Novartis' Zolgensma Under Fire Again as Nature Retracts 2010 Paper

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Novartis' gene therapy Zolgensma is again under a cloud of doubt after Nature Biotechnology retracted a 2010 article featuring early data on the treatment over data manipulation concerns. 

Two years after the FDA closed its Zolgensma data manipulation investigation, Nature Biotechnology retracted its 2010 article titled, "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN," noting "issues" regarding data cited in a key figure in the report. Original source data provided earlier this year showed multiple inaccuracies in mouse models that were used to indicate the therapeutic promise.

The error was in a Kaplan–Meier curve that represented the survival of mice with spinal muscular atrophy that received either Zolgensma or a control scAAV9-GFP vector. 

The article's initial data showed that six mice survived for more than 250 days. However, earlier this year, the original data showed that only one of the treated mice lived.

In its retraction statement, Nature Biotechnology said its editorial team is "of the opinion that the extent of the inaccuracies in Fig. 1e and associated text undermines full confidence in the study."

The now-retracted paper was a foundational study that led to the SMA gene therapy treatment being greenlit for in-human studies. Those clinical studies, including the pivotal Phase III STRIVE trial, showed that Zolgensma treated SMA patients with unprecedented survival rates. 

The children dosed with the gene therapy saw improvements in motor function and durable milestone achievement, including an ability to sit up without support.

Nature Biotechnology noted that most researchers listed as authors of the article disagree with the decision to retract. One researcher never responded to the publication's repeated attempts to reach her. 

A Treatment Shrouded in Controversy

The revelation of early data manipulation concerns regarding Zolgensma's early animal studies was first realized in 2019, one year after Novartis acquired Illinois-based AveXis, the creator of the gene therapy, for $8.7 billion. 

Novartis and AveXis notified the FDA about the preclinical data manipulation concerns one month after the gene therapy was approved. When the FDA first revealed the data manipulation, the agency said it was "limited to only a small portion of the product testing data that was contained in the marketing application." 

When the FDA closed its investigation into Zolgensma, the regulatory agency acknowledged that some early data manipulation had occurred during the preclinical testing of the therapy. However, following human clinical studies, the FDA maintained that the spinal muscular atrophy gene therapyZolgensma is safe and effective as a gene therapy treatment for spinal muscular atrophy. At the time, the FDA stated that the revelation of data manipulation did not change its positive assessment of the information from the human clinical trials. 

In its support of the gene therapy, Novartis acknowledged that the assays in question were used for initial product testing but are not currently used for commercial product release. 

In the wake of the data manipulation, Novartis terminated Brian and Allan Kaspar, AveXis' chief scientific officer and head of research and development, respectively. The Kaspars are both founders of AveXis. The Swiss pharma giant placed the blame squarely on their shoulders. 

In its response to the FDA, Novartis said the two brothers "personally manipulated or instructed others to alter some of the preclinical data" that led to the approval of the gene therapy. The company acknowledged the manipulation concerned the recorded deaths of the mice used in preclinical studies, which played a key role in the now-retracted article. 

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