Download Efforts to Support the Development of Fusidic Acid in the United States

SUPPLEMENT ARTICLE
Efforts to Support the Development of Fusidic
Acid in the United States
Prabhavathi Fernandes and David Pereira
Cempra Pharmaceuticals, Chapel Hill, North Carolina
Fusidic acid (FA), though used widely throughout the world for decades, has never been approved in the United
States. There is now a great need for an oral methicillin-resistant Staphylococcus aureus (MRSA) antibiotic with
a long track record of safety. Cempra Pharmaceuticals successfully encouraged passage of a congressional
amendment to allow for Hatch-Waxman market exclusivity when this antibiotic is approved in the United
States. A new dosing regimen has been patented, allowing FA to be used as monotherapy, and decreased
resistance selectivity has been shown. With almost no resistance to FA in the United States, the time is right for
introduction into this market.
Noting the withdrawal of resources to discover and
develop new antibiotics in parallel with the continuing
evolution of virulent and drug-resistant bacteria, the
Antimicrobial Availability Task Force of the Infectious
Diseases Society of America (IDSA) published the
now famous ‘‘Bad Bugs, No Drugs’’ article in which
the most urgent needs were described [1, 2]. In this
article, published in 2006, the same year Cempra
Pharmaceuticals was founded, it was noted that multiple anti-MRSA compounds were in late-stage development, but the authors went on to add ‘‘However,
the apparent plethora of available antibiotics for MRSA
infection is somewhat misleading. A critical need is
for effective antibiotics that can be taken orally, allowing
for effective step-down therapy for nosocomial infection
or initial therapy for infections acquired in the community.’’ Also in 2006, telithromycin (Ketek) was being
subjected to intense scrutiny because of rare reports
of serious and even fatal adverse events [3]. The events
that accompanied the Food and Drug Administration
Correspondence: Prabhavathi Fernandes, PhD, 6340 Quadrangle Dr, Ste 100,
Chapel Hill, NC 27517 ([email protected]).
Clinical Infectious Diseases 2011;52(S7):S542–S546
Ó The Author 2011. Published by Oxford University Press on behalf of the
Infectious Diseases Society of America. All rights reserved. For Permissions,
please e-mail: [email protected].
1058-4838/2011/52S7-0011$14.00
DOI: 10.1093/cid/cir170
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(FDA) advisory committee hearings on telithromycin
made it clear that future antibiotic development of new
chemical entities would face new regulatory hurdles for
approval, with a focus on risks of unexpected clinical
effects. [4, 5] In June 2006, FA was initially considered for
development by Cempra and its scientific advisory board
as a marketed antibiotic that had proven to be safe and
effective in the treatment of MRSA infections but had
never been approved for use in the United States.
EVALUATION OF FUSIDIC ACID
Cempra’s initial evaluations of the chemical features of
FA revealed a steroidlike structure (Figure 1a), but the
stereochemistry at the ring junctions is different from
that for steroids, such that the FA ring system assumes
a unique boat configuration (Figure 1b). Early texts
often described an incorrect structure for FA, which was
in fact that of lumifusidic acid, an inactive isomer of FA
formed by exposure to intense light, which results in
a rearrangement around the C17–C20 double bond
(Figure 1c).
Evaluations of FA’s product profile revealed both
positive and negative features. Among its positive attributes, FA is a unique member of the fusidane class of
antibiotics with no known cross-resistance with any
other class of antibiotic [6–8]. Reports of its clinical use
outside the United States documented a track record of
Figure 1. (A), Fusidic acid (FA) has a steroidlike structure. (B), Actual configuration of FA, taking into account stereochemistry at the ring junctions;
these are different from those for steroids, forcing the ring system into a boat configuration. (C), Earlier texts often showed an incorrect structure for FA,
and in fact, the structure of lumifusidic acid.
safety for .4 decades [9–14]. It is highly bioavailable orally,
and has a long plasma half-life [15]. Its reported spectrum
of antimicrobial activity was narrow but sufficient for targeting S. aureus, including MRSA, and b-hemolytic streptococci
[16–20]. Streptococcus pyogenes, or group A b-hemolytic streptococci, are moderately susceptible to FA; minimum inhibitory
concentrations (MICs) are reported in a narrow range of 4–
8 lg/mL, and no resistance has been described. Although FA
has moderate in vitro activity against b-hemolytic streptococci,
it has demonstrated clinical efficacy in patients with b-hemolytic
streptococcal infections, and also in coinfections with S. aureus
[14]. These results can be explained by the relatively high and
sustained blood concentrations achieved after FA dosing. The
apparent clinical niche for this product included acute bacterial
skin and skin structure infections, osteomyelitis, and other infections where staphylococci are the predominant pathogens
[11, 14, 16, 21–25]. Importantly, it was also well known that
large doses of FA could be given safely for prolonged periods of
time [10, 11, 14, 22, 26].
However, it was widely published that resistance to FA
could occur during therapy and that this agent must be used
in combination with rifampin or other agents to prevent the
emergence of on-therapy resistance [17, 20]. High plasma
protein binding of FA (up to 97%) was thought to limit free
drug availability in infected tissues [15, 27]. FA was also
known to be metabolized and excreted by the liver and
to inhibit CYP3A4, suggesting possible drug interaction
issues [16].
