(Orion Pharma) 挺進 三期運用: 肌萎縮 脊髓側索硬化症（Amyotrophic lateral sclerosis，縮寫為ALS）呼吸治療臨床: Simdax (levosimendan心衰竭藥)

Orion takes repurposed heart failure drug into phase 3 for ALS by Phil Taylor | Jul 6, 2018 Finnish drugmaker Orion Pharma is pressing ahead with a pivotal trial for its amyotrophic lateral sclerosis drug ODM-109, despite mixed results in a phase 2 trial. The first patients have now been recruited into its phase 3 trial of ODM-109—an oral formulation of Orion's heart failure drug Simdax (levosimendan)—in the hope of showing that it can help support breathing function in patients with the devastating neurodegenerative disease. Orion said it plans to enroll 450 subjects in the placebo-controlled trial at sites in Europe, North America and Australia, with patients taking the drug for a year to see if it can slow down the respiratory difficulties that are the usual cause of death in ALS. In a phase 2 trial involving 66 ALS patients, ODM-109 missed its primary endpoint of an improvement in sitting slow vital capacity (SVC)—a measure of lung function—but was able to improve SVC when patients were lying on their backs."If the results of the [phase 3] trial are positive, the aim is to file for marketing authorization in the U.S. and Europe," according to Orion. Results from the study are due in 2020.For years, ALS only had one FDA-approved therapy—Sanofi's Rilutek (riluzole)—which has limited efficacy, with most patients still dying three to five years after diagnosis. In 2017, Mitsubishi Tanabe got FDA approval for free radical scavenger Radicava (edaravone), after filing the drug at the agency's request, based on a six-month study that showed a slower decline in physical function compared to placebo. Not all are convinced by the data for Radicava just yet, however, and it's widely recognized that other new therapies are desperately needed that can definitively slow down the loss of function in ALS. Prospects for a new therapy for ALS took a big knock last year after the high-profile failure in phase 3 of Cytokinetics' tirasemtiv, despite major tweaks to the trial protocol, but the company is hoping a clutch of new drugs, along with ODM-019, could end the drought. Another European biotech, France's AB Science, had a marketing application for its masitinib drug for ALS provisionally turned down in Europe in April, with regulators saying a phase 2/3 trial that showed efficacy at the highest dose used wasn't sufficient to support approval. The company has filed additional information to the EMA and is planning a confirmatory trial that it hopes will also support a U.S. filing. Meanwhile, some of the other players in the field include Biogen and Ionis, which have a SOD1-targeting antisense drug called BIIB067 in phase 1/2 trials, Amylyx with AMX0035 (sodium phenylbutyrate and tauroursodeoxycholic acid) in phase 2 with results due later this year, and new startup QurAlis.

Levosimendan(治療慢性心衰竭) 藉由增加細胞內鈣離子與心肌的troponin C結合之敏感度而導致心臟收縮，因此，不會損害心室放鬆。此外，Levosimendan 打開位於血管平滑肌上對ATP敏感的鉀離子管道，藉此誘導全身、冠狀動脈及全身靜脈血管的擴張。體外試驗證實 Levosimendan為具選擇性的 phosphodiesterase III 抑制劑，但並不清楚其在治療濃度下的相關性。對於患有心衰竭的患者，Levosimendan之心收縮力增強及血管放鬆作用，可導致收縮力的增加，並且降低前負荷與後負荷，而不會對舒張期功能有不良的效應。在PTCA或血栓溶解之後，Levosimendan會活化患者之心肌。 Simdax輸注可增加心臟手術後病人的冠狀動脈血流量和改善心衰竭病人的心肌灌注量，但不會增加心肌的氧氣消耗量。使用Simdax輸注治療，會明顯的降低鬱血性心衰竭病人循環系統中之 endothelin-1濃度。在建議的輸注速率下，則不會增加血漿中catecholamine的濃度。