The Promise of More Effective Inhaled Endocrine-Focused Therapeutics

Next Generation Soft-Mist Inhaled human Insulin and GLP-1RA are advancing for treatment of diabetes, and other hormone therapies are just beginning development.

with Mustafa Noor, MD

Keeping up with the pace of antidiabetes therapeutics that aim to address much more than blood glucose control has become a near daily challenge. The most recent breakthrough has come from the inhaled insulins that offers several advantages: it allows for antidiabetes medications to be taken with meals, rather than needing to anticipate injecting insulin 15-20 minutes ahead of eating. Also, since inhaled insulin clears out of the bloodstream quicker, the risk of postprandial hypoglycemia is reduced.1 And there is now research indicating the benefits in next-generation inhaled therapies.2-5

“Focusing on next-generation inhaled therapy will enable us to expand beyond insulin to bring hormones, peptides, and proteins that are not yet capable of being delivered via inhalation with state-of-the-art technology that will replace injections, starting with improvements to the current inhalation insulin products for type 1 and type 2 diabetes,” said Mustafa Noor, MD, a clinical endocrinologist and consultant in clinical development to Aerami Therapeutics (formerly Dance Pharma), “and ultimately, expanding into an array of endocrine-related treatments.”

Preview of 2nd Generation Advanced Inhaled Therapeutics

Unlike currently approved oral antidiabetes medications that must travel to the stomach, get broken down and absorbed, inhaled therapies allow for a more rapid onset of action. In addition, first-generation inhaled insulin products have been able to lessen timing of delivery to meals, more closely matching individual physiological needs.1

The expectation of mealtime onset-of-action is very relevant for patients who will do best when they can take their insulin at mealtimes, in sync with hunger. This is a very important enhancement to antidiabetes medications.

The currently approved and air-expelled inhaled insulin therapies rely on carrier molecules to stabilize the solution to achieve the capability for the microparticles to enter the airways via inhaled insulin delivery, Dr. Noor told EndocrineWeb. While there are many benefits to the inhaled insulin products, there are issues with the first-generation product which introduces a preservative into the lungs, presenting expected risks associated with intolerances such as coughing and wheezing. These adverse effects arise acutely and raises the possibility of reduced lung function over the long-term.

“With these factors in mind, we are now ready to create a therapeutic administration that obviates the need for injections and matches administration to food intake. We forsee next generation inhaled antidiabetes medications (first with human insulin and eventually, a GLP-1RA,) that will be more predictable and available on-demand,” he said.

Obesity management also has been an integral action profile of exenatide, a GLP1-RA, given its proven reduction in blood sugar, especially post-prandial glucose management, and ability to stimulate weight loss.6

One puff of an inhaled GLP-1 agonist with meals, for example, will suppress the patient’s appetite, improve satiety, and lessen food cravings, all of which are anticipated to lead to better blood glucose time-in-range, Dr. Noor said. “This, in turn, will help patients avoid overeating.” 

Moving Toward Soft-Mist Inhaled Endocrine Therapeutics
The next technological advance aims to improve drug bioavailability and efficacy compared to the current once daily or even once-weekly injectable and oral insulin therapeutics. “To achieve this, we aim to bypass the use of a chemical bond to transport the desired therapeutic, replacing the first-generation drugs with a stable liquid formulation, starting with human insulin delivered as a soft-mist,” said Dr. Noor. “The technology essentially employs a naturally-occurring excipient to permit better short- and long-term action.”

The most advanced program in Aerami’s pipeline is the next generation “soft mist” inhalable fast-acting, preservative-free, human insulin formulation, particularly for patients with type 1 diabetes and type 2 diabetes. Having recently completed phase 2 studies in patients with both types of diabetes,2-5 findings from these short-term trials have been favorable supporting our readiness to initiate a phase 3 study to demonstrate efficacy, according to Dr. Noor.

“The second generation inhaled human insulin demonstrated faster onset and greater action in the first hour of administration compared to subcutaneous insulin lispro, with good tolerability in patients with diabetes. Not only does this allow for the insulin inhaled formulation to be administered shortly before meals, but the ease of use could potentially motivate more patients to better comply with standard medical guidance,” Dr. Noor said.

