S4.E5. 從一到百，IPF 藥物的無限可能

Ofev^®抑肺纖是全球首批的肺纖維化藥物之一，並於2014年在美國取得上市許可。如今Ofev^®已在全球70多個國家取得銷售許可，專門因應包含特發性肺纖維化（pulmonary fibrosis，簡稱IPF）以及因全身性硬化症導致間質性肺疾病（systemic sclerosis-associated interstitial lung disease，簡稱SSc-ILD）。

百靈佳殷格翰的科學家們採用獨一無二的研究方法：試圖判定不同疾病之間的共通點。目標是：開發一種能同時對多種類型疾病的新型藥物。

早在2007年Craig Conoscenti 就提出了這個創新的治療方法。Conoscenti 回憶，那時專門針對IPF患者開發的藥物 「Nintedanib」剛通過第二階段臨床試驗，在場人員們聽到這突破性的研究方式時都覺得不可思議，但同時也感到非常興奮。Conoscenti 與團隊成員不僅為了整個研究往前跨一大步欣喜若狂，也對於前面的路充滿希望而感到喜悅。

1990年代初期時，人們對IPF了解的非常少，Conoscenti 說：「甚至連統一的名稱都沒有，更別說治療方法了！」Conoscenti 自1985年起擔任胸腔科醫師，並在早期的職業生涯就對間質性肺部疾病（interstitial lung diseases）的研究產生興趣及關注。IPF 患者會因為肺部愈來愈多疤痕組織（scar tissue）出現，肺部功能喪失的情形也逐步出現。「當時我們除只能嘗試各種未獲得許可的藥物外，沒有別的辦法；長期看下來，那些藥物也沒有任何實際的作用。」即便Conoscenti 博士已經是胸腔科的一名醫師，他的父親也是美國境內最早獲得呼吸治療師認證的成員之一，但他父親依然因罹患IPF而過世。這是Conoscenti 堅持投入在臨床領域中鑽研IPF 的重要原因之一，最終他決定加入百靈佳殷格翰的研究團隊，投入於對抗IPF這場艱難的戰役中。

發現全方位的治療方法

百靈佳殷格翰在西元2000 年之前， 就已經開始鑽研首例具開創性的IPF 治療方法。 Conoscenti 解釋「不得不說這是個了不起的進展，主要是當時幾乎沒有人會想關注這群少數的病患。」IPF 是一種罕見、但會令人急速衰弱並且致命的疾病，全球約有300 萬人患有此疾病而受到影響。 IPF 是肺纖維化這項病症中最常見的形式。百靈佳殷格翰很早就發現IPF 療法極具潛力—它可以成為尋找其他200 多種間質性肺部疾病療法的助力。

免疫學和呼吸系統疾病研究中心負責人Jay Fine 博士說：「百靈佳殷格翰持續拓展這種全方位的研究取向已經行之有年了，重點始終放在如何開發因應多種疾病或患者的藥物，進而為提供給更多患者幫助。」初期要確定一種新開發的藥物可以治療多少種疾病，需要耗費許多心力與時間。即便如此，Fine的團隊依然為了發現「疾病叢聚（disease clusters）」的新療法，持續尋找各種疾病間的共通點。這種研究取向大幅的增加了單一藥物的範圍與價值。

以此為目標，Conoscenti的研究團隊專心致力於研究IPF、肺纖維化和其他間質性肺部疾病的研究。 整個過程中面對許多挫折，就像是最初覺得有希望成功的藥物組合，並不如他們預期的發生作用。 幸好最終有成功開發Nintedanibnintedanib。 Nintedanib可以抑止纖維化的過程，進而減緩疤痕組織的形成以及病徵發展。IPF依然是無藥可醫的疾病，但Nintedanib每年可以降速一半的肺功能喪失歷程。

Fine堅信：「Nintedanib 是我們進行纖維化研究的基礎。」 研究小組發現IPF與該疾病叢聚中的其他病症之間有許多相同點， 如：因全身性硬化症導致間質性肺疾病（SSc-ILD）；SSc-ILD 是一種罕見且無法治癒的自體免疫系統疾病，會在皮膚以及許多內臟器官中，包含肺，形成疤痕組織。 SSc-ILD 患者通常比IPF患者年輕，且通常為中年女性。這兩種罹病患者的病徵進度也很相似。

