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RARITAN, New Jersey, Dec 8 (Reuters) - Gathered for an emergency meeting, the Johnson & Johnson drug safety team painted an alarming scene: People taking the company’s new blockbuster diabetes drug were falling gravely ill.
The drug, Invokana, had been on the market less than a year, and sales were already rocketing toward $1 billion. Now, in a small conference room on J&J’s campus here, senior executives listened as the safety experts described a potential threat to the drug’s success. In separate and strikingly similar reports sent to the company and reviewed by Reuters, doctors from across the United States told of 18 patients sickened by a rare and potentially fatal buildup of acid in the blood, known as diabetic ketoacidosis, or DKA, within days or weeks of starting Invokana.
Dr Bruce Leslie, who led the safety team at the March 2014 meeting, recommended that the company alert U.S. and European regulators. “I think we should get out in front of this,” Leslie told executives in the room, as he recounted in an interview with Reuters. “Otherwise, it could come back and bite us in the ass.”
The executives weren’t persuaded. They decided to take no action.
By July 1 that year, J&J had learned of 39 cases of ketoacidosis, according to company documents reviewed by Reuters. Still the company kept mum.
It wasn’t until May 2015 – two years and four million prescriptions after Invokana hit the market – that the public first heard of the drug’s association with ketoacidosis. That’s when the U.S. Food and Drug Administration (FDA), learning of rising numbers of the dangerous episodes through its own reporting system, announced an investigation. It and European regulators subsequently ordered that a warning be added to the label on Invokana and more recent entrants to this new class of drugs, known as SGLT2 inhibitors.
The March 2014 meeting, reported here for the first time, was not an isolated incident. Based on interviews with several former J&J employees and a review of company documents related to Invokana’s development, rollout and safety from 2010 to 2014, Reuters found that in the five years prior to regulators’ intervention, J&J was repeatedly alerted to Invokana’s ketoacidosis risk and took no action.
As early as 2010, during the drug’s clinical trials, the documents show, J&J researchers learned that some patients showed increased levels of ketones, the organic compounds that, in high concentrations in the blood, can lead to ketoacidosis. Later, as injury reports piled up, J&J executives repeatedly overruled safety concerns raised internally, leaving doctors and patients in the dark about the health risk.
In the weeks after the March 2014 meeting, Leslie was warned in a letter from his boss that he could be fired for, among other things, contributing to “an unnecessarily contentious” discussion on Invokana. Just a few weeks after that, the Japanese company that developed the drug and licensed it told J&J that elevated ketones were a potential risk.
“In my opinion, they wanted to make this safety issue go away because it threatened sales,” Leslie said. He left J&J several months after the 2014 meeting. He has not been involved in any litigation with the company.
Dr Angelina Trujillo, a former J&J medical director who worked on Invokana, told Reuters that reports about patients developing ketoacidosis “was information the public needed to know.” All the while, J&J poured tens of millions of dollars into marketing Invokana as a safe, effective treatment for millions of people with type 2 diabetes.
Invokana remains on the market, with reports to the FDA of ketoacidosis and related events linked to the drug now numbering in the thousands. However, sales have declined as the drug’s label has been laden with warnings about ketoacidosis and other possible adverse effects. Still, J&J has tallied more than $6 billion in revenue from Invokana since its launch. And the drug continues to generate cash. In 2020, Invokana and a sister drug pulled in $795 million worldwide for J&J.
J&J defends its actions on Invokana and the drug’s overall safety record.
In a statement to Reuters, the company said it cares “deeply about the safety and well-being of patients treated with our medications. Both pre- and post-approval, (the company) has worked diligently and closely with regulatory authorities to monitor and investigate emerging safety data, to report credible signals to FDA, and to advise healthcare providers and their patients of the risk-benefit profile for Invokana.” J&J declined to make company executives available for an interview.
As Reuters reported in earlier articles in this series, diabetes represents a major public health failure in the United States as the prognosis for the burgeoning number of people with the disease has worsened even while spending on new treatments has soared. Years of inadequate treatment left many of the millions of Americans with diabetes particularly vulnerable here the COVID-19 virus and the isolation of lockdown, resulting in a disproportionate number of deaths and severe illness among people with the chronic disease. Further, drugmakers’ years-long marketing campaigns for an aggressive diabetes treatment target here – getting a blood glucose measure known as A1c below 7% – led to an epidemic of potentially lethal incidents of low blood sugar.
