An increase in resistant
strains of bacteria - coupled with a lack of commercial interest in developing
new antibiotics – means that useful antibiotics are in short supply, and
becoming less effective, with no new classes of antibiotics having been
developed for 25 years.
The majority of severe Clostridium
difficile infection (CDI) cases occur in a healthcare environment, such as
hospitals or care homes. Older people are most at risk from infection. Those
aged over 65 account for three quarters of all cases. The UK Office of National
statistics reported that in England and Wales, the number of CDI cases increased
from 44,107 to 51,690 between 2004 and 2005, with 2,700 deaths recorded in
Recently, the US Centers
for Disease Control (CDC) reported that hospital-based CDI incidence was
250,000, with 14,000 deaths. The most pathogenic strain of C. diff, NAP1/027,
which has emerged in recent years, tends to cause more severe infections and is
becoming globally more prevalent. In the US, it causes around 50% of all CDI infections,
in Canada, near 80%, and in in England 36%. The current therapies for CDI,
metronidazole, vancomycin, and recently fidaxomicin, have very limited activity
against this strain as they have predominantly bacteriostatic activity. By
contrast, MGB-BP-3 has a strong bactericidal effect against the majority of C.
diff strains, including the most virulent NAP1/027 strain.
The current therapeutics
for CDI are associated with high recurrence rates due to their predominantly
bacteriostatic activity, and have a weak effect on C. diff sporulation.
MGB-BP-3 has shown to be more potent in reducing C. diff sporulation
than vancomycin. In contrast to the existing CDI therapy, MGB-BP-3 is active
against vancomycin-resistant enterococci (VRE), which are found in up to 50% of
CDI patients, coinfection with which is often responsible for a patient’s poor
Additionally, MGB-BP-3 has
been shown to act against C. diff within the first hour of administration,
whilst vancomycin requires up to 24 hours to achieve an optimal effect. The
economic burden of CDI is estimated to be $7 billion, or $6,000 per
patient, for the cost of hospitalization and standard treatment. All these
factors indicate that MGB-BP-3 is more active in CDI treatment and has
the potential of substantially benefitting CDI patients and reducing
hospital days and overall CDI treatment costs.
The World Health Organization
considers drug-resistant infection to be the greatest challenge in infectious
disease. Director of the Wellcome Trust, Jeremy Farrar, claims that
drug-resistant infections are “on the scale of climate change.”
Governments have only
recently begun to grasp the scale of the problem, with health authorities in
the US and Europe introducing the GAIN Act (Generating Antibiotic Incentives
Now) in 2012, which aims to facilitate a faster and less-expensive process to
bring novel antibacterial agents to the market.
In the UK, Lord Jim O'Neill
was appointed in May 2015 by Prime Minister David Cameron to chair a review
into the crisis of antimicrobial resistance (AMR).
The AMR Review, which concludes
this summer, has so far published four of the six planned papers, analyzing key
topics affecting the global issue of antimicrobial resistance and the use of
antibiotics in agriculture; antibiotic misuse and over-prescription, and the
importance of better diagnostics.
In his review, Lord
O’Neill estimates that by 2050, infections untreatable with antibiotics could
cost the global economy $100 trillion, and kill 10 million people a year.
However, the report also shines a light on the industry as a whole, suggesting
in part that lack of research in this critical area is down to antibiotics
previously being expensive to develop, providing only small returns to drug
In January this year, at
the World Economic Forum in Davos, 85 pharmaceutical companies joined together
to call on governments around the world to develop new ways of remunerating
them in order to develop antibiotics. In a joint statement, they said that the
reward for developing antibiotics historically “did not reflect the benefits they
bring to society.”
The declaration from drug and
diagnostics companies, including Johnson & Johnson, Roche, Novartis, and
Pfizer, called for governments to “commit funding and support the development
and implementation of transformational commercial models that enhance conservation
of new and existing antibiotics."
After years of scaling
back research into new antibiotics owing to these low returns, spurred on by
this growing awareness of the antibiotic crisis, the biopharmaceutical industry
has made some moves toward re-entering the field. In particular, recent
development has focused on Gram-positive infections, responsible for a large
proportion of serious infections worldwide.
