By Carl O'Donnell and Tamara Mathias
Nov 27 (Reuters) - Eleven drugmakers led by Pfizer and Novartis have set aside a combined $2 billion to invest in gene therapy manufacturing since 2018, according to a Reuters analysis, in a drive to better control production of the world's priciest medicines.
The full scope of Novartis' $500 million plan, revealed to Reuters in an interview with the company's gene therapy chief, has not been previously disclosed. It is second only to Pfizer, which has allocated $600 million to build its own gene therapy manufacturing plants, according to filings and interviews with industry executives.
Gene therapies aim to correct certain diseases by replacing the missing or mutated version of a gene found in a patient's cells with healthy copies. With the potential to cure devastating illnesses in a single dose, drugmakers say they justify prices well above $1 million per patient.
But the treatments are also extremely complex to make, involving the cultivation of living material, and still pose a risk of serious side effects.
Drugmakers say building their own manufacturing plants is a response to rising costs and delays associated with relying on third-party contract manufacturers, which are also expanding to capitalize on demand.
They say owning their own facilities helps safeguard proprietary production methods and more effectively address any concerns raised by the U.S. Food and Drug Administration (FDA), which is keeping a close eye on manufacturing standards.
"There's so little capacity and capability at contract manufacturers for the novel gene therapy processes being developed by companies," said David Lennon, president of AveXis, Novartis's gene therapy division. "We need internal manufacturing capabilities in the long term."
The approach is not without risks.
Bob Smith, senior vice president of Pfizer's global gene therapy business, acknowledged drugmakers take a "leap of faith" when they make big capital investment outlays for treatments before they have been approved or, in some cases, even produced data demonstrating a benefit.
PUSHING THE LIMITS
The rewards are potentially great, however.
Gene therapy is one of the hottest areas of drug research and, given the life-changing possibilities, the FDA is helping to speed treatments to market.
It has approved two so far, including Novartis's Zolgensma treatment for a rare muscular disorder priced at $2 million, and expects 40 new gene therapies to reach the U.S. market by 2022.
There are currently several hundred under development by around 30 drugmakers for conditions from hemophilia to Duchenne muscular dystrophy and sickle cell anemia.
The proliferation of these treatments is pushing the limits of the industry's existing manufacturing capacity.
Developers of gene therapies that need to outsource manufacturing face wait times of about 18 months to get a production slot, company executives told Reuters.
They are also charged fees to reserve space that run into millions of dollars, more than double the cost of a few years ago, according to gene therapy developer RegenxBio.
As a result, companies including bluebird bio, PTC Therapeutics and Krystal Biotech are also investing in gene therapy manufacturing, according to a Reuters analysis of public filings and executive interviews.
They follow Biomarin Pharmaceutical Inc, developer of a gene therapy for hemophilia, which constructed one of the industry's largest manufacturing facilities in 2017.
The FDA is keeping a close eye on standards.
This comes amid the agency's disclosure in August that it is investigating alleged data manipulation by former executives at Novartis' AveXis unit.
AveXis had switched its method for measuring Zolgensma's potency in animal studies. When results using the new method didn't meet expectations, the executives allegedly altered the data to cover it up, the FDA and Novartis have said.
One of the former executives, Brian Kaspar, denied wrongdoing in a statement to Reuters. Another, his brother Allan Kaspar, could not be reached for comment.
Novartis and the FDA say human clinical trials, which found Zolgensma effective in treating the most severe form of spinal muscular atrophy in infants, were not affected. Novartis also says its investments in gene therapy production started long before it became aware of the data manipulation allegations.
But the scandal has highlighted the importance of having a consistent manufacturing process for gene therapies, industry executives say.
According to four of them, the FDA has stressed in recent meetings the need for continuity in production processes all the way from the development of a drug to its commercialization.
By bringing production in-house, drugmakers may avoid pitfalls such as the need to switch to a larger facility if contract manufacturers' capacity proves limited, executives say.
The FDA is finalizing new guidelines for gene therapy manufacturing, expected at the end of the year.
"Manufacturing consistency is always a major concern for the agency," FDA spokeswoman Stephanie Caccomo told Reuters.
Highlighting the pressures on the industry, Sarepta Therapeutics, which largely outsources manufacturing, delayed a clinical trial of its Duchenne treatment in August, telling investors it wanted to avoid any questions from regulators about consistency in producing its therapy at commercial scale.
ENOUGH GROWTH FOR ALL?
"Between the trade secrets, the cost schedules and the time lag, it makes a whole lot of sense, if you can do it, to build out your own facilities and more and more gene therapy companies have started to do that," said Krish Krishnan, chief executive of Krystal Biotech Inc.