JOINING THE RUSH
J&J promoted that A1c treatment goal in its marketing for Invokana, its first-ever diabetes drug. The company launched Invokana in March 2013 amid an industry rush to tap the fast-growing number of Americans with type 2 diabetes who could become a perpetual source of sales. At the time, spending on diabetes therapies was growing at a double-digit rate annually, far outpacing the overall market for prescription drugs.
With Invokana, J&J staked its claim in this market, beating its rivals with the first of the SGLT2 inhibitors. In January 2014, J&J Chairman and Chief Executive Officer Alex Gorsky told investors that the 350 million people worldwide with type 2 diabetes presented a huge opportunity for the company. “If we look at the projections going forward and the unmet medical need that exists in that space, it’s important that we continue to do work there,” Gorsky said.
J&J touted Invokana as the cornerstone of a new franchise. The drug formed part of a broader push to pursue faster growth from prescription drugs and rely less on iconic consumer goods such as Band-Aids and Baby Powder.
Initially, the plan appeared to be succeeding. In 2014, its first full year on the market, Invokana took a commanding lead, with sales and prescriptions three times those of Farxiga, an SGLT2 inhibitor that AstraZeneca Plc launched in January that year. Sales of Invokana more than doubled the next year.
J&J announced even bigger plans for the drug. It said it wanted to explore Invokana as a treatment for type 1 diabetes, obesity and even “prediabetes,” referring to people with slightly elevated blood sugar levels. Subsequent studies further boosted the appeal of SGLT2 inhibitors, showing they could reduce the risks of cardiovascular and kidney disease.
But a cascade of safety concerns began to erode sales of Invokana and J&J’s ambitions for the drug. In September 2015, the FDA strengthened its warning on the drug’s label about an increased risk of bone fractures, which could occur as early as 12 weeks after starting on Invokana. Three months later, it added the warning about diabetic ketoacidosis.
In 2017, the FDA slapped a black box warning, its strongest alert, on Invokana for an increased risk of amputations. Based on new studies, regulators later scaled back that warning, but the damage was done. Invokana’s sales began to lose ground to its two main competitors, which never carried the warning on fractures and amputations in the United States. In 2018, the FDA then said all SGLT2 inhibitors were linked to a rare, potentially fatal flesh-eating infection of the genital area known as Fournier’s gangrene.
After ranking first in sales among SGLT2 inhibitors for five consecutive years, Invokana was knocked from its perch in 2018. As safety concerns mounted, many doctors and patients lost confidence in the drug. Sales now trail far behind top-ranked Jardiance, sold by Eli Lilly and Boehringer Ingelheim, and Farxiga.
All SGLT2 inhibitors carry a ketoacidosis warning. A study published last year, however, found that Invokana had a higher rate of ketoacidosis than Jardiance or Farxiga in an analysis of medical records for roughly 200,000 patients in Canada and the United Kingdom. Dr Michael Fralick, one of the study’s co-authors and a clinical scientist at the University of Toronto, said more research is needed to determine definitively whether Invokana carries a greater risk.
Ketoacidosis and related reactions accounted for the largest share – about 4,000, or one in six – of the roughly 23,000 adverse events associated with Invokana reported to the FDA from 2013 to 2020. The agency has received reports of more than 450 deaths linked to Invokana during that period. Adverse events reported to the FDA, including deaths, do not establish that a drug caused the event.
In a statement, J&J said the FDA’s adverse events database “commonly contains duplicate, incomplete, and/or unverified reports from which causality cannot be determined. Relying solely on this database to draw conclusions about the safety and efficacy of Invokana is misleading, and does not accurately summarize this important discussion.”
J&J has agreed to settle many of the roughly 1,200 Invokana lawsuits gathered in multidistrict litigation in New Jersey federal court. The suits alleged fraud, negligence or failure to warn about the risk of diabetic ketoacidosis, amputation and other injuries in connection with the drug.
