by Robert MichelPosted on Posted in Innovation — No Comments ↓

hmp_imgn

The Human Microbiome Project (HMP) is a fascinating program being funded by the National Institute of Health (NIH) Common Fund. The human microbiome has been defined as: “the ecological community of commensal, symbiotic, and pathogenic microorganisms that literally share our body space”. The number of bacteria living within the body of the average healthy adult human are estimated to outnumber human cells 10 to 1. What is not well understood today is how the proportions and/or the presence of bacteria and/or fungi with a specific genetic constitution might be involved in making people sick.

What is the Human Microbiome Project?

As part of the NIH Common Fund’s Roadmap for Medical Research, the HMP, launched in 2008, a is a $157 million, five-year effort that will support a series of studies to better understand the role of the microbiome in human health. The aim of the HMP is to “characterize microbial communities found at multiple human body sites and to look for correlations between changes in the microbiome and human health”.

How Varied are the Bacteria?

Data on the Topographical distribution of bacteria on skin sites

Grice and Segre’s work provides insight into the variability of organisms populating various areas of the epidermis. As seen in the figure, wide variability in distribution by body site exists. Current and future work will further investigate how the genetic lineage may vary between these bacterial populations and if there exists a consistent disease-related genetic pattern. This type of investigation will hopefully lead to therapies for those conditions related to particular genetically constituted bacteria.

Areas of Investigation

Fifteen demonstration projects have been funded by the NIH to demonstrate hypothesized correlations between the microbiome and human health and disease”:

  • Evaluation of the cutaneous microbiome in psoriasis
  • The Vaginal Microbiome: Disease, Genetics and the Environment
  • Diet, Genetic Factors, and the Gut Microbiome in Crohn’s Disease
  • The Role of the Gut Microbiota in Ulcerative Colitis
  • Urethral Microbiome of Adolescent Males
  • The Thrifty Microbiome: The Role of the Gut Microbiota in Obesity in the Amish
  • Metagenomic Analysis of the Structure and Function of the Human Gut Microbiota in Crohn’s Disease
  • Effect of Crohn’s Disease Risk Alleles on Enteric Microbiota
  • Metagenomic study of the human skin microbiome associated with acne
  • Foregut microbiome in development of esophageal adenocarcinoma
  • The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic
  • Skin Microbiome in Disease States: Atopic Dermatitis and Immunodeficiency
  • The human virome in children and its relationship to febrile illness
  • The Neonatal Microbiome and Necrotizing Enterocolitis
  • The Human Microbiome in Pediatric Abdominal Pain and Intestinal Inflammation

Does Bacteria Therapy Work?

Patients with symptoms of Clostridium difficile (Cdiff) infection have been successfully treated by essentially replacing their current population of fecal bacteria with fecal bacteria from well people. These fecal transplants (examples here, here, and here) are typically very effective and well tolerated. It seems only reasonable to expect similar positive results for other health conditions being improved by microbiome adjustment.

What is Next?

What is likely to happen is the continued clinical studies of adjusting patients’ microbiomes in the hope of improving health. As these studies continue and positive evidence accumulates, the pharmaceutical industry will develop commercial products to meet the clinical needs that the new science can satisfy. What I think will be important for this area is how intellectual property protection is granted given that the bacteria are essentially prior art.

Information Sources

Here are links to some additional sources of information related to the microbiome and health:

  1. The Human Microbiome Project Consortium,”Structure, function and diversity of the healthy human microbiome”, June 14, 2012, Vol. 486, Nature, 207-14.
  2. “Me, myself, us”, The Economist, Aug 18th 2012.
  3. Special collection of articles in Nature on microbiome
  4. “Special Issue on the Gut Microbiota”, Science, 6 June 2012.
  5. J. L. Sonnenburg, M. A. Fischbach, Community health care: Therapeutic opportunities in the human microbiome. Sci. Transl. Med. 3, 78ps12 (2011)
  6. MetaHIT website
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by Robert MichelPosted on Posted in Innovation — No Comments ↓

PhRMA, the trade group of the Pharmaceutical Research and Manufacturers of America, recently released a report: “Innovation in the Biopharmaceutical Pipeline: A Multidimensional View”. The report provides a look at the number of products in the development pipeline. Data are provided that help to understand the number of pipeline products by development phase and by therapy area.  I wondered how the number of projects by therapy area correspond to need in healthcare. My need measure was US death rates for each condition. [A caveat, these data are fairly broad in categorization; for example, Infection can include vaccines for prevention as well as conventional antibiotics for treatment. Neurology can include Alzheimer’s, MS, etc…]

Development Pipeline and Therapy Area

Figure 1 shows the percentage of products by therapy area.

