Tuesday, March 28, 2023

The Business of Diabetes: 2023 Update on Glucose-Responsive Insulin

My readers may recall back in 2007, I interviewed the CEO of a startup then known as SmartCells, Inc. named Todd Zion (see https://blog.sstrumello.com/2007/06/conversation-with-smartcells-ceo-todd.html for my original post). In 2010, the big pharma giant Merck & Company, Inc. acquired SmartCells, Inc. (see my post at https://blog.sstrumello.com/2010/12/merck-acquires-smartcells-inc.html for my coverage of that). For its part, Merck remained rather tight-lipped about revealing much of anything about that, although it did become the first-ever glucose responsive insulin to complete a clinical trial, which was known Merck's MK-2640 to complete its Phase 1 trial in August 2016. However, that product candidate was rather unceremoniously discontinued in Q2 2017 due to negative Phase 1 results. See https://pubmed.ncbi.nlm.nih.gov/30125349/ for the disappointing trial results. In other words, the original SmartCells was officially dead.

Have Insulin Analogues Reached the End-of-the-Road Scientifically?

That said, investments in glucose-responsive insulin seem to be an acknowledgement of sorts that big insulin-makers have really seem to have reached the end of what is possible (scientifically-speaking) with insulin analogues in terms of making them work faster or longer. For example, Novo Nordisk's "me-better" version of aspart branded as Fiasp (the name means "Faster Insulin Aspart) works by the addition of some vitamins (specifically, vitamin B-6 [niacinamide]) in the insulin which marginally-improves the absorption into the bloodstream (and, truthfully, its really not all that much faster). Lilly's me-better version of lispro branded as Lyumjev works on a similar principle, hence it is also not a fundamentally new insulin analogue molecule, rather it is a slightly-improved version of the original lispro. New molecules are much more risky from a business perspective, and the odds of failure are also much higher (but so are the rewards). Because of that, big insulin (Novo Nordisk and Lilly) seem to have actually made quantitative investments in glucose-responsive insulins.

In June 2021, Novo Nordisk's glucose responsive insulin (NN-1845) became the second candidate in this innovative class of drugs to complete a Phase 1 clinical trial. Novo Nordisk did not develop NN-1845 based entirely on internal research. Instead, in August 2018, the Danish company acquired a Bristol, UK-based startup known as Ziylo Ltd. in order to accelerate its development of glucose responsive insulins. While the exact purchase price of Ziylo was never revealed, the press release (see https://www.prnewswire.co.uk/news-releases/ziylo-acquired-by-novo-nordisk-in-deal-that-could-exceed-us800m-691089451.html for details) indicated the acquisition "could exceed U.S. $800 million", presumably based upon investment milestones being met. Since then, NN-1845 has demonstrated proof-of-concept glucose sensitive properties and safety in both people with and without Type 1 diabetes. But remember, it still has not yet advanced to Phase 2 clinical trials, so even presuming development goes well, it still won't be on the market for a fair number of years at best.

Meanwhile, rival Eli Lilly and Company does not currently list a glucose-responsive insulin in the company's drug development pipeline, but in July 2021, Lilly acquired a privately-held Pasadena, California-based biotech company named Protomer Technologies (see https://www.prnewswire.com/news-releases/lilly-announces-acquisition-of-protomer-technologies-301332980.html for the news) along with its molecular engineered protein sensor technology to accelerate the development of its own glucose-responsive insulin.

On the Lilly/Protomer glucose responsive insulin initiative, we must also acknowledge the role of the JDRF T1D Fund played in that advancing to where it stands today. The JDRF T1D Fund describes itself as a "venture philanthropy" effort which was originally bankrolled (at least partially) by billionaire Sean Doherty (he formerly worked as an exec for Bain Capital) in an effort to help his son Finn who developed Type 1 diabetes as a child; Finn is now over 20 years old as of 2023 (see https://www.nytimes.com/2021/07/02/your-money/philanthropy-type-1-diabetes-research-fund.html for more). I was under the impression that the JDRF T1D Fund entity was NOT formally affiliated with the nonprofit known as the JDRF, and the JDRF T1D Fund (which I believe makes its name somewhat confusing), but it says that it only invests in companies "that are developing a T1D program with significant potential for clinical impact."

The JDRF T1D Fund requires that each of its portfolio companies "must have an investable business model so we can attract multiples of private capital and biopharma industry capital." The JDRF T1D Fund investment in Protomer was one of the companies which were subsequently acquired by a major pharmaceutical company (Lilly), which was a good omen for the prospects for the Lilly/Protomer glucose responsive insulin, although it still has a fair number of years, assuming everything goes right, so there are no guarantees.

While Sanofi does not formally have anything on glucose-responsive insulin in its development pipeline, the third-largest insulin-maker doing business in the U.S. today has actually collaborated with a startup known as Sensulin, Inc., conducting some preliminary trials along with the startup, which presumably would make that startup an acquisition target for the company if it chooses to invest further. I had the pleasure of meeting Sensulin co-founder and CEO Mike Moradi a number of years ago.

My conclusion on the status of glucose-responsive insulin as of March 2023 is as follows:

First, while newer insulin analogues could be developed which make them temperature-stable (for example, an Ohio-based startup known as Thermalin, Inc.  based largely on pioneering work by Dr. Michael Weiss on the structure and function of insulin analogues is pursuing those types of modifications). Novo Nordisk does have another basal analogue which aims to be dosed on a weekly basis called icodec in development, but the practical reality is it appears aimed primarily at the insulin-naive Type 2 patient population, and it really looks as if we've hit the end-of-the-road on making insulin analogues much faster or longer-acting with new insulin molecules. In fact, every newer prandial insulin analogue has achieved faster absorption into the bloodstream not by creating new insulin molecules, but by adding things like vitamins to the formulation in order to help them absorb into the bloodstream faster (which is how Fiasp works).

Hence, glucose-responsive insulin now appears on the development horizon for big insulin (only Merck/SmartCells is officially dead). We now see solid evidence that big insulin-makers like Novo Nordisk and Lilly views glucose-responsive insulin as the logical next-step in their efforts to continue selling patent-protected insulin molecules.

Still, we have really only started to see early investments from big insulin on glucose-responsive insulins, and none are yet imminent. However, it is important to acknowledge the commoditization of traditional insulin analogues whereby lowest prices are all that matters in terms of sales, and a growing roster of biosimilars due to hit the market (in 2024, I anticipate seeing biosimilars from Biocon, Lannett/HEC, Sandoz/Gan & Lee, Amphastar/ANP and Civica/GeneSys Biologics, which means glucose-responsive insulin makes sense as investments for big insulin makers. 

That said, don't expect to see glucose-responsive insulin for another decade at least.

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