Cempra scientists examined published reports [28] indicating resistance rates on the order of 1026–1027 when FA was
tested at twice the MIC, but much lower resistance frequencies,
on the order of 10211, when it was tested at 15–30 mg/L, concentrations of FA that could be safely achieved in plasma using
dosing regimens approved in the European Union (EU) [15].
However, when the effects of avid protein binding were taken
into consideration, it was evident that plasma levels of FA
.15–30 mg/L would be required to provide sufficient free
drug to limit the development of resistance in patients. A
Cempra-sponsored survey of US and Canadian S. aureus isolates showed that in Canada, where FA had been approved
for use for decades, the resistance rates were a manageable 8%,
while in the United States virtually all S. aureus isolates were
susceptible [8]. It was also noted that resistance was higher in
countries where topical FA was used (T. Louie, personal communication). Accordingly, Cempra decided to develop only
oral formulations of FA (CEM-102).
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SOURCING FUSIDIC ACID
The first hurdle was to obtain a supplier of FA, a fermentation
product that is difficult to synthesize commercially. Unable to
obtain supplies from Leo Laboratories, the innovator company,
Cempra established a business arrangement with Ercros (Ercros
Industrial) to obtain a supply of FA and obtain exclusive access
to this source for the US market.
APPROACHING THE FDA
Cempra, with hundreds of existing publications on FA, proceeded to consider a 505(b)(2) application strategy to obtain
approval and 5 years of market exclusivity for this product in the
United States. On meeting with the FDA, Cempra was advised
that old publications, without access to the supporting data,
could not serve as the basis for regulatory approval and that new
data were required to meet substantial parts of the nonclinical
and clinical requirements for a new drug application. After
consideration of the significant expense required to obtain
approval and market exclusivity in the United States for the
relatively short period of 5 years, Cempra nonetheless decided
that the commercial opportunity in the United States market
was significant. Forecasts indicated that FA revenues would be in
line with that expected from new patented antibiotic products,
which typically achieve sales of .$500 million within the first
3–4 years. Nonclinical development was begun, including animal toxicology studies, mutagenicity studies, microbiologic
surveillance, and other studies required for investigational new
drugs in the United States.
EXCLUSIVITY
Early in this process, though after significant work had been
performed to prove that FA could be a commercial success,
Cempra was informed by its regulatory lawyer that FA was
not eligible for Hatch-Waxman marketing exclusivity. The
FDA Modernization Act (FDAMA), which took effect on 21
November 1997, repealed section 507 of the Federal Food,
Drug, and Cosmetic (FD&C) Act, under which marketing applications for antibiotics were approved. With the enactment of
FDAMA, marketing applications for antibiotics are submitted
and approved under section 505 of the FD&C Act and are
eligible for Hatch-Waxman exclusivity. However, FA had been
the subject of a marketing application received by the FDA
under section 507 of the FD&C Act, before passage of the
FDAMA. Antibiotics that fell into this category, even those such
as FA, which were never approved in the United States, were
classified as ‘‘old’’ antibiotics and were not eligible for the exclusivity provisions afforded by section 505(c) [29]. Further
discussions with lawyers and the FDA confirmed that a
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congressional amendment to the law would be required for FA
to obtain market exclusivity in the United States.
AMENDING THE LAW
By February 2007, Cempra’s FA program came to a temporary
pause as the company considered its alternatives. Cempra’s
chemist (D.P.) challenged its president, Dr Fernandes, to speak
with elected representatives to change the law. Cempra’s data
showed that FA was too valuable to not pursue further and
decided to work toward amending US law to allow FA to obtain
Hatch-Waxman exclusivity.
Cempra sought the help of investors’ experts in Washington
DC and the IDSA to lobby for legislation to provide for
Hatch-Waxman exclusivity for ‘‘old’’ antibiotics that had never
received marketing approval in the United States. This
amendment was first proposed by Senator Burr, termed
the ‘‘Cempra Amendment,’’ and approved by the Senate and
House of Representatives [30]. It was attached to a larger
amendment being proposed by the IDSA and eventually added
to the bill for the major Prescription Drug User Fee Act
(PDUFA) [2]. This bill included many additional topics related
to antibiotic development and marketing and was strongly
endorsed by the IDSA. It was passed by the House and Senate
in September 2007 [30], but the Cempra Amendment, allowing
exclusivity for old antibiotics that had never been approved
in the United States, was removed at the last minute from the
PDUFA bill, and no changes were made to the law. The
amendment was administratively removed from the PDUFA
bill because the funding for the $14 million pay-as-you-go
(PAYGO) amount (which compels new tax changes to not
add to the federal deficit) had not been taken into account when
the bill came up for a vote in the House.
In the meantime, Cempra had conducted phase 1 studies in
Canada, where the drug is marketed, and had completed significant preclinical studies to include in an investigational new drug
application in the United States. Moreover, Cempra’s macrolide
program had also produced a lead compound that was clearly
differentiated from telithromycin. There was declining interest
among investors to push forward with the development of
FA because of difficulties in securing a viable period of market
exclusivity upon approval. Cempra’s macrolide candidate had
entered phase 1 trials, requiring significant funding, and FA was
becoming a drag on the limited resources of the company. Termination of the FA program was again considered.
