmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 µmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 µmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.

The role of baseline blood pressure in guiding treatment choice: a secondary analysis of the use of valsartan/hydrochlorothiazide as initial therapy in hypertensive adults in a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Baseline blood pressure (BP) is a strong predictor of response to antihypertensive therapy and the patient's ability to reach BP goals. The objective of this study was to evaluate the role of baseline BP as a determinant of systolic BP (SBP) and treatment outcome to assist in the choice of initial therapy. METHODS: This was a double-blind, placebo-controlled clinical trial (n = 1329) in patients with essential hypertension (mean sitting diastolic BP [DBP] > or = 95 mmHg and <110 mmHg) who were randomized to placebo, valsartan 160 mg, valsartan 320 mg, hydrochlorothiazide (HCTZ) 12.5 mg, HCTZ 25 mg, valsartan/HCTZ 160 mg/12.5 mg, valsartan/HCTZ 320 mg/12.5 mg or valsartan/HCTZ 320 mg/25 mg. Retrospective analyses were performed to determine mean BP at end of study and BP goal rates and to explore the relationship between baseline BP level and predicted final BP. RESULTS: The final SBP and DBP were lowest in the combination therapy groups across all baseline BPs and in subgroups of patients categorized by age (> or = 65 years, <65 years), race/ethnicity (White, Black, other), and severity of hypertension at baseline. The proportion of patients achieving the SBP goal of <140 mmHg was highest in the valsartan/HCTZ 320 mg/25 mg group; the overall SBP goal achievement rate was 85%, and 78% of participants with stage 2 hypertension achieved goal. By comparison, 59% of patients in the HCTZ 25 mg group and 52% in the valsartan 320 mg group achieved SBP goal. Initial combination therapy was associated with lower predicted final SBP and DBP at all baseline BP levels compared with monotherapy. Analysis of tolerability data revealed that the proportion of patients experiencing dizziness or discontinuing therapy due to adverse events was generally similar across treatment groups, whereas the BP-lowering efficacy was greatest in the groups receiving combination therapy. CONCLUSION: These secondary analyses suggest that characterizing the relationship between baseline SBP and achieved SBP can assist in the choice of initial therapy in a broad hypertensive population. Initial therapy with the combination of valsartan/HCTZ is more effective than monotherapy in lowering BP at all baseline BP levels, is consistent in this respect among all subgroups, and is well tolerated.

Blood pressure control in patients initiating antihypertensive therapy.

BACKGROUND: Although information concerning the attainment of goal blood pressure for patients commencing antihypertensive therapy is available from controlled trials, no studies have examined this issue in the context of typical clinical practice. OBJECTIVE: To examine attainment of blood pressure control over time in patients initiating antihypertensive therapy in clinical practice. METHODS: Using an electronic medical records database, we identified all adults with systolic blood pressure (SBP)/diastolic blood pressure (DBP) of 140/90 mm Hg or higher who initiated antihypertensive drug therapy. Subjects were stratified into subgroups based on the presence of high-risk conditions or characteristics described by the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in their seventh report as "compelling indications" (eg, diabetes) or "special situations" (eg, obesity). Blood pressure control was examined in terms of goal attainment and reductions in blood pressure using last available readings at days 90, 180, and 360, following therapy initiation. RESULTS: Among the 10,345 study subjects, 47% had compelling indications and 39% had special situations. In the former group, 62% (95% CI 61 to 64) of patients with Stage 1 hypertension (140-159/90-99 mm Hg) attained blood pressure less than 140/90 mm Hg by day 360; among those with Stage 2 hypertension (> or =160/100 mm Hg), the corresponding figure was 48% (95% CI 46 to 50). In the latter group, 64% (95% CI 61 to 66) and 55% (95% CI 53 to 57) of patients with Stage 1 and Stage 2 hypertension, respectively, attained blood pressure less than 140/90 mm Hg by day 360. Among those without high-risk conditions, these percentages were 63% (95% CI 59 to 67) and 55% (95% CI 52 to 59). Among patients with diabetes or chronic kidney disease, 25% (95% CI 24 to 26) attained blood pressure less than 130/80 mm Hg by day 360. CONCLUSIONS: Many patients starting antihypertensive therapy in clinical practice fail to achieve blood pressure control within the first year. Control is no better, and perhaps worse, among patients at highest risk of adverse outcomes.

Initial combination therapy compared with monotherapy in diabetic hypertensive patients.

Subgroup analyses were performed for the diabetic and nondiabetic cohorts from 3 randomized clinical trials that had evaluated the systolic blood pressure (SBP)-lowering efficacy and tolerability of an angiotensin receptor blocker, valsartan, alone or in combination with hydrochlorothiazide to determine when and how to initiate combination therapy in hypertensive patients with diabetes. Blood pressure reductions achieved with monotherapy were compared with combination therapy in the diabetic and nondiabetic cohorts. In addition, multivariate models were developed to predict the likelihood of the goal SBP of < 130 mm Hg being reached in a diabetic patient with monotherapy or combination therapy across the range of baseline SBP values. In 2 of the 3 trials, comparable reductions in SBP were seen in the diabetic and nondiabetic cohorts. In all 3 studies, however, combination therapy provided greater blood pressure-lowering efficacy than monotherapy. The probability of achieving goal SBP was greater for diabetic patients started on combination therapy compared with monotherapy.

Time to achieve blood-pressure goal: influence of dose of valsartan monotherapy and valsartan and hydrochlorothiazide combination therapy.