“In effect, we have created a vibrating mesh—utilizes nanotechnology —that enables peptides, for example, to be administered through a fine-mist, low velocity aerosol that is ideal for deep lung delivery,” he said, pointing to the favorable phase 2 trial results achieved in patients with diabetes.2,3  

“We are advancy the inhaled technology to meet the needs of patients with type 2 diabetes by employing a GLP-1RA delivered by inhalation to improve upon the currently available insulin products that not only achieves superior postprandial glucose control but will avoid undesirabe gastrointestinal effects common to these oral and injectable medications," Dr. Noor told EndocrineWeb. "In doing so, its short-acting drug delivery will be enhanced—achieving the desired effect of mealtime appetite suppression that, in turn, will lessen the potential for overeating, and thereby providing better diet control, effecting caloric intake, blood sugar control, and weight loss,” 

Would Inhaled Insulin Therapy Be Effective in Diabetes Preventive?   
The future holds significant potential for lots of beneficial applications, including diabetes prevention, However, Dr. Noor said, a patient-specific risk/benefit analysis will be necessary to account for considerations of possible nausea and vomiting—the most common side effects of the GLP-1 analog drug class—against the effects on appetite, and weight.

These factors would need to be balanced against tolerance and adherence since the clinical trials for current injectable and oral formulations of GLP-1RAs have shown a 15-20% drop out rate by the end of year one,6 and is likely higher in real world use. In addition, existing GLP-1 agnoists carry an FDA label warning for rare events such as pancreatitis and even rarer, medullary thyroid cancer, which will need to be considered and discussed with the patient.

“While there is certainly a good scientific rationale to consider this type of therapy in people with obesity and/or prediabetes, the need for a clinical trial will require a significant commitment and so will likely gain consideration in the post-marketing phase as we look to expand down the line,” Dr. Noor said. In the meantime, there is certainly room for off-label investigational use in appropriate patients by clinicians with sufficient familiarity with this class of drugs when looking to personalize disease management.

As such, any expanded indications— prevention and remission of type 2 diabetes—for use of the next generation inhaled GLP-1RA will come in the post-approval phase, once the product is on the market, when there will be time and a stronger rationale to further evaluate uses for this therapy, he said.

When Can We Expect to See the First Such Advanced Inhalation Therapy?
“Since we are starting with a medication that is already approved, we are moving to gather the data to demonstrate the ability of inhaled diabetes medications to meet the needs of specific patients who may benefit from the rapid onset of action as well as for other reason such as in those who do not wish to take medications by injection or prefer the appeal of convenience and timing. The potential is great!” Dr. Noor said.

The company is supporting two new pipeline programs focused on the development of novel soft mist inhalable formulations of biologics for people living with chronic diseases. In addition to its inhaled human insulin and an improved GLP-1 treatment for type 2 diabetes, there is preclinical work underway on an inhaled parathyroid hormone derivative for hypoparathyroidism, and a human growth hormone for growth hormone deficiency.7

Extended Use of Inhaled Insulin in Type 1 Diabetes Management

Inhaled technosphere insulin (Afrezza), may be used effectively for touch-up dosing as well as  as an alternative to mealtime insulin injections,8,9 based on outcomes of the STAT trial.

One of the most important findings was a net gain of two hours additional time-in-range among patients who used only inhaled insulin in order to reduce blood glucose that remained high one and two hours post-prandially.

The efficacy of these add-on doses (ie, a second or third inhalation when blood glucose remained elevated following meals) was attributed to the near immediate action of this insulin form of delivery,8,9 according to Mark Harmel, MPH, CDE, a research coordinator for the TrialNet studies at the University of Southern California Westside Center for Diabetes in Beverly Hills, California.

The benefit of inhaled insulin appears to reduce the risk of insulin “stacking”—when a patient takes multiple doses of rapid-acting insulin in quick succession, which has a tendency to increase the risk of hypoglycemia.

When training patients to correctly employ touch-up dosing, he recommended the following protocol:

  • One hour post-prandially—Take a 4-unit “hit” when blood glucose is between 150 - 200 mg/dl, and take an 8-unit “hit” if the blood sugar is above 200 mg/dl.
  • At two-hours following a meal—Take another correction dose of four units if blood glucose remains > 201 mg/dl and has not dropped at least 50 mg/dl between 1- and 2-hours.

And for patients who complain of coughing and wheezing, Mr. Harmel suggested advising patients to take a sip of water before using the insulin inhaler and/or to take slower inhalations (ie, breathing in without making any noise).

New Treatment Approved for Diabetic Kidney Disease and Heart Failure

The Food and Drug Administration approved canagliflozin (INVOKANA) as the only therapeutic medication in patients with type 2 diabetes (T2D) management indicated to treat chronic kidney disease as well as to reduce the risk of heart failure.10  This decision was made following review of data from the CREDENCE trial,11 which demonstrated a significant reduction in major cardiovascular events and kidney failure in in patients with diabetes and kidney disease.

This is the first drug to gain an indication to slow the progression of chronic kidney disease in individuals with diabetes in over 20 years. Having a new therapy is significant given that an estimated one in three individuals with T2D is likely to develop kidney disease.

Continue Reading:
Reducing Risk of Chronic Kidney Disease Achievable in Patients with Diabetes
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