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Background: SMA affects individuals with a broad age range and spectrum of disease severity. Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral SMN2 pre-mRNA splicing modifier. Methods: SUNFISH is a multicenter, two-part, randomized, placebo-controlled, double-blind study in patients with Types 2/3 SMA. Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels in patients with Types 2/3 SMA. Part 2 assessed the efficacy and safety of the selected dose of risdiplam versus placebo in Type 2 and non-ambulant Type 3 SMA. In Part 2, participants were treated with risdiplam or placebo for 12 months, then received risdiplam in a blinded manner until month 24. At month 24, patients were offered the opportunity to enter the open-label extension phase. Results: Change from baseline in MFM32 total score (Part 2- primary endpoint) in patients treated with risdiplam versus placebo was met at month 12. These increases in motor function were sustained in the second and third year after risdiplam treatment. Here we present 4-year efficacy and safety data from SUNFISH. Conclusions: SUNFISH is ongoing and will provide further long-term efficacy and safety data of risdiplam in a broad population of individuals with SMA.
Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.
Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.
A direct calorimetry method was developed and used to measure the electrocaloric effect (ECE). A temperature change ΔT of over 20 °C and an entropy change ΔS of over 95 J/(kgK) were procured at 33 °C and 160 MV/m in the high-energy electron irradiated poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) 68/32 mol% copolymers, which were larger than those of terpolymer blends (ΔT = 9 °C, ΔS=46 J/(kgK) at 180 MV/m and room temperature) and our earlier report on P(VDF-TrFE) 55/45 mol% normal ferroelectric copolymer (12 °C and 55 J/(kgK) at 80 °C). We observed that the β value ((8.7±0.6)×107 JmC-2K-1) in the equation of ΔS=1/2βΔD2 derived from ΔS - ΔD2 relation for irradiated copolymers was larger than that of the terpolymer blends ((5.4±0.5)×107 JmC-2K-1). It was also found that the irradiated copolymer showed a sharp depolarization peak at Td < Tm (maximum permittivity temperature), which is frequency independent, in the dielectric constant - temperature characteristics, a larger depolarization value at Td in the thermally stimulated depolarization current (TSDC) - temperature relationship, and a larger volume strain/longitudinal strain ratio over terpolymer blends. The giant ECE in irradiated copolymer is regarded as due to the greater randomness present in the relaxor state. In irradiated copolymers, the long all-trans chains are broken by the high-energy electrons, which make the small sized all-trans sequences more easily reorient along the electric field, more remarkably affecting the permittivity, TSDC, and volume strain.
The cultural and political changes that happened in Anatolia after the collapse of the Hittite Empire have only recently been recognised as a significant, but as yet unexplained, phenomenon. Here we present the results of analyses of ceramics from three sites south and southwest of the present-day town of Sorgun – Çadır Höyük, Kerkenes Dağ and Tilkigediği Tepe – to identity how regional groups within the Hittite core area regrouped in the aftermath of the collapse. Ceramic analyses provide a means to assess both cultural continuity and the scale and nature of interaction in a region. Results suggest some evidence of cultural continuity at Çadır Höyük from the Late Bronze Age into the Middle Iron Age, and highlight the variable local responses in the aftermath of Hittite collapse.
The last decade of excavations at Çadır Höyük, in the north-central region of the Anatolian plateau, has revealed a well-established Late Chalcolithic community with continuous occupation into the Early Bronze I period (mid fourth to early third millennium BC). While the Late Chalcolithic town was prosperous, with well-made houses and objects, and even monumental construction, the stability of the settlement had slipped by the Early Bronze I phase. We summarise here the results from ten seasons of work at the site and profile how the findings contribute to our understanding of Çadır's role in a larger regional context. We also offer possible explanations for the changing nature of the Çadır occupation during the periods detailed here.
Archaeological excavations were conducted at Alişar Höyük in central Turkey from 1927 to 1932 by the Oriental Institute of the University of Chicago. The six years of investigation uncovered evidence that indicated the mound had been occupied intermittently from at least the Early Bronze Age through the modern Turkish period. The premature cessation of excavations at the site, however, left many issues unresolved, a situation that has bedeviled Anatolian specialists up to the present day.
Foremost among the problems left unsettled by the Oriental Institute excavations was the question of whether a Late Bronze II settlement (1400–1200 B.C.) had existed at the site, an issue that was raised by the discovery at Alişar of cuneiform tablets written in the Old Assyrian script that referred to a town called Amkuwa, known also from Hittite texts as Ankuwa. On the basis of these references, scholars were quick to associate Amkuwa/Ankuwa with Alişar. The problem with this equation is that, on the one hand, a Hittite text dating to the reign of Hittite king Ḫattušili III makes it clear that Ankuwa was occupied in the LB II.
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