What making weight-loss drugs mean for the environment

Novo Nordisk is spending $6 billion in Kalundborg, Denmark, to develop the manufacturing of lively pharmaceutical components (APIs), together with peptides utilized in weight-loss and antidiabetic medicine. The Danish firm’s rival, Eli Lilly and Firm, lately constructed a peptide synthesis plant in Kinsale, Eire.

Novo Nordisk’s Wegovy and Lilly’s Zepbound aren’t simply altering how the general public thinks about weight reduction. These peptide-based medicine and others anticipated to observe are spurring large modifications in pharmaceutical chemical manufacturing. The 2 corporations, in addition to third-party producers, are constructing large new amenities to make the components wanted for these medicine.

However synthesizing peptides is notoriously inefficient, and with the investments come questions in regards to the environmental price of creating the favored weight-loss and antidiabetic medicine.

The lively substances in Wegovy and Zepbound are the 31-amino-acid-long semaglutide and the 39-amino-acid-long tirzepatide, respectively. Each peptides mimic the pure physique hormone glucagon-like peptide-1 (GLP-1). The medicine regulate blood sugar ranges and cut back urge for food, which leads to weight reduction and antidiabetic advantages.

The demand for such medicine has skyrocketed since their approval by the US Meals and Drug Administration. Novo Nordisk’s antidiabetic drug, Ozempic, was accepted in 2017, and Wegovy in 2021. Lilly’s corresponding medicine, Mounjaro and Zepbound, received the inexperienced mild in 2022 and 2023.

Final yr, Novo Nordisk introduced in $18.4 billion from mixed gross sales of Ozempic and Wegovy; Lilly reported $5.3 billion in complete gross sales of Mounjaro and Zepbound.

And demand is predicted to rise even additional. Novo Nordisk estimates that 813 million individuals have “weight problems,” however its medicine have reached just one.1 million. Reviews from Goldman Sachs counsel that annual gross sales might hit $100 billion by 2030.

Corporations are discovering it exhausting to maintain up with the demand even now, and shortages are occurring repeatedly. Each Novo Nordisk and Lilly are investing billions of {dollars} to scale up manufacturing. Different corporations additionally see vital alternatives within the peptide enterprise.

As an illustration, Bachem, which makes peptides and oligonucleotides for drug corporations, will spend over $1 billion at two websites in Switzerland to develop manufacturing of the molecules. The agency estimates that the present peptide API market is price $1.7 billion yearly and represents over 1,100 pharma peptide tasks worldwide.

However as enterprise booms, consultants warn that peptide-based medicine aren’t being made sustainably. Scaling up manufacturing utilizing present practices might result in an unprecedented improve in industrial waste.

Peptides will be synthesized in a handful of how, however the most typical industrial methodology is solid-phase peptide synthesis (SPPS), in line with Rodney Lax, a former enterprise improvement supervisor at PolyPeptide, a number one peptide producer. “SPPS, nonetheless, was not initially designed to make multiton manufacture of peptides in a sustainable approach, and it is a downside,” he says.

Corporations have been utilizing SPPS ever since Bruce Merrifield launched it within the Nineteen Sixties—an invention for which he received the Nobel Prize in Chemistry. Till then, the go-to method was liquid-phase synthesis, which remains to be generally used to make peptides of lengths as much as round 20 amino acids. However the liquid-phase methodology isn’t perfect for longer peptides like semaglutide and tirzepatide due to problematic purification processes.

The solid-phase methodology, which permits peptides of as much as 70 amino acids lengthy, works virtually like threading beads collectively one after one other. The method begins with fixing the primary amino acid of the specified peptide on a polymer and masking the N-terminal with a defending agent to forestall it from self-reacting. The protecting group is eliminated when the following amino acid within the sequence is added together with a coupling reagent to kind an amide bond between the 2 amino acids. This course of is repeated till all of the amino acids are joined to make the peptide, which is then purified utilizing strategies equivalent to high-performance liquid chromatography.

“The procedures require the usage of very substantial portions of natural solvents, which is basically simply natural waste. At industrial scale, it’s a soiled course of,” Lax says.

Probably the most generally used natural solvents for peptide manufacture are N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, and dichloromethane, all of that are recognized to be hazardous. However even short-term publicity to those solvents could cause well being issues equivalent to stomach ache, nausea, vomiting, jaundice, rashes, and most cancers in people and animals.

To guard employees from the well being impacts of those solvents, the European Union launched rules in 2021 that restrict publicity to DMF to six mg/m³through inhalation and 1.1 mg/kg per day through pores and skin.

Whereas these solvents are utilized in many industries, together with the manufacturing of paints, adhesives, and small-molecule medicine, the quantities wanted within the peptide sector are exceptionally giant, in line with Lax.

Relying on the size, producing 1 kg of GLP-1 receptor agonist peptide can require as much as 14 metric tons (t) of solvent, in line with a research revealed this yr (DOI: 10.1021/acs.joc.3c01494). In distinction, producing most different artificial small molecules usually takes about 0.3 t of solvent per kilogram.

“It’s worrying to see how making these weight-loss medicine appears to have an enormous implication on the surroundings,” says Matteo Villain, a vice chairman and international peptide technical lead at Piramal Pharma Options, a drug contract improvement and manufacturing group (CDMO).

