Novartis Abandons Rett Syndrome Gene Therapy AVXS-201 Amid Pipeline Restructuring

Compiled & Translated by | Fan Dongdong

Novartis has canceled the next phase of development for the Rett syndrome gene therapy AVXS-201 after trial data failed to support further advancement. The decision to discontinue development of AVXS-201 comes just after Novartis initiated efforts to collect additional data on candidate drugs in response to findings during the development of Zolgensma.

When the "black swan" event involving Zolgensma unfolded in 2019, Novartis decided to review the data quality and compliance of the preclinical work for the gene therapy AVXS-201, and to repeat and conduct additional key preclinical studies and quality control assessments. In April 2019, Novartis announced that its investigational gene therapy Zolgensma for spinal muscular atrophy (SMA) had led to the deaths of two subjects, prompting the company to investigate whether the trial fatalities were related to the gene therapy. This development added extra work to advance AVXS-201 into clinical trials and set back its R&D progress. In August 2020, Novartis stated that it had completed the majority of the preclinical studies. Although slightly behind the expected timeline set the previous year, the company remained on track to submit an Investigational New Drug (IND) application and advance AVXS-201 into clinical development.

However, the latest news indicates that Novartis has decided to discontinue the development program for gene therapy AVXS-201, revealing that “the totality of preclinical data does not support advancing gene therapy AVXS-201 to further human clinical trials.” Novartis is “exploring other options for this indication,” and gene therapy AVXS-201, which was originally planned for regulatory submission in 2022, has ultimately been scrapped.

Prior to its acquisition by Novartis, AveXis actively conducted preclinical studies for the gene therapy AVXS-201. During a quarterly earnings conference call with investors in 2017, the company presented its gene therapy initiatives, detailed the improved outcomes of AVXS-201 in murine studies, and reported on a one-month study of the therapy in non-human primates. At the time, AveXis planned to apply for human clinical trials of AVXS-201 by the end of 2018. However, developments did not proceed as anticipated; following a comprehensive data review, Novartis determined that the therapy did not meet the requisite criteria to advance into clinical trials.

Despite pharmaceutical companies' high confidence in the efficacy of gene therapies, their safety has consistently drawn external concern. In July 2020, two children with a rare neuromuscular disease died after receiving a high dose of Audentes Therapeutics' gene therapy, AT132, in a clinical trial. Just four months later, LYS-SAF302, an AAV gene therapy developed by Lysogene, resulted in the death of a five-year-old girl with Mucopolysaccharidosis type IIIA (MPS IIIA) during treatment. In September 2021, another fatal incident occurred with the Japanese pharmaceutical company Astellas' experimental gene therapy AT132 for patients with X-linked myotubular myopathy (XLMTM). Notably, this marked the fourth death attributed to the AT132 gene therapy in just two years of clinical trials.

In its third-quarter earnings report, Novartis announced its decision to discontinue the gene therapy AVXS-201 and provided updates on its other product pipeline. The company’s list of discontinued R&D projects also includes 177Lu-PSMA-R2 for prostate cancer. Novartis acquired this asset through its acquisition of Advanced Accelerator Applications and initiated a Phase 1/2 trial in 2018 for PSMA-positive, castration-resistant prostate cancer. However, the company has now announced it will halt the development of 177Lu-PSMA-R2 to prioritize other projects.

In addition, Spartalizumab, also known as PDR001, is another discontinued candidate drug from Novartis. This PD-1 inhibitor failed in a Phase 3 combination trial for advanced melanoma last year, but research into other indications is ongoing. Novartis has listed its Phase 2 work for "malignant melanoma (combination)" as discontinued. Furthermore, in its quarterly results, Novartis disclosed a delay in the anticipated regulatory submission for SAF312 (for the treatment of chronic ocular surface pain). While the company previously planned to file in 2024, it now states that due to challenges in patient enrollment, the expected submission timeline has been postponed to 2025 or later.

Source: Novartis dumps Rett gene therapy caught up in Zolgensma scandal in cull of pipeline prospects