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Takeda got its hands on popular attention-deficit/hyperactivity disorder med Vyvanse through its Shire acquisition in 2019. After 16 years on the market, Takeda's blockbuster attention-deficit/hyperactivity disorder (ADHD) med Vyvanse has finally reached its patent cliff.  The med, which is also approved for binge-eating disorder, has been in short supply since June due to a “manufacturing delay compounded by increased demand,” the company said in a statement earlier this summer. Now, generics may soon help ease the supply situation. On Aug. 25, the FDA cleared many copycats of the drug. The now-approved generics range in dosage from 10 mg to 70 mg and come in capsule and chewable forms. Manufacturers such as Teva, Sun Pharmaceutical, Actavis, Mylan, Hikma and others have cleared the agency's regulatory bar with their generics. It's not clear whether any of the companies have actually launched their copycats in the U.S. Takeda's patents on its branded version expired Aug. 24. Whenever they debut, the generics will surely be welcomed by patients. A 100-day supply of the branded drug goes for $1,305, according to Drugs.com. Meanwhile, 30 capsules are priced at around $460. Takeda's Vyvanse shortage emerged after Adderall and its generics began to face similar shortfalls last summer, when top supplier Teva started struggling to keep up with demand. In Takeda's financial outlook for 2023, the company said it anticipated “significant headwinds” throughout this year because of U.S. generic erosion for Vyvanse. In Vyvanse’s last quarter of exclusivity, the drug brought in sales of 123 billion Japanese yen (about $880 million), good for 16% growth at constant exchange rates. Takeda acquired Vyvanse in its 2019 buyout of Shire. The drug won its original FDA approval in 2007.

Pictured: Series of outcroppings with steep cliffs down to the ocean/iStock, honster The biopharma industry has been creeping over a patent cliff for months, with several drugs losing their primary patents and more patents expected to expire in the next seven years. This opens the door for new generics to enter the market, lowering drug prices and therefore reducing how much manufacturers can rake in from brand name products. Maria Whitman, global head of ZS Associates’ pharmaceutical and biotech practice, previously told BioSpace that drugs going off-patent could impact between up to 79% of a company’s revenues. Drug prices go down any time a new generic becomes available, but the impact may be more pronounced around patent cliffs. One analysis found that the steepest price declines for brand name drugs between 2008 and 2014 occurred when the first three generics were introduced. Not every company will experience this decline in the same way. For example, Eraxis, an antifungal drug owned by Pfizer, is expected to lose its exclusivity in September. But loss of exclusivity probably won’t have a major impact on the company, said S. Sean Tu, a law professor at West Virginia University and affiliated faculty at Harvard Medical School’s Program on Regulation, Therapeutics and Law. “Even if a lot of generics [for Eraxis] went on the market tomorrow, I don’t think it would hurt Pfizer’s bottom line. They have a pretty diverse portfolio,” Tu told BioSpace. Smaller companies like Eiger Pharmaceuticals may have more to lose. The company has one commercial product, Zokinvy, that will start losing exclusivity soon. In SEC filings, Eiger warns investors that it may never be profitable. Just because the primary patent for a drug expires, it doesn’t automatically mean other companies are free to start marketing generics. For example, AbbVie filed hundreds of patents for its biologic drug Humira, preventing other companies from producing generic adalimumab. It was only after a 2017 settlement that Amgen was able to start marketing biosimilars overseas, and eventually in the U.S. in January of this year. Then, last month, a flood of new Humira biosimilars hit the market. Owning multiple patents for a single drug, what’s known as patent thickets, help drug companies make up for lost time and costs during the FDA approval process, according to Tu. However, more companies are relying on them to limit competition. A research letter authored by Tu and others found that recently approved drugs have more patents filed and more patents litigated compared to older drugs, leading to delays in generics entering the market. Here are some drugs that may see generic versions enter the market soon. Takeda’s Vyvanse, Aug. 24 Vyvanse (lisdexamfetamine dimesylate) is an oral amphetamine used for attention-deficit hyperactive disorder. New River Pharmaceuticals filed a provisional application for the drug in 2003 and the patent was issued in 2007. It was eventually acquired by Shire and later Takeda, bringing in $2.52 billion for the Japanese company between March 2021 and 2022. The patents covering adult indications of Vyvanse expired on