Headlines about so-called "smart insulin" that could automatically react to shifting blood sugars have been circulating for years. The notion of glucose-responsive insulin that could someday relieve us PWDs of all the calculation, guesswork, and dose corrections required is such an exciting prospect -- yet many are disillusioned after so little progress, and the recent news that pharma giant Merck scrapped its most-promising plans in this area.

Yet, take heart! All three Big Insulin makers (Novo, Sanofi and Lilly) have significant investments in the game, and while others continue exploring this area the JDRF remains gung-ho on the prospects for smart insulin.

In fact, JDRF tells us they've spent millions over the years to make this an R&D focus, and while we're not close to seeing anything hit market yet, the organization is supporting roughly a dozen ongoing glucose-responsive insulin (GRI) projects at different stages and remains optimistic.

"I'm confident that glucose-responsive insulin will succeed, but of course the big question is when," says Dr. Sanjoy Dutta, JDRF's Associate VP of Research and International Partnerships. "I like to call it the non-device closed loop, and while it's certainly not an easy task developing this, there is still high promise."

 

Smart Insulin Research Continues

Here's the latest on what's happening in the smart insulin universe:

Novo Nordisk: On Aug. 17, Novo announced acquisition of a startup called Ziylo in order to focus in-house its glucose-responsive insulin efforts. Ziylo was originally a spin-off of Bristol-Myers Squibb, and prior to this acquisition, parts of the Ziylo research activities were apparently spun into a new company, Carbometrics, which had entered into a research collaboration with Novo. Carbometrics has licensed rights for all non-therapeutic uses of glucose-binding molecules, so it will be focusing on applications in diagnostics and glucose monitoring. Novo's Senior VP of Global Drug Delivery commented: "We believe the glucose-binding molecules discovered by the Ziylo team together with Novo Nordisk world-class insulin capabilities have the potential to lead to the development of glucose responsive insulins, which we hope can remove the risk of hypoglycemia and ensure optimal glucose control for people with diabetes."

That brings Novo on par with the other two insulin manufacturers who've been focusing more on this concept in recent years.

Eli Lilly: The Indianapolis-based pharma giant in 2016 acquired the Seattle-based startup Glycostasis to develop this type of insulin. That little company was created by Dr. John Mulligan, spun out from the Pacific Northwest Diabetes Research Institute (PNDRI) that had been exploring the idea of smart insulin. There's been no recent update on that, but it's not surprising given the R&D process takes so long.

Sanofi: This insulin manufacturer has been working with JDRF on smart insulin research for several years in a few different ways. They first teamed up on this front in 2014, and expanded that collaboration in 2016 to provide as much as $4.6 million toward research projects aimed at creating smart insulin. The collaborative group reviewed more than a dozen applications for R&D focused on this, and four were chosen to receive the funding over three years --

  • Dr. Danny Chou, assistant professor of biochemistry at the University of Utah, who's been developing an insulin formulation that has a biochemical trigger or "switch" that only works when activated by glucose in the system. This has been tested on diabetic mice, delivered by syringe and dermal adhesive strip. (More info at this USTAR news release.)
  • Dr. Alborz Mahdavi, a chemical and biomolecular engineer who founded California-based Protomer Technologies that's focused on using "bio-inspired" approaches to allow blood sugar levels to be sensed and used to activate a smart insulin. Dr. Mahdavi describes his approach as similar to a light switch that can be turned on and off.
  • Dr. Christoph Hagemeyer, a nanobiotechnology professor from Monash University in Australia, whose work in diabetes and heart health has involved targeted delivery of medications and molecular imaging. In developing a smart insulin, his team is creating nanoparticles to produce the insulin’s glucose-sensing effect.
  • Dr. Zhen Gu, a biomedical engineer and professor at North Carolina State/UNC, who's developing a microneedle patch design for delivering glucose responsive insulin. His research has also evolved more recently into testing this patch design tech covered in beta cells, which could deliver the new smart insulin in much the same way.

