Novartis Says SMA Baby Death Not Due To Zolgensma
Executive Summary
The Swiss major has new data on its SMA gene therapy which has been found not to be the cause of the death of a six-month-old patient earlier this year.
Novartis AG has presented more data showing the long-term benefits of its spinal muscular atrophy treatment Zolgensma and revealed that the death of a baby in one of its trials was not caused by its one-time gene therapy.
In April, the company reported the death of a symptomatic six-month-old SMA Type 1 patient in its the Phase III STR1VE-EU study, telling Scrip that preliminary findings indicated this occurred in the context of a severe respiratory infection followed by neurological complications. This "was deemed possibly related to treatment by the investigator," Novartis said at the time, adding that an autopsy had been performed and results were pending.
The company has now said that according to the coroner’s report, the immediate cause of death was hypoxic-ischemic brain damage with respiratory tract infection as the underlying cause and these were "considered unrelated to the gene therapy by the investigator." SMA Type 1, the most severe form of the disease, was indicated as the underlying cause for the respiratory tract infection, Novartis added that "there was no evidence of an inflammatory CNS process or a toxic or a treatment-related brain damage."
The final autopsy report did indicate that Zolgensma, the world's most expensive therapy, could have potentially contributed to the concurrent events of abnormal liver function and blood tests, as well as low blood pressure, but those were not unexpected.
The findings should ease concerns about the safety of Zolgensma at a time when Novartis finds itself under scrutiny from the US Food and Drug Administration and the country's politicians over manipulation of preclinical safety data on the gene therapy. The company was aware of the latter issue in March this year and investigated the matter internally but did not inform the FDA until June, a month after Zolgensma was approved in the US. (Also see "Novartis Battens Down Hatches Over Falsified Zolgensma Data" - Scrip, 7 Aug, 2019.) (Also see "Novartis Wants More Time To Answer EMA’s Zolgensma Questions" - Pink Sheet, 19 Sep, 2019.)
“We are seeing further robust evidence of the potential of gene therapy to effectively halt motor neuron loss, help patients achieve motor milestones and alter the course of SMA with a one-time treatment.” - STR1VE investigator Eugenio Mercuri
Despite the furore over how Novartis handled the data manipulation issue, the FDA said in August when it brought the matter to light that it believed Zolgensma was safe and should remain on the market. The company will be hoping that the positive data it presented at the European Paediatric Neurology Society (EPNS) congress in Athens on 19 September will turn the spotlight on the gene therapy for the right reasons. (Also see "Novartis Swaps Two AveXis Executives For One Following Zolgensma Data Manipulation" - Scrip, 14 Aug, 2019.) (Also see "Novartis CEO Explains Delay In Telling US FDA About Zolgensma Data Fraud: We Wanted To Understand It First" - Pink Sheet, 7 Aug, 2019.)
Speaking to journalists ahead of the meeting in Greece, Olga Santiago, chief medical officer of Novartis’s gene therapy unit AveXis, acquired last year for $8.7bn, highlighted new interim data from the SPR1NT study in children aged less than six weeks.
SPR1NT Data
As of 30 May, of the babies who had two or three copies of the SMN2 gene (n=22) all had normal swallow function and were fed exclusively by mouth and were free of permanent ventilation. Of patients with two copies of SMN2, six (60%) were able to sit without support for at least 30 seconds at an average age of 7.6 months. Three of these patients were able to stand with assistance at an average age of 10.1 months, Santiago noted, adding that the natural history of untreated patients with SMA indicates that patients with two copies of SMN2 will never sit without assistance.
Three serious treatment-emergent adverse events were reported in three patients - croup, lethargy and hypercalcemia - but all were resolved and considered unrelated to treatment. Santiago said the data showed that "early invention before symptoms arise is critical for improved outcomes consistent with age-appropriate motor milestone gain," such as crawling, sitting and standing.
AveXis CEO Dave Lennon added that the introduction of neonatal screening in the US for SMA and other rare diseases has been an important advance for early diagnosis "and we don't have to wait for symptoms to develop." However, most countries in Europe do not offer it, Novartis noted.
STR1VE Update
Santiago also updated results from the global STR1VE study in SMA Type 1 patients who are less than six months old. Eleven patients (50%) in the STR1VE-US trial and two patients (6%) in the STR1VE-EU study achieved the ability to sit without support for at least 30 seconds, an achievement babies with SMA Type 1 never reach in the natural history of the disease.
Five of the six patients in the US who reached 18 months of age (study completion) had achieved the milestone of sitting independently for 30 seconds and one of them could pull to a stand and walk with assistance.
“These updated data reinforce what we have seen in other Zolgensma studies, including survival of children with SMA type 1 who would have in the past died or required permanent ventilation before the age of two,” commented Eugenio Mercuri of the Catholic University in Rome, one of the STR1VE investigators. “We are seeing further robust evidence of the potential of gene therapy to effectively halt motor neuron loss, help patients achieve motor milestones and alter the course of SMA with a one-time treatment.”