百靈佳殷格翰於一項大型臨床研究中測試發現Nintedanib 可以在一年內將肺功能喪失的進展減緩44%。2019 年9 月上旬，美國食品藥品監督管理局（FDA）批准Nintedanib 作為治療SSc-ILD 的第一種藥物。歐洲藥品管理局（The European Medicines Agency，EMA）人類藥物委員會也於2002年3月時給予百靈佳殷格翰正面評價。 2020 年3 月，FDA准許Nintedanib 可以用於治療惡化性間質性肺病（暫譯）（chronic (long lasting) interstitial lung disesase in which lung fibrosis continues to worsen (progress)）治療，以減緩肺纖維化的程度。 完全新創藥物為IPF患者帶來希望 對Fine以及他的團隊所進行的研究，這個完全新創的藥物（first-in-class）具有非凡的意義。他們希望發現嶄新、獨特的疾病治療機制。「我們的願景是藉由開創『以患者立場為驅動因素』的研究取向，將發炎以及纖維化疾病的治療進行轉化。」

Fine 的團隊專注於三大原則：設定目標、修復和預防。發炎性疾病的導火線通常是因過度反應的免疫系統—免疫系統攻擊人體自身的組織，導致相關器官功能受損，因此降低患者生活品質。 團隊首先將目標設定在「驅動組織受損的關鍵機制」，選出阻斷或能驅使組織進行自身修復的最佳方法。如果纖維化過程已經開始，目標則設定為盡可能的阻止疾病發展。

這種全面性的研究方法也能用於其他形式的發炎性病徵以及纖維化疾病。例如：研究小組開發了一種名為spesolimab的藥物， 可以阻斷白細胞介素36（interleukin 36，或縮寫為IL-36）受體的作用機制。 很多人認為spesolimab具備標靶以及具備多種發炎性疾病以及纖維化疾病的潛力功能， 近期也在化膿性乾廯（pustular psoriasis）患者中獲得相當正面的研究成果。 Fine解釋說：「即便這項研究仍在初期階段，spesolimab確實具備改善患者生活的潛力。」

當研究取得突破的那一瞬間，他們都清楚的感受到「自己的確幫助了患者」，這也是他們能「持續投入於這項工作的原因」。

創意發想，全球人人有責

對百靈佳殷格翰而言，與外部夥伴合作能刺激更多的創意發想非常重要，以共同創造更多新奇的產品組合。夥伴合作關係可以補強團隊的工作內容，大家都能更專注於尋找新的治療方案，給予為過去未能被滿足的醫療需求或被忽略的疾病（像是纖維化疾病）更多關注。

藉由更廣並且多元的全球創意夥伴社群，我們能學習並實踐更多知識。百靈佳殷格翰與來自學術機構以及全球其他企業的開創性先驅合作，為有高度醫療需求的患者發掘新的治療方法。

自2020年1月已經開始與來自新加坡的生技公司Enleofen Bio 攜手合作了。 目標為運用Enleofen Bio的臨床前期介白素IL11（interleukin-11，或IL-11），開發能廣泛因應纖維化以及發炎性疾病的新療法。IL-11是一種細胞介素（cytokine），為人體中某些細胞用來交流的一種蛋白質，在纖維化和發炎性疾病中具備關鍵作用。目前已經證明，阻斷IL-11可以抑制許多器官（肝、肺、腎、視網膜、腸、心臟和皮膚）疾病。我們將重點優先放在研究非酒精性脂肪性肝炎（Nonalcoholic Steatohepatitis，簡稱NASH）與間質性肺疾病（interstitial Lung Diseases，ILDs）的新療法上，這是百靈佳殷格翰的兩項重點疾病領域，並有可能以IL-11為基礎，進一步發展並找出更多應用於纖維化以及發炎性疾病的療法。

另一項合作起始於2016年，與美國劍橋哈佛幹細胞研究所（Harvard Stem Cell Institute，HSCI）的哈佛纖維化網絡（Harvard Fibrosis Network）串聯。纖維化疾病會波及許多器官，我們與HSCI希望能找到新的療法以治療IPF、NASH和慢性腎臟病（Chronic Kidney Disease，CKD）等疾病，並找出它們的共通點。 

The long battle against pulmonary fibrosis

Boehringer Ingelheim has developed one of the first medicines for people with fibrotic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Their scientists adopted a unique research approach: They sought to identify commonalities across different groups of diseases. The goal was to develop a novel medicine that would be effective against a wide range of diseases.

