Advancing Diabetes Care: Longer Use FreeStyle Sensor, Nasal Glucagon

Food and Drug Administration recognized potential for a variety of clinical advances in diabetes care including approval of 14-day use of Freestyle Libre CGM sensor, IND trial of new drug to improve vision in severe diabetic retinopathy, and NDA to market nasal glucagon for hypoglycemia rescue.

With Alexander Seibold, MD, Megan Baldwin, PhD, and Larry C. Deeb MD

Popularity of Freestyle Libre CGM May Grow with Extended Sensor Life

The Food and Drug Administration (FDA) has granted Abbott Diabetes Care approval to extend the use of the FreeStyle Libre Flash continuous glucose monitor (CGM) sensor to 14 days of continuous use, increased from 10 days.1 This product has been approved for use in adults (18 years of age or older), replaces the need for fingerstick checks, and requires a prescription. Notice of approval was received on July 23, 2018.

FDA approved extended wear for FreeStyle Libre Flash CGM sensor.

In granting the supplemental request to market this wearable sensor,1 the FDA considered the data sufficient to warrant its use for an additional three days as well as a reduction in warm-up time to only one hour, which is a considerable decrease from the 12 hours that had been required.

The clinical performance was derived from results of a 21-day sensor use pivotal study that required five in-clinic visits after the initial enrollment, a screening visit, and a visit to insert the sensor.2

“All participants wore two sensors simultaneously and paired to its own reader to assess the similarity and therefore the precision of the data,” said Shridhara Alva, PhD, director of clinical affairs at Abbott.

The patient population (mean age 49.7 +/- 16.1) was primarily Caucasian (80%), and 53.7% women (n = 51, and n = 44 men).1 Most of the participants (80%) were diagnosed with type 1 diabetes and only 45.3% were reported to be using an insulin pump. Of note, 34.7% were within a healthy weight range, while the remaining 64.2% were overweight or considered at some stage of obesity.2

Despite the high proportion of Caucasian patients, the findings should be conveyable to all patient types since “the relationship between the glucose in interstitial fluid and whole blood is not expected to be dependent on race,” Dr. Alva told EndocrineWeb.

Benefits from Extended Wearability Promise to Win Over More Patients

Since the functional lifespan of the sensors is of utmost importance to patients, 95 sensors were tested, of which 75.8% lasted the full 14 days, and 90.5% lasted for more than 7 days while 12 sensors failed worked properly for less than 7 days.2

“As a precaution, patients choosing to use the Freestyle Libre should be instructed that the performance of each sensor may vary and that there is a risk that each sensor may perform differently at different times and under different conditions,”    

As for cost, while the company indicated that they are not disclosing the pricing for the 14-day version of the Freestyle Libre at this time, “the ‘per day’ cost will remain in the same range and is significantly lower than competitive CGM systems,” Dr. Alva said.

In addition to cost savings, the possible adverse side effects including localized erythema, irritation, infection, pain or discomfort at the insertion site are reduced by the extended days of use.

During the American Diabetes Association 2018 annual meeting, cost model data from a  prospective trial were presented, indicating significant savings with the FreeStyle Libre system (10-day use) in the U.S. as compared with routine self-monitoring of blood glucose.2 The results indicated that patients testing their glucose six times per day with FreeStyle Libre system could save more than $120 a month compared to the cost of six test strips per day,3 according to Alexander Seibold, MD, medical affairs director at Abbott Diabetes Care based in Germany.

“This has the potential to increase to $290 a month for people testing 10 times per day, which is in line with the ADA recommendation for testing blood glucose up to six to ten times daily for some populations.”

In addition to expected cost savings, the possible adverse side effects including localized erythema, irritation, infection, pain or discomfort at the insertion site would be lessened by the extended days of sensor use.

According to the FDA,1 the approval was limited to changes in wear time, duration of the blinded warm-up period, a new brand name, and an updated algorithm in the reader software.

Investigational New Drug Promises Improved Vision for Severe Diabetic Neuropathy

Opthea Limited, a biopharmaceutical company based in Australia focused on developing novel biologic therapies to treat ocular diseases, has begun enrolling patients in a Phase 2a randomized, controlled clinical trial to evaluate the safety and efficacy of OPT-302 in patients with persistent center-involved diabetic macular edema (DME).4

Of the estimated 100 million Americans with a diagnosis of diabetes in the US as of 2017, according to the Centers for Disease Control and Prevention, at least one-third of them has developed diabetic retinopathy with 30% of this group having the severest form, including DME, which potentiates complete loss of vision.5

A soluble form of VEGFR-3 may restore vision in patients with diabetic macular edema.

The Phase 2a trial has been granted Food and Drug Administration approval under the Investigational New Drug program for trialing in adult patients with both type 1 diabetes and type 2 diabetes.4

The aim of the multicenter—20 sites across the United States and six sites in Australia—masked trial is to enroll 108 individuals (at least 18 years of age) with a diagnosis of persistent or recurrent central-involved macular edema who responded poorly to prior anti-vascular endothelial growth factor receptor (VEGFR) therapy. These patients will receive treatment in a 2:1 ratio with a combination therapy of OPT-302 (2 mg) and aflibercept (Eylea) or aflibercept monotherapy, administered once monthly for three months.4

This next phase of the trial was initiated following results of a Phase 1b dose escalation safety review in people diagnosed with DME. OPT-302 was administered by intravitreal injection at three escalating doses (0.3 mg, 1 mg, 2 mg) in combination with aflibercept, all doses were well-tolerated with no reported dose-limiting toxicities or treatment-related ocular or systemic adverse events.4 Results are expected in the second half of 2019, according to the company.

