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Image courtesy of Zealand Pharma

Up until a few years ago, the only emergency glucagon rescue product available to revive someone having a severe low blood sugar was a complicated mix-and-inject kit with a scary-large needle.

But now, a third new quick and easy, ready-to-use glucagon device has been approved by the Food and Drug Administration (FDA) for sale in the United States.

Regulators gave the green light on March 22, 2021, to Zegalogue, from Denmark-based Zealand Pharma, which will be sold as both an auto-injector (like an EpiPen) and a prefilled syringe.

This makes Zealand the third company since 2019 to get a new easy-to-use glucagon approved, signaling a further shift away from the complicated mix-and-inject kits that have dominated the market for six decades.

In 2019, the FDA approved both Eli Lilly’s nasal glucagon Baqsimi (absorbed into the nasal lining and begins working within minutes), as well as the Gvoke HypoPen auto-injector and prefilled syringe from Chicago-based Xeris Pharmaceuticals. (In December 2020, the FDA also approved the first generic glucagon, but that’s a traditional mix-and-inject form seen more as a price-lowering attempt than innovating on glucagon use.)

The newest Zegalogue product is planned to launch in late June 2021, timed to be available just before the next school season. It too will be ready to use at a moment’s notice if a dangerous low blood sugar emergency occurs.

“There is still a large unmet need in the diabetes community,” said Frank Sanders, CEO of Zealand Pharma U.S. in Boston. “We think Zegalogue is an attractive new option.”

Zegalogue essentially kickstarts the pancreas to release glucagon, which tells the liver and muscle cells to convert stored energy into glucose and release that into the bloodstream to raise sugar levels.

Zegalogue is an analogue for the human hormone glucagon, and that likely shaped the brand name of this compound, scientifically known as dasiglucagon.

For years, Zealand had referred to this product under development as “HypoPal,” but eventually dropped that name. Given the similarity of the product name of the competing HypoPen from Xeris, it’s reasonable to think the FDA might have concerns about a similar name and wanted to avoid confusion by people with diabetes (PWDs), prescribing clinicians, and payers alike.

How does it work?

Both the auto-injector and prefilled syringe forms are one-time doses that can’t be reused, containing 0.6 mg (or 0.6 mL) of liquid glucagon. Zealand plans to sell both versions in single or two-packs.

  • The auto-injector pen comes in a protective red plastic case, and the pen itself has a protective gray cap that you take off before use. You simply press the pen down onto the skin and inject for 10 seconds. Then a clear window turns red to indicate that the glucagon has been fully dosed.
  • The prefilled syringe also comes in a red plastic protective case and it functions the same way as an insulin injection. You take off the protective cap before pinching the skin, injecting the syringe, and pressing the plunger down fully.

(See the FDA-approved product label for more details.)

Can kids and adults both use this?

Zegalogue is labeled for both adults as well as children 6 and older. This is a difference from the Xeris and Lilly glucagon products, both of which can be used for those as young as ages 2 and 4 respectively. Zealand points to market research showing the vast number of PWDs who’d be using glucagon are 6 and older.

How fast does it raise blood sugars?

It starts working within minutes and most PWDs in clinical studies saw their blood glucose levels rising by 20 mg/dL or more within 10 minutes. In the main Phase 3 study with adults, 99 percent recovered from their low blood sugar episode within 15 minutes.

By comparison, it can take 35 to 45 minutes for blood sugars to start responding and rise to safer levels without the use of glucagon.

The study data also shows only a 2-minute median difference between Zealand’s new Zegalogue (10 minutes to action), and the traditional GlucaGen kit made by Novo Nordisk (12 minutes to action).

Does it need to be refrigerated?

Zegalogue lasts for 12 months at room temperature, and it can also be refrigerated for up to 36 months. The company believes this offers flexibility for storage, compared to other existing products that don’t require refrigeration.

Are there side effects?

Anyone who has ever used emergency glucagon is keen to the common side effects: nausea, vomiting, headaches, etc. — that can last up to 48 hours. This is due in large part to the quick spike in glucose levels that cause our bodies to react, rather than a reaction to something inside the particular glucagon product.

In Zegalogue’s three pivotal clinical studies, the most common side effects reported in roughly 2 percent of participants were nausea, vomiting, headache, diarrhea, and injection site pain in adults; and nausea, vomiting, headache, and injection site pain in pediatrics.

Notably, the research did show that that adolescents using the Zealand glucagon compared to a traditional mix-and-inject brand saw more side effects, mainly nausea and vomiting. But that didn’t hold true for younger children or adults, as the side effects were minimal and similar to the traditional glucagon.

How much does Zegalogue cost?

Of course, access and affordability are critical and often determine what products PWDs actually use. Most companies do not disclose their pricing plans at the time of FDA clearance, and this is true for Zealand as well.

The company will say it plans to offer “parity pricing” (on par with competing products) for Zegalogue once it launches in mid-2021. If so, that translates to roughly $280 for a single Zegalogue injector pen, and roughly $561 for a two-pack.

The company also says it will be working with insurers/payers to get coverage and formulary inclusion, and expects “broad coverage” at the time of launch. It also plans to target healthcare providers and schools for promoting Zegalogue.

Like most pharma companies, Zealand says it will also offer copay assistance programs and discount cards to help people afford Zegalogue — both for people without health insurance and also for those with commercial insurance. Details are not yet finalized, but like with other Patient Assistance Programs, eligibility requirements are likely to be strict.

With future products on the horizon aimed at shifting the paradigm in how we think about glucagon overall, Zealand believes it has the potential for a game-changing line of products.

The company is working on some exciting products beyond just this first-generation of Zegalogue rescue pen and syringe.

Mini dosing

Zealand is also developing a multi-use glucagon pen, which could be used not only for emergency situations but also for non-emergencies, offering small doses of glucagon in the event that a PWD’s blood sugars are trending lower and they need a less-dramatic boost. Many PWDs are excited about the potential to use a product like this during exercise in particular.

This is at least a couple years out, as Phase 2 studies are ongoing for a mini-dose version. This is also something Xeris is working on with its Gvoke glucagon, aiming to develop a mini-dosing pen in the coming years.

Using glucagon in an insulin pump

There’s also a lot of buzz about a future iteration of this shelf-stable glucagon that can be used in a dual-hormone delivery device: an insulin pump that can also dose glucagon.

Beta Bionics in Boston is on the forefront of this, developing the much-anticipated iLet Bionic Pancreas system.

Unlike other closed loop (aka artificial pancreas systems) being developed — such as the Tandem Control-IQ, Medtronic Minimed 670G/780G, and Insulet’s Omnipod 5 that adjust basal and bolus insulin amounts — the iLet will deliver both insulin and glucagon to address both high and low blood sugars.

The pump-compatible version of stable glucagon that Zealand’s developing is in Phase 2 trials, and is already being used for investigative clinical studies with the Beta Bionics device. The hope is for that iLet system to get FDA approval by 2023-24.

Zealand believes there’s a strong unmet need in the diabetes community, especially at a time where glucagon use for severe hypoglycemia grew in 2020 by 10 percent, according to the company’s internal research. This is notable, given the lower number of doctor visits and school season being muted due to the pandemic.

Zealand’s Sanders estimates that 4 million PWDs in the United States use multiple daily injections (MDIs), yet Zealand’s market research shows that only 14 percent — or 540,000 people — were prescribed glucagon for severe hypos in 2020.

It’s certainly a win for all to have more and better options to treat severe hypoglycemia. Yet, affordability remains a significant burden that’s not being adequately addressed by our healthcare system at large.