Post-Bariatric Hypoglycemia Treatment Research by Xeris

Severe hypoglycemia and seizures are both serious conditions that require rapid interventions, yet current treatments are burdensome. We're ready to change that.

Severe Hypoglycemia

Xeris makes medications to successfully treat severe hypoglycemia with confidence and peace of mind

Hypoglycemia occurs when a person experiences an abnormally low blood sugar level. Hypoglycemia is a daily concern for persons with diabetes and their caregivers.

If hypoglycemia is not adequately treated, then it can progress towards severe hypoglycemia. Severe hypoglycemia is an emergency condition where very low blood sugar may lead to confusion, seizure, unconsciousness, and if left untreated, death. Severe hypoglycemia requires immediate treatment with fast-acting carbohydrates or the use of glucagon.

Glucagon is a drug that requires multiple steps in order to prepare and administer successfully. Thus, during emergency situations it is difficult for someone who experiences severe hypoglycemia to receive a full dose of glucagon. Xeris is dedicated to developing tools, for persons with diabetes and their caregivers, that simplify the administration and provide a full dose of glucagon—to immediately and successfully treat severe hypoglycemia.

Using our patented XeriSol technology, Xeris is developing a ready-to-use, room-temperature–stable, liquid glucagon inside a single-use auto-injector pen in 2 premeasured doses (0.5 mg and 1 mg). The needle in the single-use auto-injector pen retracts and autolocks after use and is not visible at any point in the administration process.

 

Severe hypoglycemia can have serious consequences and requires immediate treatment

What is hypoglycemia?

Hypoglycemia is a condition defined by an abnormally low blood sugar level in the body. Hypoglycemia of any severity is a daily concern for people with diabetes. The fear of having hypoglycemia is a critical impediment to good psychological well-being and quality of life for persons with diabetes and their caregivers, and it represents a major barrier to the control of normal blood sugar.

Who is at risk?

Persons with type 1 and type 2 diabetes who are treated with insulin are at the highest risk of experiencing hypoglycemia.

How is it categorized?

Hypoglycemia is categorized by level of severity—expressed as mild, moderate, or severe hypoglycemia.

How often does it occur?

Mild or moderate hypoglycemia can occur multiple times a month, while severe hypoglycemic events can occur multiple times a year.

What are the symptoms?

Signs of mild or moderate hypoglycemia often include confusion, irritability, anxiety, feeling shaky, sweating, chills, dizziness, and a rapid heartbeat.

Severe hypoglycemia is characterized by confusion, drowsiness, odd behavior, speech difficulty, and incoordination. It can progress to seizure, unconsciousness, irreversible brain damage, and if left untreated, death.

How is it treated?

Mild or moderate hypoglycemic events can generally be addressed by consuming carbohydrates, such as orange juice.

Severe hypoglycemia is an emergency that requires immediate external assistance from a family member, friend, or coworker. Successful treatment of severe hypoglycemia includes fast-acting carbohydrates (eg, sugar pills) or the use of glucagon.

Glucagon is a drug that works to immediately raise the blood glucose levels in a person’s blood by causing the liver to convert glycogen, a type of stored sugar in the body, into glucose. According to the ADA, glucagon should be prescribed for all individuals who are at increased risk of severe hypoglycemia. During an episode of severe hypoglycemia, a full dose of glucagon should be administered by a caregiver or other individual whenever a person with diabetes:

  1. Is unable to safely take carbohydrates by mouth
  2. Is unwilling to take carbohydrates by mouth, as when an individual is combative or confused
  3. Is unresponsive and needs assistance (eg, seizure or unconscious)

What are the health consequences if severe hypoglycemia is not promptly and effectively treated?

Severe hypoglycemia is characterized by confusion, drowsiness, odd behavior, speech difficulty, and incoordination. It can progress to seizure, unconsciousness, irreversible brain damage, and if left untreated, death.

Post-Bariatric Hypoglycemia (PBH)

Xeris is working to offer patients relief from PBH

While bariatric surgery can offer various health benefits, it also carries some risks. Among them is PBH, which can result in recurrent episodes of severe hypoglycemia after meals.

Xeris is currently investigating the use of glucagon administration (given after a meal) to address PBH. These investigations are intended to support the use of a stable, liquid glucagon formulation as a new approach to address PBH.

 

PBH can be an unintended consequence of bariatric surgery

What is bariatric surgery?

Bariatric surgery is a highly effective treatment for morbid obesity, resulting in significant weight loss and normalizing obesity-related illnesses. In the US alone, approximately 200,000 bariatric procedures are performed each year. Despite the benefits, there are associated long-term risks that include PBH.

What is PBH?

PBH is a potentially life-threatening complication of bariatric surgery that is characterized by severe hypoglycemia. Typical onset is 1-8 years after the surgery, and it tends to occur 2-3 hours after a meal. This severe hypoglycemia is most likely related to an excessive increase in insulin in response to eating meals.

How is PBH treated?

Once diagnosed, the goal of PBH treatment is to reduce the frequency and severity of the hypoglycemic events. Approaches such as strict dietary management (carbohydrate restriction) and medications (that reduce surges in glucose) provide improvement to most patients. However, a small subset of patients can still experience recurrent, severe hypoglycemic episodes after meals.

Congenital Hyperinsulinism (CHI)

Xeris is working to make the use of glucagon possible for babies and children with CHI

Glucagon is well described for the acute management of severe hypoglycemia. There is considerable interest in the research community for the use of long-term glucagon administration to help normalize the blood sugar levels of patients with CHI. These investigations are intended to support the use of a stable, liquid glucagon formulation for continuous infusion to treat the chronic and severe hypoglycemia associated with CHI.

 

CHI can create a challenging start to life

What is CHI?

CHI is a very rare disease that causes severe, persistent hypoglycemia in newborn babies and children. In most countries, it occurs in approximately 1/25,000 to 1/50,000 births. About 60% of patients with CHI are diagnosed within the first month of life, with most patients diagnosed within the first year of life.

What are the typical symptoms?

Common symptoms include irritability, sleepiness, lethargy, excessive hunger, and rapid heart rate. More severe symptoms such as seizures and unconsciousness can occur with prolonged or extremely low blood sugar levels.

What are the health risks associated with CHI?

The recurrent and chronic episodes of severe hypoglycemia expose babies and children with CHI to a very high risk of constant seizures that may lead to severe and irreversible brain damage. Many children with CHI do not live to adulthood.

Hypoglycemia in CHI occurs frequently. Therefore, babies and children with CHI require constant care and vigilance by their caregivers, to maintain normal blood sugar levels and to rapidly and adequately address hypoglycemic events.

How is CHI treated?

Treatments to elevate the blood sugar to normal levels range from oral medications, continuous glucose infusion, and diet management, to surgical procedures such as partial or complete removal of the pancreas. Glucagon treatment to reduce glucose requirements and normalize blood sugar has been performed successfully in CHI, within a hospital setting.

Hypoglycemia-Associated Autonomic Failure (HAAF)

Xeris aims to help patients with HAAF

HAAF is a serious condition where persons with diabetes do not experience the physical symptoms of low blood sugar (hypoglycemia awareness); they are at increased risk for hypoglycemia that worsens to severe hypoglycemia. The restoration of hypoglycemia awareness is important in the self-treatment of low blood sugar, and to prevent severe hypoglycemia. Recent research suggests that this hypoglycemia awareness is restored when blood sugar is kept within normal range for an extended period of time.

Xeris is developing continuous-infusion glucagon to help maintain blood sugar within normal range and minimize hypoglycemia for extended periods of time. These investigations are intended to support the use of a stable, liquid glucagon formulation to help treat HAAF by restoring the patients' hypoglycemia awareness.

 

The silent nature of HAAF makes it very dangerous

What is HAAF?

With recurrent episodes of chronic hypoglycemia, persons with diabetes lose hypoglycemia awareness—the physical symptoms of low blood sugar such as sweating, palpitations, and hunger. This serious condition is called hypoglycemia-associated autonomic failure, or HAAF. Persons with diabetes who have HAAF are at increased risk for severe hypoglycemia.

What causes HAAF?

Hypoglycemia is an everyday risk for persons with diabetes. HAAF occurs when recurrent episodes of hypoglycemia desensitize the body's nervous system to hypoglycemia. There are insufficient physical (autonomic) symptoms of hypoglycemia such as anxiety, sweating, and palpitations. Thus, persons with diabetes with HAAF lose hypoglycemia awareness.

What are the risks of HAAF?

HAAF contributes a significant risk for persons with diabetes to develop severe hypoglycemia. Severe hypoglycemia can lead to seizure, unconsciousness, irreversible brain damage, and if left untreated, death.

Exercise-Induced Hypoglycemia

Xeris believes that pragmatic approaches to exercise-induced hypoglycemia are possible

Xeris is currently investigating the use of intermittent glucagon administration (given prior to exercise) as a treatment option to reduce the risk of hypoglycemia during continuous exercise. These investigations are intended to support the use of a stable, liquid glucagon formulation as a new approach to address the barriers associated with exercise-induced hypoglycemia.

