FDA小組拒絕Naproxcinod用於骨關節炎

作者：Fran Lowry  
出處：WebMD醫學新聞

　　May 12, 2010 — 在今天的聯合會議中，美國食品藥物管理局的關節炎建議委員會以及藥物安全與風險管理建議委員會並未核准抗發炎新藥naproxcinod用於緩解骨關節炎的徵兆與症狀，要求該藥品的法國廠商向申請委員會提出更多的安全性與效果研究。
　　
　　全部18個委員中只有1人投票同意核准，16人投反對票，委員會主席Kathleen O'Neil醫師則棄權。
　　
　　此項藥品是由總部設於法國Sophia Antipolis的NicOx藥廠提出申請，產生了相當多的傳聞，因為該公司宣稱naproxcinod —環氧化酵素抑制一氧化氮產生者(cyclooxygenase-inhibiting nitric oxide donator，CINOD)這類中的第一種藥物 — 是一個有良好胃腸道耐受度與安全性的抗發炎劑，且不會增加血壓。
　　
　　Naproxcinod設計包括釋出naproxen以及一個一氧化氮產生單元，NicOx 藥廠相信，產生一氧化氮的這個性質使naproxcinod可緩和胃腸道效應與naproxen常見的血壓升高。
　　
　　該小組喜歡這個觀念，但是認為藥廠並未展示出足夠的效果或安全性資料。
　　
　　O'Neil醫師在總結中表示，總之，該小組希望看到更多有關這個藥物的資料，該小組認為此藥物有其潛力，但是更希望這個潛力可以變成動力。
　　
　　杜克大學醫學中心、杜克臨床研究中心主任、內科教授Robert Harrington醫師表示，我投反對票，但是我要對藥廠表示，我投的是鼓勵性的反對票，我真的很喜歡這個藥物的觀念，希望可以實際邁向用於照護。但是，我不認為現有的研究符合一般獲得核准並上市的證據標準。
　　
　　該小組中的兩位病患代表之一、William O. Brackney表示，鼓勵NicOx藥廠整合它的行動，如果這個藥品如同它們所說的那麼好，希望找到方式證明它，以讓它上市。
　　
　　華盛頓特區公民健康研究小組主任Sidney Wolfe醫師也投反對票，因為他不認為naproxcinod有任何優於naproxen的好處，他也不同意藥廠所主張的該藥可以減少心血管事件。
　　
　　Wolfe醫師解釋，我認為，減少naproxen帶來的傷害的觀念是個好的開始，但是我們真的需要結果證明。就這類藥品的心臟副作用而言，我們還有許多研究要做，藉以用來判斷。
　　
　　他表示，Naproxen是較多毒性的胃腸道藥物之一，希望naproxcinod可以緩解這個胃腸道毒性，這的確需要進一步研究，所以，如果我們有關於心血管和胃腸道毒性這兩方面的安全性結果、也有效果方面的結果，那就很棒了，但是，目前這些都沒有。
　　
　　德州大學西南醫學院McGee基金會關節炎研究主席、內科教授Nancy Olson醫師表示，她投反對票的理由是，因為她不認同該公司提出的血壓資料。
　　
　　她表示，如果有血壓顯著降低的資料可以說服我，就可以推翻其他一些顧慮，因為需有明顯的好處且沒有其他疑慮，那我才比較不擔心胃腸道與長期心血管事件，這需要更多資料，我們需要比13或26週更久的資料。
　　
　　唯一投贊成票的委員表示，她相信藥廠的資料，naproxcinod有相當大的潛力。華盛頓特區Walter Reed陸軍醫學中心肝臟研究主任Maria Sjogren醫師表示，我不擔心安全性，因為已經相當瞭解naproxen的分子，我不認為有任何會發生壞消息的徵兆。
　　
　　Sjogren醫師指出，萬一我發生骨關節炎且有高血壓時，我希望我的醫師能讀到相關文獻且對我試用這個藥品，看看我會怎樣的結果，我不認為會有問題。我投贊成票是相當問心無愧的，我認為這個藥品可以適用此類病患。
　　
　　但是，俄亥俄州克里夫蘭凱斯西儲大學醫學副教授David Blumenthal醫師表示，他希望看到更多安全性的資料，因為naproxcinod是一個新分子，藥廠在這些方面未能有足夠訊息，它說這是一個新分子，我們都應對其血壓方面的潛力感到興奮，但是，就迄今的安全資料而言，只知道它類似於naproxen，我們對於這個藥物釋放一氧化氮之性質的安全效果尚無完整資料，除非將這個病患族群進行同樣的安全研究，就像其他所有的新分子一樣，所以，我個人沒有投下贊成票。
　　
　　所有小組委員都呼籲進行更長期的研究，如同Harrington醫師所說的，風濕科的同事一整天都跟我說，骨關節炎病患人數眾多，若真如此，我們應該可以進行大型試驗。如果你希望治療更多病患，就應採實用主義方式進行大型病患研究，探討那些有風險的患者。如果大約有2000萬人有這個疾病，我們應找到幾千人願意參與研究。


FDA Panel Nixes Naproxcinod for Osteoarthritis

By Fran Lowry
Medscape Medical News

May 12, 2010 — In a joint meeting, the US Food and Drug Administration's Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee today failed to endorse the approval of the novel anti-inflammatory drug naproxcinod for the relief of signs and symptoms of osteoarthritis, sending the drug's French sponsor back to the drawing board for additional safety and efficacy studies.