Krystal, which is developing therapies for rare skin diseases, has built one manufacturing facility and plans to invest more than $50 million in a new one it will start constructing in December.
MeiraGTx, which focuses on gene therapies for eye conditions, estimates it is currently spending roughly $25 million a year on manufacturing, including process development.
Despite such moves, however, contract manufacturers like Lonza and Thermo Fisher are confident their businesses will continue to grow due to the strength of demand.
Thermo Fisher has told investors its Brammer gene therapy manufacturing division, acquired in May, could soon earn $500 million in revenue a year, double its projected 2019 earnings.
Lonza CEO Marc Funk is also optimistic.
"Demand in gene therapy has increased," he said in an interview. "We believe this is going to continue in the coming years." (Reporting by Carl O'Donnell in New York and Tamara Mathias in Bengaluru; Editing by Tomasz Janowski, Michele Gershberg and Mark Potter)
据路透社( Reuters )分析,辉瑞( Pfizer )和诺华( Novartis )为首的11家制药公司自2018年以来共拨出20亿美元投资于基因治疗制造业,以求更好地控制全球最贵药品的生产.
他们说，拥有自己的设施有助于保护专利生产方法，并更有效地解决美国食品药品监督管理局（Food and Drug Administration）（ FDA ）提出的任何问题， FDA 密切关注生产标准。
诺华（Novartis）公司基因治疗部门 AveXis 总裁 David Lennon 说：“合同制造商研发的新型基因治疗方法的能力和能力非常有限。”“我们需要长期的内部制造能力。”
辉瑞( Pfizer )全球基因治疗业务高级副总裁鲍勃•史密斯( Bob Smith )承认，制药企业在获得批准之前为治疗项目投入大笔资金，或者在某些情况下甚至生产出能显示出效益的数据时，会“跃跃欲试”。
基因治疗是最热门的药物研究领域之一，鉴于生命变化的可能性， FDA 正在帮助加快治疗进入市场。
该公司迄今已批准了两项治疗方案，包括诺华( Novartis )的 Zolgensma 治疗一种罕见的肌肉疾病，价格为200万美元。该公司预计，到2022年，将有40种新的基因疗法进入美国市场。
根据基因治疗开发商 RegenxBio 的数据，他们还收取费用，以保留价值数百万美元的空间，是几年前的两倍多。
因此，根据路透社( Reuters )对公开文件和高管访谈的分析，包括蓝鸟生物( Bluebird Bio )、 PTC Therapeutics 和 Krystal Biotech 在内的公司也在投资基因治疗制造。
他们紧随 Biomarin Pharmaceutical Inc .之后，该公司是血友病基因治疗的开发商，该公司于2017年建造了业内最大的生产设施之一。
今年8月，该机构披露，正在调查诺华( Novartis )旗下 AveXis 部门前高管涉嫌操纵数据的行为。
AveXis 已经改变了测量 Zolgensma 在动物研究中的效力的方法。FDA 和诺华（Novartis）表示，当使用这种新方法的结果没有达到预期时，高管们据称改变了数据以掩盖数据。
一位前高管布赖恩·卡斯帕在给路透社的一份声明中否认有不当行为。另一个人，他的兄弟 AllanKaspar ，不能得到评论。
诺华（Novartis）公司和 FDA 称，人类临床试验发现佐尔甘斯玛治疗婴儿最严重的脊肌萎缩症并没有受到影响。诺华（Novartis）还表示，早在意识到数据操纵指控之前，它就开始投资基因治疗产品。
其中四个国家指出， FDA 在最近的会议上强调，从药物研发到商业化，生产过程都需要连续性。
FDA 发言人斯蒂芬妮·卡科莫对路透社说：“生产一致性一直是 FDA 关注的主要问题。”
萨雷普塔治疗公司( Sarepta Therapeutics )今年8月推迟了杜氏疗法( Duchenne )的临床试验，这突显出该行业面临的压力。该公司告诉投资者，它希望避免监管机构对在商业规模上生产该疗法的一致性提出任何疑问。
Krystal Biotech Inc .首席执行官 KrishKrishn Krishnan 表示：“在商业机密、成本计划和时间滞后之间，如果你能做到，建立自己的设施是非常有意义的，越来越多的基因治疗公司已经开始这样做了。”
尽管采取了这些措施，但龙沙（Lonza）和 Thermo Fisher 等合同制造商相信，由于需求强劲，他们的业务将继续增长。
Thermo Fisher 告诉投资者，5月份收购的 Brammer 基因治疗制造部门很快就能实现5亿美元的年收入，是2019年预期收益的两倍。
龙沙（Lonza）首席执行官 MarcFunk 也持乐观态度。