GlucaPen: The Way Glucagon Ought To Be

I have written about the GlucaPen before, but recently I had the chance to meet with the company, and to see the device in person. As before, I found the GlucaPen to be an obvious solution to an obvious problem—the kind of solution that makes you think, “Well, why didn’t I think of that?”

What’s the problem? The beginning of the problem is the fact that diabetics on insulin—both type 1 and type 2—suffer from hypoglycemia, or low blood glucose levels, due to the difficulties of dosing and predicting the body’s response. If blood glucose levels get too low, a diabetic risks loss of mental acuity, loss of coordination, and loss of consciousness.

Fortunately, there’s a quick, chemical means of increasing blood glucose levels if a diabetic reaches the point of losing self-awareness or becoming unconscious: glucagon. Glucagon is a hormone made by the body that raises blood glucose levels, and a formulation is available from Eli Lilly and Novo Nordisk that can be injected intramuscularly or intravenously.

Unfortunately—and here’s where the obvious problem comes in—the formulations as manufactured and packaged by Lilly and Novo Nordisk are not user-friendly, to say the least.  The current glucagon kits are throwbacks to the Lon Chaney days of Hollywood, something that would be found in the hands of Dr. Frankenstein or the Wolf Man.

And by that I mean, the needle is gigantic, and the procedure is cumbersome. Because the glucagon peptide is very unstable in solution, it is stored in its lyophilized form (that is, as a powder), and the user must mix the glucagon into solution at the time of use.

This mixing process is not that hard in theory, or even in controlled circumstances. However, no one needs glucagon under calm conditions. The person responsible for the mixing and administering is not a professional, or even a diabetic used to daily injections. It’s the diabetic’s poor friend or coworker, freaking out as they try to remember what their now comatose colleague told them about the glucagon. And this person has never given someone an injection in his life, much less with a needle the length of his thumb.

So if we’re lucky, the friend figures it out, administers the glucagon, and everyone turns out okay. If we’re not, the friend uncaps the needle, stabs himself as his shaking hands try to mix the solution with the powder, and passes out.

Okay, that’s perhaps a little bit melodramatic, but—come on, we’ve sent men to the moon! There must be a better way.

Glucagon Kit

Glucagon Kit

And there is. Enter the GlucaPen. Enject, Inc., a biotech start-up, has developed and prototyped a two-chamber glucagon pen designed to automatically mix the glucagon and liquid, and to inject the solution with a simple press of the pen to the patient’s skin. The needle itself is hidden through the whole process, and remains shielded for easier disposal afterwards. The packaging on the pen displays the three easy steps that are necessary to operate the device.

The prototypes are there, the company is ready; what’s the hold up?

Well, in the biotech world, it seems there are three recurring answers to the question, “Why don’t I have one yet?” The first is that there are technical difficulties; that’s not a problem here, as the GlucaPen has been designed and manufacturing procedures are standing in waiting. The parts of pen itself will be manufactured by third-parties, Bachem AG, Vetter Pharma AG and SHL Group.

The second common reason for delay is that the product is waiting for regulatory approval. The GlucaPen has yet to go through the necessary trials to get the desired 505b2 approval from the FDA, but Enject anticipates that the requisite studies will proceed without any technical difficulties. There are two main points they have to prove for the FDA—the first is that their formulation of glucagon, from the Swiss company Bachem, Inc., is bioequivalent to the formulations still on the market. The difference between the GlucaPen’s glucagon and the glucagon currently in glucagon kits is that the GlucaPen uses what’s called synthetic glucagon, rather than recombinant glucagon. The difference between the two is how they’re made– synthetic glucagon is made using a technique called peptide synthesis, in which the desired protein is made in vitro (that is, outside of any living organism) by linking together the desired amino acids. Recombinant glucagon, like recombinant insulin, involves inserting the gene’s DNA into a host bacterium like E. coli and collecting the protein that the bacteria then transcribe.

