Month: December 2023

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Pfizer’s twice-daily version of its experimental weight loss pill has now joined a long list of other scrapped drugs that aimed to treat obesity but came with unintended consequences. 

The drugmaker on Friday said it will stop developing the twice-daily treatment, danuglipron, after obese patients taking the drug lost significant weight but experienced high rates of adverse side effects in a midstage clinical trial. Pfizer noted that it will release data on a once-daily version of the pill next year, which will “inform the path forward.” 

The announcement came six months after Pfizer scrapped a different once-daily pill in June, citing elevated liver enzymes. Pfizer’s move to drop two obesity drug candidates in just a few months demonstrates how difficult it is to develop an effective, safe and tolerable treatment for losing weight, even after recent breakthrough medications entered the space. 

That includes Novo Nordisk‘s Wegovy and diabetes treatment Ozempic as well as Eli Lilly‘s diabetes drug Mounjaro. They have all skyrocketed in popularity — and slipped into shortages — over the last year for safely and successfully causing significant weight loss. An estimated 40% of U.S. adults are obese, making those drugs the pharmaceutical industry’s newest cash cow. 

But before the current weight loss industry gold rush, the path to treating obesity was strewn with failures dating back decades.

The main reason many experimental treatments were scrapped by drugmakers, rejected by U.S. regulators or eventually pulled from the market were unintended side effects, including elevated liver enzymes, cancer risks, cardiovascular risks and serious psychiatric problems, such as suicide. 

Eisai’s lorcaserin

One of the most recent casualties among experimental obesity drugs is Japanese drugmaker Eisai’s lorcaserin, which was removed from the market in 2020 due to causing an increased risk of cancer in patients. 

The Food and Drug Administration greenlit lorcaserin in 2012 based on several clinical trials but required Eisai to conduct a larger and longer study on the drug after the approval.

That study on about 12,000 patients over five years found that more people taking lorcaserin were diagnosed with cancer compared with those taking a placebo, which led the FDA to pull the drug from the market.  

Lorcaserin, marketed under the brand name Belviq, didn’t appear to gain much traction while it was commercially available. In its full-year 2019 earnings, Eisai reported that Lorcaserin had sales of $28.1 million in the U.S. for the year. Global sales of the drug were about $42 million. Eisai’s total sales for the year were roughly $4.42 billion.

Sanofi’s rimonabant

An obesity drug called rimonabant from Sanofi and Aventis was withdrawn from all markets in 2008 due to the risk of serious psychiatric problems, including suicide. 

Notably, the treatment never won approval in the U.S. because a panel of experts to the FDA rejected the drug amid fears that it may cause suicidal thoughts. But European regulators approved rimonabant, marketed under the name Acomplia, in 2006 based on extensive clinical trials. 

Two years later, European regulators recommended the suspension of rimonabant after one of its committees determined that the risks of the treatment — particularly psychiatric issues — outweighed its benefits. 

The treatment suppressed appetite by blocking the receptor of cannabinoid substances in the brain, which plays an important role in regulating the body’s food intake and metabolism. 

Due to rimonabant’s limited time on the market and failure to win U.S. approval, the drug never reached Sanofi’s lofty projection that it would eventually generate $3 billion a year or more. 

Abbott Laboratories’ sibutramine

Several obesity drugs have also been discontinued, rejected or pulled from the market due to unintended cardiovascular risks. 

That includes sibutramine from Abbott Laboratories, which was once widely used as a treatment for obesity along with diet and exercise.

The drug was first approved in 1997, but carried warnings about high blood pressure and a risk of heart attack and stroke in cardiovascular patients. 

A large, long-term trial on nearly 10,000 adults confirmed that sibutramine was associated with a significant increase in cardiovascular events, which prompted regulators in the U.S. and Europe to pull the drug from those markets in 2010.

Sales of sibutramine had been dwindling ahead of its removal from the market. The drug raked in only $80 million globally, including $20 million from the U.S., in the first nine months of 2010.

Recent evidence suggests that the newest slate of approved weight loss drugs may have the opposite effect on heart health: Weekly injections of Wegovy slashed the overall risk of heart attack, stroke and death from cardiovascular causes by 20%, according to a recent clinical trial. 

Pfizer on Friday said it would stop developing the twice-daily version of its experimental weight loss pill after obese patients taking the drug lost significant weight but had trouble tolerating the drug in a mid-stage clinical study. 

The drugmaker observed high rates of adverse side effects, which were mostly mild and gastrointestinal, among patients. A significant share of patients also stopped taking the pill, which aims to be a more convenient alternative to highly popular weight loss injections.

