The source of this article: Times Finance Author: Zhang Yuqi
On October 6, a paper titled Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN was withdrawn from the internationally renowned journal Nature Biotechnology (IF=68) draft. The paper is related to orphan drug research, pointing directly to the SMA (Spinal muscular atrophy) treatment drug “Zolgensma” (sovaprevir).
According to Times Finance’s understanding on the official website of Nature Biotechnology (IF=68), the paper is an article related to the preclinical research of “Zolgensma”, and the reason for retraction is due to data errors and omissions.
As early as 2021, Nature Biotechnology (IF=68) has raised the issue of data errors and omissions in this paper, and the original data file submitted by the author for the second time in 2022 has confirmed the error. The data shows that the 6 mice mentioned in the article that survived for 250 days do not match the facts. In fact, only 1 mouse survived. However, the relevant authors of the paper disagree with the retraction statement. Nature Biotechnology (IF=68) has contacted the author many times since then, but has not responded.
Image source: Tu Wo Creative
In the spring of 2018, Novartis Pharmaceuticals (NVS.NYSE) acquired a gene therapy biotechnology company called AveXis Inc. for $8.7 billion (approximately RMB 61.8 billion) in cash. Opening a new chapter in SMA gene therapy. Facts have proved that the acquisition has achieved remarkable results. Once the orphan drug “Zolgensma” came out, it caused heated discussions. Around its efficacy, safety, and the sky-high price of 14 million yuan per injection, there were constant concerns, constant benefits, and ongoing disputes.
“The retraction has nothing to do with the drug itself. The research on this paper is only a preclinical animal model of effectiveness and has no connection with the safety of the drug itself.” Dr. Zhou Yebin, the author of “Science Science Park” and a practitioner of new drug research and development, told Times Finance, “With the controversy over the retraction, the public has once again paid attention to Zolgensma. In fact, the retraction is just a piece of news, from the specific research involved in the retraction and the pre-marketing process. Judging from the review process of the US FDA, there should be no follow-up actions due to this.”
“The withdrawal has nothing to do with the drug itself”
SMA is an autosomal recessive neuromuscular disease caused by functional SMN1 gene deficiency. Ultimately it affects basic motor function, swallowing, and even breathing. Children under the age of 2 are the main infected group. If untreated, 90% of the children will be accompanied by a ventilator or die.
Currently, there are three treatments for SMA worldwide. Among them, Nosinasena, developed and produced by Bojian, is the world’s first SMA precision targeted therapy drug. It was approved for marketing in China in February 2019 and has now entered the national medical insurance, with a price of no more than 33,000 yuan per injection; Roche’s risprom oral solution (trade name: Ai Manxin) is the first oral drug approved for marketing in China in June 2021. It is the first oral disease-modifying drug for the treatment of SMA in China, with an initial price of 6.38 10,000 yuan (60mg/bottle).
After Lisporan oral solution entered the Chinese market, the price in some areas was lowered, for example, the price of Shandong Province’s recruitment platform dropped to 14,500 yuan per bottle. Taking the maximum dose of more than 20 kg for 2-year-old children as an example, the annual burden is reduced to 450,000 yuan.
The controversial drug Zolgensma is an AAV gene drug developed by Novartis and used to treat SMA.
On May 24, 2019, AveXis, a subsidiary of Novartis Pharmaceuticals, announced that the U.S. Food and Drug Administration (FDA) approved its Zolgensma 2 for the treatment of biallelic mutations in the SMN1 gene. It is the first and only FDA-approved gene therapy for SMA in patients with SMA under the age of 12. Patients only need one injection in their lifetime to express SMN protein in their cells for a long time, thereby achieving long-term remission or even cure.
Zolgensma is not currently available in China. On October 21, 2021, the clinical trial application submitted by Novartis in China for “OAV101 Injection (Sovaprevir, Zolgensma)” has been reviewed. According to the drug clinical trial registration and information publicity platform, Zolgensma is still in the clinical trial stage.
Although Zolgensma has not yet entered the Chinese market, Zolgensma has been attracting attention as an orphan drug, and this retraction event has brought it back into the public eye.