‘SLOWLY KILLING ME’
Among those who sued was Veronica Ryan, a 58-year-old type 2 diabetes patient in Chattanooga, Tennessee. Ryan was prescribed Invokana in September 2015. Over the next few weeks, she told Reuters, she felt increasingly weak and nauseated. Her heart raced, and she couldn’t sit up in bed without feeling out of breath.
She was admitted to the hospital with a diagnosis of ketoacidosis, her medical records and court documents show. Doctors couldn’t determine what caused the reaction, Ryan said, and Invokana was never mentioned. She was discharged the next day. Ryan, a legal assistant at the Social Security Administration at the time and a mother of two, filled another Invokana prescription two weeks later.
A few days after Thanksgiving, her symptoms returned. She struggled to walk. Back at the hospital, doctors remained stumped. At one point, Ryan said, the doctors asked her husband if she purposely harmed herself by drinking antifreeze.
Ryan’s medical records show she had lapsed into ketoacidosis again. She struggled to breathe, and her kidneys had begun to shut down. Her closest friends gathered at the hospital to pray. Her husband called her family to tell them her condition was critical.
“They thought it was my last day,” Ryan said.
During Ryan’s 12-day hospital stay in December 2015, the FDA announced that it would require Invokana and other drugs in its class to add warnings about ketoacidosis.
Ryan returned home in mid-December. But she didn’t feel strong enough to go back to work until two months later. Ryan dropped her lawsuit against J&J in 2019. She said she couldn’t comment on the resolution of her case. J&J declined to comment on Ryan’s case.
“I warn anybody who has diabetes to be cautious of Invokana,” Ryan said. “It was like it was slowly killing me.”
APPLE TREE BARK
Invokana is J&J’s trade name for a compound called canagliflozin. It and other SGLT2 inhibitors lower blood sugar levels – a key goal for diabetes patients – by increasing the amount of glucose the kidneys remove from the bloodstream and flush from the body in urine. Persistently high glucose levels can lead to heart disease, nerve damage and kidney failure, among other serious complications.
In the early 2000s, Mitsubishi Tanabe Pharma Corp invented the initial compound – a synthetic version of a chemical first isolated in the 1830s from the bark of apple trees – and later licensed it to J&J’s Janssen Pharmaceutical subsidiary for development and marketing.
J&J was targeting a huge market. In the United States alone, an estimated 32 million people now have type 2 diabetes, a condition linked to genetics, weight gain and inactivity. Type 2 patients don’t produce enough insulin or don’t respond normally to it. Cells need insulin, a hormone produced by the pancreas, to absorb glucose, a form of sugar, from the bloodstream for energy. Diet and exercise can help manage the disease, but many patients also need medication. SGLT2 inhibitors are not FDA approved for the 1.6 million Americans with type 1 diabetes, an autoimmune disease that requires insulin injections.
Ketoacidosis is a possible complication for anyone with diabetes. It happens when, unable to burn glucose as fuel, the body begins to burn fat instead. That process can lead to a buildup of acids, or ketones, in the bloodstream and escalate to ketoacidosis. SGLT2 inhibitors can create a similar situation by removing glucose through the kidneys, triggering ketone production.
The first red flags about Invokana’s possible link to ketoacidosis popped up while J&J was working with Mitsubishi in early clinical trials.
“There is emerging evidence from Phase 2 studies that some canagliflozin-treated subjects have increases in urinary ketone concentrations and corresponding increases in plasma ketone body concentrations,” David Polidori, a J&J researcher working on the drug, wrote in an October 2010 report reviewed by Reuters.
Polidori urged J&J to research the increased ketone levels. It’s unclear whether the company did. Polidori declined to comment and referred questions to the company.
J&J launched Invokana with few restrictions on its use among type 2 patients. That meant busy doctors wouldn’t have to think twice about a lengthy list of side effects or screen out patients who were a bad match for the medication. J&J’s sales pitch focused on lowering patients’ A1c score, a key barometer for blood glucose levels over the previous three months.
And the company touted another benefit that emerged in clinical trials: Invokana “may help you lose weight,” its commercials said.
