The startup that manipulated the data to market a miracle drug

But in a hurry to keep the promise of the drug, AveXis has manipulated the data that has been approved by the drug, now say Novartis and the Food and Drug Administration.

And some former AveXis employees said there were other barriers, distinct from the manipulation cited by the FDA. They say the company has struggled to manage a rapid ramp-up of its research and manufacturing activities. They describe a drug development race that sometimes led to errors, including inaccurate dosage numbers from preliminary drug trials.

AveXis has experienced a "fundamental shift in capabilities," said a spokesman for Novartis. He stated that "this has evolved from an academic background to a commercial organization with leaders who better understand the requirements of the pharmaceutical industry and the FDA approval process." The spokesman said the new management has put in place processes "consistent with the needs of a company, this was aimed at product approval and marketing."

In this area, the incentives to act quickly are numerous. Gene therapy – which essentially involves treating a defective gene with a healthy gene – is one of the most popular areas of pharmaceutical research, with billions of dollars of investment. Early pioneers, under the pressure of patients and potential investors, are encouraged to move quickly from promising research results to the manufacture of a safe and marketable version of their breakthroughs.

Along the way, these agile start-ups may find it difficult to adapt to the stringent requirements of regulatory bodies and large pharmaceutical companies that generally adhere to them. The FDA has encouraged acceleration, offering companies more and more expedited approval for promising and life-saving drugs.

The stakes are high for Novartis, which spent $ 8.7 billion on AveXis. The data manipulations – recognized by AveXis and Novartis – took place prior to the acquisition of the company by Novartis. Novartis learned of the existence of the problem later, but did not alert the FDA while the agency was reviewing the drug. The FDA opened a criminal investigation and the chief executive, Vas Narasimhan, struggled to justify his decision to delay disclosure. Novartis said it wants to conduct an internal investigation before alerting the FDA.

The drug AveXis, called Zolgensma, is one of the first commercially available gene therapies – and the most expensive drug in the world, with $ 2.1 million. Many doctors consider that it is a revolutionary treatment for spinal muscular atrophy, or SMA, a rare but particularly devastating genetic disease in the baby. AMS sufferers do not have a crucial gene for muscle control and gradually weaken, struggling to move, eat or breathe. Untreated, those with the most severe form, called type 1, usually die before their second birthday. The FDA has stated that the problem of data manipulation does not change its view that Zolgensma is safe and effective and has allowed the treatment to remain on the market.

Zolgensma, administered intravenously in a single dose, promises to end the disease. The first clinical trial of the drug, conducted in 2014 and 2015, treated 15 babies. The first three received a lower dose and the others a higher dose. The 12 people who received the highest dose were past their second birthday, most of them reaching key milestones such as standing up, eating by mouth and sitting unaided. So far, there is no evidence that the effect of the drug decreases over time.

Scientist

Brian Kaspar

and other researchers at Nationwide Children's Hospital in Columbus, Ohio, had been experimenting with possible gene therapy therapy for ADM for years. In 2013, AveXis granted a license to use this technology, which ultimately led Dr. Kaspar to become the scientific founder.

The first successful trials sparked enthusiasm as the industry's interest in gene therapy increased. The company was listed on Nasdaq in 2016. A year later, a video showing the progress of some of the babies participating in the clinical trial resulted in a standing ovation in a crowded auditorium at a prestigious neurology conference in Boston. .

Working for the Chicago-based company, as it tried to gain FDA approval and increase production on a commercial scale, was both exhilarating and exhausting, according to its former employees.

The long hours were the norm, they said. CEO Sean Nolan and Dr. Kaspar regularly reminded employees of the importance of new gene therapy. "We were doing [in three years] It takes 10 years for most businesses, "said a former executive.

Some employees say they have identified botched practices related to early clinical trials. In 2016, employees found that the calculations made by Mr. Kaspar two years earlier were imprecise. They reported this to the executives, according to a former employee familiar with the file. These calculations overestimated by a factor of two the dose of gene therapy that had been administered to babies during early phase clinical trials, said this person.

