Similar to a class of compounds known as incretins (which includes glucagon-like peptide-1 (GLP-1)) Byetta is thought to exert its action by enhancing pancreatic beta-cell insulin secretion, suppression of elevated glucagon secretion, and the slowing of gastric emptying.  In all three pivotal clinical trials supporting Byetta’s original approval body weight decreased at Week 30 in the 10 mcg treatment groups.   We reviewed a 2008 Lancet article by Drucker et al involving 295 patients with type 2 diabetes which demonstrated that exenatide once weekly performed better in terms of glycemic control than exenatide twice daily over a 30 wk period with no increased risk of hypoglycemia.

Byetta, a first in class therapy,  was approved in 2005 and was originally used as an adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sufonylurea, or some combination of the two and have not achieved adequate blood sugar control.  In 2009 Byetta’ s indication was expanded to include its use as a stand alone or monotherapy in addition to diet and exercise to improve blood sugar control in Type 2 diabetes.  Since the drug’s approval, safety concerns have arisen around the risk of  acute pancreatitis with complications, including death and altered kidney function associated with Byetta use. 

CDC data suggest that more than 1 000 000 Americans are diagnosed with diabetes annually and that there are in excess of 14 000 000 Americans currently afflicted with the disease. It is estimated that about 5 000 000 diabetics require daily insulin injections to control their blood sugars. Complications commonly associated with uncontrolled or poorly controlled diabetes include heart disease, stroke, kidney failure and blindness. Diabetes and its complications may account for more than $100 billion annually in healthcare costs in the United States.

At the risk of stating the obvious – we believe that if exenatide once weekly recieves FDA approval, simplification of the exenatide dosing regimen from twice daily to once weekly would be seen as very favourable by patients and physicians alike. 

Thanks for reading.

For those who are unfamiliar with the Exubera story, Pfizer received approval for Exubera(R)(insulin human (rDNA origin) Inhalation Powder) in January 2006.  As the first approved alternative to injectable insulin,  many thought this would represent a milestone in diabetes care destined to take a prominent  place in the diabetes therapeutic armamentarium.  Things did not turn out this way at all. In October of 2007 Pfizer announced that it was ending production, citing Exubera’s failure to gain acceptance with physicians and patients. 

It would be easy to dismiss any inhaled insulin product in the wake of a  failure  of this magnitude (apparently Pfizer took a 2.8 billion dollar charge as a result of the discontinued Exubera progam). However, developing a sound analytical approach to AFREZZA(TM) should be very informative and allow for an objective assessment of its chances for success. 

At BioHorizon, we are emerging health technology-focused. What follows is a list of questions that we have put together that could help to inform your analytical approach to this drug:

1. Does AFREZZA represent true innovation?  Is it a first in class therapy, a me-too drug, or something in between? 

2. Does it work?  In this case we are talking about glycemic control – do patients who take AFREZZA experience better, worse, or similar control of their blood glucose compared to insulin injection? 

3. What is the epidemiology of diabetes? In other words, how many new cases,  and how many exisiting cases are there in North America? This helps us to understand demand for diabetes treatment.  What about the clinical epidemiology?  The clinical epidemiology sheds light on how diabetics are treated and tells us about outcomes.  This information helps us to establish whether or not there is an unmet medical need and gives us an idea as to where would AFREZZA fit in diabetes treatment protocols. 

We ask these three very important questions because we believe that innovative drugs that meet unmet medical needs for highly prevalent conditions change the practice of medicine for the diseases they target. So-called ‘copycat’ therapies that offer incremental or no benefit seldom have the same impact.  Answering these questions will give you much needed insight into where AFREZZA sits along this spectrum.

There are two other questions that come to light specifically after examining the Exubera(R) experience. 

4. Will patients be required to commit to ongoing pulmonary (lung) function tests once AFREZZA therapy is started?  This was the case with Exubera and is felt by some to have been a disincentive to both patients and physicians. 

5. Will cost, dosing and inhaler use be acceptable to insurers, patients and physicians?  Cost and coverage questions dominate the discussion around medical innovation in this day and age, so having some sense of where insurers stand concerning AFREZZA is important.  With Exubera the inhaler was considered large and cumbersome by certain standards and patient and physician feedback indicated that dosing may have been too complicated.  Cost, ease of administration and simplicity of dosing changes are important to diabetic patients and physicians contemplating  a change in insulin regimens. Do not underestimate these factors in your analysis. 

Of course some of these questions will remain unanswered, but we believe that the use of  this approach will allow you  to establish some important objective parameters and in doing so,  help you make better decisions concerning this emerging health technology.

Let us know what you think, and how this approach helped or didn’t help your analysis.  Thanks.

BioHorizon

Clinical Presentations
Streptococcus pneumoniae causes acute bacterial infections. Also referred to as the pneumococcus bacteria, it was first isolated by Pasteur in 1881. Prior to the introduction of Prevnar, this bacteria was the most common cause of invasive bacterial infections and acute otitis media (middle ear infections) in North America. Sinusitis, pneumonia, and conjunctivitis are all commonly caused by S. pneumoniae and it remains one of the two most common causes of bacterial meningitis in infants and young children.
Invasive pneumococcal disease (IPD) is defined as the isolation of S. pneumonieae from a normally sterile site (CSF, blood, joint fluid, etc.). For example, bacteremia and meningitis are examples of IPD while otitis media and conjunctivitis are not.

