With crucial lessons learned from the manufacturing shortages of injectable GLP-1s, experts say securing adequate supply of the upcoming oral options will be the sector’s next great challenge.
As Novo Nordisk and Eli Lilly begin to put the challenges they faced stocking their blockbuster weight loss drugs behind them, the next great manufacturing challenge is lurking: orals.
Lilly is already taking action to stockpile doses of its oral GLP-1 candidate orforglipron, spending $550 million to manufacture commercial quantities well ahead of potential approval. The drug is currently undergoing Phase III trials for both type 2 diabetes and obesity, with eagerly anticipated readouts expected later this year.
Even companies with weight loss candidates earlier in development are already planning well in advance. Viking Therapeutics, for example, signed a long-term partnership this month with CordenPharma to produce 1 billion tablets of the investigational oral weight loss drug VK2735, as well as 100 million autoinjectors and 100 million vial and syringe products of an injectable version of the asset. The oral version is currently in Phase II while Viking plans to kick off a Phase III trial for the injectable later this year. Similarly, weight loss startup Metsera has already secured manufacturing capacity despite only being in Phase I.
“What’s coming next, in terms of treatment options, are oral versions . . . for which manufacturing will be simpler,” Chris Shibutani, a senior analyst at Goldman Sachs, said on a 2023 podcast. “Oral versions will enhance the ability to supply a broader, potentially, global market. Several companies, with Lilly and Novo in the lead, are recognizing that is where the puck will go.”
Simpler To Take and To Manufacture
Both Novo and Lilly faced unprecedented demand for their injectable GLP-1s—Wegovy and Zepbound, respectively—and have been attempting to scale up their capabilities as quickly as their capital reserves allow . Novo essentially received an entirely new company to boost capacity as quickly as possible, with Novo Holdings’ $16.5 billion acquisition of Catalent last year. Lilly, meanwhile, has also bolstered manufacturing capacity.
With both drugs now off the FDA’s shortage list, supply constraints have eased. But neither are available in all the countries they have been approved in. The companies have been launching slowly to ensure they have the correct amount of starter doses and maintenance doses for new patients.
One of the reasons injectable GLP-1 peptides are difficult to manufacture and scale is the need for a sterile production environment, Mimoun Ayoub, global head, peptides and oligonucleotides platforms at CordenPharma, told BioSpace. This demands specialist manufacturing facilities set up specifically for the peptides, which has resulted in both Lilly and Novo investing significant capital into additional capacity. In addition, manufacturing injectable GLP-1s requires sufficient production of the injector pens and vials.
The specialized nature of producing these peptides has led to some quality control issues with compounders. Drug developers like Novo and Lilly have suggested that the manufacturing process is too complex for them to handle.
That also means that the number of contract manufacturing organizations (CMOs) capable of providing end-to-end manufacturing at high capacity is relatively limited. Catalent was one of them. Novo Holdings’ acquisition led to a squabble among executives over whether the deal was anti-competitive.
A report by Roots Analysis published in 2020 found that around 50 CMOs provided peptide services, but just 46% of these were capable of producing both peptide active pharmaceutical ingredients (APIs) and finished dose formulation peptides, with only 5% able to provide fill/finish services. The intervening years have witnessed a boom in investment by CMOs providing these services, however, this will take time to come online.
According to Matt Phipps, a partner at William Blair, the complexity of peptide manufacturing presents a barrier to new entrants in the weight loss drug market.
“Are fast-followers going to want to spend $10 billion to have a facility that will be ready in four years that may produce an injectable only similar to Novo Nordisk and Lilly’s treatments?” he asked. This is where oral GLP-1 treatments may hold the advantage because CMOs will have the capacity to meet the demand for such treatments.
In contrast to the complex manufacturing of injectable peptide-based drugs, “the manufacturing process for oral GLP-1s is simpler and more straightforward, utilizing standard solid dose manufacturing assets with high throughput,” Ayoub explained. CMOs will have a greater ability to support manufacture for oral treatments because the processes involved use standard solid dose manufacturing equipment for small molecule medicine, he added. A reported 281 CMOs have capabilities in solid dose manufacturing, according to GlobalData.
Oral GLP-1s will need to be taken at least once daily compared to the once-weekly treatment schedules of Lilly’s Zepbound and Novo’s Wegovy, meaning many more doses will need to be created. Even so, high-throughput manufacturing capabilities, which can allow for many thousands to millions of tablets to be produced per hour, will allow for this demand to be met, Ayoub added.
A spokesperson for Novo Nordisk confirmed with BioSpace plans to file for FDA approval of its oral semaglutide treatment Rybelsus in weight loss in the coming months. The company is also developing the oral amycretin. Novo will have a nice heads up on the manufacturing challenge because it already markets Rybelsus, which became the first oral treatment for type 2 diabetes when it received FDA approval in 2019.
Higher Capacity, Bigger Patient Population
There will be competition among CMOs looking to attract potential oral GLP-1 drug developers, creating an entirely different market to the injectable side of GLP-1s, Ayoub predicted.
One area that could help set CMOs apart,Ayoub stated, is the ability to increase oral bioavailability or improve stability, as the body’s capacity to absorb the oral versions of these drugs is a potential barrier to use. He added that CordenPharma is working to increase oral bioavailability and reduce API amount in formulations through hydrophobic ion pairing and lipid-based formulations.
The capacity of drug developers and the CMO industry to scale manufacturing for oral GLP-1s will depend on the level of demand. With its $550 million stockpiling investment, Lilly is hoping to “meet anticipated future demand,” a company spokesperson told BioSpace. Patients in many markets prefer oral medications over injectables and their manufacture and distribution is easier, which “lends itself to global scaling,” the spokesperson said.
Analysts like Phipps are split on how the market will settle between orals and injectables. “Some people very much think that it has to go to an oral approach because that just holds so many manufacturing advantages, and could serve a much broader patient population,” he said.
Should the oral approach end up being the one reaching the most patients, CMOs would face major pressure on capacity. In the case of CordenPharma, Ayoub said the company could quickly leverage existing space at its manufacturing sites to expand capacity to meet any demand that grew “far beyond our expectations.”
Judging by Viking and Metsera’s outlays into manufacturing, smaller players should be better positioned to establish competitive production capacity in orals than with injectables, whether through in-house production or through CMOs. Eventually, this could allow the GLP-1 market to open up beyond the current duopoly.
