Who Owns Leucovorin?

Leucovorin's history begins with the broader scientific discovery of folic acid and its role in cellular metabolism. Folic acid (vitamin B9) was isolated and characterized in the 1940s, and researchers quickly recognized its essential role in nucleotide synthesis and cell division. The discovery of folic acid antagonists, including aminopterin and methotrexate, as anticancer agents in the late 1940s by Sidney Farber at Boston Children's Hospital created the need for a rescue agent that could reverse the toxic effects of these antifolate drugs on normal tissues.

Leucovorin (folinic acid, 5-formyltetrahydrofolate) is a reduced, active form of folic acid that can bypass the enzyme dihydrofolate reductase (DHFR), which is inhibited by methotrexate. By providing cells with a form of folate that does not require DHFR for activation, leucovorin can rescue normal cells from methotrexate toxicity without significantly reducing the drug's antitumor effect, because cancer cells take up methotrexate more avidly than normal cells and are more dependent on DHFR activity.

Lederle Laboratories, a pharmaceutical division of American Cyanamid Company headquartered in Pearl River, New York, developed leucovorin calcium as a pharmaceutical product in the late 1940s and early 1950s. Lederle was one of the leading pharmaceutical companies in the United States at the time, with expertise in vitamins, antibiotics, and other pharmaceutical products. The FDA approved leucovorin calcium injection in 1952, establishing it as a prescription drug for the prevention and treatment of methotrexate toxicity and for the treatment of megaloblastic anemia due to folic acid deficiency.

The clinical applications of leucovorin expanded significantly over subsequent decades. In the 1970s and 1980s, oncologists discovered that leucovorin could enhance the antitumor activity of fluorouracil (5-FU), a widely used chemotherapy drug for colorectal cancer and other solid tumors. Leucovorin stabilizes the ternary complex formed between 5-FU's active metabolite (fluorodeoxyuridine monophosphate, FdUMP), the enzyme thymidylate synthase (TS), and the reduced folate cofactor, inhibiting TS more effectively and enhancing 5-FU's cytotoxic effect. This discovery led to the widespread use of leucovorin as a biochemical modulator of 5-FU in colorectal cancer chemotherapy.

The development of combination chemotherapy regimens for colorectal cancer in the 1990s and 2000s established leucovorin as an essential component of standard treatment. The FOLFOX regimen (leucovorin, fluorouracil, and oxaliplatin) and the FOLFIRI regimen (leucovorin, fluorouracil, and irinotecan) became the standard first-line and second-line treatments for metastatic colorectal cancer, respectively. These regimens are used in hundreds of thousands of patients worldwide each year, making leucovorin one of the most widely used drugs in oncology.

Lederle Laboratories was acquired by American Home Products Corporation (later renamed Wyeth) in 1994 as part of a broader consolidation of the pharmaceutical industry. Wyeth continued to manufacture and market leucovorin under the Lederle brand. Pfizer acquired Wyeth in 2009 for approximately $68 billion, bringing the Lederle pharmaceutical business, including leucovorin manufacturing, into the Pfizer portfolio. Pfizer subsequently acquired Hospira, a major manufacturer of injectable drugs, in 2015 for approximately $17 billion, further consolidating its injectable drug manufacturing capabilities.

As leucovorin's patents expired long ago, the drug has been manufactured by numerous generic pharmaceutical companies for decades. The generic leucovorin market is characterized by multiple competing manufacturers, price competition, and periodic supply shortages when manufacturing disruptions affect one or more suppliers. The FDA's drug shortage database has listed leucovorin calcium injection as a shortage drug on multiple occasions, reflecting the challenges of maintaining consistent supply of a critical oncology drug manufactured by a limited number of suppliers.

LevoLeucovorin (also known as levoleucovorin or l-leucovorin, the active levo isomer of leucovorin) is a more recent development, marketed under the brand name Fusilev by Spectrum Pharmaceuticals. Levoleucovorin contains only the pharmacologically active levo isomer of leucovorin, compared to the racemic mixture in conventional leucovorin, and is approved for the same indications as leucovorin at half the dose.