Lower A1c scores and possible weight loss added to SGLT2 inhibitors’ appeal as another option beyond metformin. A safe, cheap generic, metformin has for years been the first-line treatment for people with type 2 diabetes. J&J also rolled out a pill that combined Invokana and metformin, dubbed Invokamet.
‘THE NEXT MAGIC PILL’
Invokana “was going to be the next magic pill. You lose weight, improve A1c,” said Dr Neelima Chu, an endocrinologist at Sharp HealthCare in San Diego. Endocrinologists specialize in diabetes and other hormonal disorders. “Doctors were giving out Invokana like candy.”
Patients came in asking for the drug by name, Chu said. J&J offered co-pay coupons that made it available at no cost to some patients for up to a year. The company paid $104 million from 2013 to 2020 to more than 100,000 U.S. doctors for speaking and consulting fees and in-kind expenses like travel and meals to help promote the drug, a Reuters analysis of federal data found.
Four months after the drug’s launch, on Aug. 6, 2013, the first three reports of ketoacidosis surfaced at an internal J&J meeting, company records show. But the review “did not identify” any potential safety problem, according to the meeting minutes.
Later that year, J&J hired Bruce Leslie, a nephrologist, or kidney specialist, who had worked on a diabetes drug at Bristol Myers Squibb. At J&J, he soon took charge of a safety team for a cardiovascular drug and later for Invokana.
Leslie said he was getting up to speed on Invokana when he noticed about a dozen cases of ketoacidosis in February 2014 and wondered if they merited further investigation. A month later, a more exhaustive search of J&J data turned up a total of 18 cases.
Ketoacidosis is less common with type 2 diabetes than in type 1. Though patients can recover with prompt treatment, once severe symptoms kick in, it can be fatal.
The link between the condition and type 2 patients who weren’t otherwise ill at the time surprised safety department staff. On March 5, 2014, records show, Leslie registered ketoacidosis in the company’s computer system as a “validated safety signal,” meaning an adverse event meriting closer monitoring.
Leslie also asked whether ketoacidosis should be turned up another notch in severity and labeled an “emerging safety issue,” a term used by regulators and drugmakers to describe major risks that trigger swift action and can lead to a public announcement. Under European rules at the time, drug companies had three business days to notify authorities once an emerging safety issue was identified. U.S. reporting requirements were less specific, but notifying one regulator often leads to information being shared more widely by government officials or the company.
Leslie’s supervisor, Shujian Wu, a safety manager, passed Leslie’s concerns up the chain of command. Later that day, Seong Won Han, a vice president for global medical safety, responded in an email reviewed by Reuters.
“If this is a new consideration for the cana team,” Han wrote, using shorthand for the drug’s chemical name, “then it makes sense to inform” the European Medicines Agency. Leslie and his safety team “should conduct their due diligence and assess the need for label updates.”
Leslie shared the news about ketoacidosis with more executives in a March 7, 2014, email marked “high” in importance. At a meeting focused specifically on ketoacidosis, he asked a J&J regulatory affairs executive, Jacqueline Coelln-Hough, to explain government reporting requirements related to emerging safety issues, internal records show.
The following week, on the morning of Friday, March 14, about 20 people gathered in the conference room at the Raritan campus. At the head of the table sat Dr Norm Rosenthal, vice president of clinical development for cardiovascular and metabolism drugs and co-author of studies describing Invokana’s benefits, and Coelln-Hough, the regulatory affairs executive.
Dr Gary Meininger, a metabolism drugs executive who had spearheaded development of Invokana, also was there. A year earlier, Meininger and Coelln-Hough had led the company’s presentation at an FDA meeting crucial to winning agency approval of the drug.
At the March 2014 meeting, members of the safety team took turns presenting their evidence, describing “multiple spontaneous and study reports of ketoacidosis in patients taking canagliflozin,” slides reviewed by Reuters show.
‘RISKS COULD BE MITIGATED’
The safety team suggested steps to reduce harm, saying “patients vulnerable to ketoacidosis associated with SGLT2 inhibition may be identifiable, and their risks could be mitigated.” For instance, they said, the company could advise doctors to closely monitor ketone levels and warn patients against mixing the medication with low-carbohydrate diets or abruptly stopping their insulin.
