On October 6, 2022, Nature Biotechnology (IF=68) withdrew a preclinical study of “Zolgensma” due to “inaccurate data”.
This drug is an AAV gene therapy drug from Novartis for the treatment of spinal muscular atrophy (SMA) in children under 2 years of age. Zolgensma is priced at US$2.1 million (approximately RMB 14 million) per dose and can be administered intravenously in a single dose, which has caused controversy in the industry due to its high cost.
Image source: Nature Biotechnology
Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder that affects 90% of infants with SMA who do not live past the age of 2.
Mao Shanshan, chief physician of the Department of Neurology, Children’s Hospital Affiliated to Zhejiang University, introduced: “From a clinical therapeutic point of view, since 2016, disease modifying therapy (DMT) drugs for SMA have been Nusinersen is the world’s first DMT drug for the treatment of SMA, and Zolgensma, the first gene replacement therapy drug, was launched abroad in May 2019.
In June 2021, the small-molecule drug risprom oral solution was launched in China.At the same time, an international multi-center clinical trial of gene therapy for late-onset SMA is also being carried out in China Although gene therapy has been approved for use in children with SMA under two years of age abroad, whether its efficacy is clear for children over two years of age remains to be explored.
Currently there are only two drugs on the market in China: Nosinagen Sodium Injection and Risprom Oral Solution Powder, and gene therapy has been used in clinical practice abroad. Many parents of SMA are still High expectations for this. “
How will the retraction of this paper affect this highly anticipated drug?
What’s the impact?
Back in 2019, the FDA announced that an early animal test of the drug had falsified data. The FDA pointed out that although the data issue was an unsolicited notification, AveXis Inc. (acquired by Novartis in 2018) knew about the drug before it was launched, but did not notify the FDA until the product was approved.
The incident sparked heated discussions. In March 2020, however, the U.S. FDA closed its investigation into the case, saying the data would not affect the safety or efficacy of Zolgensma.
Image credit: RAPS
The retracted article by Nature Biotechnology is Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN published in 2010.
In 2021, the authors of the article alert the journal to an inaccuracy in Figure 1e: a Kaplan-Meier curve representing gene therapy with scAAV9-SMN or control scAAV9- Survival of spinal muscular atrophy mice with GFP vectors.
In 2022, the authors provided the source data file for this graph, confirming that there were multiple discrepancies in their reported mouse lifespan, and the process of including or excluding animals from specific analyses. It is particularly noteworthy that the original article reported that 6 mice that received gene therapy survived for more than 250 days, but only 1 actually survived.
Therefore, the editors and reviewers of the journal judged that the data of the article was no longer sufficiently credible and decided to withdraw the manuscript.
Combining the actual research content and the attitude of the journal, Dr. Mao Shanshan believes that the impact of the retraction of the manuscript on the clinic may be relatively limited: “Judging from the retraction of this manuscript, the content of the article mainly involves Preclinical research, but in fact, because the follow-up clinical data of gene therapy is relatively considerable, even if the author of the preclinical data problem has reminded the journal a year ago, the current result is only a retraction, and it has not been given to Novartis or its partners. Products with more severe penalties.
In fact, Novartis has started clinical trials of gene therapy for children with late-onset SMA in China. If such a retraction event occurs, the SMA patient group will inevitably have certain concerns. However, it is more important for doctors to communicate with patients in detail and tell the truth. Most parents are still willing to “give it a try” because they may pay more attention to the data of clinical trials. ”
Back to the drug itself, many clinical data have been disclosed abroad.
In 2014, Novartis began a study evaluating the safety and efficacy of intravenous AVXS-101 (trade name: Zolgensma) in spinal muscular atrophy type 1 (SMN1), according to the US Clinical Trials Registry. effectiveness test.
Results showed that motor function was assessed using Zolgensma in children with clinical symptoms before 6 months of age and the CHOP INTEND test for infants with neuromuscular disease at Children’s Hospital of Philadelphia 1 month after infusion. Significant improvement.
Image source: Novartis
JAMA Neurology published an article in 2021 entitled Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy. In the study, 13 children with SMA type 1 received a single low-dose or usual dose of onasemnogene abeparvovec (brand name: Zolgensma) for 6.2 years after administration.
Study results indicate that onasemnogene abeparvovec provides sustained, durable efficacy in patients treated with usual doses, with all patients alive and without the need for permanent ventilation. Eight patients (62%) reported serious adverse events, but no adverse events of special interest were reported, and no elevated liver enzymes, hematologic diseases, new malignancies, or autoimmune diseases were reported.
The US FDA also added a boxed warning to its label because of the risk of acute severe liver injury, acute liver failure, and elevated transaminases.
Image source: US FDA
Senior pharmaceutical industry practitioner Ke Nan (pseudonym) believes: “From the retraction statement, the main impact is the efficacy data of experimental model animals, and the mechanism of action of Zolgensma has not been overturned.” strong>In drug research and development, the transformation from mechanism of action to actual clinical benefit depends more on the results of clinical trials and applications.
Zolgensma’s current clinical data (more than 2,000 patients treated) have demonstrated its efficacy. Therefore, this retraction will not have a huge impact on the drug. While regulators focus primarily on safety in animal test data, flaws in efficacy data are unlikely to have serious consequences. ”
Medications: Serving Patients
Just this January, Zolgensma (OAV101 injection) received implied approval for clinical trials in China. Previously, on October 21, 2021, the clinical trial application submitted by the drug in China was accepted.
The so-called “implicit license for clinical trials” means that after the applicant submits an application for clinical trials, it is automatically approved if no negative or challenge comments are received within 60 days. This “expiration default system” began after the State Food and Drug Administration issued an announcement on July 27, 2018 on adjusting the review and approval procedures for drug clinical trials.
This also means that the drug is one step closer to application.
Returning to the patient’s perspective, Dr. Mao Shanshan believes that the long-term suffering of the disease makes them not easily give up hope: “Gene therapy has not yet been launched in China, but some local companies have begun to develop it. Gene therapy drugs, some of which have entered Phase I clinical trials.
For a child with a completely normal intelligence, but with increasingly weak limbs and a gradual decline in quality of life, the difficulty is beyond ordinary people’s imagination. Therefore, if there is a drug for treatment, whether it is gene therapy, nosinathan or risprom, as long as it is a disease-modifying drug, it will be a “new life” for them. ” (curated by Leu.)
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