BACKGROUND: Our objective was to assess time to achieve blood-pressure (BP) goal with incremental doses of valsartan alone, and together with hydrochlorothiazide (HCTZ), in patients with uncomplicated hypertension. METHODS: This analysis pooled patient-level data from nine randomized, double-blind, fixed-dose, placebo-controlled trials (N = 4278) of once-daily valsartan 80 mg, 160 mg, and 320 mg, and valsartan/hydrochlorothiazide (HCTZ) 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg. Kaplan-Meier methods estimated the cumulative proportion of patients achieving BP <140/90 mm Hg over 8 weeks and the median time to BP goal. The HCTZ 12.5-mg and 25-mg doses were pooled for the time-to-goal analysis in patients receiving combinations with valsartan 160 mg or 320 mg. RESULTS: Overall, the median time-to-goal was 8.1 weeks with valsartan 160 mg, 6.1 weeks with valsartan 320 mg, 2.6 weeks with valsartan 160 mg/HCTZ, and 2.1 weeks with valsartan 320 mg/HCTZ. In patients with stage 2 hypertension, the median time-to-goal was 4.3 weeks with valsartan 160 mg/HCTZ and 2.4 weeks with valsartan 320 mg/HCTZ. Goal rates by Week 4 for valsartan/HCTZ exceeded rates by Week 8 with the same doses of valsartan alone. Overall, the proportion that achieved BP goal by Week 8 was 32.6% with valsartan 80 mg, 48.4% with valsartan 160 mg, 54.2% with valsartan 320 mg, 74.6% with valsartan 160 mg/HCTZ, and 84.8% with valsartan 320 mg/HCTZ, versus 24.2% with placebo. With valsartan 320 mg/HCTZ, 75.8% of stage 2 patients and 94% of stage 1 patients reached BP goal by Week 8. Discontinuation rates due to adverse events were generally low across doses. CONCLUSIONS: In both stage 1 and stage 2 hypertension, BP control is achieved more frequently and promptly when patients receive higher doses of valsartan monotherapy or valsartan combination therapy, with a favorable benefit-risk profile.

Evaluation of the dose response with valsartan and valsartan/hydrochlorothiazide in patients with essential hypertension.

This patient data meta-analysis included 9 randomized, double-blind, placebo-controlled trials (N=4278) of once-daily valsartan 80, 160, or 320 mg or valsartan/hydrochlorothiazide 80/12.5, 160/12.5, 160/25, 320/12.5, or 320/25 mg given for 4 to 8 weeks. Efficacy variables included: (1) mean change in systolic blood pressure (BP) and diastolic BP; and (2) proportion of patients reaching BP goal (<140/90 mm Hg) at the end of the study. Results showed that incremental systolic and diastolic BP reductions were achieved with increasing doses. Starting doses of valsartan 160 mg provided greater BP reductions and a higher proportion of patients reaching goal than 80 mg; combination therapy was more effective than monotherapy. BP goal rates increased incrementally with higher doses. With valsartan/hydrochlorothiazide 320/25 mg, 74.9% overall, 88.8% of stage 1, and 62.1% of stage 2 patients reached BP goal. The rate of discontinuation due to adverse events was low with both monotherapy and combination treatment. Higher starting doses may enable patients to achieve greater initial BP reductions and reach BP goal more rapidly.

Predicting age- and dose-related responses to antihypertensive therapy: pooled analysis of two randomized clinical trials of valsartan alone and combined with hydrochlorothiazide.

We evaluated the relationship between age and treatment response from pooled data from two randomized trials in which 1,464 patients with Stage 2 hypertension were treated with valsartan alone or in combination with hydrochlorothiazide (HCTZ). Multivariate models were constructed for two response variables: systolic blood pressure (SBP) achieved at week 8 and change from baseline in SBP at week 8. Increasing age and higher baseline SBP were associated with proportionally higher final SBP values. The highly significant age-related decline in treatment response was substantially reduced with valsartan plus HCTZ compared with valsartan alone. Adverse event rates were generally comparable across the treatment groups. This analysis indicates that both age and baseline SBP should be considered when selecting antihypertensive therapy for patients with Stage 2 hypertension; for many older patients, initial therapy with both valsartan and HCTZ may be necessary, but in younger patients, one drug may be appropriate. However, because >87% of the study participants were White, it is unclear whether these results are applicable to other ethnic groups.

Effectiveness of add-on therapy with amlodipine in hypertensive patients receiving valsartan.

OBJECTIVE: To describe the real-world effectiveness of amlodipine add-on therapy for hypertensive patients receiving valsartan. METHODS: Retrospective cohort study based on USA electronic medical records. The study population included hypertensive patients who, between January 1998 and December 2005, were receiving valsartan and subsequently initiated add-on therapy with amlodipine. Change in systolic blood pressure (SBP)/diastolic blood pressure (DBP), and attainment of goal SBP/DBP (i.e. < 140/90 mmHg), were examined based on last available reading prior to day 180 following initiation of amlodipine. RESULTS: Mean (+/- SD) baseline SBP/DBP of study subjects (n=155) was 152.5 (+/- 21.1)/84.0 (+/- 13.5) mmHg. Add-on therapy with amlodipine reduced SBP by 13.3 mmHg (95% CI 9.4-17.1) and DBP by 6.1 mmHg (95% CI 4.2-8.1). Among patients with baseline SBP/DBP > or = 160/100 mmHg (n=69), corresponding reductions were 28.8 mmHg (95% CI 23.4-34.2) and 11.4 mmHg (95% CI 8.4-14.3). Goal SBP/DBP was achieved by 46% (95% CI 37.7-55.6) of subjects; rates of goal attainment were similar for patients with and without diabetes or chronic kidney disease, and those aged > or = 65 years versus younger. CONCLUSIONS: Adding amlodipine to valsartan for treatment of hypertension results in clinically meaningful reductions in blood pressure, on an overall basis and in high-risk subgroups who may benefit the most from blood pressure control.