Epidemiology
Pneumococci commonly colonize the upper respiratory tract of adults and children. Bacteria are spread person to person by contact with respiratory droplets. Within one month of acquiring the bacteria in the upper respiratory tract about 15% of children will develop disease. Infections are more common in winter months and certain populations are at higher risk including infants, young children, the elderly, black, Alaskan Native and some American Indian populations. Individuals with congenital or acquired immunodeficiency, absent or diminished splenic function, cochlear implants, and a number of other chronic conditions are at increased risk of disease as well. Since Prevnar’s introduction in the United States in 2000 the incidence of all invasive pneumococcal infections has decreased by 80% in children less than 2 years of age, and by 90% for those serotypes included in Prevnar. Corresponding decreases have also occurred in older children and adults as well, possibly due to the interruption of transmission from infants and young children to these older contacts. It should be noted that an increase in incidence of disease caused by serotypes not contained in Prevnar has occurred in some areas.

This overview of clinical presentations and epidemiology is helpful background to those trying to understand the potential impact of a new generation of pneumococcal vaccines, however, greater detail is required to compare and contrast the vaccines of interest. Make sure to visit us again as we explore the unique characteristics of these vaccines in greater detail and thanks for tuning in to the BioHorizon.

GLP-1 is a naturally occurring 36 amino acid peptide delivered with ConjuChem’s drug affinity complex, DAC™. Essentially, DAC is a chemical ‘coupler’ that allows for GLP-1 to selectively bind with the body’s naturally occurring albumin. Albumin is a protein present in the blood stream that, when bound to GLP-1, will significantly increase its half-life. GLP-1 not bound to albumin has a half-life of minutes. There are several mechanisms of action hypothesized for GLP-1, such as the stimulation of insulin secretion, the delay of gastric emptying, the induction of Beta cell proliferation, the restoration of Beta cell sensitivity and the increase of peripheral sensitivity to insulin.

According to the National Center for Chronic Disease Prevention and Health Promotion, diabetes is becoming more prevalent in the United States. Diabetes surveillance indicates that between 1980 and 2002, the number of cases of diabetes more than doubled (from 5.8 million to 13.3 million). In 2002, 1.3 million adults between the ages of 18 and 79 years were newly diagnosed with diabetes. This represents an incidence of 7 new cases per 1000 population between the ages of 18 and 79 years of age.

Given the powerful epidemiologic trends currently being experienced in the United States concerning diabetes and risk factors leading to diabetes (obesity, diet, etc.), therapies that represent true innovation in the treatment of diabetes or the prevention of its complications have the potential to become High Impact Technologies. There are numerous companies looking at GLP-1 and similar peptides in the treatment of diabetes, perhaps most notably Amylin Corp. However to date, none have been approved for use in the United States. Given GLP-1’s early Phase II stage of development and the necessity for ongoing pivotal Phase III trials, no early assessment activities are required for DAC-GLP-1 at this time.

Technology Details
Target Disease / Indication: Type II Diabetes
Technology Classification: Drug
Body System: Endocrine System
Program Area: Medicine/Endocrinology
Regulatory Status: Phase II
BioHorizon Impact Score: 47/100 – Moderate

Pfizer and Aventis are collaboratively developing Exubera, a dry powder form of insulin, for patients with Type 1 and Type 2 diabetes. They have entered into a global agreement to co-develop, co-promote (where permitted by local law) and co-manufacture inhaled insulin. Pfizer is also in collaboration with Nektar Therapeutics, developers of the inhalation device and formulation. We believe that if equivalent safety and efficacy with injectable insulin is demonstrated, diabetic patients and their physicians will find the inhaled route of insulin delivery highly desirable. There has been some speculation that delays in FDA filing for Exubera have centered around concerns pertaining to adverse effects on lung function in clinical trials comparing the inhaled insulin vs. standard injected insulin. The financial media has recently carried stories estimating the potential value of Exubera’s sales to be in the 1 to 2 billion dollars per year range. There are currently no FDA approved forms of inhaled insulin.

Data from the National Health Interview Survey suggest that in the year 2000, 1, 104, 000 Americans were diagnosed as having diabetes. Complications commonly associated with uncontrolled or poorly controlled diabetes include heart disease, stroke, kidney failure and blindness. Diabetes and its complications may account for more than $100 billion annually in healthcare costs in the United States.

Due to the sheer size of the diabetic population in the United States and the potential for transformation of insulin delivery from the injected to inhaled routes, we have designated this innovative technology as High Impact. However, due to the unknowns surrounding price and a FDA submission, we recommend no preliminary assessment activities at this time.

Technology Details
Target Disease / Indication
Diabetes

Technology Classification
Drug

Body System
Endocrine System

Program Area
Medicine/Endocrinology

Regulatory Status
Phase III

BioHorizon Impact Score
71/100 – High