Practically speaking, there should be very little difference between the two chemicals, and in fact the synthetic formulation of glucagon is used in humans in Japan, but Enject must prove this to the FDA. The first step is to make sure the glucagon is safe; Enject anticipates that the FDA will require only a small animal toxicology study. The second step is to make sure the synthetic glucagon behaves equivalently to the recombinant form in human subjects. For this, Enject plans a clinical trial with 32 non-diabetic adult volunteers. After fasting overnight, the patients will be randomized to receive injections of the Bachem glucagon and Novo Nordisk’s version in turn, a week apart. If the effect of the synthetic glucagon is statistically similar to that of the recombinant glucagon, this should be sufficient to establish bioequivalence.

The second sticking point for the FDA will be CMC—chemistry, manufacturing, and controls. Are the manufacturing processes consistent and error-free? Does each batch of pens come out the same? Here, too, Enject is confident that they will pass with flying colors, and is ready to begin setting up production of there first batch of pens that will serve as the test batch for the FDA.

That, then, brings us to the third reason a product gets held up—cold, hard cash. Enject is ready to take on the FDA, and thinks that regulatory approval is forthcoming; the problem is that the clinical trials and manufacturing approval will take an estimated fifteen million dollars to complete, according to Enject. That sum would get Enject to the point of having 120,000 – 180,000 pens ready for distribution, but raising that sum is no easy task.

Thus far, Enject has raised about four million dollars (a pittance, in the biotech world) from angel investors and private parties, but for the additional 15 million, they will need more substantial funding. They are in ongoing discussions with potential investors and interested parties in the pharmaceutical industry. According the company, the challenges they have to routinely overcome include the misconception  that the current glucagon kits are sufficient, and there is no substantial market opportunity for GlucaPen.

Enject, of course, believes there is a market, and is going a long way to demonstrate that,  commissioning a survey-based study distributed via the internet  to characterize the impacts of severe hypoglycemia according to both patients and caregivers (mostly parents). The study, with survey questions designed in collaboration with Dr. William Polonsky, a well-known figure in the field of diabetes psychology, incorporates the opinions of 655 respondents, 420 of which were diabetic patients.

Notably, the vast majority– 96% of caregivers and 99% of patients– of both patients and caregivers had seen at least one severe hypoglycemic event since diagnosis. Further, a third of caregivers had actually administered a glucagon injection. Many patients and caregivers agreed—86% and 93%, respectively—that glucagon kits were lifesavers.

However, despite the reported use-cases and respect for the glucagon kits, 45% of patients felt that the current kits were “too complicated for my family or friends to use.” And, though that’s less than half of patients, I can’t help but wonder—if 45% of patients have no able responder nearby, the likelihood of a severe hypoglycemic event turning fatal or permanently damaging is greatly increased.

So where does the GlucaPen fit in to that likelihood? Based on pictures and a video demonstration, 93% of caregivers and 77% of patients thought the GlucaPen was an improvement over the current kits, and 98% of caregivers and 90% of patients expressed interest in obtaining at least one pen when they are available.

These figures, though, hide the ebullience and excitement that is visible in patient and caregiver commentary. One caregiver said, “I love it! I have always thought that our current kit would be difficult to deal with in a high stress situation. I would immediately buy one of your new Glucagon pens! Long overdue!” Another, capturing well the anxiety about anxiety that colors my consideration of glucagon, noted, “Absolutely brilliant! Would be much easier for another person to use and I could stop worrying so much!”

The implication, then, is that there is a market for glucagon pens, beyond even the very basic concern that many caregivers, school personnel, and emergency responders feel inadequately prepared to save lives with the current product. The trick for Enject, then, will be convincing investors and strategic partners that this is the case, and then moving the pen through the pipeline into pharmacies.

Will they be able to do it? It looks like the product is ready, the market is ready, and even the regulatory landscape is ready. All that’s left, then, is some business magic— which is to say, some combination of luck, the right handshakes, and favorable financial conditions to bring the GlucaPen to us.

Karmel Allison is ASweetLife’s science editor and a regular contributor.  She writes the blog Where is My Robot Pancreas?

