今年6月，一批生物科技行業的代表人物匯聚舊金山。他們此行的目的是競購制藥公司Achaogen的資產，后者于今年4月申請了破產保護。經過一番商討和爭奪，最大的競購者以1600萬美元的價格帶走了Achaogen的幾乎所有資產。

一家制藥公司被迫關門本身未必是異常之事或者有新聞價值，但Achaogen并不是一個典型的生物科技公司破產事件。

2017年7月，Achaogen的市值還在10億美元以上（Venrock對Achaogen 投資的時間是2004年）。更重要的是，Achaogen已經成功發現并開發出了一種針對嚴重抗藥性感染的抗生素，并且通過了美國食品與藥品監督管理局（FDA）的審批。此外，該公司藥物是第一種獲得美國食品與藥品監督管理局突破性療法認定的抗生素。

與此同時，在美國東海岸，設在波士頓的抗生素廠商Tetraphase在取得了類似成功后也開始陷入困境。和Achaogen一樣，Tetraphase開發的針對抗藥性細菌感染的抗生素也通過了美國食品與藥品監督管理局的審批，這是一項壯舉。Tetraphase的市值也曾經接近20億美元，但現在已經跌至1000萬美元以下。

旨在推動抗生素創新的合作組織CARB-X的執行董事凱文·奧特森在今年夏天曾經向生物制藥網站發表聲明稱：“[抗菌劑]公司呈直線下滑狀態，需要采取緊急行動來阻止這個行業的崩潰。”

雖然普通大眾越發意識到抗菌劑公司的麻煩正在不斷增大，但在生物科技領域以外，幾乎沒有人知道抗生素行業正在面臨著另一場商業危機。

為什么像Achaogen和Tetraphase這樣“成功”的抗生素公司發現自己在商業領域難以立足呢？歸根到底是新抗生素面臨的兩大問題：量少和價低。

第一個因素是量少，這在一定程度上和新抗生素的管理有關。在知道病人需要針對耐藥感染的抗生素前，醫生對于開這些新抗生素持有保留態度。此外，和其他許多藥物不同，大多數抗生素都需要添加到醫院的處方集中，而這需要院方進行三到四輪的審核。結果就是新抗生素在上市的頭幾年中的銷量微乎其微。

第二個因素是價低，其原因是抗生素的報銷方式。在感染病人到醫院后，醫院會拿到一筆錢，被稱為診斷相關資金（DRG），其中包括病人在醫院接受的所有治療，包括開給他的抗生素。

要點在于，診斷相關資金中未使用的部分都會稱為醫院的利潤。這就促使醫院盡可能地使用平價抗生素。此外，這就意味著當醫院選擇開非常貴的抗生素時，通過診斷相關資金根本報銷不了，而醫院必然會出現虧損。

因此，創新抗生素的平均價格遠低于其他治療領域的創新藥價格，而且大多數藥費都不是通過診斷相關資金支付的。

受此影響，風投資金對新抗生素的興趣不斷減弱。生物科技行業組織Biotechnology Innovation Organization的一項分析顯示，2009-2013年為開發創新抗生素投入的風投資金總額約為6億美元。而在此期間，神經藥物開發公司一共籌集了17億美元風投資金，抗腫瘤藥制造商的風投融資額為42億美元。

我們怎樣才能矯正這種動力上的偏差呢？可能方法之一是立法。2018年由民主、共和兩黨聯合提出的DISARM法案建議將抗生素排除在診斷相關資金之外。具體來說，該法案允許美國聯邦醫保向使用合格抗生素的醫院另行支付一筆錢。

民主、共和兩黨共同推出的另一項法案是REVAMP，其目的是向開發出新型重大抗生素的公司頒發證書，使其獲得更長的獨占權。隨后，另一家公司可以買下這樣的證書，以確保自身產品也有更長的獨占權。

可以用兒科優先審核證書（針對兒科疾病的證書）來估算抗生素證書的價格；而且有很多兒科優先審核證書的售價都超過了1億美元。

考慮到這些數字，一本這樣的證書實際上是一份現金獎勵，從而使抗生素開發公司不受獲批頭幾年銷售增長緩慢的影響。這段時期一家公司的支出通常會超過收入，這本證書則可以帶來關鍵的資金支持。

