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.

Multiple sclerosis is a chronic, debilitating autoimmune disease that affects the brain and spinal cord. MS causes the body to direct antibodies and white blood cells against proteins in the myelin sheath that surrounds the nerves in the brain and spinal cord. This may cause inflammation and areas of scarring on nerves resulting in loss or decrease in function. An estimated 400,000 Americans have MS with about 2.5 million cases worldwide. 

Current therapy for MS is focussed on prevention of relapses and/or slowing of disease progression using immunomodulatory drugs.  FDA approved therapies include Avonex (interferon beta-1a IM ), Betaseron  and Extavia, (interferon beta-1b SC ),  Copaxone (glatiramer acetate SC),  Rebif (interferon beta-1a SC), Novantrone (mitoxantrone IV) and Tysabri (natalizumab IV).   Some analysts place worldwide expenditures on these drugs at greater than 8 billion dollars annually.  Unlike fingolimod and cladribine which are pills taken by mouth, all of the above therapies are delivered by the intramuscular (IM) route, the subcutaneous (SC) route or the intravenous (IV) route. 

Fingolimod is a sphingosine-1-phosphate-receptor modulator that is thought to work by preventing movement of lymphocytes from lymph nodes and in doing so decreases the damage that these lyphocytes can exact on the central nervous system.  Cladribine’s mechanism of action is different – 2-chlorodeoxyadenosine triphosphate – an active metabolite of cladribine accumulates in cells, disrupts their metabolism and leads to cell death.   Cladribine preferentially impacts lymphocytes and in doing so decreases the number of so called ‘autoagressive’ cells available to attack the nervous system. 

The two recently published clinical trials in the New England Journal of Medicine showed efficacy for cladribine (CLARITY trial) and fingolimod (FREEDOMS trial) when compared to placebo over a 2-year period.  Statistical significance was achieved for the primary endpoint – which was the annualized relapse/recurrence rate in both trials.  In fact, the relative risk reduction was reported as an impressive 50%+ reduction in both trials.  In  a third trial comparing fingolimod to interferon beta 1a, fingolimod was superior. 

Those familiar with the Tysabri story are well aware of the importance of safety when considering immune response modifiers in the treatment of multiple sclerosis and  the safety profile of cladribine and fingolimod will surely be closely scrutinized going forward.  A detailed discussion of the safety of these oral therapies is not possible here however adverse events of note described in these three trials included herpetic infections,  solid tissue cancers, macular edema, basal cell carcinoma, melanoma, breast cancer, transient bradycardia, first- and second-degree heart block,   and lymphocytopenia.  Should approval of either of these agents occur, physicians and patients will need to do the requisite risk/benefit analysis before initiating treatment and FDA mandated post marketing surveillance will likely be critical in addressing any long term safety concerns.

This brings us to the next question – will physicians and patients get the chance?  Well, as mentioned in the first paragraph Merck KGaA was issued a ‘refuse to file’ letter for cladribine suggesting anything but imminent approval while Novartis  filed its NDA for fingolimod in late January 2010.    Interested readers are directed to www.nejm.org to access the three clinical trials referred to above in their entirety as well as an excellent accompanying editorial.  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.

Since its approval in the United States in 2000 Wyeth’s Prevnar vaccine against pneumococcal disease has helped to transform what was thought of as a mature, marginally profitable segment of the pharmaceutical business into a much more dynamic and profitable one. Prevnar has proven to be both effective and innovative while filling an unmet need in the prevention of serious pediatric infections caused by the pneumococcal bacteria. According to CNN Money.com, Prevnar sales surged 24% in 2007 to $2.4 billion, making it the first vaccine to exceed $2 billion in annual sales.

Prevnar has been the only conjugate pneumococcal vaccine available to immunization programs and clinicians throughout North America and European Union looking to prevent pneumococcal disease. However, GSK’s new 10-valent conjugate pneumococcal vaccine (Synflorix) could soon start changing this.

There are two significant differences between Synflorix and Prevnar that our readers should be aware of. First, Prevnar contains antigen from seven different serotypes of pneumococcal bacteria while Synflorix contains antigen from ten different types. The second difference is in the carrier protein that these polysaccharide antigens are attached to. In Prevnar the protein is called CRM-197 and it has been critical in the success of Wyeth’s product. The carrier protein is more than a passive molecule, it greatly enhances the immunogenicity of the vaccine and makes it more effective. In Synflorix, the carrier protein (NTHi) not only does this, but because it is derived from non-typable Haemophilus Influenza bacteria, provides protection against infections with this pathogen as well. GSK has filed for Synflorix approval in the EU and the vaccine has recently been approved for sale in Canada but we have no word on when or even if approval will be sought in the United States.

The story does not end here as Wyeth is countering with an enhanced version of Prevnar that contains protection against thirteen different serotypes of the pneumococcal bacteria and has filed for approval in both the United States and the European Union.

There are some fundamental questions that need to be explored further concerning the safety and effectiveness of these new vaccines, the changing epidemiology of pneumococcal disease, and of course the cost-effectiveness data that is all important to vaccine program planners. Readers should stay tuned as we plan to explore these crtical areas in the coming days. Thanks for joining us today on the BioHorizon.

Tarceva is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor. By inhibiting the addition of phosphate to the EGFR associated tyrosine kinase, Tarceva may interrupt important cellular signaling pathways and thereby suppress cancer cell growth. Astra Zeneca’s Iressa® is an example of an EGFR tyrosine kinase inhibitor already approved by the FDA for use in NSCLC. According to Astra Zeneca’s third quarter financial statements for 2004, sales of Iressa for the first 9 months in the United States were $160,000,000. We have given Tarceva 10 demand/diffusion points and 65 innovation status points.