Top executives were skeptical. Meininger suggested that most cases might involve type 1 patients, who are not the FDA-approved audience for Invokana, but who can receive “off-label” prescriptions, according to minutes of the meeting. Rosenthal echoed that idea, Leslie said.
Initial injury reports filed by doctors or hospitals often lack details. But only four of the 18 ketoacidosis cases under review indicated the patient had type 1 diabetes. Executives saw no need to escalate the matter internally or notify regulators, concluding that ketoacidosis “is not an emerging safety issue,” according to minutes of the meeting.
Meininger, a type 1 patient himself who left J&J in 2019, declined to comment. He now serves as an industry representative on the FDA’s advisory committee for endocrinology and metabolism drugs. Coelln-Hough and Rosenthal didn’t respond to requests for comment, and the company declined to make them available for an interview.
Minutes after the meeting ended, one attendee praised the presentation. “Excellent meeting!” Dr Mehul Desai, a senior director in clinical development and a former FDA medical officer, wrote to Leslie. “Thanks so much for your time and effort.” Desai didn’t respond to requests for comment.
But three weeks later, medical safety vice president Han summoned Leslie to his Titusville, New Jersey, office. He handed Leslie a three-page warning about his performance and warned him that he was at risk of being fired. The April 3, 2014, letter, reviewed by Reuters, criticized Leslie for failing to modify his ketoacidosis presentation in advance of the meeting to “ensure a more comprehensive analysis of the data” and for not adequately consulting with other company experts who oversaw clinical trials and conducted medical research.
“Your failure to work with the appropriate functional experts in advance of the presentation resulted in an unnecessarily contentious … discussion,” Han wrote.
The reprimand advised Leslie to “use better judgment” when writing emails and documents. “You must take care not to document your opinions or the opinions of others as fact,” Han wrote. The letter also chastised him for swearing at Meininger during a disagreement over the safety of Invokana in patients with chronic kidney disease and failing to properly apologize.
Leslie felt blindsided, he said. He told Reuters that contrary to Han’s accusations, he consulted with multiple colleagues on the ketoacidosis presentation. He said he inadvertently used an expletive when Meininger demanded prior review of any potential meeting topics, which Leslie thought threatened the safety team’s ability to protect patients.
Four months earlier, J&J had honored Leslie with a “Gold Encore Award” for his safety work on another medication – a heart drug that was dropped from development in early clinical trials after Leslie highlighted life-threatening complications.
‘THESE KEEP ROLLING IN’
Several colleagues embraced Leslie’s attempt to address the mysterious incidents of ketoacidosis.
Trujillo, a senior medical director working on Invokana at the time, invited Leslie to present his findings to her staff. She talked with doctors outside the company who were “key opinion leaders” for Invokana and worked with company employees who met regularly with doctors, nurses and pharmacists.
She began forwarding ketoacidosis cases to Leslie’s team. “These keep rolling in,” Trujillo wrote in an April 7, 2014, email.
Three days later, J&J put another manager in charge of Invokana’s safety team alongside Leslie. In an April 10 email, Wu said Dr Michael Clark, a safety officer who had worked on immunology, and Leslie “will work in close collaboration with the canagliflozin team to deliver on our strategic objective of ensuring patient safety through proactive and timely assessments of canagliflozin safety data.”
Meantime, a week later, Trujillo told Leslie in an email about a pharmacist in Oxford, Mississippi, who reported that three patients had been hospitalized with diabetic ketoacidosis after starting Invokana. Two days later, on April 18, Trujillo shared another incident from an Alabama pharmacist.
In many instances, medical professionals had trouble identifying the problem because patients’ blood glucose levels were below what’s typically associated with ketoacidosis.
“I thought there was a virus going around,” said Dr Anne Peters, a professor of clinical medicine and director of the Clinical Diabetes Program at the University of Southern California, after encountering several cases of ketoacidosis among type 2 patients. She said the complication had rarely been seen in such patients. Peters later co-wrote a paper warning physicians how Invokana and similar drugs could lead to a type of ketoacidosis without high blood glucose levels.
