The quest for effective weight loss medications has intensified, with pharmaceutical giants vying to create pills that rival the efficacy of popular weight loss shots. At the forefront of this race is Pfizer, a company with a complex history in the field, marked by both promising collaborations and significant setbacks. This article delves into Pfizer's journey in developing diet pills, from its early involvement with GLP-1 research to its current pursuit of oral weight management solutions.
The Race for Weight Loss Medications
The development of drugs with the same potency as weight loss injections has spurred competition among some of the largest drug companies in the world, with tens of billions of dollars at stake. The pharmaceutical giant Pfizer announced on Thursday that it is developing a once-daily version of an experimental medicine called danuglipron. The revolutionary power of GLP-1, a hormone that regulates appetite and blood sugar, has already been demonstrated by Novo Nordisk and Eli Lilly. Their injections, known as Wegovy or Zepbound, imitate this hormone and have been proven to reduce weight by about 10% to 20%.
Pfizer's Shifting Priorities and Challenges
Pfizer shares have lost almost half of their value since late 2022 due to declining revenue from COVID-19 products. In response, the company has cut costs, made leadership changes, and identified weight management as a potential source of growth. However, Pfizer has encountered difficulties in making progress in the obesity sector. Last summer, it discontinued a different oral GLP-1 medication due to safety concerns. A mid-stage trial revealed that patients on that version had 8% to 13% greater weight reduction than those on a placebo. More than half of the participants in the drug arms, however, stopped treatment.
Umer Raffat, an analyst at Evercore ISI, believes that Pfizer's update on Thursday is "likely buying time" to gather more data from a backup once-daily drug it has been developing. Raffat added that the prudent thing for Pfizer to do was not overcommit, and that is exactly what they did today. However, he noted that Pfizer has one of the largest primary care sales forces in the world, and obesity is poised to become the largest pharmaceutical market in history.
The Promise of GLP-1 Analogs
GLP-1 analogs are a class of medications designed to lower blood sugar levels and aid in weight loss. These molecules mimic the action of glucagon-like peptides, which are naturally produced in the gut. In recent years, GLP-1 drugs have experienced significant growth in popularity. With several GLP-1 drugs currently available, the market is expected to reach at least $100 billion by 2030. GLP-1 drug sales are projected to surpass PD-1 inhibitors, which help the immune system fight cancer cells, as the top-selling drug class this year.
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A Missed Opportunity in the 1990s
Pfizer potentially missed an opportunity to establish itself in the GLP-1 market due to a decision made in the 1990s. While the first GLP-1 drug received FDA approval in 2004, the history of this class of drugs dates back to the 1980s. Jeffrey Flier, who was involved in the early GLP-1 work, provided a detailed account of GLP-1 development in an article published in Perspectives in Biology and Medicine.
Early GLP-1 Research: A Nasal Spray Insulin Formulation
In 1982, John Baxter, an endocrinologist from UCSF, founded California Biotechnology (CalBio) to develop a drug for acute congestive heart failure. During this time, Jeffrey Flier, Alan Moses, and Martin Carey, three Harvard Medical School colleagues, explored a side project to develop a nasal spray insulin formulation for mealtime blood glucose control. The team sought industry support and partnered with CalBio. A collaboration with Eli Lilly began but Lilly withdrew from the project a few years later.
Metabolic Biosystems (MetaBio): A New Focus on Diabetes and Obesity
Baxter later enlisted Flier to start a new company focused on diabetes and obesity, called Metabolic Biosystems (MetaBio), under the CalBio umbrella. Flier recruited Rob Kahn and Bruce Spiegelman from HMS for this task. CalBio sought investment from large pharmaceutical companies, seeking financial support and expertise. Pfizer agreed to provide $30 million over five years, gaining exclusive rights to the program and spearheading clinical development. The partnership began in 1988.
The Rise and Fall of an Early GLP-1 Collaboration
The MetaBio/Pfizer collaboration focused on identifying insulin analogs, secreted factors from adipocytes, and gut factors that affect metabolism. The project that gained traction involved studying gut factors affecting metabolism. In 1987, Flier attended a talk by Joel Habener, who reported the discovery of GLP-1 and its ability to promote insulin secretion dependent on glucose concentration in islet cells and perfused rat pancreas. MetaBio obtained an exclusive worldwide license to GLP-1 as a therapy for diabetes.