The breakthrough is fresh in the mind of Dr. Craig Conoscenti. “We all looked at each other. It was an incredible feeling,” he remembers. Conoscenti and his col-leagues were not only excited because they had taken a step forward: There was something else in the air. “Suddenly,” says Conoscenti, “there was hope.” That was in 2007 and nintedanib, a drug in development for patients with idiopathic pulmonary fibrosis (IPF), had just passed the second phase of clinical testing. For Boehringer Ingelheim’s research teams in Ingelheim, Germany, and Ridgefield, Connecticut, USA, one thing was now clear: A potential medicine for people with this rare, chronic lung disease might actually exist. Before this discovery, the disease had brought a swift death for those affected within a few years of diagnosis.

Very little was known about IPF in the early nineties. “There wasn’t even a standardized name for the disease, let alone a standardized treatment,” says Conoscenti. Having worked as a pulmonologist since 1985, he took an early interest in interstitial lung diseases early in his career. Patients living with IPF face progressive loss of lung function due to the formation of scar tissue in their lungs. The reason for this is unknown. “At the time, nothing could be done for these patients other than trying out various non-approved medicines, none of which helped over the long term.” While he was already working as a pulmonologist, Conoscenti’s father, who was one of the first registered respiratory therapists in the US, died of IPF. This was another reason for Conoscenti to push ahead and continue to work on IPF in a clinical setting and eventually join Boehringer Ingelheim to be part of the team to discover a treatment for this devastating disease.

A HOLISTIC THERAPEUTIC APPROACH

Boehringer Ingelheim had been working on the first therapeutic approaches even before the turn of the millennium. “This was remarkable,” explains Conoscenti, “mainly because hardly anyone else was interested in this small group of patients.” IPF is a rare, debilitating and fatal lung disease, which affects approximately three million people worldwide. Still, IPF is the most common form of pulmonary fibrosis. Early on, Boehringer Ingelheim noted the potential for a number of diseases beyond IPF – namely, whether it could aid in finding a therapy for the more than 200 other interstitial lung diseases.

“Boehringer Ingelheim has continuously expanded this holistic therapeutic approach over the years,” says Dr. Jay Fine, Global Head of Immunology and Respiratory Diseases Research. Fine has been working on new lung disease treatments for more than a decade, including the last five years at Boehringer Ingelheim. “Our focus is always on how we can develop potential medicines for multiple diseases or populations and therefore help the most patients,” says Fine. At first, it is often unclear how many diseases a novel medicine can treat. Nonetheless, Fine’s team looks for common pathways between individual diseases to uncover unique “disease clusters” for each new therapy. This increases the scope and value of an individual medicine enormously.

With this goal in mind, the research team around Conoscenti continued studies on IPF, pulmonary fibrosis, and other related interstitial lung diseases. There were setbacks along the way: An initially promising combination of medications did not work as they had hoped. But the working group ultimately developed nintedanib. This medicine inhibits processes that occur in fibrosis, thus slowing the formation of scar tissue and the progression of the disease. IPF remains incurable, but nintedanib reduces the degree of lung function lost each year by roughly half. After its breakthrough in the middle 2000s, nintedanib was approved as Ofev^® for US patients for the first time in 2014. Since then it has been approved in more than 70 countries and has offered hope to many IPF patients.