“At this time, twice-daily danuglipron formulation will not advance into Phase 3 studies,” the company said.

But Pfizer said it still plans to release data on a once-a-day version of the drug in the first half of 2024, which will “inform a path forward.” The pharmaceutical giant will wait to see that data before deciding whether to start a phase three study on the once-daily pill, which Wall Street views as the more competitive form of the treatment.

Shares of Pfizer closed 5% lower Friday after it announced the trial results.

Still, the data on the twice-daily drug is a blow to Pfizer’s hopes to win a $10 billion slice of the booming weight loss drug market, which CEO Albert Bourla has said could grow to $90 billion. The company is betting on a successful weight loss pill to help it rebound from plummeting demand for its Covid products and a roughly 40% share price drop this year. 

But investors have been pessimistic about Pfizer’s potential in the weight loss drug space since the company scrapped a different once-daily pill in June and proceeded with the less attractive danuglipron. Now, Friday’s data puts Pfizer even further behind the dominant players in the weight loss drug market, Eli Lilly and Novo Nordisk, which are racing to develop pill versions of their blockbuster weight loss and diabetes injections. 

Pfizer’s phase two trial on its twice-daily pill followed around 600 obese adults who did not have Type 2 diabetes. The trial examined the drug’s effect on weight loss after 26 or 32 weeks, at different dosage amounts ranging from 40 milligrams to 200 milligrams.

Like Novo Nordisk’s Wegovy and Ozempic, Pfizer’s pill works by mimicking a hormone produced in the gut called GLP-1, which signals to the brain when a person is full.

Pfizer said the trial on danuglipron met the primary goal of demonstrating “statistically significant” reductions in body weight.

Patients who took the pill twice a day lost 6.9% to 11.7% of their body weight on average at 32 weeks, and from 4.8% to 9.4% at 26 weeks.

Meanwhile, patients on a placebo gained 1.4% of their body weight at 32 weeks and 0.17% at 26 weeks.

When adjusting for the difference between the weight gain observed in patients who took the placebo, Pfizer’s twice-daily pill caused 8% to 13% weight loss on average at 32 weeks and 5% to 9.5% at 26 weeks.

The company said high rates of adverse events were observed among patients in the study, with up to 73% experiencing nausea, up to 47% vomiting and up to 25% experiencing diarrhea. More than 50% of patients across all dose sizes stopped taking the pill, compared to roughly 40% among those on the placebo, according to Pfizer.

No new safety issues were observed, and danuglipron was not associated with increased liver enzymes like Pfizer’s other discontinued weight loss pill.

Data from the phase two trial will be presented at a future scientific conference or published in a peer-reviewed journal.

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Wall Street’s expectations

The tolerability issues align with some analysts’ predictions ahead of the data release. 

Leerink Partners analyst David Risinger wrote in a Monday note that the proportion of patients who discontinue treatment with Pfizer’s twice-daily danuglipron in the phase two trial would likely be higher than those who stopped taking a once-daily pill from Eli Lilly.

By comparison, 10% to 21% of patients who took Eli Lilly’s pill, orforglipron, in a mid-stage trial discontinued the treatment at 32 weeks due to adverse side effects, he noted.

Risinger said that’s likely because danuglipron’s total daily dose is far higher, which may cause more adverse effects. Patients on the highest dose size of Pfizer’s pill took 400 milligrams each day, while those on the highest dosage of Eli Lilly’s drug took 45 milligrams a day.

Pfizer’s phase-two trial also didn’t allow downtitration, or decreasing the dose of a drug over time once a specific response has been achieved. Eli Lilly’s mid-stage trial on its pill did. 

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There is hope that patients will better tolerate the once-daily version of danuglipron compared to the twice-daily form. Pfizer appears to believe a once-daily version of the drug could lessen gastrointestinal side effects, according to some analysts.

They pointed to Pfizer’s second-quarter earnings call, when the company’s chief scientific officer, Mikael Dolsten, suggested that a once-daily version may improve a patient’s tolerability of the drug, which could lessen the gastrointestinal side effects “that have been seen as limiting” danuglipron.

But Barclays analyst Carter Gould wrote in a Friday note that he remains skeptical that a once-daily version will “move the needle on tolerability given the starting point for this conversation.”

He added that it’s “increasingly apparent the company will have to look to external assets to deliver on the market opportunity it had portrayed.”

Notably, the weight loss caused by twice-daily danuglipron appeared to fall short of some analysts’ expectations. 

Wall Street was looking for the pill to show 14% to 15% weight loss to be competitive, Cantor Fitzgerald analyst Louise Chen wrote in a Friday note. Physicians believe that 15% weight loss is “good enough” to convince them to switch from prescribing injectable weight loss drugs to oral versions, Chen said.

