Alexion cost cutting is 'all about building pipeline' by Phil Taylor | Sep 12, 2017 Alexion is slashing its workforce by around 20% and closing sites in a bid to save $250 million a year, with R&D bearing the brunt and accounting for around two-thirds of the cost cutting. The restructuring will claim around 600 jobs and, according to senior management, is intended to answer a "critical need to rebuild pipeline" as Alexion starts to prepare for the loss of patent protection for cash cow drug Soliris (eculizumab)—which currently accounts for the bulk of the company's revenues—within the next few years. Alexion first revealed its intention to revamp the business earlier this year under new CEO Ludwig Hantson and CFO Paul Clancy, and has already pared down R&D to four key areas, namely hematology, nephrology, neurologic and metabolic disorders, and scrapped a series of partnership deals. Around $100 million of the savings will be routed back into R&D and business development, said Alexion, with the biotech expecting to make a series of licensing, partnerships and bolt-on acquisition deals to add to its current R&D portfolio. It wants to be spending 18%-19% of sales on R&D by 2018-2019, according to Clancy, who also said that the new deals are expected to be relatively small and not add too much debt. Among the other big decisions is the relocation of its headquarters from New Haven to Boston within the next 12 months, with Boston having around 400 positions and New Haven retaining around 450 staff, including 150 focusing on lab and process development work for Alexion's top priority complement R&D program. Explaining the HQ move, Hantson said on a conference call that it is important to be close to Boston hub to tap into talent pool and future partners. Complement—and specifically lead candidate ALXN1210, an anti-C5 antibody in late-stage development for paroxysmal nocturnal hemoglobinuria (PNH)—is now the key R&D focus, he said. The company also confirmed it is "eliminating the spend and headcount" in lower priority programs including enzyme replacement drug ALXN1101 for molybdenum cofactor deficiency (MoCD) Type A and cancer candidate ALXN6000 (samalizumab). Hantson said on the call that the company's research focus is "moving from ultrarare to rare, but staying in the orphan disease space." As it stands, ALXN1210 is the main focus, and head of R&D John Orloff, M.D., told analysts on the call that a trial in untreated PNH patients and a second in patients switched from other medicines are now fully enrolled and due to generate results in the first half of 2018, setting up possible approvals a year later. The shake-up at the firm followed sales fraud investigations involving Soliris that resulted in the resignation of long-serving CEO David Hallal. Other initiatives include the closure of a Rhode Island manufacturing plant and shuttering of multiple offices worldwide, with the total cost of the downsizing expected to come in at between $340 million and $440 million.
Alexion Pharma (ALXN) Granted New Indication for Soliris (Eculizumab) for the Treatment of Patients with Refractory Generalized Myasthenia Gravis by EU Commission (StreetInsider) August 21, 2017 Alexion Pharmaceuticals, Inc. (NASDAQ: ALXN) announced today that the European Commission (EC) approved the extension of the indication for Soliris® (eculizumab) to include the treatment of refractory generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody-positive. Soliris is the first and only complement-based therapy approved in the European Union (EU) for this ultra-rare subset of patients.1-4 Patients with refractory gMG can have difficulties walking, talking, swallowing and breathing normally despite therapies currently used for MG. Exacerbations and crises of their disease may require hospitalization and intensive care and may be life-threatening.5-7 Soliris will be launched for this new indication initially in Germany, and Alexion is evaluating launches in additional EU countries."Patients with refractory gMG have exhausted multiple therapies and continue to suffer from severe symptoms and complications that markedly impact their daily lives," said Renato Mantegazza, MD, from the Department of Neuroimmunology and Neuromuscular Diseases, at the Istituto Neurologico Carlo Besta in Milan, Italy, and an investigator in the Phase 3 REGAIN study. "There is an urgent need for therapy for these patients, and it's exciting to have a product such as Soliris available that has demonstrated in clinical studies that it improves patients' symptoms and their ability to undertake daily activities." Chronic uncontrolled activation of the complement cascade, a part of the immune system, can play a major role in the debilitating symptoms and potentially life-threatening complications of refractory gMG.8-10 Soliris is a first-in-class complement inhibitor that specifically and effectively inhibits the terminal part of the complement cascade."Our deep understanding of complement-mediated diseases enabled us to develop Soliris for the treatment of patients with refractory gMG," said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. "We are grateful to the investigators and patients who participated in our clinical program, and we are excited about the opportunity to bring Soliris to patients who continue to suffer from this debilitating disease despite current therapies." The EC based its approval of the extended indication for Soliris on comprehensive clinical data from the Phase 3 REGAIN study (MG-301) and its long-term open-label extension study (MG-302). Alexion's supplemental Biologics License Application (sBLA) in the U.S. and a supplemental new drug application in Japan for Soliris as a treatment for patients with anti-AChR antibody-positive refractory gMG have been accepted for review by the U.S. Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW), respectively. Soliris has received Orphan Drug Designation (ODD) for the treatment of patients with MG in the U.S. and EU, and for the treatment of patients with refractory gMG in Japan.