What Do Clinicians Need to Know about Treating Severe Vision Loss in Diabetics

“Of particular interest to clinicians caring for people with diabetes who have been diagnosed with DME may be the potential of OTP-302 to improve their visual acuity,” Megan Baldwin, PhD, chief executive officer, and managing director told EndocrineWeb.

“Chronically elevated blood glucose levels in both type 1 and type 2 diabetics can lead to inflammation, vascular dysfunction, and hypoxia, causing upregulation of the VEGF family of growth factors. VEGFs, including VEGF-A and VEGF-C, stimulate vascular permeability, leading to fluid accumulation in the macula at the back of the eye and retinal thickening that adversely affects vision,” she said. 

“Existing standard of care treatments for DME have been limited to inhibitors of VEGF-A (aflibercept, ranibizumab), steroids and laser therapy. Despite these treatments, many patients remain refractory and have a sub-optimal response to therapy with persistent fluid and impaired vision,” said Dr. Baldwin, “OPT-302, a blocks VEGF-C and VEGF-D, which stimulate vessels to grow and leak. Used in combination with a VEGF-A inhibitor, OPT-302 has the potential to improve clinical outcomes in diabetic patients with DME (as well as wet AMD).”

OPT-302 is a soluble form of VEGFR-3 or ‘trap’ molecule that works by blocking the activity of two proteins, VEGF-C and VEGF-D, responsible for blood vessel growth and processes that contribute to the pathophysiology of retinal diseases.

It is being developed for use in combination with inhibitors of VEGF-A inhibitor (eg, Lucentis/Eylea) and is expected to deliver more complete growth factor blockade, achieving near complete preservation of vision through the inhibition of disease progression along the pathways involved diabetic macular edema.

“We anticipate that Opt-302 would be used long-term, similar to that of existing VEGF therapies, which are administered by intravitreal injection to the eye every four to eight weeks,” said Dr. Baldwin.

Lilly Seeks FDA Approval for Nasal Glucagon Rescue

A new drug application was submitted to the FDA for investigational nasal glucagon delivered by nasal spray for the treatment of severe low blood sugar in adults and pediatric patients with diabetes, according to an announcement issued by Eli Lilly. A similar marketing authorization application was simultaneously submitted to the European Medicines Agency.

FDA reviewing new drug application for rescue glucagon administrated as nasal spray.

If granted, this form of glucagon would be the first nasal dry powder spray administration for rescue during a hypoglycemic emergency in people with diabetes.

The basis of these applications was supported by data from two phase 3 multicenter studies,6,7. The first, published in Pediatric Diabetes,x was initiated to assess real-world efficacy and ease of use in children (n=14) with type 1 diabetes while at home.

“My coordinator spent 15 to 20 minutes with caregivers, demonstrating the proper use of the device,” said Larry C. Deeb MD, a pediatric endocrinologist at Tallahassee Memorial Healthcare in Florida who led the pediatric study. “When a child’s glucose fell below 60 or reported feeling really low, the caregiver used the device and then documented the glucose before and at specific times afterward. The goal of this trial was to capture data on up to four events per patient.” 

“However, not all [patients] had four events and some stopped early because of burning in the nose. To complete the study in a timely fashion, we didn't wait for unconsciousness and ethically couldn't ask people not to rescue children when they complained of lows so the decision to treat when the patient felt low or was documented as falling into the 50's,” Dr. Deeb told EndocrineWeb.

"Following administration of the nasal glucagon, blood sugar levels in all patients returned to normal within 15 minutes to a maximum of 30 minutes.x  “It took about 3 months to gather sufficient data to satisfy the requirements set forth by the FDA,” he said.

Of the 60.6%  hypoglycemic events, caregivers were able to administer the trial treatment within 30 seconds of need with no serious adverse events and for nearly all (93.9%) hypoglycemic events, caregivers indicated that the nasal glucagon was easy to administer. There were no serious adverse events reported, and none of the children required oral carbohydrates to boost blood sugar levels, nor emergency department care.6

“Clearly it works and even for the patients who decided to stop after fewer than 4 events, they reported being happy with something available and easier to use since in a real emergency with severe hypoglycemia,” said Dr. Deeb. “Parents universally felt it was far easier to use than having to remember how to mix and give a shot.

Similar findings were reported in a prospective, open-label real-world study of adults across nine centers in 2014-2015.7

This nasal glucagon product, if approved, would provide the first innovative solution to manage severe hypoglycemia in the form of a needle-free, user-friendly, one-time application with no preparation needed to administer it, said Dr. Deeb.

These submissions offer promise for an innovative rescue treatment that addresses an important need: ease of use and quick to deliver for worrisome low blood sugar events in people with diabetes, as such Lilly is in the final stages of development for nasal glucagon and is ensuring manufacturing capabilities are in place to distribute nasal glucagon, if approved, according to the company.

 

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