A spokesman for Novartis said AveXis employees had discovered this vagueness after switching to a more precise method of calculating the dosage. AveXis corrected these calculations nearly four years after their first execution, according to a document filed by Novartis with the FDA last year.

AveXis staff also raised questions about the role of university labs in drug development, according to former employees. In his first clinical trial, Dr. Kaspar's lab staff conducted blood tests (used to track the immune response of babies to treatment) in a laboratory at Nationwide Children's Hospital. This lab has not been certified to perform tests on patients, say former employees. AveXis then used a certified external laboratory to perform tests for subsequent clinical trials, according to these former employees.

A Novartis spokesman said that it was not uncommon for this type of test to be performed in a university lab "given the emergence of the field of gene therapy at that time". Andrew Wachler, a health care attorney, said any laboratory that performs patient-specific tests must be certified.

The scaling up of AveXis "was in many ways very difficult" for Dr. Kaspar, said a former AveXis executive, adding that Kaspar was sometimes frustrated by the fact that the organization was becoming more and more bureaucratic and decisions were taking longer.

For possible FDA approval, the fledgling company had to demonstrate that it could accelerate the commercial production of the treatment. AveXis has launched a new manufacturing facility in Libertyville, Illinois, near Chicago. The plant was to handle dozens of successive batches of gene therapy and provide meticulous documentation.

According to former employees, the operation was happening 24 hours a day. According to former employees, it was not unusual for quality assurance employees to be out of bed in the middle of the night , if a potential problem arose.

A spokesman for Novartis said that AveXis had a sense of urgency to get the product to children in need. He said many biotechnology manufacturing plants are working day and night.

To win the FDA, AveXis had to show that the gene therapy performed at the company's new Libertyville facility matched the treatment being made and tested at the hospital. To do this, the scientists compared the results obtained with the Libertyville product by mice with SMA and the results obtained with the original gene therapy of the hospital.

These comparisons were done at AveXis facilities in San Diego. They were then submitted as part of the drug approval application. The FDA found them satisfactory, according to FDA records.

But while the FDA was assessing demand, an AveXis whistle-blower warned AveXis executives that there was a problem with some of this data. The question was forwarded to the CEO of Novartis

Vas Narasimhan

early May, but the company did not alert the FDA until late June, about a month after the drug was approved by the FDA and put on sale.

After Novartis reported the problem, the FDA went to the San Diego site where the tests had been done. The inspectors have discovered a host of problems, according to an FDA inspection report. Staff did not thoroughly investigate data discrepancies, for example, and did not maintain satisfactory records. FDA inspectors found a diary dating back to August 2018 describing how the lifespan of mice used to test the potency of the drug was recorded differently by location, according to their report. In the most extreme case, the difference was 19 days. The inspectors added in the report that they had seen no evidence indicating that the staff, informed of the mistakes made by the quality control inspectors, had made an effort to understand what was wrong with them. It was past. Novartis said it responded to FDA's concerns.

Novartis replaced Dr. Kaspar following the problem of data manipulation. Dr. Kaspar denied having committed wrongdoing related to the manipulation of data, but did not respond to requests for comment for this article.

The manipulation "is the antithesis of the culture we have built," said a former AveXis executive, who said the vast majority of AveXis employees "were exceptional and were acting with a great integrity ".

Although the FDA allowed the drug to remain on the market, claiming that the manipulation of the data did not affect its effectiveness or safety, this episode nevertheless caused concern among parents of babies with AMS. Cure SMA, a charitable organization that raises money for ADM research, quickly organized a webinar with representatives from AveXis and the FDA to address concerns raised after disclosure of manipulation information. A participant asked if Zolgensma was safe and if the FDA had been deceived in approving it.

The FDA official said the agency would have withdrawn the treatment if she had doubts. Dozens of babies have been successfully treated with this medication. In some cases, babies who have already struggled to sit down without help are walking now.

Isaac Olthoff, 11 months, was to receive Zolgensma when the manipulation of the data would be revealed. Her mother, Michelle, said the announcement had given her a break, but she was quickly reassured by the FDA's decision to keep the treatment on the market. Isaac received Zolgensma a week later.

-Joseph Walker
contributed to this article.

Write to Denise Roland at [email protected]