Comments (11)

  1. dejahthoris at

     The rights to Glucapen which was invented by Richard Rylander’s company Enject, was bought by Merck, then Lilly, now the parent company Marcadia Biotech was bought by Roche as of Jan 2011. No matter who you contact regarding it’s production you get no response. This is exactly the same as what is happening with SmartInsulin, developed by Todd Zion of Smartcells then bought out by Merck of a nice chunk of change.  I know of many Type 1 parents who have attempted to contact Merck about SmartInsulin and have gotten NO response. Big pharma buys out these live saving inventions and bury them so they will not cut into their huge profits. 

  2. Daniel at

    dejathoris is incorrect. Enject, the company that is developing GlucaPen is independent and has no relationship with Merck, Lilly or Marcadia Biotech who are developing a glucagon analog which may be suitable for use in artificial pancreas applications. Different product, different companies.

  3. dejahthoris at

    Here are the links that verify all I said. Us parents o type 1 diabetic children follow these developments, of lack thereof. pretty closely:) This refers to the fast acting glucagon pen, not the artificial pancreas.  I do know the difference between a glucagon pen and an intergrated pump and cgm.
    http://www.ibj.com/roche-acquires-marcadia-biotech/PARAMS/article/24299
    http://www.ibj.com/marcadia-enlists-lilly-to-help-develop-new-diabetes-drug/PARAMS/article/20795

  4. dejahthoris at

    OR lack thereof- sorry- trying to get dinner on the table

  5. Leslie at

    This is a LONG time coming.  I HATE the Glucagon needle…like being stuck with a dull pencil.  I have had to give myself a Glucagon injection…not a pretty sight when my blood sugar was 25(yes, I was “awake” and walking.) My family would LOVE this new pen, as it would be easier to give me a Glucagon type injection when I am…lets just say, “argumentative<G>” when my blood sugar is too low.

  6. Sandi at

    We need this!!!  I do hope that funding will come through for this product.  Our daughter is in kindergarten and this would be SO much easier for the school staff to use.  I think of the mom who forgot to mix the glucagon and injected only saline.  Her son died.  This pen would have saved his life.  Not mention, it would be much less bulky to carry around everywhere than the current kits.  I wish I had money to invest in this because I definitely would!

  7. Mark at

    Dejahthoris gave a couple of links that had no bearing on the facts. Enject was and is an independent Company whose shares continue to be owned by its original investors and management. Please show me the press release showing the acquisition of the Company.

    As for the pen – its looking like a really decent innovation. For me it solves the problem of the “insurance premium”. What is the point of life insurance paying for a policy that excludes all the things that are going to kill you? In a glucagon pen you need something you are certain will work – and that can be operated by anyone other than a Fox News viewer.

    This should do the job…

  8. Karmel, I posted a quick note about the GlucaPen on my blog. My wife has had to use a glucagon kit in the past and now just calls 911. Trying to recombine the glucagon while I may be having a seizure on the floor is just too difficult for her. I have no doubt that a GlucaPen would save use time, effort, money and emotional distress.

  9. Natalie ._c- at

    A Type 1 diabetic friend and I had to administer a glucagon shot to another friend once at a meetup. I didn’t actually administer the shot, but had to walk my friend through the preparation steps, because she couldn’t hold the paper and prepare the shot at the same time. She was shaking like a leaf, she was so scared. It doesn’t look so complicated when you’re not under stress, but it’s hella scary when you’ve never done it before, and the language of the pamphlet is not all that readable anyway. We did succeed in doing it, but sometimes I think it was a miracle. This GlucaPen looks like it would be a lot more manageable, even though I never want to be in the position of having to give a glucagon shot again. And I CERTAINLY don’t want to have to do it to myself!

  10. Doug at

    Are you familiar with Xeris Pharmaceuticals?  They are also developing a glucagon pen. 

  11. Lindsay at

    This saddens me. I have almost died several times from low blood sugar. My body does not always process food in a timely manner and sometimes I am left with no food to counterbalance the insulin. My husband administers the glucagon kit and it’s a mess. He does he best. I would very much like to see a product like this, at an affordable price, on the market. It would improve diabetics’ lives around the globe. Keep your heads up, diabetics!

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