Merck: Many of us in the D-Community were bummed to hear news recently that Merck had scrapped the most advanced and promising smart insulin project to date. After its 2010 acquisition of the startup SmartCells that had been working on smart insulin, Merck went largely off the grid but finally broke that silence in May 2014 when announcing to investors they'd soon be starting human trials -- the first for any glucose-responsive insulin! That first phase of research and follow-up study crept along quietly, and unfortunately we've now learned from Merck that their early clinical study results weren't good enough. They've scrapped that product, which at one time was dubbed MK-2640. Merck tried to remain positive, though, by pointing to its Lantus copycat insulin still in the pipeline. **UPDATE: Unfortunately in Ocober 2018, Merck poured salt in its insulin-pipeline wound by announcing that due to the pricing and production pressures it would also be scrapping its follow-on biosimilar insulin dubbed Lusduna Nexvue, which had gained tentative FDA approvals in July 2017 and February 2018 but was awaiting resolution of a pending lawsuit by Sanofi.

Sensulin: Beyond those mentioned above, another we've seen bantered about over the past several years has been Oklahoma-based biotech startup Sensulin, founded in 2011 and working on a one-a-day injectable glucose-responsive formulation of its own. Much like the others in this field, Sensulin is still in the early animal study and fundraising phases and isn't near the human trials point. CEO Mike Moradi has spoken publicly for the past several years that it was nearing the time for human trials, even saying in early 2018 that it could be the end of next year (really?!) when the company's finalized its human trials candidate product and is able to start on that path. But still, all of that's reliant on the GRI prospect actually working out and the funding allowing it to move forward, as well as the likelihood of a Pharma partner to step in and take over R&D from there.

 

JDRF Focus on Smart Insulin

Dutta, who's been with the JDRF for close to a decade leading the organization's smart insulin focus, says that in that time he's seen huge growth in pharma and commercial interest in this area.

"At the time when we began, only the JDRF was funding this along with some NIH funding and a bit from Helmsley (Charitable Trust). Now we see the Big Three showing interest in smart insulin."

JDRF has also been working to support smaller research efforts beyond big pharma.

One of the most recent efforts there was announced in June 2018: a JDRF partnership with Denmark-based startup Gubra to develop a smart insulin. They describe this one as a unique approach that essentially combines meal-time boluses and long-acting basals into one insulin molecule that works quickly but also stays in the system longer. This initial one-year partnership is aimed at proof of concept via clinical research and eventual commercial development, and Dutta tells us they expect to have early results at some point in late 2019.

He also points out that the Gubra R&D is just one of the roughly 12 projects they have going on smart insulin and they look forward to more updates on those as well. 

 

Smart Insulin Likened to the Closed Loop

As Dutta suggests, it's interesting to compare the path of smart insulin to that of closed loop technology (aka Artificial Pancreas).

For decades, we heard the promise of how this amazing miracle tech would someday transform our lives, but for many it felt like a pipedream that would never materialize. Then in 2006, the JDRF developed an actual plan to make closed loop technology happen, and over the next decade worked to help D-industry and policy-makers put the pieces in place.

The development of those pieces -- better insulin pumps, more accurate CGM sensors, better designed mobile apps, intelligent dosing algorithms -- all made the puzzle come together. Eventually we got Low Glucose Suspend and Predictive Glucose functionality that gave birth to the first-ever Hybrid Closed Loop from Medtronic in 2016, not to mention the #WeAreNotWaiting Do-It-Yourself community using open-source versions of all this new tech to close the loop on their own.

Bottom line: Closed loop is now a reality, ableit in early form -- but it's getting more sophisticated by the day.

So from that POV, it may not be too much of a stretch to believe that smart insulin will become a reality before long too.

Of course, access and affordability are top of mind these days, so it's good to hear Dutta say that JDRF will prioritize those aspects once the initial clinical R&D becomes more mature. That will likely come in the Phase II and III research stages, when JDRF will begin talking to payers and working to get coverage decisions in place even before anything's submitted to FDA for review, Dutta tells us.

Yes, it's still a long road ahead and as Merck's experience shows, some research just isn't successful. But Dutta notes that even those failures bring a positive element to scientists because they can learn from that work and move forward -- either evolving that strain of research or going in a new direction.

"Science has the mood of a child," Dutta says. "You have to follow the science and see where it takes you, and though it doesn't always bring what you expect, it's always a process that scientists can learn from."

Yep, JDRF and other Powers That Be continue to nurture the smart insulin child.