DISARM或REVAMP法案獲得通過都有可能極大地促進新抗生素的開發。但不幸的現實是，目前對付耐藥性對兩黨來說都不是很緊迫的任務。市場力量讓開發新抗生素變得如此困難，而要出現改變市場力量的希望，就要先改變這種局面。

如果等式的一邊是調整市場，那么另一邊就是增加新的后備抗生素。美國食品與藥品監督管理局的高級官員珍妮特·伍德科克對目前的后備抗生素的描述是“薄弱而且乏力”，這在很大程度上是因為上文談到的投資者不感興趣問題。

考慮到生物制藥的周期，后備產品薄弱會帶來特別大的問題，因為開發新藥的時間很容易就會達到甚至超過10年。

美國政府、健康和人類服務部（Department of Health and Human Services）以及CARB-X等行業組織正在資助公司推進新抗生素的開發。CARB-X已經從美國和英國政府以及維康信托基金會、比爾及梅琳達·蓋茨基金會等慈善組織手中獲得了約5億美元資金。

這筆資金非常關鍵，但實際上可能不夠多。要明白其中的理由，大家可以考慮一下，美國健康和人類服務部下屬的生物醫藥高級研發局（Biomedical Advanced Research and Development Authority）為Achaogen提供了近1.5億美元資金，目的是推動該公司的抗生素完成三期臨床實驗。就連這種規模的政府資金也不足以讓這家公司在商業層面上生存下來。實際情況證明，量少和價低的組合問題極難解決。

為重新打造后備抗生素并應對不斷增強的耐藥性，公司需要政府和非營利組織提供的資金。但這些資金還不夠。我們還必須修正市場，因為首先是市場給抗生素開發帶來了如此巨大的挑戰。

如果新抗生素仍然以不合理的低價進行報銷并且用在非常少的病人身上，開發這些藥在商業上仍然無法立足。非營利組織和政府支持這些公司的時間段可能不光是在爭取美國食品與藥品監督管理局審批的過程中，它還包括獲得美國食品與藥品監督管理局審批后收入微薄的那幾年。

這可能意味著政府要改變以往鼓勵藥物開發的模式，但實際情況也證明，抗生素獨具一格。無法及時解決這個問題就可能影響美國（乃至全世界）為下一輪嚴重抗藥性感染做好準備。（財富中文網）

梅根·布盧伊特是風投公司Venrock的投資人。

鮑勃·柯歇爾是風投公司Venrock的投資人、南加州大學謝弗衛生政策和經濟中心高級研究員以及斯坦福大學兼職教授。

鮑比·謝迪是醫療科技公司Renew Health的首席增長官。

譯者：Charlie

審校：夏林

This June, a group of biotech representatives converged on San Francisco. They had come to bid on the assets of pharmaceutical company Achaogen, which filed for Chapter 11 bankruptcy in April. When all was said and done, the top bidders walked away with virtually all of the company’s assets for $16 million.

A pharmaceutical company having to close its doors, in itself, is not necessarily uncommon or newsworthy. But Achaogen’s was not a typical biotech bankruptcy story.

As recently as July 2017, Achaogen had a market capitalization of over $1 billion. (Venrock invested in Achaogen in 2004.) More importantly, Achaogen had succeeded in discovering and developing an FDA-approved antibiotic to treat serious, drug-resistant infections. Furthermore, its drug was the first antibiotic to ever receive breakthrough therapy designation from the FDA.

Meanwhile, on the opposite coast, Boston-based antibiotic maker Tetraphase is now also struggling after a similar track record of success. Like Achaogen, Tetraphase has developed an FDA-approved antibiotic for drug-resistant bacterial infections—a herculean feat. It once boasted a market cap of nearly $2 billion but now sits at a market cap of under $10 million.

Kevin Outterson, executive director of CARB-X, a partnership dedicated to accelerating innovation in the antibiotic space, issued the following statement to Endpoints News this summer: “[Antimicrobial resistance] companies are in free fall and urgent action is needed to stop the collapse of the sector.”

While the general public is increasingly aware of the growing toll of antimicrobial resistance, few outside the biotech community are aware of this other, commercial crisis facing the antibiotic sector.

Why are “successful” antibiotics companies like Achaogen and Tetraphase finding themselves in commercially untenable situations? It boils down to two problems facing new antibiotics: low volumes and low price points.

The first driver, low volumes, is due in part to stewardship of new antibiotics; doctors are reticent to prescribe a new antibiotic for drug-resistant infections before they know patients need it. In addition, most antibiotics, unlike many other medicines, need to be added to hospital formularies, which can require three or four rounds of review from the hospital. The result can be negligible sales for the first several years after the launch of a new antibiotic.