Feb. 24, and those for the pediatric indications are due to expire Aug. 24. As of July 31, there were 12 tentative approvals for Vyvanse generics, with some issued as early as 2014 and others as recently as June 14, 2023. Companies looking to market these generics include Teva, Mylan and Sandoz. Tu predicted that the breadth of Takeda’s portfolio would minimize the impact of the loss. Indeed, a financial forecast filed by the company July 27 says that growth and launch of new products are “largely offsetting” the impact of losing Vyvanse’s exclusivity. Pfizer’s Eraxis, Sept. 22 Eraxis (anidulafungin) is an intravenous antifungal drug. Its patent expired in 2020, but it’s under an exclusivity clause for the treatment of a new patient population that expires Sept. 22. Tu noted that he didn’t see any generic approvals in the pipeline for anidulafungin and therefore doesn’t anticipate a major loss of sales. The lack of generics runs contrary to predictions that generic anidulafungin would enter the market between early 2020 and mid-2022. Johnson & Johnson’s Stelara, Sept. 25 Stelara (ustekinumab) is a biologic used for psoriasis and Crohn’s disease. A patent for one of the molecules involved in Stelara expires Sept. 25. The drug already has some competition: J&J settled with Alvotech and Teva earlier this year preventing them from marketing biosimilars until 2025. Stelara is not the only drug driving pharmaceuticals sales growth, according to SEC filings, but it brought in more than 10% of the company’s revenue in 2022. Analysts predict that Stelara sales will fall $2 billion in 2024. Merck’s Isentress, Oct. 3 Isentress (raltegravir) is an antiretroviral drug used to treat HIV. It brought in $633 million in 2022, but sales have been declining due to competition, according to SEC filings. Some of the drug’s patents expired earlier this year, and two more are expected to expire soon, starting in October. Hetero Labs has received a tentative approval for generic raltegravir. Eiger’s Zokinvy, Oct. 17 Zokinvy (lonafarnib) is the first drug for rapid aging disorder progeria and Eiger Pharmaceuticals’ first commercial product. The drug, acquired from Merck, brought in $12 million for the company in 2022 and $4.1 million in the first quarter of 2023. The drug’s patents are expected to expire Oct. 17, 2023, and July 26, 2024, respectively. However, it has exclusivity clauses extending into 2027, which will protect the drug for a while. Additionally, there do not appear to be any immediate competitors. Astellas’ Myrbetriq, Nov. 4 Myrbetriq (mirabegron) is a urinary incontinence drug that garnered $1.35 billion for Astellas in 2022. More than one patent is expiring Nov. 4, and additional patents are expected to expire in May 2024. A recent court decision invalidated a patent that was set to expire in 2030, which the company plans to appeal. Zydus Cadila and Lupin Labs are among the companies that have tentative approvals for mirabegron generics. Novartis’ Entresto, Nov. 27 Entresto is a heart failure medication that combines sacubitril and valsartan. Some patents expired earlier this year, and more are slated to expire in November and the first half of 2024. Additionally, a patent set to expire in 2025 was recently invalidated by a court. Mylan is one company looking to offer generic Entresto. Novartis has settled with other companies looking to market the drug, according to SEC filings. Amgen’s Otezla, Dec. 9 Otezla (apremilast) is a psoriasis drug. Multiple patents for this drug expired in March of this year, and a patent for a specific formulation of the drug is expected to expire in December. Some of its exclusivity clauses also expired earlier this year. There are already multiple tentative approvals for generics in the wings, but recent court rulings have blocked drugmakers from marketing generic apremilast until 2028. Novo Nordisk’s Victoza and Saxenda, Dec. 30 Novo Nordisk’s liraglutide recombinant injections have patents expiring at the end of this year and in the first half of 2024. This includes the primary patent for diabetes drug Victoza, which brought in $1.8 billion in 2022. Teva, Pfizer and Mylan are expected to launch their generic liraglutide products in June 2024, per SEC filings. Sandoz is also cleared to launch its version of Victoza in 2024. Saxenda brought in $1.5 billion in 2022, and the weight loss drug’s main patent expired in February of this year. Novo sued Orbicular Pharmaceutical Technologies and Sun Pharma in 2022 for attempting to market generic versions of the drug. Novo still maintains a stronghold in the diabetes drug industry with Ozempic, which has also lost patents but likely won’t see generics until 2031. Ozempic sales will likely offset any losses from Victoza and Saxenda; the former brought in $2.9 billion in the first quarter of 2023, compared to $415 million for Victoza and $483 million for Saxenda. Nadia Bey is a freelance reporter in North Carolina. She can be reached at beynadiaa@gmail.com.