Leerink’s Risinger also wrote in October that Pfizer’s danuglipron needs to show weight reduction in the “mid-teens” percentages to be considered competitive with Eli Lilly’s once-a-day pill in particular.

Obese or overweight patients who took 45 milligrams of Eli Lilly’s pill once a day lost up to 14.7% of their body weight, or 34 pounds, after 36 weeks, according to the company’s phase-two trial results.

Eli Lilly’s results appear consistent with the weight reduction caused by a high-dose oral version of Novo Nordisk’s semaglutide – the active ingredient used in the diabetes drug Ozempic and weight loss treatment Wegovy – but came over a shorter trial period.

Both pills from Eli Lilly and Novo Nordisk appear to be “superior to danuglipron at this stage,” TD Cowen analyst Steve Scala said in a note Friday.

“Overall, this is a worse than anticipated outcome for a program that was already playing catch-up,” Scala said of Pfizer’s pill data.

More than 2 in 5 adults have obesity, according to the National Institutes of Health. About 1 in 11 adults have severe obesity.

Clarification: This story was updated to reflect that some weight-loss data was adjusted to include results from the placebo group.

A 0.25 mg injection pen of Novo Nordisk’s weight loss drug Wegovy is shown in this photo in Oslo, Norway, on Aug. 31, 2023.

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Novo Nordisk on Thursday said it sued two compounding pharmacies in Florida for allegedly selling impure and “potentially unsafe” drugs claiming to contain semaglutide, the active ingredient in the drugmaker’s blockbuster weight loss treatment Wegovy and diabetes medication Ozempic. 

The actions come as Novo Nordisk grapples with shortages of Wegovy and Ozempic in the U.S. as demand skyrockets for the drugs, which are known for their ability to cause significant weight loss. 

That has left patients scrambling to find alternative, but sometimes dangerous and unproven, methods for shedding unwanted pounds.

Novo Nordisk is the sole patent holder of semaglutide and does not sell that ingredient to outside entities, which raises questions about what compounding pharmacies, clinics and other companies sell to patients. Compounding pharmacies prepare custom-made versions of commercially available treatments to meet the specific needs of a patient. 

The Danish drugmaker found that all the products tested from Wells Pharmacy Network and Brooksville Pharmaceuticals were impure, meaning that they contained unknown and unauthorized substances other than semaglutide, according to the two lawsuits filed in federal court in Florida. One product’s level of unknown impurities was 33%.

The unknown impurities in the products “potentially pose safety risks” to consumers, including “possibly serious and life-threatening reactions,” Novo Nordisk said in the suits.

The Danish drugmaker is not seeking monetary damages but is asking the court to bar the pharmacies from selling their products.

Wells Pharmacy Network and Brooksville Pharmaceuticals did not immediately respond to CNBC’s requests for comment.

Novo Nordisk first sued Brooksville Pharmaceuticals over copycat versions of Wegovy and Ozempic in July. A federal judge in Florida dismissed the suit in October and later gave the drugmaker time to refile its complaint against the pharmacy.

Including the newest lawsuits, Novo Nordisk has filed 12 legal actions against compounding pharmacies, medical spas and weight loss clinics allegedly selling dupes of Wegovy and Ozempic. The company said it has received preliminary injunctions in six of those cases.

Rival Eli Lilly has taken similar action against businesses selling knockoffs of its popular diabetes drug Mounjaro, including its own lawsuit against Wells Pharmacy Network. 

Novo Nordisk’s new suit against Wells Pharmacy Network claims that its products contained a substance called BPC-157, which was banned by the U.S. Food and Drug Administration in September. The FDA said it did not have enough data to know whether the substance was harmful to humans but noted it could cause dangerous immune system reactions.

Novo Nordisk added in the lawsuit that products from Brooksville Pharmaceuticals had lower levels of semaglutide than advertised. That puts patients “at risk of taking drug products that are less effective than expected based on their labeling,” according to Novo Nordisk. 

“Compounded products do not have the same safety, quality and effectiveness assurances as FDA-approved drugs, and adulterated and misbranded injectable compounded drugs may expose patients to significant health risks,” Jason Brett, Novo Nordisk’s executive director of medical affairs, said in a statement. 

The FDA in May warned about the safety risks of unauthorized versions of Ozempic and Wegovy after reports emerged of adverse health reactions to compounded versions of the drugs. 

Several states have also threatened to take legal action against compounding pharmacies that make or distribute unapproved variations of Novo Nordisk’s weight loss treatments.

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