Lax and Villain—each trade veterans—say that whereas the dimensions of the peptide trade has grown, the methods to make them haven’t modified a lot. About 15 years in the past, the trade was making solely three therapeutic peptides, every of which had been produced at a scale of about 100 kg per yr, Lax says. “At present, we’re speaking about multi-metric-ton portions of peptides. It is a scale-up of about 700 to about 1,000 instances utilizing the identical methodology.”

Lilly and Novo Nordisk take totally different approaches to peptide manufacture.

Lilly outsources the manufacturing of fragments of tirzepatide to CDMOs after which assembles these fragments at its personal amenities, together with on the Kinsale website.

No less than two main CDMOs, China-​based mostly WuXi AppTec and the German agency CordenPharma, make peptide fragments for Lilly’s medicine utilizing SPPS.

WuXi AppTec executives say the corporate has tripled its peptide-making capability since January and now has the infrastructure and functionality to supply 32,000 L of peptides yearly utilizing SPPS. “The demand for peptide medicine instantly modified with GLP-1 weight-loss medicine,” says Minzhang Chen, the agency’s co-CEO.

WuXi AppTec opened two peptide crops in China in January, one at its Changzhou facility and one other at its new website at Taixing. “Yearly, we’ll add capability for small-molecule APIs and peptides,” Chen says.

CordenPharma has additionally elevated its footprint within the peptide enterprise. In 2023, the corporate inaugurated a $60 million addition to its facility in Boulder, Colorado, which it calls the world’s largest SSPS facility. Roche initially constructed the plant to supply the peptide-based AIDS drug Fuzeon.

“We’re seeing a rising demand from our clients. And if there’s a additional demand, we will accommodate it,” says CordenPharma CEO Michael Quirmbach. Novo Nordisk makes use of a yeast-based fermentation method to engineer the spine for semaglutide, which is then chemically modified. “This methodology is probably going a bit bit greener when utilized to large-scale manufacturing,” Villain says.

However Lilly’s tirzepatide is extra complicated than semaglutide and could possibly be difficult to make through fermentation, in line with Villain. “With the rising complexity of peptides, chemical synthesis turns into the one environment friendly option to make them,” he says.

Villain thinks {that a} pervasive downside is that innovators seeking to launch a brand new drug typically take into consideration greener manufacturing strategies solely within the late levels of improvement.

Some observers say the trade must do extra to maneuver away from SPPS. “The demand for the quantities of peptides is past creativeness,” says Leendert van den Bos, CEO of the peptide producer EnzyTag. “In fact, you may simply assemble 50 soccer fields with new solid-phase peptide synthesis reactors, however I don’t assume that’s the best way to go.” The Dutch firm has codeveloped a know-how that makes use of peptiligases, a category of enzymes that facilitate the coupling of peptide fragments with out the usage of solvents.

Paramjit Arora, a professor of chemistry at New York College and president of the American Peptide Society, says the give attention to greener processes has intensified in recent times.

“Till 5 years in the past, when any individual talked about inexperienced chemistry processes for peptide synthesis, we thought we’d ultimately like to make use of them,” he says. “However now, if we don’t urgently undertake them, the sphere might undergo drastically.”

Arora’s lab is concentrated on growing catalysts that would allow the elongation of amino acids with minimal use of solvents. However the analysis isn’t prepared for industrial adoption. “As of at present, there is no such thing as a viable catalyst for chemical synthesis of peptides and proteins from commonplace amino acids,” he says.

CDMOs too are discovering new methods of creating peptides which might be much less damaging to the surroundings. In 2022, CordenPharma collaborated with the Swedish instrument maker PeptiSystems on a brand new idea that permits the solid-phase manufacturing of peptides in steady mode, a change that the agency says reduces solvent consumption by not less than 40%. The corporate put in the know-how in its Germany plant however not at its larger facility in Boulder.

PolyPeptide, Lax’s former firm, says it invested almost $266 million between 2020 and 2023 to scale up peptide manufacturing. Final yr, the corporate deployed what it calls the “percolation-based washing methodology,” which decreased its general solvent consumption by 24% in contrast with 2022. PolyPeptide can be increasing its utilization of inexperienced solvents, which have a smaller environmental influence.

“Final yr we managed to begin 13% of our tasks with inexperienced solvents,” John Lee, an R&D chemist at PolyPeptide, says in an e mail.

However Arora notes that inexperienced solvents can’t be used for the synthesis of every kind of peptides. And Lee says that the trade is mostly reluctant to make the shift to greener solvents. “Many corporations are ‘mounted’ on a normal approach of doing issues,” he says.

Villain factors out that there’s a false impression that inexperienced peptide synthesis solely means utilizing environmentally pleasant solvents. “It additionally means utilizing nasty solvents in as little portions as attainable and recycling them,” he says.

Though he agrees that inexperienced peptide synthesis is a sizzling matter within the scientific and industrial communities, Villain doesn’t see hazardous solvents going away anytime quickly. “There are vital efforts to make peptide manufacturing greener, however we’re removed from the optimum level when it comes to inexperienced chemistry within the peptide world,” he says. “Individuals are engaged on it, simply not in a concerted approach.”