According to CDC estimates, more than 170,000 people will be diagnosed with lung cancer in the United States in 2004. Anywhere from 75-85% of these will be the non-small cell type, the most common form of lung cancer in the US. In addition, lung cancer is the most common cause of cancer death in the United States accounting for more than 25% of cancer deaths on an annual basis. Using the BioHorizon burden of illness methodology, NSCLC receives a burden of illness rating of 21.

Overall, Tarceva receives a BioHorizon Emerging Health Technology score of 46, placing it in our Moderate Impact Technology category. However, the EGFR tyrosine kinase inhibitors represent true innovation and are likely to see increasing uptake for NSCLC as well as other cancer indications. Health services clients are advised to begin or continue preliminary assessment activities for Tarceva and Iressa this quarter.

Technology Details
Target Disease / Indication: Non-Small Cell Lung Cancer
Technology Classification: Drug
Body System: Respiratory
Program Area: Medicine/Oncology
Regulatory Status: Approved
BioHorizon Impact Score: 46/100 – Moderate

Nabi describes Altastaph as a polyclonal antibody for the prevention and treatment of S. aureus infections in patients at immediate risk for infection or patients with immune systems unable to respond adequately to vaccine. Altastaph is produced by vaccinating healthy volunteers with the company’s StaphVAX vaccine, and then harvesting the anti-staphylococcus antibodies to capsular polysaccharides (protective outer sugar coatings on S. aureus bacteria) from S. aureus types 5 and 8. Nabi reports that these two types account for upwards of 85 % of all S. aureus infections.

The use of specific antibodies for the prevention and treatment of infectious diseases is by no means a novel concept. Specific antibodies are used in the prevention of Hepatitis B, Rabies, RSV and in the treatment of Tetanus and Diptheria. A search of the BioHorizon.com Emerging Health Technology Surveillance System database yields two other antibody-based therapies targeted against S. aureus: Aurexis (Phase 2) and Veronate (Phase 3). We have assigned 45 innovation points to Altastaph.

S. aureus infections are responsible for significant morbidity and mortality in low birth-weight neonates. Estimates of the incidence of VLBW in the United States are in the 14-15/100, 000 population range corresponding to a burden of illness score of 11. Demand/diffusion scoring is difficult at this stage of development; we have assigned the default score of 10.

Altastaph receives a final BioHorizon Emerging Health Technology Impact Score of 28 placing it in our Low Impact Technology category. No assessment activities are recommended for health services clients at this time.

Technology Details
Target Disease / Indication: Staph. Aureus infections
Technology Classification: Drug
Body System: Multiple Systems
Program Area: Medicine/Infectious Disease
Regulatory Status: Phase 2
BioHorizon Impact Score: 28/100 – Low

ABT–874 is a fully human, monoclonal antibody directed against an inflammatory cytokine known as IL-12. IL-12 is a known mediator of inflammation and may be important in Crohn’s disease. Given the inflammatory nature of Crohn’s, many targets related to immune system function are being pursued. Already, approved infliximab targets the tumor necrosis factor, another member of the class of inflammatory cytokines. We have assigned ABT-874 a score of 60 for innovation status.

Crohn’s disease is a chronic, inflammatory disease of the gastrointestinal tract that affects between 500,000 and 1 million Americans. Usually diagnosed before age 30, symptoms include diarrhea, cramping, abdominal pain, weight loss, fever, and in some cases rectal bleeding. There is no cure for Crohn’s disease. Incidence estimates for this disease vary greatly, ranging from 1/100, 000 cases per year to 70/100, 000. Published studies seem to cluster around the 5-10/100, 000 range resulting in a burden of illness score of 10.

We have scored the demand/diffusion variable at 10 resulting in an overall BioHorizon Emerging Health Technology Impact Score of 30, placing ABT-874 in our Low Impact Technology category. No preliminary assessment activities are required at present.

Technology Details
Target Disease / Indication: Crohn’s Disease
Technology Classification: Drug
Body System: Gastrointestinal
Program Area: Medicine/Gastroenterology
Regulatory Status: Phase 2
BioHorizon Impact Score: 30/100 – Low

BiDil is a fixed dose, combination therapy consisting of 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate per tab taken three times daily. Although hydralazine and isosorbide dinitrate are both approved for use in several cardiovascular indications, their use together in a fixed dose format for the treatment of CHF is unique and merits an innovation score of 65. Nitric oxide is important in myocardial remodeling. BiDil may exert its therapeutic effect as both a source and preserver of nitric oxide in the heart.

Estimates of the prevalence of congestive heart failure range from 3 to 5 million Americans. We use an incidence of 400, 000 new diagnoses per annum; this translates into a burden of illness variable value of 35. Congestive heart failure results from an impairment in pump function in which the heart fails to maintain the circulation of blood adequately. In the New York Heart Association’s functional classification of CHF, class III is characterized by a marked limitation in normal physical activity. Class IV is defined by symptoms at rest or with any physical activity.

If approved, we expect significant demand/diffusion of this emerging technology. The integration of BiDil into the CHF therapeutic armamentarium will create an increase in the pharmacologic treatment cost per patient per year. BiDil will be added to existing patient specific therapeutic regimens. We have assigned the demand/diffusion variable a value of 30 and an overall BioHorizon Emerging Health Technology Impact Score of 53. If FDA approval occurs, we intend to recommend early assessment activities.

Technology Details
Target Disease / Indication: Congestive Heart Failure
Technology Classification: Drug
Body System: Cardiovascular System
Program Area: Medicine/Cardiology
Regulatory Status: Phase 3
BioHorizon Impact Score: 53/100 – Moderate