The second factor, low price points, is the result of how antibiotics are reimbursed. When a patient is admitted to a hospital with an infection, the hospital receives a lump sum known as a diagnosis-related group (DRG) payment. This covers all the care the patient receives while admitted, including the antibiotics they are prescribed.

Importantly, any money under the DRG amount that the hospital does not spend is profit. This incentivizes hospitals to prescribe inexpensive antibiotics whenever possible. Furthermore, this means that when hospitals choose to prescribe a very expensive antibiotic, there is no way to get it reimbursed through the DRG and they are certain to lose money.

As a result, the price points for novel antibiotics are much lower on average than the price points for novel medicines in other therapeutic areas; most medicines are not paid for under a DRG.

In response, VC interest in new antibiotics has dwindled. According to an analysis by the Biotechnology Innovation Organization, a trade group representing the biotech industry, venture funding for companies developing novel antimicrobials totaled around $600 million from 2009 to 2013. During the same time period, companies developing neurology medicines raised a total of $1.7 billion in venture funding, and oncology companies secured $4.2 billion in venture investment.

How do we go about fixing this case of misaligned incentives? One possibility is legislation. The bipartisan DISARM Act, put forward in 2018, proposes to remove antibiotics from the DRG. Specifically, it would allow Medicare to offer an add-on payment to hospitals that use a qualifying DISARM antibiotic.

A second piece of bipartisan legislation, the REVAMP Act, aims to grant companies that develop crucial new antibiotics vouchers to extend their exclusivity. Another company could then buy that voucher to secure additional exclusivity for its own product.

Pediatric priority review vouchers (vouchers for conditions affecting children) can be used to estimate the price points one might achieve for antibiotics vouchers: A number of pediatric vouchers have sold for over $100 million.

Given these numbers, a voucher program would, in essence, provide a cash prize to allow the antibiotic developer to weather the slow sales uptake in the early years post-approval. This would provide critical funding during a period when a company’s spending typically exceeds its revenue.

Passage of either the DISARM Act or the REVAMP Act could significantly incentivize the development of new antibiotics. But the unfortunate reality is that—at the moment—combating antibiotic resistance is not a high priority for either political party. This needs to change if there is to be any hope of fixing the market forces that make it so challenging to develop new antibiotics.

If one side of the equation is fixing the marketplace, the other is bolstering our pipeline of new antibiotics. Senior FDA official Janet Woodcock has described the current antibiotic pipeline as “fragile and weak,” driven in large part by the lack of investor interest described above.

A weak pipeline is particularly problematic when one considers typical biopharma timelines: It can easily take 10 years or more to develop a new medicine.

Government and philanthropic groups like the Department of Health and Human Services (HHS) and CARB-X are funding companies to advance the development of new antibiotics. CARB-X has secured some $500 million in funding from the U.S. and U.K. governments and philanthropic organizations such as the Wellcome Trust and the Bill & Melinda Gates Foundation.

This money is critically important but—in reality—likely not sufficient. To understand why, consider this: Achaogen received nearly $150 million in funding from HHS’s Biomedical Advanced Research and Development Authority (BARDA) to progress its antibiotic through phase 3 clinical trials. Even this level of government funding was not enough to carry the company to commercial viability. The combination of low volumes and low price points proved insurmountable.

In order to rebuild our antibiotic pipeline and defend against mounting antibiotic resistance, companies will need capital from government and nonprofit organizations. But this funding is not enough. We must also fix the marketplace that has made antibiotic development so challenging in the first place.

If new antibiotics continue to be reimbursed at disproportionately low price points—and prescribed to a very small number of patients—developing these medicines will remain commercially untenable. Nonprofits and the government will likely need to support companies not only in the process leading up to FDA approval, but also in the years afterward when revenues are meager.

This would represent a shift in how the government has historically incentivized drug development, but antibiotics have proven to be in a class of their own. Failure to address this problem in a timely manner would undermine our country’s (and the world’s) preparedness for the next wave of serious, drug-resistant infections.

Megan Blewett is an investor at the venture capital firm Venrock.

Bob Kocher is an investor at Venrock, a senior fellow at the University of Southern California Schaeffer Center, and an adjunct professor at Stanford University.

Bobby Shady is the chief growth officer at Renew Health.