Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease

Background: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. Methods: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded. Results: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018). Conclusion: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains

Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies

Refining seismic parameters in low seismicity areas by 3D trenching: The Alhama de Murcia fault, SE Iberia.

Three-dimensional paleoseismology in strike-slip faults with slip rates less than 1 mm per year involves a great methodological challenge. We adapted 3D trenching to track buried channels offset by the Alhama de Murcia seismogenic left-lateral strike-slip fault (SE Iberia). A fault net slip of 0.9 +/- 0.1 mm/yr was determined using statistical analysis of piercing lines for one buried channel, whose age is constrained between 15.2 +/- 1.1 ka and 21.9-22.3 cal BP. This value is larger and more accurate than the previously published slip rates for this fault: The minimum number of five paleo-earthquakes identified since the deposition of dated layers suggests a maximum average recurrence interval of approximately 5 ka. The combination of both seismic parameters yields a maximum slip per event between 53 and 63 m. We show that accurately planned trenching strategies and data processing may be key to obtaining robust paleoseismic parameters in low seismicity areas. (C) 2016 Elsevier B.V. All rights reserved

The Quaternary Active Faults Database of Iberia (QAFI v.2.0)

The Quaternary Active Faults Database of Iberia (QAFI) is an initiative lead by the Institute of Geology and Mines of Spain (IGME) for building a public repository of scientific data regarding faults having documented activity during the last 2.59 Ma (Quaternary). QAFI also addresses a need to transfer geologic knowledge to practitioners of seismic hazard and risk in Iberia by identifying and characterizing seismogenic fault-sources. QAFI is populated by the information freely provided by more than 40 Earth science researchers, storing to date a total of 262 records. In this article we describe the development and evolution of the database, as well as its internal architecture. Aditionally, a first global analysis of the data is provided with a special focus on length and slip-rate fault parameters. Finally, the database completeness and the internal consistency of the data are discussed. Even though QAFI v.2.0 is the most current resource for calculating fault-related seismic hazard in Iberia, the database is still incomplete and requires further review

A High Dynamic Range ASIC for Time of Flight PET with monolithic crystals

The HRFlexToT is a 16-channel ASIC for SiPM anode readout designed for Positron Emission Tomography (PET) applications that features high dynamic range (>8 bits), low input impedance, common cathode connection, high speed and low power (~3.5 mW/ch). The ASIC has been manufactured using XFAB 0.18 mm CMOS technology. The main characteristics of the HRFlexToT, compared to its predecessor, are a new energy measurement readout providing a linear Time Over Threshold (ToT) with an extended dynamic range, lower power consumption and better timing response. Initial measurements show a linearity error below 3%. Single Photon Time Resolution (SPTR) measurements performed using a Hamamatsu MPPC S13360-3050CS (3x3 mm2 pixel, 50 umm cell) shows 30% improvement with respect to the previous version of the ASIC, setting this specification in the order of 141 ps FWHM and reducing 3 times power consumption. It is important to highlight that an SPTR of 141 ps FWHM is, according to the best of our knowledge, the best resolution achieved so far for this sensor. Coincidence Time Resolution (CTR) measurements are expected to be performed during 2018

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease:a phase III open-label extension study (ATB200-07)

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and − 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was − 0.6 (7.5) for cipa + mig and − 3.8 (6.2) for the ERT-experienced switch group, and − 4.8 (6.5) and − 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD. Trial registration number: NCT04138277; trial start date: December 18, 2019.</p

Isolation of human fibroadipogenic progenitors and satellite cells from frozen muscle biopsies

Altres ajuts: Association Française contre les Myopathies (22525)Altres ajuts: Fundación Isabel GemioSkeletal muscle contains multiple cell types that work together to maintain tissue homeostasis. Among these, satellite cells (SC) and fibroadipogenic progenitors cells (FAPs) are the two main stem cell pools. Studies of these cells using animal models have shown the importance of interactions between these cells in repair of healthy muscle, and degeneration of dystrophic muscle. Due to the unavailability of fresh patient muscle biopsies, similar analysis of interactions between human FAPs and SCs is limited especially among the muscular dystrophy patients. To address this issue here we describe a method that allows the use of frozen human skeletal muscle biopsies to simultaneously isolate and grow SCs and FAPs from healthy or dystrophic patients. We show that while the purified SCs differentiate into mature myotubes, purified FAPs can differentiate into adipocytes or fibroblasts demonstrating their multipotency. We find that these FAPs can be immortalized and the immortalized FAPs (iFAPs) retain their multipotency. These approaches open the door for carrying out personalized analysis of patient FAPs and interactions with the SCs that lead to muscle loss

P.025 Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in participants with late-onset Pompe disease (LOPD)

Background: Phase 3 COMET trial (NCT02782741) compares avalglucosidase alfa (n=51) with alglucosidase alfa (n=49) in treatment-naïve LOPD. Methods: Primary objective: determine avalglucosidase alfa effect on respiratory muscle function. Secondary/other objectives include: avalglucosidase alfa effect on functional endurance, inspiratory/expiratory muscle strength, lower/upper extremity muscle strength, motor function, health-related quality of life, safety. Results: At Week 49, change (LSmean±SE) from baseline in upright forced vital capacity %predicted was greater with avalglucosidase alfa (2.89%±0.88%) versus alglucosidase alfa (0.46%±0.93%)(absolute difference+2.43%). The primary objective, achieving statistical non-inferiority (p=0.0074), was met. Superiority testing was borderline significant (p=0.0626). Week 49 change from baseline in 6-minute walk test was 30.01-meters greater for avalglucosidase alfa (32.21±9.93m) versus alglucosidase alfa (2.19±10.40m). Positive results for avalglucosidase alfa were seen for all secondary/other efficacy endpoints. Treatment-emergent adverse events (AEs) occurred in 86.3% of avalglucosidase alfa-treated and 91.8% of alglucosidase alfa-treated participants. Five participants withdrew, 4 for AEs, all on alglucosidase alfa. Serious AEs occurred in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated participants. IgG antidrug antibody responses were similar in both. High titers and neutralizing antibodies were more common for alglucosidase alfa. Conclusions: Results demonstrate improvements in clinically meaningful outcome measures and a more favorable safety profile with avalglucosidase alfa versus alglucosidase alfa. Funding: Sanofi Genzym

First measurement of the CP-violating phase in B0s→J/ψ( → e+e−)ϕ decays

A flavour-tagged time-dependent angular analysis of B0 s → J/ψφ decays is presented where the J/ψ meson is reconstructed through its decay to an e +e − pair. The analysis uses a sample of pp collision data recorded with the LHCb experiment at centre-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3 fb−1 . The CP-violating phase and lifetime parameters of the B0 s system are measured to be φs = 0.00 ± 0.28 ± 0.05 rad, ∆Γs = 0.115 ± 0.045 ± 0.011 ps−1 and Γs = 0.608 ± 0.018 ± 0.011 ps−1 where the first uncertainty is statistical and the second systematic. This is the first time that CP-violating parameters are measured in the B0 s → J/ψφ decay with an e +e − pair in the final state. The results are consistent with previous measurements in other channels and with the Standard Model predictions