As early as 2019, the US FDA mentioned Zolgensma’s early animal experiment tampering. Although the data tampering was an active notification, AveXis (before it was acquired) The inside story was known before the drug was marketed. Until March 2020, the controversy ended with the US FDA closing the investigation of the case, and its notification pointed out that the problem of data tampering did not affect the safety and effectiveness of the drug.
“The reasons for retraction vary widely, such as data fraud, blurred data, academic reputation, etc., which can also be divided into active retraction or passive retraction.” Huang Jia (pseudonym), a senior medical practitioner, told the Times Caijing explained that there may be an impact after the retraction, but for the drug itself, the impact is limited. If the study is not part of the clinical study, it will not have a substantial impact on the drug declaration procedure, but whether the event will ferment remains to be observed. “
Zhou Yebin also expressed similar views to Times Finance. He pointed out that the retraction can only show that the company’s effectiveness data cannot be perfectly reproduced in animal model experiments. Preclinical efficacy studies just test whether the theory works. For example, the data problems in the paper just show that the effectiveness in animal models is not as good as predicted.It is perfect, but it is still effective, and the effectiveness of its drug has been verified in subsequent more critical and large-scale clinical trials; in terms of safety, animal model experiments have not shown that the drug is ineffective. safety.
Zhou Yebin mentioned that retractions are disappointing but not uncommon in the academic world. According to its understanding, AveXis was a smaller biotech company before it was acquired by Novartis, and it seems that it was a bit sloppy in data management at the time. Previously, the founder of AveXis ran away due to data management issues.
Controversial whirlpool of high-priced orphan drugs
The controversy surrounding “Zolgensma” isn’t the only one. Previously, Zolgensma caused heated debates in various countries because of its high price.
Zolgensma was launched in the United States in May 2019, priced at US$2.125 million, equivalent to nearly 14 million yuan, setting a new record for the world’s most expensive drug.
It wasn’t until this year that this figure was eclipsed by two of Bluebird Bio’s (BLUE.NASDAQ) gene therapy products, Zynteglo and Zynteglo, the first to treat patients with beta-thalassemia. The world’s first adrenoleukodystrophy (ALD) gene therapy Skysona has been broken. The two orphan drugs are priced at US$2.8 million (approximately RMB 20 million) and US$3 million (approximately RMB 21.37 million).
The financial report of Novartis Pharmaceuticals shows that Zolgensma has considerable revenue, with sales increasing from US$361 million (approximately RMB 2.57 billion) in 2019 to US$1.351 billion (approximately RMB 9.62 billion) in 2021 Yuan), with a growth rate of 274%. Revenue in the first quarter of 2022 alone will reach $363 million (approximately RMB 2.58 billion).
Zolgensma’s sales are expected to rise to $1.6 billion this year (about 11.4 billion yuan), according to investment firm Jefferies.
As a “life-saving drug”, the early research and development costs of gene therapy drugs are high, the production process is complicated, and the cost is immeasurable. Mark Nuijten, a Dutch pharmacoeconomics doctor, analyzed the rationality of Zolgensma’s drug price in his research paper. According to the results of the price in line with the calculation model, Zolgensma is actually not profitable.
Price is also the first factor that hinders patient treatment, and the negotiation of orphan drugs to enter the medical insurance of various countries has also become the only way for them, and the price tug of war is fierce in various countries.
Currently, Zolgensma has been approved for marketing in more than 40 countries and regions around the world. In March 2020, the drug was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of children with SMA under 2 years old, and the approved price was reduced to 167.07 million yen (about 8.2 million yuan). In May of that year, Japan had included the drug in its health insurance, and patients only had to pay 30% of the cost, or nearly 3 million yuan.
In the U.S. market, Novartis has cooperated with relevant insurance companies, and the family members of patients can pay in installments for a total of five years, with an average annual payment of US$425,000 (about RMB 3,028,300). In Europe, in March 2021, the UK’s National Health Service (NHS) has included Zolgensma in the service and has agreed a discount with Novartis. In March this year, the National Institute of Health and Clinical Research (NICE) in the United Kingdom completed a survey report recommending Zolgensma to be included in the reimbursement ranks. At present, the drug has been included in the British medical insurance.