Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Clinical studies in lysosomal storage diseases: past, present and future.

Lysosomal storage disorders (LSDs) are made of over 40 diseases. Costly treatments have been developed. In this review, we consider the regulatory context in which LSDs studies are performed, and highlight design specificities and operational aspects. Orphan drug legislations in Europe and US were effective to stimulate LSDs drug development. However the flexibility of regulators to facilitate approval is inconsistent leading to worldwide differences in access to LSD treatments. Study designs are impacted because only few patients can be studied. This implies LSDs treatments need to demonstrate a large efficacy effect. Otherwise the level of evidence is difficult to demonstrate. While biomarkers could accelerate approvals, in LSDs none have been accepted as primary outcome of efficacy. Enrichment of study population can increase the chance of success, especially with clinical outcome. Adaptive designs are challenging. Innovative methods of analysis can be used, notably using a patient as his/her own control and responder analysis. Other characteristics include extension phases and patient registries to further data collection. Few patients are available per centers and more centers need to be initiated in multiple countries. This impacts time-lines and budget. For LSDs, development program should be individualized. Regulators flexibility will be essential to provide patients access to innovative treatments.

Risk Evaluation and Mitigation Strategies (REMSs): Are They Improving Drug Safety? A Critical Review of REMSs Requiring Elements to Assure Safe Use (ETASU).

Risk Evaluation and Mitigation Strategies (REMSs) with Elements to Assure Safe Use (ETASU) are requested for drugs with significant safety risks. We reviewed REMS programs issued since 2011 to evaluate their rationales, characteristics, and consistencies, and evaluated their impact on improving drug safety. We conducted a literature search and a survey of relevant websites (FDA, manufacturers, and REMSs). ETASU characteristics were summarized. REMS risks were compared with labeled risks, including black box warnings. Forty-two programs were analyzed. Seven incorporated drugs of the same class. Most drugs (57%) were indicated for an orphan disease. A single risk was mentioned in 24 REMSs, and multiple risks in 18. Embryo-fetal toxicity and abuse or misuse were the most frequent risks. All risks were identified during clinical development but some were hypothetical. Thirty-six drugs had a black box warning. REMS risks and black box risks differed for 11 drugs. A drug with multiple indications could have a REMS for one of them but not for another. Most REMSs required prescriber training and certification, half required dispenser certification and patient enrolment. REMSs were revised multiple times and only three (7%) were discontinued. No data were available to establish whether REMSs were effective in improving drug safety. Some REMSs were deemed inefficient. REMSs with ETASU continue to be implemented but their impact on improving drug safety is still not documented. Hence, one of the main requirements of the FDA Amendments Act of 2007 is not being addressed. In addition, REMSs are complex and their logic is inconsistent; we recommend a thorough re-evaluation of the REMS program.

The Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination with Febuxostat When Treating Hyperuricemia Associated with Gout.

OBJECTIVE: Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety. METHODS: Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2. RESULTS: Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC)(0-t) of ARH acid + FBX/ARH acid was 108%. The AUC(0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe. CONCLUSION: ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe. TRIAL REGISTRATION: NCT02252835.

Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.

BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.

The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee.

Ximelagatran is a new oral anticoagulant that acts by direct and reversible inhibition of thrombin and has the potential to replace warfarin. In 2004, the FDA Cardiovascular and Renal drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program. Three indications were proposed: the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR), the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF), and the long-term secondary prevention of VTE after standard treatment of an episode of acute VTE. The database consisted of a total of 30,698 subjects and included five phase III pivotal studies. During the advisory panel debate, widely divergent analyses of the benefits and risks of ximelagatran were presented. Ximelagatran hepatic toxicity was a key feature leading the CRAC to conclude that the benefit risk ratio of ximelagtran was unfavorable for the three proposed indications. Some design issues also undermined the strength of efficacy data. This paper reviews the benefits and risks of ximelagatran and analyzes the reasons leading to conflicting conclusions among various experts. The aim of this review is to facilitate the interpretation of benefits and risks associated with a new drug product and to improve future clinical drug developments.

A Randomized, Double-Blind, Active- and Placebo-Controlled Efficacy and Safety Study of Arhalofenate for Reducing Flare in Patients With Gout.

OBJECTIVE: Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout. METHODS: This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure. RESULTS: A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups. CONCLUSION: Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy.

Gene therapy as a new treatment option for inherited monogenic diseases.

BACKGROUND: Gene therapy, replacing a defective gene by a functional copy, has been in development for more than 40years. Initial efforts involved engineering viral vectors to deliver genes to the appropriate cells. Early successes in severe combined immunodeficiency (SCID) were later derailed by safety issues including host reaction to the vector and gene insertion near promoters that favored secondary leukemia. METHODS: Systematic review of the literature using PubMed.gov with key word gene therapy from 1972 to March 2013. Google search with key word gene therapy. RESULTS: Despite early setbacks, progresses for monogenic diseases continued unabated. Patients with SCIDs have been cured and the first gene therapy has been approved for lipoprotein lipase deficiency. Many clinical research studies are ongoing as part of systematic clinical development program with a view to have more gene therapies approved. CONCLUSION: Our review highlights progresses and questions that remain to be answered to make gene therapy an integral part of our therapeutic arsenal.

Clinical studies in lysosomal storage diseases: Past, present, and future.

Lysosomal storage disorders (LSDs) consist of over 40 diseases, some of which are amenable to treatment. In this review, we consider the regulatory context in which LSDs studies are performed, highlight design specificities and explore operational challenges. Orphan drug legislations, both in Europe and US, were effective to stimulate LSDs drug development. However, regulators flexibilities toward approval vary leading to global discrepancies in access to treatments. Study designs are constrained because few patients can be studied. This implies LSDs treatments need to demonstrate large levels of clinical efficacy. If not, an appropriate level of evidence is difficult to achieve. While biomarkers could address this issue, none have been truly accepted as primary outcome. Enrichment of study population can increase the chance of success, especially with clinical outcomes. Adaptive designs are operationally challenging. Innovative methods of analysis can be used, notably using a patient as his/her own control and responder analysis. The use of extension phases and patient registries as a source of historical comparison can facilitate data interpretation. Operationally, few patients are available per centers and multiple centers need to be initiated in multiple countries. This impacts time-lines and budget. In the future, regulators flexibility will be essential to provide patients access to innovative treatments.

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies.

BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. METHODS: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. RESULTS: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients' increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. CONCLUSIONS: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing.