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.

First of all, on behalf of  the entire BioHorizon staff, let me welcome you to the BioHorizon Health Technology Surveillance Update.  Long time clients  and readers will remember that Surveillance Updates last graced these pages in 2005-2006 and based on your feedback we have changed the focus of this feature to better meet your needs -  we hope you  agree!

Lets start by turning our attention to  FDA approvals of note in January and February 2010.  On January 11th, Genentech Inc.’s rheumatoid arthritis therapy, Actemra (tocilizumab),  was approved for treatment of adults with moderate to severe rheumatoid arthritis who have not adequately responded to or cannot tolerate other approved drug classes  for this disease.  Serious safety concerns associated with this interleukin-6 blocker were cited as the basis for the FDA’s requirement for a post-marketing clinical trial to evaluate long term safety as well as a Risk Evaluation and Mitigation Strategy that directs Genentech to implement a communication plan for prescribing physicians detailing the appropriate approach to obtaining informed consent and side effect monitoring.

Acorda Therapeutics’ Ampyra (dalfampridine) extended release tablets were approved on January 22nd, to improve walking in multiple sclerosis patients representing the first drug approved for this use.  The FDA cautioned that Ampyra can cause seizures when given at greater than recommended doses. 

Turning to medical devices for a moment, Thoratec Corp.’s HeartMate II Left Ventricular Assist System was approved on January 20th for severe heart failure patients who are not acceptable transplant candidates.  The HeartMate II was already approved for certain patients waiting for complex medical treatments including transplants.   The FDA directed Thoratec to conduct a post-approval study to further characterize the device’s performance.

 On January 25th,  Novo Nordisk Inc got the nod for Victoza (liraglutide (rDNA) injection) the company’s once daily GLP-1 receptor agonist which is indicated for treatment of type 2 diabetes in adults and joins Eli Lilly’s twice daily Byetta in the injectable GLP-1 agonist class.

GlaxoSmithKline’s Tykerb (lapatinib) got an expanded indication from the FDA on January 29, and can now be used in combination with the Novarits product Femara (letrozole) in the treatment of hormone positive and HER2-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated.

And finally, on February 2nd the FDA approved Auxillium Pharmaceuticals’  injectable Dupuytren’s contracture therapy, Xiaflex (collagenase clostridium histolyticum) – this is the first FDA approved non-surgical therapy inidicated for this progressive hand disease. 

We encourage our readers to visit www.fda.gov as well a company or product specific website for more details, in subsequent weekly updates we will begin to include some discussion of interesting clinical trial results from the week that was in additon to setting the table for the next week in emerging health technology.  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.

The questions may be obvious, but the answers–frustratingly–are often not.

When trying to interpret the seemingly elusive language and technical complexities of a clinical trial report, it is all too common for the experience to end in confusion and decision paralysis. Even worse is the potential for important decisions to be made based on a flawed analysis.

It doesn’t have to be this way. You just need the right information, and the right approach–and this is exactly what our team of expert clinical trial analysts has provided for you below. We’ve demystified the process of interpreting clinical trial results for you in an easy-to-follow, 5-step guide. Using our approach, you will improve your analytical skills, and have the clarity and confidence to make better decisions. So, let’s get started!

How to Read and Interpret Clinical Trial Results

Whether the clinical trial results are coming from a company press release, a conference abstract, or a peer-reviewed medical journal, following these 5 steps every time will improve your analysis and interpretation of trial results.

1.Determine the Trial Type: Preclinical or Clinical (Phase 1, 2 or 3)?

Is this a preclinical trial where the intervention is tested in a lab using an animal model, or a clinical trial where the intervention is tested using human participants?  Preclinical trials are important in determing whether a drug is safe and potentially effective enough to enter human trials. Preclinical studies are only the first step in a lengthy process that investigators must complete to move towards approval.

If this is a clinical trial, is it a  phase 1, phase 2 or phase 3 clinical trial?  Each stage of development is designed to show the investigators and the regulator something different.

Phase 1 clinical trials use a very small number of participants and represent the first use of the drug in humans.  Participants may be healthy volunteers or patients with an incurable condition. The focus of phase 1 trials is demonstration of safety, determination of dose range that can be safely administered, and to gain an understanding of how the new drug is metabolized in humans. Phase 1 trials do not tell us about the effectiveness of the new drug.

