Smarter insulin?

insulinInsulin was the first hormone to be genetically engineered for human use, and synthetic insulins now control blood glucose levels for almost everyone with type 1 diabetes and millions of those with type 2 diabetes. Many variants of the molecule have been designed to act quickly or slowly or in between, but the Holy Grail is smart insulin—which would not only work over many hours but automatically adjust its own release to keep blood glucose levels in a good range.

Many labs have taken a stab at smart insulin since the first attempt in 1979. New approaches keep cropping up, and a few show particular promise in animal tests. A “nanoparticle network” reported in 2013 is one of the more interesting. These nanoparticles combine insulin, dextran (a complex sugar often employed to slow down glucose effects) and enzymes that target glucose. Given opposite electrical charges, the nanoparticles are thought to clump together in the body rather than wander off in the bloodstream, doing their duty like a tiny pancreas.

The current commercial champion for smart insulin, though, began back in 1999 with research by Todd Zion, then an MIT graduate student in chemical engineering. Zion came up with a design that combined modified insulin with a sugar gel, and worked dramatically well in rats. He and his colleagues spun out a startup firm called SmartCells in 2003 and honed the technology well enough to get the attention of Merck, which snapped up SmartCells in 2010. Last spring, Merck remarked that it would bring a L-490 smart insulin based on the company’s technology into a clinical trial this year.

But there’s been no news from Merck since, and the National Institutes of Health’s clinicaltrials.gov site doesn’t mention a trial for L-490.

So we’re still in the animal labs.

But I’m still encouraged by last month’s paper in the journal PNAS on a different approach to smart insulin, developed by a team led by MIT’s Daniel Anderson and Robert Langer. This group found that an engineered insulin with the sprightly name of Ins-PBA-F performed very well, maintaining good glucose levels in the blood of mice without functioning pancreases over more than 12 hours and also behaving itself in normal mice.

Which sounds like L-490. But the researchers suggest that the approach Ins-PBA-F spearheads may offer better control and safety in the long run than L-490 because it’s more like normal insulin.

Ins-PBA-F starts with a molecular structure of a long-acting synthetic insulin, and adds a chemical group called “phenylboronic acid” (PBA) that binds to glucose and other sugars. When the surrounding glucose levels climb high enough to occupy the PBA group, the insulin itself is released for action. (Curiously, though PBA is often used to sense sugars and other carbohydrates, the PNAS paper acknowledged that the exact mechanism by which Ins-PBA-F responds to higher glucose levels in the blood isn’t yet clear.)

In theory, such a directly modified insulin molecule may be safer from immune reactions and other side effects than smart insulins that add gels or other types of protein barriers for glucose, as do L-490 and most other approaches. If so, that benefit will appeal mightily to the FDA, which will give extremely tight scrutiny to a radical new drug that could be used around the clock by many millions of people.

A successful smart insulin will be very far from a niche product. Anderson and Langer (who may well hold the world record for co-founding biomedical startups) have the attention of the venture capital community. I hope that successors to Ins-PBA-F will indeed move toward clinical trials, and eventually the clinic. That might be a very smart bet.

Update: Merck actually but very quietly moved its smart insulin into a two-part clinical trial in fall 2014.

Encapsulating answers to type 1 diabetes

People with type 1 diabetes are understandably excited about progress toward an “artificial pancreas” but they never lose the hope for a true cure, in which they can live like everyone else, without juggling synthetic hormones and hardware clomped on their skin that pierces their skin and will never work perfectly.

A true cure is a blue-sky goal built on two sets of major medical advances, and we have no idea what year those advances might arrive.

One set is to understand the autoimmune onslaught that brings on type 1 and then find a way to stop it. Serious and sometimes brilliant research keeps charging ahead, but autoimmune diseases hold extremely devious secrets and guard them very well.

The second set is to create a cells that replace those wiped out by the autoimmune attack and can generate insulin (and maybe related pancreatic hormones) at appropriate levels. Stem cell research aimed to do so is going gangbusters but is generally a long way from clinical trials.

With one big exception:

Yesterday Viacyte filed with the FDA for permission to run a trial for its VC-01 device, which encapsulates human progenitor cells—human embryonic stem cells that in this case have gone partly down the development path to hormone-producing cells. (The company, then known as Novocell, began work with embryonic stem cells years before the 2006 discovery of ways to create induced pluripotent stem cells, which possess very similar abilities to differentiate into almost any kind of cell but can be created from adult cells.)

Viacyte’s encapsulation container is a Teflonish cartridge about the size of a band-aid and thickness of a credit card, with holes too small for immune cells to enter but big enough to allow oxygen, glucose and other key ingredients to flow in and to allow insulin and other hormones to flow out.

The theory is that the capsule is inserted via an outpatient procedure, the immune system mostly ignores it, blood vessels build up to feed the cells, the cells are driven by signals within their fairly normal local human microenvironment to differentiate into a range of hormone-producing cells, the cells churn out insulin and its hormone cousins, and normal blood glucose levels and related metabolism are maintained. A functional cure, in short, for a year or two or three while the device functions properly.

This all works nicely in mice, but mice are not always man’s best friend in diabetes research. Investigators have struggled with encapsulation techniques for many years, and stem-cell-derived cells are unproven. The list of what could go wrong in the Viacyte trial is very long. Patients might reject the capsule. The cells might die quickly or slowly or never gather suitable blood vessels or fail in other ways. They might generate side effects that no one has imagined.

But Viacyte seems to have the science on its side and its head on straight and a good step-by-step plan. Assuming the FDA agrees, I don’t expect a home run in the first trial, but simply getting on base would be huge. And we should know within a year.

Viacyte Encaptra

Smart insulin readies for trial

If you have type 1 diabetes, your body produces little or no insulin, and you survive on injections of synthetic insulin. You always have a little too much or too little insulin running through your blood, except for times when you have a lot too much or too little. Too much, and you may start to slide rather quickly toward serious wooziness and maybe unconsciousness. Too little, and you increase your risk of serious complications down the road.

Thus the appeal of the concept of “smart insulin”, an insulin derivative designed to automatically react to the level of blood glucose and adjust the amount of insulin released so that glucose levels remain in a healthy range.

Back in 1979, Michael Brownlee and Anthony Cerami presented one smart insulin approach in Science. There’s been plenty of research on the concept since then, but it has remained a concept.

In 2010, though, Merck announced plans to buy the MIT spinoff SmartCells for a purchase price that may eventually exceed $500 million. And last week at a Merck investor briefing, Roger Perlmutter, executive vice president and president of Merck Research Laboratories, noted that the company plans to move a smart insulin candidate based on SmartCells work forward into clinical trials.

At the briefing, Perlmutter displayed just one slide, showing that injections of a drug candidate called L-490 could maintain blood glucose levels at normal levels in dogs using smaller dosages than needed with regular synthesized human insulin, thus suggesting that L-490 indeed was releasing insulin only as needed.

Merck’s plan for a trial drew little attention outside the type 1 community, as the markets concentrated on other drugs headed for bigger markets sooner. But if smart insulin works it might radically improve treatment not only for the millions with type 1 diabetes but for the substantial group of people with type 2 diabetes who already use insulin among their other therapies.