The MetaBio team found that GLP-1 infusion increased insulin secretion in people with and without type 2 diabetes. In those with type 2 diabetes, GLP-1 lowered blood glucose levels over several days. They also found that GLP-1 slowed gastric emptying and decreased hunger cues.
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The Short Half-Life Challenge and Pfizer's Exit
The short half-life of GLP-1, lasting only minutes, led MetaBio to search for the protease that degraded it, aiming to increase GLP-1's half-life by inhibiting the protease or designing a protease-resistant GLP-1 analog. However, Pfizer withdrew support from the program before MetaBio could identify the protease, which was later identified as dipeptidyl-peptidase IV (DPP-4) in 1998 by scientists at the University of Copenhagen. The FDA approved the first DPP-4 inhibitor, sitagliptin, developed by Merck & Co., for treating diabetes in 2006. This class of drugs now generates about $11 billion per year in the US.
Despite positive data from human GLP-1 infusion, Pfizer concluded that there wouldn't be another injectable besides insulin to treat diabetes. Pfizer pushed for a transnasal or transcutaneous route of administration for GLP-1, but the team knew that would be unlikely given its short half-life. After three years, Pfizer announced its withdrawal from the collaboration after four years into the program.
Repercussions of Pfizer's Decision
With Pfizer's exit, the MetaBio founders urged CalBio to seek additional funding for the GLP-1 work. However, CalBio prioritized its acute congestive heart failure drug, Natrecor, which was eventually FDA-approved in 2001 and led to the company's acquisition by Johnson & Johnson in 2003 for $2.4 billion. Without finances from Pfizer, CalBio could not simultaneously support the GLP-1 work. Other companies like Eli Lilly and Novo Nordisk were not interested at the time.
The MetaBio founders were not interested in leaving academia to focus on GLP-1. CalBio bought out the founders, ending the work on GLP-1 for this small startup.
Novo Nordisk's Rise in the GLP-1 Market
With MetaBio/Pfizer out of the picture, Novo Nordisk acquired rights to Haberner's patents. Novo Nordisk, known as an insulin company at the time, now holds the largest share of the GLP-1 market. In 1995, they created liraglutide, a GLP-1 analog with an acylated fatty acid to extend its half-life. In 2008 and 2009, they published phase 3 clinical trial data, and by 2009, liraglutide was approved for diabetes in the EU and in the US by 2010. This drug was then approved for obesity in 2014. Liraglutide, with a half-life of 13 hours, was the first approved GLP-1 analog for once-daily dosing.
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Novo Nordisk's Ozempic and Wegovy, both once-weekly injectables, have made Novo Nordisk Europe's most valuable company. It currently has the only oral GLP-1 drug on the market.
Pfizer's Attempt to Re-enter the GLP-1 Arena
Pfizer re-entered the GLP-1 arena decades after dropping MetaBio. Its current candidate, danuglipron, is undergoing pharmacokinetics and safety studies. Danuglipron, designed as an oral, once-daily pill for obesity, has faced challenges in its development. Previously, Pfizer designed the drug as a twice-daily pill, but it faced discontinuation rates of over 50%, possibly due to side effects. Pfizer needs to conduct clinical trials before seeking FDA approval to move danuglipron forward.
Can Pfizer Catch Up?
It remains uncertain whether Pfizer can compete with its competitors already in the market. If approved, it would be a case of profoundly delayed gratification.
Hindsight and Missed Opportunities
Pharmaceutical companies cannot predict the future, and hindsight reveals mistakes in decision-making. Other instances of missed opportunities include the head of research at Schering-Plough, which now manufactures Claritin, stating that there aren't any nonsedating antihistamines, and a large pharma company deciding not to develop metformin to treat type 2 diabetes. Metformin is now one of the most commonly prescribed drugs worldwide.
Institutions tend to bury such decisions under layers of rubble for obvious business and psychological reasons. While Pfizer ended its partnership with MetaBio one year early, it is uncertain whether the outcome would have been different had they continued for another year. It is possible that Pfizer could have made enough progress on a GLP-1 analog and gotten it onto the market sooner.