About Refractory Generalized Myasthenia Gravis Patients with refractory generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive represent an ultra-rare subset of MG patients1-4 who continue to suffer from severe disease symptoms and complications despite therapies currently used for MG.1-2,11 MG is a debilitating, chronic and progressive autoimmune neuromuscular disease that can occur at any age but most commonly begins for women before the age of 40 and men after the age of 60.5,6,12,13 It typically begins with weakness in the muscles that control the movements of the eyeballs and eyelids, and often progresses to the more severe and generalized form, known as gMG with weakness of the head, neck, trunk, limb and respiratory muscles.13 While most symptoms in patients with gMG are managed with therapies for MG, 10% to 15% of patients are considered refractory—meaning they do not respond to multiple therapies for MG and continue to suffer profound muscle weakness, and severe disease symptoms that limit function.1-2,11 Patients with refractory gMG can suffer from slurred speech; impaired swallowing; double or blurred vision; disabling fatigue; immobility requiring assistance; shortness of breath, and episodes of respiratory failure. Complications, exacerbations and myasthenic crises can require hospital and intensive care unit admissions with prolonged stays and can be life-threatening.5-7 In patients with anti-AChR antibody-positive MG, the body's own immune system turns on itself to produce antibodies against AChR, a receptor located on muscle cells in the neuromuscular junction (NMJ) and used by nerve cells to communicate with the muscles these nerves control.5,6 The binding of these antibodies to AChR activates the complement cascade, another part of the immune system, which leads to a localized destruction of the NMJ. As a result, the communication between nerve and muscle is impaired, which in turn leads to a loss of normal muscle function.8-10,14
About Soliris® (eculizumab) Soliris® is a first-in-class complement inhibitor that works by inhibiting the terminal part of the complement cascade, a part of the immune system that, when activated in an uncontrolled manner, plays a role in serious ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS) and anti-acetylcholine receptor (AChR) antibody-positive refractory generalized myasthenia gravis (gMG). Soliris is approved in the U.S., EU, Japan and other countries as the first and only treatment for patients with PNH and aHUS, and in the EU as the first and only treatment for refractory gMG in patients who are anti-AChR antibody-positive. Soliris is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome (STEC-HUS). Alexion and Soliris have received some of the pharmaceutical industry's highest honors for the medical innovation in complement inhibition: the Prix Galien USA (2008, Best Biotechnology Product) and France (2009, Rare Disease Treatment).