Only one of the 18 committee members voted in favor of approval. Sixteen voted no, and one, Kathleen O'Neil, MD, the committee chair, abstained.

The new drug application by NicOx, headquartered in Sophia Antipolis, France, had generated considerable buzz with the company touting naproxcinod — a first-in-class cyclooxygenase-inhibiting nitric oxide donator (CINOD) — as an anti-inflammatory agent that had good gastrointestinal tolerability and safety but did not raise blood pressure.

Naproxcinod is designed to release naproxen and a nitric oxide donating moiety. NicOx believes that these nitric oxide donating properties permit naproxcinod to mitigate the gastrointestinal effects and rise in blood pressure commonly seen with naproxen.

The panel liked the concept, but felt that the sponsor had not presented enough efficacy or safety data.

"All told, this is a drug that the panel would love to see more data on," said Dr. O'Neil in her summary. "The panel in general was enthusiastic about the potential for this drug but would like to see the potential become kinetic."

"I voted no, and to the sponsor, I'll say I vote an encouraging no," said Robert Harrington, MD, professor of medicine and director, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina. "I actually like the concept of the drug. There is a lot to be hopeful about here that might actually offer a step forward in care. But I don't believe that the studies that have been presented meet the typical evidentiary standard that is required to be able to gain approval and get onto the market."

William O. Brackney, one of 2 patient representatives on the panel, urged NicOx to get its act together and "find a way to get this drug to market if it truly is as good as it portends to be."

Sidney Wolfe, MD, director of Health Research Group of Public Citizen, Washington, DC, voted no because he wasn't convinced that naproxcinod had any more benefit than the tried and true naproxen. Nor was he convinced about the company's claim that it reduces cardiovascular events.

"I think the idea of looking at its reduction of the harm that otherwise comes with naproxen is a good start, but we really need outcomes. We have had too much going on in terms of adverse cardiac outcomes with this family of drugs to just sort of blow that off," Dr. Wolfe explained.

"Naproxen is one of the more toxic gastrointestinal drugs and the theory that the company came with — that naproxcinod is going to relieve the GI toxicity — really needs to be studied further. So if we had the 2 safety outcomes with regard to cardiovascular and GI toxicity, as well as the efficacy outcomes, that would be fine, but we don't have any of them," he said.

Nancy Olson, MD, professor of internal medicine and McGee Foundation Chair in Arthritis Research at the University of Texas Southwestern Medical School, Dallas, said the reason she voted no was because she was not convinced by the blood pressure data the company presented.

"If I had been really convinced that there was a significant decrease in blood pressure that would have overridden some of the other concerns because that would have been an obvious benefit that nothing else out there offers," she said. "I would be less concerned about GI and long-term cardiovascular events. There needs to be more data. We need longer than 13 or 26 weeks."

The single committee member who voted yes said she had been convinced by the sponsor's data that naproxcinod has great potential. "I'm not worried about the safety because the molecule of naproxen is quite known and I didn't see any signal that would worry me that something bad was going to happen," said Maria Sjogren, MD, MPH, director, Hepatology Research, Walter Reed Army Medical Center, Washington, DC.

"I wish I could be so lucky that when I develop osteoarthritis and I have high blood pressure that my physician will be reading the literature and will try me on this drug and see how I do," Dr. Sjogren added. "I don't see a problem with that. I'm voting yes with full conscience of what this drug could do for patients in such a situation."

But David Blumenthal, MD, associate professor of medicine, Case Western Reserve University, Cleveland, Ohio, said that he wanted to see more safety data, because naproxcinod is a new molecule. "The company can't have it both ways. It says it is a new molecular entity and we should all be excited about its potential effects on blood pressure, but as far as the safety data goes, it gets a pass because it's so similar to naproxen. We don't have the full story on the safety effects of the nitric oxide releasing properties of this medicine unless you subject this patient population to the same safety studies that all other new molecular entitities are subjected to. So I personally am not willing to give the company a pass on that."

All panel members called for longer-term studies. As Dr. Harrington said, "I've heard all day from my rheumatology colleagues that the osteoarthritis population is a large population. If it is, we ought to be able to do a large trial. If you want to treat large numbers of patients you should study large numbers of patients and you should study them in a pragmatic way, addressing the populations at risk. If some 20 million people have the disease, we ought to be able to find a few thousand who would be willing to be in studies.