On Monday, Teva Pharmaceuticals and Glenmark Pharmaceuticals became the sixth and seventh drugmakers to resolve criminal charges as a result of the Department of Justice’s yearslong investigation into generic drug price fixing. The settlement agreement requires both companies to pay hefty fines as well as divest their drug lines for pravastatin, a widely used statin that lowers cholesterol. In 2019, the DOJ showed that it was serious about cracking down on generic drug price fixing by issuing two multi-million dollar fines to Heritage Pharmaceuticals and Rising Pharmaceuticals. The legal case at the center of Monday’s settlement dates back to 2020, when the DOJ indicted Teva over alleged price fixing conspiracies with four other generic drugmakers — Glenmark, Sandoz, Apotex and Taro Pharmaceuticals. The indictment charged the pharma companies with raising prices, rigging bids and allocating customers for generic drugs. These medications included pravastatin, as well as generic drugs for autoimmune diseases, pain, cancer and cystic fibrosis. In 2020, Taro, Sandoz and Apotex admitted their roles in the alleged schemes and paid fines respectively totaling $205.7 million, $195 million and $24.1 million. With Monday’s settlement, Teva and Glenmark have also admitted to their roles in running a price fixing scheme and agreed to pay criminal penalties. The DOJ ordered Teva to pay a $225 million penalty, which the department said is the largest fine to date for “a domestic antitrust cartel.” As for Glenmark, the DOJ issued the firm a $30 million fine. The settlement agreement also requires both Teva and Glenmark to divest their respective drug lines for pravastatin, which was at the center of the companies’ alleged price fixing scheme. In addition to the $225 million penalty, the DOJ ordered Teva to donate $50 million worth of drugs to humanitarian organizations. Those drugs are antifungal medication clotrimazole and antibiotic drug tobramycin The prices of both were affected by the conspiracy, the DOJ said. If either company violates the terms of their settlement agreement, they will face prosecution. If convicted, they would likely get banned from federal healthcare programs like Medicare and Medicaid, according to the DOJ’s statement. “When a firm is criminally convicted, it is barred from participating in U.S. federal healthcare programs. Teva Pharmaceuticals is one of the largest generic pharmaceutical firms in the world, so barring it from much of the healthcare industry would be dangerous. The right response is to shrink the firm and force it to disgorge illicit profits, which is what the antitrust division did,” Matt Stoller, director of research at the antitrust advocacy group American Economic Liberties Project, said in a statement. In a press release issued Monday, Teva said it “fosters a culture of compliance” and “has robust and consistent compliance controls in place” to prevent price fixing schemes from recurring in the future. Glenmark did not respond to MedCity News’ request for comment. In 2019, Heritage agreed to pay more than $7 million to settle its price fixing case, and Rising was issued a penalty totaling more than $3 million. Collectively, seven drugmakers have agreed to pay nearly $700 million as a result of the DOJ’s crackdown on generic drug price fixing.