By late April 2014, the number of ketoacidosis cases reported to J&J had reached 26, internal documents show. But the company remained in a holding pattern.
Company executives “did not opine whether ketoacidosis is a new adverse drug reaction, safety issue, or emerging safety issue for canagliflozin,” according to the minutes from an April 25, 2014, safety meeting.
The next month, Mitsubishi Tanabe, J&J’s Invokana partner, shared an update with J&J about ongoing clinical studies. In the presentation, reviewed by Reuters, Mitsubishi flagged the “safety of ketone increase” as one of several “important potential risks.” A spokesperson for Mitsubishi declined to comment, citing the pending litigation.
J&J drug safety staff continued calling doctors and collecting details. In June 2014, they reached out to a doctor in Portland, Oregon, who reported a patient on Invokana had suffered ketoacidosis twice in two weeks.
In a June 17, 2014, phone call, Leslie reiterated to a colleague that the company should alert regulators. At the time, J&J’s internal guidelines for employees recommended being proactive about safety problems even when they are still under investigation, company records show.
Clark, the J&J safety expert assigned to work with Leslie after his reprimand, disagreed. “We cannot go to regulators with our problems. We must wait for them to ask us,” Leslie recalled Clark telling him. Leslie’s account is supported by notes he took at the time. Clark didn’t respond to requests for comment.
J&J had reports on 39 patients with ketoacidosis tied to Invokana by July 1, 2014, just over a year after the drug entered the market, according to an email Leslie sent to Trujillo on that date.
However, two days later, in a regular safety report prepared for regulators, J&J identified 22 cases of ketoacidosis, records reviewed by Reuters show.
At least nine cases from 2013 were excluded because the company chose to disclose incidents that fit the report’s specific time period of Nov. 15, 2013, to May 15, 2014. Cases after that period may have been left out as well. “The data presented in this interval review of DKA were deemed insufficient to confirm that DKA represents a new safety concern,” J&J wrote in the report.
‘THIS IS WORRISOME’
Less than three months later, FDA officials came to a different conclusion.
Regulators expressed alarm after reviewing 20 cases of ketoacidosis linked to Invokana and Farxiga, launched in January 2014. Thirteen of the 20 patients had taken Invokana. Fourteen of the 20 were identified as type 2, according to the Sept. 24, 2014, internal FDA report obtained by Reuters.
“This is worrisome,” FDA officials Christine Chamberlain and Ali Niak wrote in the report, “because health care providers and patients may not suspect DKA in type 2 diabetics, resulting in significant morbidity, and potential mortality.”
The FDA investigators recommended a label warning, based on the “seriousness of this event and the potential for healthcare professionals to not suspect DKA as a diagnosis” in type 2 patients.
However, the public didn’t learn about the risk until May 2015, when the FDA announced an investigation into Invokana and other SGLT2 inhibitors. The next month, European authorities launched a similar inquiry. Both U.S. and European officials said they hadn’t received any specific warning about ketoacidosis from J&J.
Dr Susan Bersoff-Matcha, an FDA medical officer, said that the agency acted on “routine post-marketing surveillance” and that she wasn’t aware of any communications from J&J. The FDA collects and monitors reports of adverse events related to drugs and medical devices after they are on the market.
The FDA ordered a formal warning and label change about ketoacidosis for all SGLT2 inhibitors in December 2015, nearly two years after J&J discussed it internally.
Leslie, who had left the company in July 2014 after being reprimanded, said the delay was unconscionable. “In my opinion, the company wasn’t sufficiently proactive at notifying regulators, and hundreds of people got sick. That is the tragedy to me,” said Leslie, 74, who has continued to work in the industry on drug safety.
Han, the former executive who reprimanded Leslie, left J&J in 2018 and now serves as a vice president of product safety for a Chinese drugmaker. He declined to comment on specific decisions by the company. He praised J&J’s overall handling of safety issues and told Reuters that the disciplinary action against Leslie was appropriate.
Still, he said he also stood by his March 2014 email that supported notifying regulators based on the information known at the time. “You always go prospectively to health authorities to give them a heads-up rather than wait to hear from them,” Han told Reuters. “It is always better to be up front.”
Edited by Michele Gershberg and John Blanton.
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