FDA 拒絕 Northfield Laboratories 血液替代製劑 PolyHeme 之上市許可

FDA於2009年4月底告知總部位於美國伊利諾州Evanston的生技公司Northfield Laboratories Inc.其經歷將近20年所研發的血液替代製劑PolyHeme之上市許可申請將被拒絕。此消息嚴重打擊Northfield Laboratories Inc.的股價，由前4月30日收盤的0.49美元暴跌至5月1日開盤的0.11美元，跌幅接近80%，隨後股價回升至0.25美元附近盤整，跌幅約50%。另兩家類似產品的生技公司為Enzon及Biopure，Enzon最近正在打官司對抗意圖撤換其CEO的市場派，Biopure則因FDA一直未核准其IND申請而無法進行臨床試驗。

目前血液替代製劑的研發大致上朝三個方向：

1.針對血紅素進行相關修飾或處理：此類主要針對像血紅素進行pyridoxylation、pegylation或是polymerization，基本上要維持血紅素蛋白完整性、調整血紅素的攜氧能力及終產物分子大小，以解決氧平衡及分子過小經血管滲漏的問題。此法還有一個基本障礙是vasoconstriction，也就是血紅素在血管運行時導致血管窄化及血壓上升；另外一個主要問題是誘發心臟病 (myocardial infarction, MI)。Northfield Laboratories Inc. 的PolyHeme (pyridoxylated Glutaraldehyde-polymerized human Hb)、Enzon 的 PEG-conjugated bovine Hb、Biopure 的Hemopure (Glutaraldehyde-polymerized bovine Hb)、Hemosol的hemolink都屬於這一類產品，是目前市場的主流。

2.針對紅血球進行相關修飾或處理：此類研究主要需解決血球抗原所誘發的免疫問題，一般採取覆蓋醣化修飾區的作法。

3.嘗試以化學成分取代血紅素的攜氧功能：主要以perfluorocarbon (過氟碳化合物，PFC) 為主，PFC是一種將碳以氟加以飽和的分子，目前主要應用於造影及氧氣運送。由於分子本身的鈍性，進入人體後比較沒有毒性方面的問題。此類分子水溶性不佳，使用前須以水相溶液(例如血漿)打成乳液狀，才能導入血流中，而且PFC與氧氣的結合與釋放不像血紅素的主動運輸，其氧結合曲線呈直線而非乙狀曲線，使用此類產品的患者必須同時使用高濃度氧氣以提高PFC的帶氧率。

 

 

至於PFC排除，目前認為身體內PFC的排除主要經由reticuloendothelial macrophages (RES) 對乳化顆粒的吞噬作用，再運送至肺部以氣體排出。此過程之效率與所使用PFC之蒸氣壓及親脂性成正比，而與PFC之分子量成反比。目前此方法的主要副作用有肺部過度充氣、發燒、類感冒症狀等。

目前看起來針對血紅素進行相關修飾或處理的產品似乎都未能消除FDA對產品安全的疑慮。以PolyHeme為例，其三期臨床試驗結果發表在2009年1月份的 Journal of the American College of Surgeons，其結果就統計角度而言雖未顯示PolyHeme使用組有統計上的顯著差異高於對照組，但就多重器官衰竭、一般及嚴重副作用等來看，PolyHeme組皆略高於控制組，且PolyHeme組發生冠狀動脈缺氧的比率為3%，高於對照組的1%。

 

看來，上帝把血紅素留在紅血球內必有祂的道理！

 

Human Polymerized Hemoglobin for the Treatment of Hemorrhagic Shock when Blood Is Unavailable: The USA Multicenter Trial
Journal of the American College of Surgeons, Volume 208, Issue 1, January 2009, Pages 1-13

Abstract: BackgroundHuman polymerized hemoglobin (PolyHeme, Northfield Laboratories) is a universally compatible oxygen carrier developed to treat life-threatening anemia. This multicenter phase III trial was the first US study to assess survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury.

Study Design: Injured patients with a systolic blood pressure≤90 mmHg were randomized to receive field resuscitation with PolyHeme or crystalloid. Study patients continued to receive up to 6 U of PolyHeme during the first 12 hours postinjury before receiving blood. Control patients received blood on arrival in the trauma center. This trial was conducted as a dual superiority/noninferiority primary end point.

Results: Seven hundred fourteen patients were enrolled at 29 urban Level I trauma centers (79% men; mean age 37.1 years). Injury mechanism was blunt trauma in 48%, and median transport time was 26 minutes. There was no significant difference between day 30 mortality in the as-randomized (13.4% PolyHeme versus 9.6% control) or per-protocol (11.1% PolyHeme versus 9.3% control) cohorts. Allogeneic blood use was lower in the PolyHeme group (68% versus 50% in the first 12 hours). The incidence of multiple organ failure was similar (7.4% PolyHeme versus 5.5% control). Adverse events (93% versus 88%; p=0.04) and serious adverse events (40% versus 35%; p=0.12), as anticipated, were frequent in the PolyHeme and control groups, respectively. Although myocardial infarction was reported by the investigators more frequently in the PolyHeme group (3% PolyHeme versus 1% control), a blinded committee of experts reviewed records of all enrolled patients and found no discernable difference between groups.

Conclusions: Patients resuscitated with PolyHeme, without stored blood for up to 6 U in 12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme is favorable when blood is needed but not available.

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後記：

Northfield Laboratories Inc.在FDA拒絕核准其PolyHeme之後不久，於2009-05-09宣佈結束營運，將裁撤所有人員，位於伊利諾州Evanston的總部與原本準備量產PolyHeme的工廠都將關閉。在此為Northfield Laboratories Inc.的從1994到2009的股價曲線圖留下紀錄...............畢竟，那美好的一仗已經打過。