陣發性夜間血紅素尿症--疾病介紹成因：陣發性夜間血紅素尿症（簡稱PNH；paroxysmal nocturnal hemoglobinuria）是一種罕見而複雜的血液疾病，民國99年3月19日經衛生署公告為罕見疾病。重要特徵包括：慢性溶血、造血機能異常、血栓等。患者體內某些造血幹細胞帶有X染色體上PIGA基因的突變，且出現異常增生現象，造成很多紅血球缺乏CD55和CD59兩種表面蛋白質，容易受到補體系統攻擊破裂，引發慢性溶血並反覆發作。PNH雖罕見，不過世界上許多族群都有相關報告：發病年齡從6到82歲都有可能，通常在40到50歲間診斷；女性患者似乎比男性多一點點，但我國長庚醫院過去的較大規模報告中則以男性居多。此疾病是體細胞突變後造成，並沒有家族遺傳的傾向。
症狀：患者睡覺時較容易發生溶血，推測是睡眠時體內二氧化碳濃度較高或水分較少的緣故，目前還沒有定論。溶血會釋出血紅素，並經腎臟排到尿液中，因此半夜起來小便，尤其是剛睡醒後第一泡尿，會出現異常的紅色、茶色甚至黑色，讓人嚇一大跳！由於溶血現象時好時壞，夜間小便顏色異常一陣子後又會恢復正常，故歐洲醫師19世紀發現此疾病時，將它命名為「陣發性夜間血紅素尿症」。夜間血紅素尿現象雖然很能令人警覺，但其實只有約四分之一的患者曾出現典型血紅素尿。大部分病患最初的症狀，都與溶血或貧血有關，例如腹絞痛、下背痛、頭痛、倦怠感，甚至發燒等，小便顏色未必真的有什麼不對勁。此外，約有30%的PNH患者還有其他血球（血液細胞）數目的異常，甚至出現相關症狀：白血球偏低時可能容易感染、血小板不足時皮膚上出現紫斑等。這時需懷疑合併其他骨髓造血機能異常，例如PNH再生不良性貧血（aplastic anemia；AA）、PNH骨髓生成不良症候群（myelodysplastic syndrome；MDS）等，應做骨髓檢查。血管栓塞，特別是靜脈血栓，是一種比較少見但可能相當嚴重的併發症，會增加疾病的危險程度。常影響部位有腹部、皮膚、腦部靜脈，此外也有15-30%患者出現肝臟靜脈栓塞（Budd-Chiari症），故患者需特別注意是否有頭痛、肚子痛、噁心、嘔吐、黃疸、腹部積水、胃或食道靜脈區張出血、肝功能指數異常等現象。台大醫院曾報告過PNH造成罕見的腦部血管炎（moyamoya症）個案，故當有不明原因或特殊部位的血栓，又合併溶血或其他血球數目異常時，也要將PNH列入考量。其他症狀如：溶血引起腎功能異常、吞嚥困難或疼痛、勃起障礙等。
診斷：當醫師懷疑血紅素尿或溶血現象時，會做詳細的問診與身體檢查，看看是否有黃疸、肝臟腫大、脾臟腫大、紫斑等現象。初步的驗血包括全血球記數與分類（CBC/DC）、溶血相關生化與血液檢查（包括乳酸去氫酶）、腎功能檢查、鐵含量、尿液分析等。血中的乳酸去氫酶（LDH）是一種非專一性的指標，通常可作為溶血嚴重程度的重要參考。一旦確實懷疑PNH，需再抽血做「流式細胞儀（flow cytometry）」分析，檢查紅血球、白血球細胞表面是否缺乏CD55和CD59等用來穩定補體系統的蛋白質，並測定異常細胞的比例以判斷疾病嚴重程度。此外若有血管栓塞症狀，需安排相關腹部或腦部影像檢查。合併血球異常的患者，則應做骨髓檢查搭配細胞染色體檢查，以確實查明病因。
治療：PNH的治療以症狀處理為主：針對貧血，必要時需輸血，並考慮補充鐵質和葉酸，少數患者可能對雄性激素或皮質類固醇治療有反應；出現靜脈血栓的病人，應考慮接受抗凝血治療。美國食品藥物管理局（FDA）在民國96年核准上市的新藥eculizumab（商品名SolirisR），能透過抑制C5補體來阻止溶血，有效地減輕症狀、減少輸血、改善生活品質、降低靜脈血栓發生率。在我國需透過醫師與醫院向衛生署申請專案分批進口，經核准後以自費方式使用。使用前需接種流行性腦膜炎疫苗，以預防因補體下降而增加的感染風險。目前，只有異體骨髓或周邊造血幹細胞移植可以完全治好PNH，對於年紀較輕或合併血球數目異常的患者，若有白血球抗原配對相合的兄弟姊妹，值得考慮。不過其風險較高，對大部分症狀不嚴重的病人來說似乎顯得太過危險。
預後：PNH患者約有四分之一能存活超過25年，主要的危險性來自血管栓塞，以及合併血球下降後的出血和感染。一旦診斷確定，務必要長期規則追蹤，並隨時注意是否有疼痛、血尿、神經症狀等與溶血或栓塞有關的表現，以便儘早對相關併發症作適當的處理。
參考文獻：1. Brodsky RA: How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009;113:6522-7.2. Parker C, Omine M, Richards S, et al.: Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005;106:3699-3709.3. Lin HC, Chen RL, Wang PJ: Paroxysmal nocturnal hemoglobinuria presenting as moyamoya syndrome. Brain Dev 1996;18(2):157-9.4. Dunn P, Shih LY, Liaw SJ: Paroxysmal nocturnal hemoglobinuria: analysis of 40 cases. J Formos Med Assoc. 1991 Sep;90(9):831-5. 撰文：劉彥麟、楊永立、顏玎安文章出處: 罕見疾病基金會
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