C&EN: Lilly to invest $5.3 billion for a Lebanon, IN plan

Via C&EN, this good news for American manufacturing (article by Aayushi Pratap):

To meet astronomical demand for its weight-loss and antidiabetes drugs, Eli Lilly and Company says it will double its investment at a drug active-ingredient manufacturing site now under construction in Lebanon, Indiana.

The company will inject an additional $5.3 billion, increasing its total investment in the site to $9 billion. The expansion will boost the production of tirzepatide, the peptide-based active pharmaceutical ingredient (API) used in Zepbound and Mounjaro, weight-loss and antidiabetes medicines that the US Food and Drug Administration approved in 2023 and 2022, respectively.

Construction of the Indiana facility began in 2023. Lilly expects to start manufacturing at the site in 2026 and says it will increase production over the subsequent years. Once the facility is fully operational, it will employ 900 workers, including engineers, scientists, operating personnel, and lab technicians.

Since 2020, Lilly says, it has committed to spending $16 billion on new manufacturing sites in the US and Europe.

In a press release, Lilly CEO David A. Ricks says the overall project is “the largest manufacturing investment in our company’s history and, we believe, represents the single largest investment in synthetic medicine API manufacturing in US history.”

The investment comes as Lilly and Novo Nordisk, which manufactures the competing peptide-based drugs Wegovy and Ozempic, struggle to keep up with demand...

It will be really interesting to see what the site will look like eventually, but I could imagine 25-40ish chemists (of one stripe or another) at this site eventually? It will be interesting to see! 

C&EN: "Novo Nordisk parent to acquire Catalent to shore up weight-loss drug production"

Via C&EN, this news (article by Aayushi Pratap)

Novo Holdings, the Danish investment giant that also controls Novo Nordisk, has agreed to acquire Catalent, one of the largest US drug-manufacturing contractors, for $16.5 billion. The deal could help Novo Nordisk boost production of its weight-loss drug Wegovy, which has gained immense popularity since the US Food and Drug Administration approved it in June 2021.

Novo Holdings expects to close the acquisition by the end of 2024, after which it will sell three of Catalent’s sites—in Anagni, Italy; Bloomington, Indiana; and Brussels, Belgium—to Novo Nordisk for $11 billion. Novo Nordisk is trying to boost the supply of Wegovy and a similar diabetes drug, Ozempic. The drugs, which contain the active substance semaglutide, work by mimicking a hormone called glucagon-like peptide-1 (GLP-1), which reduces appetite, leading to weight loss.

Last year, Novo Nordisk announced it will spend over $8 billion to expand manufacturing sites in France and Denmark to boost production of drugs in its chronic illness portfolio, which includes Ozempic and Wegovy. However, as of early February, semaglutide injections continued to be labeled as being in short supply by the FDA.

I know I am a weirdo for harping on this, but it seems evident to me. Novo should have made these moves years ago, and I am genuinely curious if they will ultimately find themselves on the back foot because they were not able to ramp up manufacturing fast enough. 

Also, I think it is ridiculous that Lilly is complaining that Novo bought Catalent - surely you fellas could have done that too! 

Interview with a senior Novo Nordisk scientist

Fascinating and very... European interview in Der Spiegel with the inventor of liraglutide, Lotte Bjerre Knudsen: 

DER SPIEGEL: We have a different supposition: Novo Nordisk grew up with insulin, which will now be used less in the fight against diabetes. And your company didn’t want to give up its old revenue generator.

Knudsen: I’m not buying that. Why didn’t Merck, Bristol-Myers Squibb, Pfizer and all the other manufacturers prioritize anti-obesity drugs?

DER SPIEGEL: But you had to struggle against resistance within the company.

Knudsen: It’s true that over the years I’ve clashed with some colleagues who focus on insulin. People told me directly that they thought the GLP-1 peptide was a bad idea. We wouldn’t need new injectors for diabetes or obesity. Even our former CEO jokes today that he didn’t believe in a successful anti-obesity drug. But I was allowed to continue researching.

I'm genuinely very impressed with people who worked on a hard problem for many years and have had it shown fruit. I suspect that all of us have these moments, but it's always very cool when their passions turn out to be very, very successful. Congratulations to her, and best wishes to all of us in our individual endeavors. 

FDA: "FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain"

 Via FDA's website: 

FDA continues to investigate counterfeit Ozempic (semaglutide) injection 1 milligram (mg) in the legitimate U.S. drug supply chain and has seized thousands of units of the product. The agency advises wholesalers, retail pharmacies, health care practitioners and patients to check the product they have received and not distribute, use, or sell products labeled with lot number NAR0074 and serial number 430834149057 as pictured below. Some counterfeit products may still be available for purchase.

FDA and Novo Nordisk (manufacturer of Ozempic) are testing the seized products and do not yet have information about the drugs’ identity, quality, or safety.

Additionally, analysis found the needles from the samples are counterfeit. Accordingly, the sterility of the needles cannot be confirmed, which presents an increased risk of infection for patients who use the counterfeit products. Based on analyses completed to date, other confirmed counterfeit components within the seized products are the pen label, accompanying health care professional and patient information, and carton. 

FDA is aware of five adverse events from this lot, none of which are serious and are consistent with known common adverse reactions to authentic Ozempic, which are nausea, vomiting, diarrhea, abdominal pain and constipation.