Fine is convinced:“Nintedanib serves as a foundation for our research on fibrosis.”The research team has identified a number of parallels between IPF and other illnesses in its cluster, such as systemic sclerosisassociated interstitial lung disease (SSc-ILD), a rare, incurable autoimmune disease in which scar tissue forms in the skin and numerous internal organs including the lungs. The affected patients are typically younger than IPF patients and are often middle-aged women. The progression of the disease, however, is similar for both patient groups. Boehringer Ingelheim tested the effect of nintedanib on SSc-ILD patients in a large-scale clinical study. The study, called SENSCIS, found that the medicine was able to slow the loss of lung function by 44 percent within one year. In early September 2019, the FDA, the US regulatory authority, approved nintedanib as the first medication for treating SSc-ILD. Boehringer Ingelheim also received positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) in SSc-ILD in February 2020. In March 2020, the FDA also approved nintedanib to treat people with a chronic (long lasting) interstitial lung disesase in which lung fibrosis continues to worsen (progress).

“ FIRST IN CLASS ” MEDICINES

For Fine,“first-in-class”medicines like these give meaning to his team’s research; they hope to discover new, unique mechanisms of action for treating disease. “Our vision is to transform the treatment of inflammatory and fibrotic diseases by pioneering a patient insight-driven translational approach,” says Fine.

His team pursues this vision on the basis of three principles: Target, Repair, and Prevent. Inflammatory illnesses are often triggered by an over-expressed immune system, which attacks the body’s own tissues, leading to impaired function of the affected organs and a loss of quality of life. For this reason, Fine’s team first targets mechanisms that are central to driving tissue injury. They then investigate the best approaches to selectively block these responses or to repair the tissue itself. If the fibrotic process has already begun, the goal is to obstruct it as much as possible to prevent disease progression.

This holistic research approach has also proven itself with other forms of inflammatory and fibrotic disorders. For example, the research team has developed an investigational medicine called spesolimab which blocks a mechanism called the interleukin (IL)-36 receptor. Spesolimab is believed to have potential to target and prevent a range of inflammatory and fibrotic diseases, and has recently shown promise in patients with pustular psoriasis. “While still early in its development, spesolimab has the potential to improve the lives of many people affected by this cluster of diseases,” Fine explains. He knows how a research breakthrough feels – the moment it becomes clear: We did it; we helped people. “This,” says Fine,“is why we do this job.”

HOW CELLS CAN COMMUNICATE

The cell membrane is strewn with receptors: These molecules help cells to communicate with each other and to control the organism. If an outside signal reaches the receptors, they transmit the signal into the cell. This triggers different cellular effects, such as cell division or growth.

This is how it works: Nintedanib is a potent inhibitor of specific cell communications and signaling cascades and interferes with processes active in fibrosis such as fibroblast proliferation and secretion of collagen. In addition, nintedanib has shown not only onsistent anti-fibrotic, but also anti-inflammatory activity.

Through a bigger and more diverse global community of innovation partners, more can be learned, and achieved. That is why Boehringer Ingelheim collaborates with leading pioneers from academic institutions and other companies around the world to identify new treatments for patients with high medical need.

One of the most recent partnerships is with Singaporean biotech company Enleofen Bio, which began in January 2020. The goal: leverage Enleofen’s preclinical interleukin-11 (IL-11) platform to develop first-inclass therapies across a broad range of fibrotic and inflammatory diseases. IL-11 is a cytokine, a protein certain cells of the body use to communicate, and plays a key role in fibrotic and inflammatory conditions. Blocking IL-11 action has been shown to inhibit disease across many organs (liver, lung, kidney, retina, bowel, heart and skin). The initial focus will be on novel therapies for patients with Nonalcoholic Steatohepatitis (NASH) and Interstitial Lung Diseases (ILDs), two of Boehringer Ingelheim’s core disease focus areas, with a potential to expand into further fibrotic and inflammatory conditions based on IL-11’s central role in disease.

Another collaboration started in 2016 with the Harvard Fibrosis Network of the Harvard Stem Cell Institute in Cambridge, USA. Since fibrotic diseases can affect many organs, the partners aim to find new therapies for diseases like IPF, Nonalcoholic Steatohepatitis (NASH) and Chronic Kidney Disease (CKD) – and to identify commonalities among them.