GRAM-POSITIVE PATHOGENS & THE RISE OF CLOSTRIDIUM DIFFICILE
include bacteria, such as Methicillin-resistant and susceptible Staphylococcus
species, pathogenic Streptococcus species, and Vancomycin-resistant and
susceptible Enterococcus, as well as Clostridium difficile (C.
difficile infections are on the rise, for example, with recent estimates suggesting
that up to a half a million cases a year currently occur in the US alone. The UK
Office of National statistics reported that in England and Wales, the number of
CDI cases increased from 44,107 to 51,690 between 2004 and 2005 in the over
65s, with 2,700 deaths recorded in 2011. Similarly in the US, 95% of 14,000
deaths attributed to CDI were in those aged 65 and over. The direct economic
burden of managing CDI in developed countries is estimated to be approximately $7
Data also shows cases of
CDI more than double the risk of death within 30 days of diagnosis, and causes
or contributes to 40% of deaths that occur within 3 months of diagnosis.
Furthermore, recently evolved hyper-virulent strains of C. diff.
produce robust amounts of the disease-causing toxins, more spores and
additional surface proteins that help it to persist in the gut environment. Up
to 25% of treated patients have a CDI recurrence within a month after initially
successful therapy; the total cost of CDI in the US or Europe is estimated to
be up to $6 billion a year.
A NEW CLASS OF ANTI-INFECTIVE MEDICINE
Glasgow’s MGB Biopharma
began operations in April 2010, funded by an Angel syndicate and the Scottish
Co-Investment Fund. The company has since been working on a new agent for
Gram-positive infections based on Minor Groove Binder (MGB) technology evolving
from the University of Strathclyde in Scotland.
management team has dedicated its focus to the development of a new class of
small molecules, with specific antibacterial activity against susceptible and
resistant bacteria – making rapid progress against Gram-positive pathogens such
as C. difficile.
The company is currently
advancing lead product MGB-BP-3, which is being developed for the oral
treatment of CDI.
MGB-BP-3 is a synthetic
polyamide directed against Gram-positive bacteria, developed by Professor Colin
Suckling at the University of Strathclyde. It binds to the minor groove of
bacterial DNA; these are the grooves created from the close proximity of DNA
Research into minor groove
binders, an entirely novel drug class, including its failures, has proved to be
an important event in advancing the development of new antibiotics that could
be resistant to potentially increasingly fatal pathogens. Consequently, this is
the first time that minor groove binders are being investigated as an
antibacterial agent, creating an entirely new class of antibacterials with a new
mechanism of action. Minor groove binders as a class are chemically very
heterogeneous, with their respective antibacterial, antifungal, antiviral,
anti-parasitic, and anticancer activity.
The common feature of
these compounds, including MGB-BP-3, is that they recognize specific regions of
DNA and appear to be able to achieve high selectivity and efficacy by
interrupting the biochemistry of a cell at a fundamental level. The activity of
minor groove binders are determined by their ability to bind to sequences that
are rich in the amino acid base pairs A and T within the minor groove of DNA,
in a sequence and conformation-specific fashion.
As a result, this process
interferes with transcription factors and alters genetic regulation. Some
compounds belonging to this group are already under clinical development or are
even commercially available, such as pentamiden and furamidine against a range
of human parasitic diseases, and brostacillin as an anticancer agent.
MGB-BP-3 has the potential
to provide substantial benefit to patients, particularly the elderly and the
immuno-compromised, in an area of increasingly unmet medical need, as the problem
of bacterial resistance to current therapies is becoming acute. In combatting
CDI and reducing its recurrence, MGB-BP-3 has the potential to alleviate the ever-increasing
financial strain placed upon healthcare systems. The current gold standard for
CDI treatment is vancomycin, and resistance to this drug is increasing, with
recurrence rates now estimated to be approximately 30%. MGB-BP-3 is able to
offer a potential cure to CDI by providing superior treatment. In contrast to
vancomycin, which is mainly bacteriostatic, MGB-BP-3 is, with its novel mode of
action, strongly bactericidal against the majority of C. diff strains,
including the most virulent strain NAP1/027. As such, it reduces the sporulation
process responsible for the survival of C. diff and its regrowth, which
causes disease recurrence.