 

Fear of hypoglycemia and lack of options are significant barriers to exercise

Why is exercise important for persons with diabetes?

Physical activity (exercise) is a cornerstone for effective diabetes management. Physical activity for persons of all ages living with diabetes is associated with many well-established health benefits, including improved glucose control, improved cardiovascular fitness, better bone health, and enhanced psychological well-being.

Although there are many obstacles to safe and effective exercise participation, persons with diabetes should become and remain physically active to improve their overall health and reduce the impact of diabetes.

What are some obstacles to safe exercise for persons with diabetes?

The American Diabetes Association recommends at least 150 minutes of moderate exercise per week. Many persons with diabetes participate less frequently than these recommendations because of their concerns that continued exercise may lower their blood sugar to dangerously low levels. Although there are various reasons for limited physical activity, the significant barriers to increasing physical activity in persons with diabetes appear to be:

  1. The fear of hypoglycemia
  2. A lack of awareness regarding effective strategies to avoid hypoglycemia
  3. A limited variety of treatment options that reduce the risk of hypoglycemia during continued exercise

Acute Repetitive Seizures (ARS)

Xeris believes that ready-to-use diazepam is a critical need for the treatment of ARS

For people with ARS, immediate delivery of rescue treatment is needed to stop the seizure.

Current treatment approaches include benzodiazepine drugs such as diazepam rectal gel. However, the rectal administration of diazepam gel is considered cumbersome and problematic by many patients and their caregivers. Thus, new routes of administration for diazepam rescue therapies are desired.

New routes of administration for diazepam are being researched, such as the intranasal and buccal routes. Xeris investigations are intended to support the use of diazepam within a ready-to-use, single-use auto-injector to treat ARS.

 

ARS is a serious condition that requires immediate medical attention

What is epilepsy?

Epilepsy is diagnosed when a person has had at least 1 or more unprovoked seizures.

How common is epilepsy?

Worldwide, it is estimated that 50 million people have epilepsy. Epilepsy is the fourth most common neurological problem in the US. Every year, an additional 2.5 million people worldwide and 150,000 people in the US are diagnosed with this condition.

What is ARS?

ARS is a condition where a person with epilepsy experiences >3 seizure episodes within a 24-hour period and is observed in approximately 3% of the epilepsy population. ARS tends to occur most often in very young (0-4 years) pediatric patients, approximately 5.9 per 10,000 of the general pediatric population. It is different from status epilepticus (SE) because ARS patients recover between seizure episodes.

What are the risks of ARS?

Although the population of ARS patients is relatively small, people with ARS are at risk for serious medical complications like self-injury, SE, and permanent brain damage. People with ARS may require frequent emergency room visits and possible hospital admissions.

How is ARS managed?

Optimal management of ARS begins immediately upon seizure recognition where treatment is delivered immediately by a caregiver before emergency healthcare professionals can arrive.

Type 1/Type 2 Blood Sugar Control

Xeris believes that a pramlintide-insulin coformulation can become readily available

Pramlintide is the drug that resembles amylin, a human hormone that slows the absorption of carbohydrates through its effects on stomach emptying. Pramlintide administration mimics the human body's natural interaction between insulin and amylin to regulate normal blood sugar levels with meals.

Xeris is currently developing a ready-to-use pramlintide-insulin coformulation to help maintain normal blood sugar levels of patients with type 1 or type 2 diabetes after a meal.

Other investigations are intended to support the easier administration of pramlintide within a pump device, both as an intermittent and continuous infusion.

 

Pramlintide is an important partner to insulin, but current formulations require additional multiple injections

What is amylin?

Amylin is a hormone that works alongside insulin to efficiently maintain blood sugar levels within normal range. Amylin slows the emptying of the stomach during meals, and thus slows the absorption of sugars during meals.

Why do persons with diabetes have a problem with amylin levels?

Persons with diabetes may have a significant loss of pancreatic cells, which release both amylin and insulin. This leads to a deficiency of both hormones. Amylin secretion, in response to meals, is also delayed in persons with diabetes.

How are low amylin levels treated with pramlintide?

Pramlintide is an injectable drug that closely resembles amylin. Many clinical studies that treat patients with a combination of pramlintide and insulin have demonstrated improved control of blood sugar, lower hemoglobin A1c, and better patient satisfaction and well-being.

What are some limitations of pramlintide therapy?

The benefits of pramlintide are well-known. However, it is burdensome for persons with diabetes to begin and continue daily pramlintide therapy because of the required additional multiple injections, and many stop pramlintide within the first few months. Other reasons include queasiness and vomiting, and the burden to tailor the individual insulin and pramlintide doses over time.

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