Weekly roundup: More questions for Novartis in Zolgensma scandal

It’s been a tough month for Novartis, with the company facing a deepening scandal over data manipulation for its spinal muscular atrophy (SMA) gene therapy Zolgensma.

Novartis has high hopes that Zolgensma (onasemnogene abeparvovec) will start a revolution in gene therapy, as a highly expensive but highly effective treatment for the debilitating muscle wasting disease.

The drug had already courted controversy with its $2 million price tag – making it the highest-priced pharmaceutical product of all time – though Novartis maintains that the current 10-year cost of chronic SMA therapy, which is given over the patient’s lifetime, can often exceed $4 million in just the first 10 years of life, while Zolgensma is only administered over 5 years.

Crucially, the company had the backing of the authoritative Institute for Clinical and Economic Review (ICER).

“Zolgensma is dramatically transforming the lives of families affected by this devastating disease, and given…new efficacy data for the pre-symptomatic population, the price announced today falls within the upper bound of ICER’s value-based price benchmark range,” said Steven Pearson, ICER’s president.

But the latest controversy is proving harder to step away from.

On 28 June AveXis – the company that originally developed Zolgensma and was bought by Novartis last year – informed the FDA that some of the animal testing data for the product contained in the marketing application was compromised.

The sticking point for many, though, is that the company appears to have been aware of the problem before Zolgensma was approved.

A 26 July memo from Wilson Bryan, director of the FDA’s Office of Tissues and Advanced Therapies, suggests Novartis could have been aware of the data issue as early as 14 March, more than two months before approval.

He has recommended that the FDA should conduct an inspection of AveXis testing sites “to gather additional data on the nature and extent of the data manipulation”.

Both the FDA and Novartis were quick to emphasise that the incident shouldn’t have any impact on Zolgensma’s availability.

For now, the FDA says its concerns are “limited to only a small portion of the product testing data that was contained in the marketing application,” and it thinks the totality of evidence for Zolgensma “continues to provide compelling evidence supporting an overall favourable benefit-risk profile.”

Meanwhile, Novartis said that it “does not expect this to impact the timing of our ongoing Zolgensma regulatory filings and development programmes”.

Explaining the delay in disclosing the data manipulation, the company added: “Once AveXis became aware of allegations of data manipulation in a specific animal testing procedure used in the development of the product…an investigation was immediately initiated to rapidly understand any implications and address the situation. Once we had interim conclusions from our investigations, we shared our findings with the FDA.”

But several developments since then have prevented the story from dying down as quickly as Novartis might have hoped.

US politicians quickly became involved, urging the FDA to come down hard on Novartis.

Five Democrats – including presidential candidates and long-time drug industry critics Bernie Sanders and Elizabeth Warren – sent a letter to acting FDA commissioner Ned Sharpless urging the agency “to use your full authorities to hold AveXis accountable for its malfeasance, including through all appropriate criminal, civil, and regulatory actions against the company”.

“It is unconscionable that a drug company would provide manipulated data to federal regulators in order to rush its product to market, reap financial perks and charge the highest amount in American history for its medication,” the letter says.

“Anything short of a forceful response would signal a green light to future pharmaceutical misbehavior.”

They also asked the FDA for a written explanation as to why it withdrew a proposed regulation in October 2018 that would have required companies to promptly report suspected data falsification.

The senators have asked if the FDA plans to reissue these regulations in light of Novartis’ delays.

Meanwhile, Republican and US Senate Finance Committee chairman Chuck Grassley has asked Novartis to provide all records of its internal inquiry into the drug, as well as details such as the date when it became aware that it had submitted manipulated data and the number of employees terminated as a result.

Novartis said it has received the senator’s letter and is reviewing the request.

Executive questions

Novartis was hit by two more revelations that continued to put the company on the defensive.

Firstly, it emerged that it had replaced the two top executives at AveXis around the time that the data manipulation was discovered.

AveXis chief scientific officer Brian Kaspar, and his brother and senior vice president of research and development Allan Kaspar have not been involved in any operations since early May 2019, Novartis said.

Novartis’ statement suggested that the brothers were replaced around the time of the internal investigation into Zolgensma, but well before the company notified the FDA about the issue.

Following on from this, it was reported that a senior manager at Novartis sold almost $1 million worth of stock just before the FDA probe became public.

The company insists that the person selling the shares – reported to be an executive member of the  board of directors or a member of the executive committee at Novartis AG – had no materially-relevant information about the Zolgensma data issue.

Nevertheless, the revelation that the sale occurred after the company had informed the FDA of the problem but before the news became public raised eyebrows.

Again, there is no suggestion that the clinical data used to support the filing has been manipulated, and currently there are no concerns about the safety and efficacy of the therapy – the biggest question marks here surround the length of time taken to make the issues known.

Nevertheless, the piecemeal unfolding of the story, driven by negative headlines, isn’t helping Novartis’ image, especially when the company was already to rebuild trust in the US after it emerged earlier this year that it paid $1.2 million to Donald Trump’s former personal lawyer Michael Cohen in an attempt to gain influence with the president.

The current feeling in the company, then, was perhaps best summed up by Novartis AG CEO Vas Narasimhan, who, according to Bloomberg, said to managers in a company call that the situation “could have been handled better”.