A BRIGHT FUTURE
In December 2015, MGB
Biopharma successfully completed a Phase I clinical trial of an oral
formulation of MGB-BP-3. The double-blinded, placebo-controlled Phase I
clinical trial assessed the safety, tolerability, and pharmacokinetics of
single and multiple ascending doses of oral MGB-BP-3.
In the single ascending
dose element of the study, dose levels of MGB-BP-3 were increased from 250 mg
to 2000 mg. In the multiple dose part of the study, 250 mg, 500 mg, and 1000 mg
doses of MGB-BP-3 were given twice daily for 10 days. The Phase I study showed
that MGB-BP-3 was well tolerated with no serious side effects being observed.
MGB Biopharma has
undertaken extensive formulation work aimed at developing a freeze-dried
product that can be administered intravenously. This formulation of MGB-BP-3 will
address systemic Gram-positive infections, such as MRSA, VRE, and Streptococcus.
Pivotal proof-of-concept and ADME studies assessing IV MGB-BP-3 against Staphylococcus
aureus (including MRSA), Streptococcus pyogenes, and S. pneumoniae
have been completed. Metabolism studies using radiolabelled MGB-BP-3 to
determine metabolite profile and identification, and in parallel, an in vivo
study to determine mass balance and tissue distribution of MGB-BP-3 are
ongoing. Preliminary nonclinical safety and tolerability studies are ongoing, and
we expect formal GLP safety pharmacology and toxicology studies to follow.
MGB successfully completed
a topical formulation feasibility study with its lead antibacterial MGB-BP-3 in
November last year. The pre-clinical study assessed two preliminary topical
formulations of MGBBP-3 in a skin infection model against a methicillin
resistant Staphylococcus aureus (MRSA). The study showed that both
formulations of MGB-BP-3 were successful in killing approximately 60% of the
MRSA present. These very promising findings pave the way for MGB Biopharma to
begin a full topical formulation development programme for MGB-BP-3 with the
goal of commercializing this novel antibacterial for a range of important skin
The successful completion
of Phase I study with oral MGB-BP-3 was a major milestone for MGB Biopharma and
means the company is well-placed to commence a Phase II study with oral
MGB-BP-3, a further important step as it works to bring this truly novel antibiotic
to market as quickly as possible.
It is encouraging to see
that drug development companies are realizing that, while innovation needs to
be rewarded, public health also has to be safeguarded at all costs. MGB
Biopharma now intends to work with partners to fully capitalize on the multiple
value-creating opportunities offered by its broad and innovative
With political pressure on
drug companies around the world, one thing is clear. The AMR Review and GAIN
Act show how far and how quickly the debate into tackling antimicrobial
resistance is moving. The political support now exists, and this needs to be
matched with commitment from the broader industry – as well as companies like
this issue and all back issues online, please visit www.drug-dev.com.
Dawn Firmin is responsible for planning, managing, and executing the pharmaceutical
development of the MGB Pharma’s programs and providing leadership to the
project teams. She is a scientific professional with 10 years of combined
experience in immunology and infection, toxicology management, and the
management of drug development of NCEs. Her expertise lies in her knowledge and
experience of managing all preclinical and Phase I activities of the drug
development process, including pre-IND meetings. Dr. Firmin was a Post-Doctoral
Immunology Research Scientist at the University of Glasgow, specializing in a
mechanistic in vivo model of Ankylosing Spondylitis. Prior to this, she worked
for Charles River Laboratories, where she was a Senior Assistant Scientist and
Project Manager of toxicology studies. Before joining CRL, she earned her PhD
in Immunology and Infection at the University of Aberdeen and her MSc in Medical
Diagnostics at Cranfield University. She has authored and coauthored academic
papers and is a member of the Scottish Life Science Association.