REVISITING AND PASSING OF THE US
AMENDMENT
Although work on the FA product was slowed and almost
halted, Cempra decided not to abandon the program, and
continued to pursue passage of a Congressional amendment.
The ‘‘old’’ antibiotics exclusivity topic had to be reintroduced
into the Senate and House, and new champions in both houses
of Congress had to be found. Coincidently, Senator Edward
Kennedy was admitted to Duke Hospital at that time, and his
office was alerted to a publication in Clinical Infectious Diseases
reporting the high probability of suffering a postsurgical infection due to MRSA [31]. This publication was duly sent to
the Kennedy offices asking for support in reintroducing an
amendment. This time, funding for the $14 million PAYGO
amount was secured with the help of government consultants
and the Congressional Budget Office to help pay for the
amendment. In the summer of 2008, it was added to a supplemental Medicare bill, which was unanimously passed by both
houses of Congress [32]. In October 2008, President Bush signed
this bill into law (Public Law 110–379), reenergizing Cempra’s
further development of FA.
FUNDING TRIALS AND MOVING FORWARD
Despite this major legislative success, Cempra was still faced
with the significant challenge of raising money to fund the
clinical development of CEM-102 in the worst downturn in
the US economy since the Great Depression. Nonetheless, FA
was considered by its investors to be a safe and effective product
and relatively low risk compared with new chemical entities
in development. These investors were persuaded to stand fast
and support Cempra’s CEM-102 program based on FA’s known
mode of action, its extensive track record of clinical safety,
and its excellent activity profile against MRSA and other
pathogens. Investors wanted a safe bet on an important project,
and FA fit the bill. Cempra successfully closed a substantial
financing round in April 2009 and moved forward through
phase 2 trials [33].
A NEW DOSING REGIMEN: GIVING AN OLD
DRUG NEW TRICKS
Through the expertise of Drs Ronald N. Jones and Paul
G. Ambrose and their colleagues at JMI laboratories and
the Institute for Clinical Pharmacodynamics, respectively,
Cempra realized that dosing regimens used in Europe had
not been optimized. Pharmacokinetic-pharmacodynamic (PKPD) models were designed and executed to identify a new frontloaded dosing regimen that took advantage of FA’s nonlinear
PK-PD profile [34]. Some were concerned that high doses would
result in unacceptable nausea, as reported in some clinical
publications [23]. However, during Cempra’s phase 1 trials,
in which escalating doses of CEM-102 were tested in healthy
subjects, it was discovered that very high blood concentrations
of FA could be rapidly achieved without eliciting gastrointestinal
intolerance (nausea) using a novel front-loaded dosing regimen
[35]. By design, and as shown in phase 1 trials, initial loading
doses provided trough levels of FA near-steady state levels within
24 h and subsequent maintenance doses sustained these levels of
free drug at more than 10–20 times the MIC of target pathogens
[35]. This dosing strategy was also intended to minimize FA
resistance selection and obviate negative effects of protein
binding on FA activity. A patent application was filed to protect
this novel dosing regimen, and a phase 2 clinical trial was designed to evaluate this regimen along with the dosing regimen
that is approved outside of the United States. Linezolid was
chosen as the comparator for this trial, as it is the only oral
antibiotic approved for treating MRSA infections in the United
States [33].
VALUE CREATION FOR PATIENTS AND
INVESTORS
Cempra’s FA development saga may yet create real commercial
value for its investors, who have taken considerable risks under
uncertain and challenging circumstances. Unquestionably, this
potential value is due to the hard-earned opportunity to develop
an ‘‘old,’’ yet dose-optimized, oral antibiotic with 5 years of
exclusivity on approval of a new drug application as well as
protection by a novel loading dose patent for at least 18 years.
Beyond commercial value objectives, Cempra has overcome
many scientific, regulatory, and legal hurdles to meet one of the
most important current antibiotic needs within the United
States, as emphasized by the IDSA, public health care agencies,
and the medical community [1, 36]. Future studies will determine whether a novel FA formulation and dosing regimen
will perform as well as predicted by PK-PD modeling and early
clinical trial results. The results to date predict that it could be
a safe and effective oral alternative for the treatment of acute
bacterial skin and skin structure infections if approved and
marketed in the United States [33, 35].
Acknowledgments
The authors especially thank and acknowledge Dr Don Cox for suggesting that a change in the law was possible, Ms Nancy Buc, for Regulatory
Law guidance, Mr Stephen Conafay and Mr Joel Johnson for helping to
‘‘show the way’’ in Washington DC, and Ms Erin Fry for her tireless support
and resolve to never give up.
Supplement sponsorship. This article was published as part of a supplement entitled ‘‘Fusidic Acid Enters the United States,’’ sponsored by
Cempra Pharmaceuticals.
Potential conflicts of interest. P. F. is president and chief executive
officer and D.P. is vice president of chemistry at Cempra Pharmaceuticals.
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