Figure 1. Number of Products in Development by Therapy Area

Figure 2 shows the percentage of total products in development by therapy area by time.  I created two buckets for time: Future (sum of Preclinical and Phase I products; estimated available in perhaps 6-10 years) and Near Term (sum of Phase 2-3 and those Filed/Approved but not yet marketed products; estimated available within 1-5 years).

Figure 2. Distribution of Products and Projects by Therapeutic Area and Phase

The highest number of products in development are for cancer with 20% of the Near Term and 25% of the Future products.  The next highest grouping is for Infections, which represent about half of those for Cancer.

Is Development Matching Need?

Figure 3 illustrates the percentages of leading causes of death in the US (an obvious measure of need) versus the percentage of pipeline products being developed for the therapy area (a measure of  innovation and investment). There appears to be a  mismatch of pipeline effort vs. need for heart disease (not enough pipeline). You might think the reverse for Septicemia (too much pipeline) but given the immediate crises with resistant bacteria such an investment is warranted.

Figure 3. Leading Causes of Death, Near and Future Pipeline

Questions

What cannot be determined from this report is the motivation behind the support for the pipeline projects. There is almost always need for a new and improved therapeutic no matter the condition. But in the spirit of being candid, I offer some questions, perhaps rhetorical:

  • How many of these cancer pipeline products will offer only a modicum of therapeutic outcome improvement (say statistically increased but realistically not a meaningful increased survival of a few weeks/months) versus available therapies, with the innovating company wanting to charge a premium price for their new product? Of the 12 cancer medications approved by the Food and Drug Administration in 2012, 11 cost more than $100,000 annually, reported physicians in an article in Blood, the journal of the American Society of Hematology, published online in April 2013.
  • Can the health care funding system continue to pay multiple thousands of dollars per cancer patient per month of therapy with really no significant change in outcomes?
  • Are there too many cancer products being developed just to take advantage of a high-priced therapy area?
  • Could the effort/expense developing these excess cancer products be better applied to an area with higher unmet needs, say Alzheimer’s product development?

Moving Forward

Given the future payer environment, the value of future innovations in cancer and other disease therapies will have to meet or exceed the needs of patients, prescribers, and payers. To remain relevant and to survive, companies in the biopharmaceutical industry must understand this reality and adjust business strategies and tactics accordingly. Biopharmaceutical companies operate in a high risk environment but if innovation satisfies significant medical need, the systems are in place to properly reward the innovator.

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by Robert MichelPosted on Posted in Clinical, Innovation — No Comments ↓

movie poster artwork for War of the Worlds film

Remember The War of the Worlds movie? One of the great sci-fi flicks of the 50s. In the film, the seemingly invincible alien invaders are finally vanquished by infections from ubiquitous and innocuous (to humans) bacteria. Yesterday, the US Center for Disease Control (CDC) released a study Antibiotic Resistance Threats in the United States, 2013 that is a cautionary warning that the US and the rest of the world are engaged in a very real war of the worlds: humans vs. bacteria.

 

CDC Report: Antibiotic Resistance Threats in the United States, 2013-Report-front-cover

For those who are not familiar with antibiotic resistance, the World Health Organization explains antimicrobial resistance as “Antimicrobial resistance (AMR) is resistance of a microorganism to an antimicrobial medicine to which it was originally sensitive. Resistant organisms (they include bacteria, fungi, viruses and some parasites) are able to withstand attack by antimicrobial medicines, such as antibiotics, antifungals, antivirals, and antimalarials, so that standard treatments become ineffective and infections persist increasing risk of spread to others. The evolution of resistant strains is a natural phenomenon that happens when microorganisms are exposed to antimicrobial drugs, and resistant traits can be exchanged between certain types of bacteria. The misuse of antimicrobial medicines accelerates this natural phenomenon. Poor infection-control practices encourage the spread of AMR.”

The key learning from yesterday’s CDC report: “CDC estimates that in the United States, more than two million people are sickened every year with antibiotic-resistant infections, with at least 23,000 dying as a result. The estimates are based on conservative assumptions and are likely minimum estimates.”

The report’s first section provides context and an overview of antibiotic resistance in the United States. In addition to giving a national assessment of the most dangerous antibiotic resistance threats, it summarizes what is known about the burden of illness, level of concern, and antibiotics left to defend against these infections.

