June_New Drugs|Microbiome therapy is back in the spotlight with FDA approval of new oral bacterial drug

Published On: 2023/06/13|Categories: 大健康(Healthcare)|

It is important to create healthy "good bacteria"! Therapeutic microbiome back in the spotlight

The intestinal tract and intestinal flora are considered as the second brain and the second genome of the human body. The intestinal bacteria affect the brain and even the whole body through the cerebral-intestinal axis, and the "bacteria-intestinal-brain axis" is based on the roles of intestinal bacterial metabolites (neurohormones), the vagus nervous system (neurotransmitters), the intestinal immune system, and the HPA axis (hypothalamus-pituitary-gland-adrenal gland), which reveal that the microflora affect the metabolic, immune, and neurological health of the body, either directly or indirectly. Although probiotic supplementation has become an important part of modern health care, it is still considered a health food rather than a therapeutic pharmaceutical product. In medicine, although intestinal flora reconstruction (or fecal microbiota transplant, FMT) is a more mature treatment, there is no US FDA-approved product on the market (Remarks: Probiotics are used as live biotherapeutic products (LBP), except for vaccines). (Note: the use of probiotics as active biotherapeutic products (live biotherapeutic products (LBP), except for vaccines), because the mechanism of microbial therapy is still unclear and controversial, so there has been no translation of the medical products used for treatment for a long time, the use of specific bacterial flora for the treatment of specific diseases of the microbiome treatments (microbiome treatments) has always been a cold medical field, but with the approval of the FDA to market the live oral bacterial drugs, the microbiome treatment has once again become the market chase! However, with the FDA's approval of new oral bacterial drugs, microbiome therapy has once again become the focus of market pursuit, symbolizing the opportunity for microbiome to move toward clinical therapeutic applications, and unveiling the prelude to the research and development of new microbiome drugs.

微生物組療法是利用一組微生物菌群或微生物相關的生物活性分子,來進行治療的手段,可包含新藥開發,以及需要醫療專業人士操作的糞便微生物移植療法,截至目前為止,US FDA核准上市的微生物組新藥分別為,2022/11由輝凌(Ferring Pharmaceuticals)開發全球首款糞便微生物直腸劑(灌腸劑) Rebyota®,以及2023/4由Seres Therapeutics和Nestle (雀巢)聯手打造首款糞便微生物口服新藥Vowst®,這兩項產品的開發策略皆來自糞便菌群移植的微生物療法。Rebyota®和Vowst®都是活菌治療劑,從健康人群捐贈的糞便進行樣本處理清除病原體和汙染物,經嚴格淨化分離篩選,Rebyota®是擬桿菌屬(Bacteroides)菌群懸浮液,而Vowst®則純化出大約50種厚壁菌門(Firmicutes)細菌的細菌孢子,兩者都是通過重建腸道菌群,來抑制複發性艱難梭菌的生長,幫助恢復腸道健康。保健品大廠Nestle和Seres Therapeutics的合作始於2021/07總交易額達2.25億美元的合作協定,其中Seres Therapeutics負責Vowst®新藥開發和商品化,而雀巢旗下公司Aimmune Therapeutics則負責Vowst®銷售運營,Vowst®使用方式為每天服用乙次,每次服用四粒膠囊,連續三天,藥物定價估計為每療程1.75~2萬美元,預計 2033 年在美國的銷售額將可達7.5億美元。

全球人類微生物組治療市場夯,預估未來將有5倍爆發成長

根據Market&Market預估,2023年全球人類微生物組治療市場規模約2.69億美元,預估2029年可成長 5.1 倍達到 13.7 億美元,複合年增長率為31.1 %,其中又以復發性艱難梭菌感染為大宗,復發性艱難梭菌感染者大都發生在醫院,是造成住院病人抗生素相關腹瀉的主要原因,復發性艱難梭菌感染也是醫院和老年護理機構最大的細菌感染問題,艱難梭菌感染通常是由於長期使用抗生素所引起,抗生素會消滅有益的結腸細菌破壞腸道微生物生態系,症狀從輕微腹瀉至結腸發炎或潛在致命性腹瀉,在美國每年約50萬例艱難梭菌感染,死亡人數約為1.3-3萬人,其中25%-65%的美國患者在初次感染後,容易再次感染復發性艱難梭菌導致該治療複雜化。除艱難梭菌感染外,目前微生物組臨床熱門新藥開發領域包含發炎性腸道疾病如潰瘍性結腸炎和克隆氏症、癌症(大腸癌/腦癌/肝癌)、糖尿病、焦慮症、苯丙酮尿症,以及移植物抗宿主疾病,微生物與特定疾病的關聯性為治療型微生物新藥帶來新的契機。

 

未來商機關注新一代益生菌功效發展及個人化微生物保存、移植服務興起

隨著醫藥科學逐漸了解腸道微生物在疾病治療的潛力,以及DNA合成與測序、多體學(omic)和基因編輯等創新技術應用,微生物組資源已成為創新藥開發的寶庫。微生物組療法發展主要可分為新藥研發和療法開發二個領域,(1)在新藥研發方面,如表一,活菌生物藥是利用微生物菌群如天然單菌藥物和天然複合菌藥物,以及基因工程菌藥物,或促進微生物菌群生長的物質(益生元, Prebiotic),或微生物菌群產生的生物活性分子(後生元, Postbiotics),製成活性生物治療產品,來預防或治療人類疾病,具有安全性高和成本低的優勢,有別過去傳統益生菌改善消化系統、提升免疫力和呼吸疾病等保健功效,新一代益生菌更關注在菌群與醫學疾病的關聯性,其療效著重在改善發炎性腸道疾病、移植物抗宿主疾病、新陳代謝疾病、免疫疾病、精神疾病和抗癌。(2)在療法開發方面,以糞便微生物移植服務為導向的衍生商機如新加坡糞便銀行、香港中文大學捐糞計劃、或林口長庚微菌銀行,將人體(含糞便)微生物為資源如臍帶血,進行保存和研究,是個人化微生物保存、移植治療服務的新興產業。

表一、微生物組新藥研發代表公司

Source of information:Organized by Ji-Pu Industrial Trend Research Institute

在新興微生物組療法領域競賽中,獲取功能性菌種仍是關鍵,除了如何掌握關鍵技術將菌株分離培養、菌株篩選優化、菌群監測保存和移植外,更重要的是以新藥開發標準,在明確適應症和充分驗證醫藥機轉下,進行系統性菌株安全性、藥效、CMC和臨床評價,並依據US FDA指南建立鑒定菌株的穩定性、抗生素敏感性、耐藥性、產品生產控制與穩定性等制定嚴謹活菌生物藥規格,隨著微生物組療法的產業發展,也將為益生菌產業注入新一波活力商機。

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