It seems to me that this sort of thing is to be expected with such a revolutionary drug. It seems to me that the only thing that Novo could have done was to ensure a plentiful supply of Ozempic from the start, but I'm not sure there was enough fill-and-finish capacity available, especially with them surely competing with every vaccine manufacturer for available lines... 

Reuters: German medicines regulator considering export ban on Ozempic

Via Reuters: 

FRANKFURT, Nov 15 (Reuters) - German regulator BfArM is considering banning Ozempic exports as Europe's health systems grapple with shortage of the diabetes drug, which is in high demand for its weight-loss benefits.

Use of Novo Nordisk's (NOVOb.CO) Ozempic for weight loss has caused shortages across Europe, where Britain and Belgium have temporarily banned its use for weight loss to secure availability for diabetics.

Novo's launch of anti-obesity drug Wegovy, a high dose version of Ozempic, in Britain, Germany, Norway and Denmark, has so far done little to temper the craze for Ozempic as volumes of Wegovy have been limited due to production bottlenecks... 

...BfArM's Broich said some Ozempic was being moved out of the country because it is cheaper there than elsewhere, and demand was driven by use for weight loss.

Broich cautioned that export restrictions can only be rarely used and legal hurdles were high because of the European Union's single market.

Nothing has stopped me from being convinced that Novo Nordisk badly underestimated demand for Ozempic and failed to ramp up manufacturing sufficiently to meet both current and future demand. It will be interesting to watch the race between Novo and Lilly to see who will ultimately capture the most market share for GLP-1 drugs.  

Novo's semaglutide API plant in North Carolina had a 483 in May 2022

Via Reuters, this bit of news: 

LONDON, Sept 21 (Reuters) - U.S. drug regulators issued a report detailing quality control lapses at Novo Nordisk's (NOVOb.CO) main factory in North America as early as May last year, according to the report obtained by Reuters via a Freedom of Information Act request.

The inspection by the U.S. Food and Drug Administration (FDA) was at Novo's facility in Clayton, North Carolina, which the company says produces the active pharmaceutical ingredient (API), semaglutide.

The site makes oral semaglutide for Novo's diabetes drug Rybelsus, a spokesperson told Bloomberg on Thursday. A spokesperson declined to comment when asked by Reuters to confirm this.

Semaglutide is also used in Novo's hugely popular weight-loss drug Wegovy and type 2 diabetes drug Ozempic, which are injections.

There is no evidence that compliance failures flagged in the report known as a Form 483 resulted in harm to users of Wegovy and Ozempic. A Form 483 is a type of agency report containing "observations" that FDA inspectors "deem to be objectionable".

The issues were with the factory's control systems to prevent microbial contamination, the same as those raised in the more recent inspection this July, which was first reported by financial news agency MarketWire and pushed Novo's shares down 3%.

Novo declined to comment on the May 2022 report, which was first reported by Reuters, but repeated its statement on Monday in response to the FDA's report from its July inspection that the Clayton site was "running and producing for the market".

As regular readers know, I am very interested in understanding the supply chain of semaglutide. What is really remarkable to me is that there have been almost immediate shortages from launch. Some of this is clearly demand -  I have long suspected that Novo, being Europeans, did not accurately anticipate either 1) off-label use of Wegovy/Ozempic for weight loss 2) the demand for this in the United States or both. 

I also imagine that a lot of this is about available manufacturing capacity, either for sterile injectables or for API. It seems to me pretty clear that part of the supply problem has been about sterile injectable manufacturing capacity available to Novo. That there may have also been a crimp in API supply in May 2022 might add another piece of the puzzle as well. 

Who is making "generic" semaglutide, part 2

I know I've covered this before, but it continues to bother me - who is making "generic" semaglutide? (via the New York Times): 

...Because the F.D.A.’s drug shortage website lists as Ozempic as “currently in shortage,” compounding pharmacies are allowed to buy semaglutide from pharmaceutical ingredient manufacturers and compound it into an injectable medication they dispense. They also often mix it with B vitamins or a metabolic compound called L-carnitine, which limited research has shown may contribute to weight loss. Some compounding pharmacies are distributing a different active ingredient altogether: semaglutide sodium, the salt form of semaglutide.

In recent weeks, regulators have raised concerns about semaglutide sodium, which is sometimes sold as a research chemical. Semaglutide sodium does not appear to meet standards for compounding in federal law, in part because the substance is not part of any F.D.A.-approved medication — and officials have expressed alarm at how widespread it is.

I don't wish to cover the questions that I've already asked, but I'll note some other questions that I have about this situation: 

• Are we basically in a world where US consumers are ordering API from Chinese manufacturers directly?  
• (answer, yes, it appears so) 
• Why isn't the FDA stopping these shipments from coming in? 
• Semaglutide doesn't appear to be a particularly easy peptide to make, but I suppose that these sorts of efforts are run by solid-phase synthesizers? Is it the fact that the dosages are relatively low that allow Chinese peptide manufacturers to participate in this? 

I'm genuinely surprised that people are willing to entrust their lives to a supply chain that is completely opaque and untraceable, but it is around weight loss, and so folks are pretty motivated to get themselves access to Ozempic, whether it's through their physicians or not.