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.
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?