Phase 2 clinical trials involve a somewhat larger number of patients with the condition the drug is targeting for the purposes of determining the relative efficacy of different doses and frequencies of administration as well as providing more safety data. If the drug appears to work and has acceptable toxicity, investigators will begin the much larger and more expensive phase 3 clinical trial.

Phase 3 clinical trials (sometimes referred to as ‘pivotal clinical trials’) are designed to compare the new drug with an existing drug known to be effective.  They involve hundreds if not thousands of patients randomly divided into ‘treatment’ (patients get the new drug) or ‘control’ (patients get an existing effective drug).  Most phase 3 trials are randomized and controlled, hence the term Randomized Controlled Trials or RCTS.  In most cases new drugs must be shown to be as safe and effective (if not more so than existing therapies) in a phase 3 clinical trial before approval is obtained.

2. If  the clinical trial is phase 3, make sure it is a randomized, double blinded, controlled trial.

Most phase 1 and 2 trials are not RCTS.  Randomization (random assignment of trial participants to treatment or control), double blinding (investigators and patients don’t know whether they got treatment or not), and controlled (one group gets treatment as is compared to a second group which did not) are the foundations on which the RCT is built. They are critical for the demonstration of a drug’s effectiveness and the prevention or mitigation of  the clinical trials worst enemy–bias. 

Think of bias as a tendency of a measurement to deviate in one direction from the true value; when it is allowed to run rampant through a clinical trial, it can obscure true beneficial effects of a drug, or worse–hide harmful ones. There may be some very limited medical interventions where double blinding is not possible (surgical interventions, for example). However, checking a trial for randomization, blinding, and a control group is quick, easy andvery important. It should be one of the first things you do in your analysis in order to ensure that the investigators have taken all possible steps to minimize bias and to give you the highest degree of confidence in the trial’s findings.

3. Describe the primary endpoint or outcome of the trial. 

The primary endpoint is the main outcome of interest that the investigators were trying to measure.  It’s the trial’s “ reason for being”, so to speak.  It might be survival in a cancer trial, blood pressure change in a anti-hypertensive drug trial, blood glucose in an oral hypoglycemic trial etc. etc. If you can’t determine the primary endpoint from your information source, you need to dig deeper–most likely you’ll need to find an additional information source (for example, the company website, clinicaltrials.gov, etc.)

Ever wonder why a positive sounding news release is met with an unexpected negative reaction (by investors, for example)?  It’s often because the primary endpoint was not met; that is, the treatment effect that the investigators were hoping to measure was not found.

4. Determine if statistical significance was achieved for the primary endpoint.

If statistical significance* was achieved for the primary endpoint, it’s usually stated explicitly by the sponsor if it’s a press release, or included in the results section of an abstract or peer reviewed article.  It’s pretty safe to say that if it is not stated explicitly, it didn’t happen! 

Be careful of language like ‘results in the treatment group trended towards significance’, or ‘the treatment group improved’ with no reference to statistical testing.  Regulators and physicians like treatments that produce statistically significant improvements in primary endpoints, enough said.

*Statistical significance: the probability that an observed outcome of an experiment or trial is not due to chance alone.

5. Look for evidence of poor trial quality.

Before clinical trials are started, all aspects of the trial must be laid out in painstaking detail in the trial protocol.  The number and type of patient to be include in the trial, the precise treatment they will be given, the frequency and type of medical follow-up to be received by each participant, even the statistical test that will be used to analyse the results are all examples of the details included in a clinical trial protocol.   Once the clinical trial is underway, the protocol should not change. If the protocol changes, be very, very leery of the conclusions reached. Protocol changes will often be difficult to detect so close attention must be paid to company news releases, etc. 

Next, look for a description of participant withdrawals in both the treatment and control groups.  Withdrawals occur in all trials to some degree; however, large numbers of drop-outs in a treatment group with no explanation is always cause for concern and should serve as a flag to proceed with caution!

So, there you have it.  5 steps we would like you to take every time you read a report of a clinical trial:

1. Determine the trial type
2. If a phase 3 trial – make sure the trial is randomized, double blinded and controlled
3. Describe the primary endpoint or outcome
4. Determine if the drug produced a statistically significant improvement in the primary outcome
5. Look for evidence of poor trial quality

Following the steps above will enable you to more accurately interpret clinical trial results. This will allow you  to make better, more informed decisions.

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