The second section describes what can be done to combat this growing threat, including information on current CDC initiatives.

The third section provides summaries of each of the bacteria in this report. These summaries can aid in discussions about each bacteria, how to manage infections, and implications for public health. It also includes information about what groups such as states, communities, doctors, nurses, patients, and CDC can do to combat antibiotic resistance.

The CDC for the first time has prioritized bacteria in this report into one of three categories: urgent, serious, and concerning.

Urgent Category: Clostridium difficile: causes life-threatening diarrhea. These infections mostly occur in people who have had both recent medical care and antibiotics. Often, C. difficile infections occur in hospitalized or recently hospitalized patients.

data for C. Difficile

 

 

 

 

 

Carbapenem-resistant Enterobacteriaceae (CRE): An estimated 140,000 healthcare-associated Enterobacteriaceae infections occur in the United States each year; about 9,300 of these are caused by CRE. Up to half of all bloodstream infections caused by CRE result in death. Fortunately, bloodstream infections account for a minority of all healthcare-associated infections caused by Enterobacteriaceae. Each year, approximately 600 deaths result from infections caused by the two most common types of CRE, carbapenem-resistant Klebsiella spp. and carbapenem-resistant E. coli.

Carbapenem-resistant Enterobacteriaceae (CRE)

 

 

 

 

 

Drug-resistant Neisseria gonorrhoeae: causes gonorrhea, a sexually transmitted disease that can result in discharge and inflammation at the urethra, cervix, pharynx, or rectum. It causes severe reproductive complications.

Drug-resistant Neisseria gonorrhoeae-facts

 

 

 

 

 

Serious Category:

  • Multidrug-resistant Acinetobacter
  • Drug-resistant Campylobacter
  • Fluconazole-resistant Candida (a fungus)
  • Extended spectrum β-lactamase producing Enterobacteriaceae (ESBLs)
  • Vancomycin-resistant Enterococcus (VRE)
  • Multidrug-resistant Pseudomonas aeruginosa
  • Drug-resistant non-typhoidal Salmonella
  • Drug-resistant Salmonella Typhi
  • Drug-resistant Shigella
  • Methicillin-resistant Staphylococcus aureus (MRSA)
  • Drug-resistant Streptococcus pneumoniae
  • Drug-resistant tuberculosis

Concerning Category:

  • Vancomycin-resistant Staphylococcus aureus (VRSA)
  • Erythromycin-resistant Group A Streptococcus
  • Clindamycin-resistant Group B Streptococcus

What is Being Done?

    • New medicine development: according to Research and Markets 2013 industry report on antibiotics in development, there are a bit over 100 new antibiotics in the development pipeline:

chart showing number of Antibiotics in Development

      • Biologists at the University of California, San Diego have developed a revolutionary new method for identifying and characterizing antibiotics, an advance that could lead to the discovery of new antibiotics to treat antibiotic resistant bacteria. The learnings from the U of C technology should help to accelerate antiinfective innovation. 
      • The Generating Antibiotic Incentives Now (GAIN) Act of 2011 (H.R. 2182): The GAIN Act seeks to create incentives to encourage the development of products to treat, prevent, detect and diagnose antibiotic-resistant infections. It extends the length of time an approved drug is free from competition and clarifies the regulatory pathway for new antibiotics. The key carrot in this bill is the granting of an additional five years of market protection at the end of the existing exclusivity for qualified infectious disease products. Additional benefits to the innovator are an additional six months of exclusivity to be granted for drugs for which a companion diagnostic test is cleared or approved and eligibility for Priority Review and Fast-track Approval by FDA.
      • Prudent use of available antibiotics: proper use of antibiotics can help to slow the further development of new drug-resistant strains. The WHO lists the following as key in developing antimicrobial resistance:
        • Lack of a comprehensive and coordinated response;
        • Weak or absent antimicrobial resistance surveillance and monitoring systems;
        • Inadequate systems to ensure quality and uninterrupted supply of medicines;
        • Inappropriate use of antimicrobial medicines, including in animal husbandry;
        • Poor infection prevention and control practices;
        • Insufficient diagnostic, prevention and therapeutic tools.

Now is the time to heed the CDC’s warning and support the continued innovation in antiinfectives.  The war of the worlds continues and humanity cannot afford to end up like the aliens in the film.   War of the Worlds picture courtesy of Clarksville Online

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