1. Discovery and development of the world’s most powerful antiviral agent against shingles.
Submitting InstitutionCardiff University
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Organic Chemistry
Medical and Health Sciences: Medical Microbiology, Pharmacology and Pharmaceutical Sciences
Summary of the impact
A new family of antiviral agents, bicyclic nucleoside analogues (BCNAs),
discovered in Cardiff University has led to a highly potent anti-VZV
(shingles) molecule, FV-100. On a worldwide basis more than two million
patients are affected by shingles annually. FV-100 has successfully
completed Phase II clinical trials, showing it is safe, potent and
effective and with clinical advantages over the current standard of care.
FV-100 has received more than $30 million in R&D investment,
generating patents and creating highly skilled jobs in the UK and the USA,
with the parent company currently valued at $397 million. It will enter
registration trials in late 2013.
Discovery of novel antiviral agent
In the mid-1990s, researchers in the medicinal chemistry laboratory at
Cardiff University led by Professor Chris McGuigan (Reader 94-96 then
Professor of Medicinal Chemistry 1996 - present) discovered an entirely
new family of antivirals, the bicyclic nucleoside analogues (BCNAs). The
antiviral activities of Cardiff's BCNAs were screened in virology tests
performed by Professor Jan Balzarini and his team at the Rega Institute of
Katholieke Universiteit Leuven, Belgium.
These two collaborators filed a US and worldwide composition of matter
patent in 1997 and first reported their findings on the BCNA family in
1999 [3.1]. The Cardiff/Rega team found the alkyl BCNAs to be
potent and selective agents active against the Varicella zoster virus
(VZV), the cause of human chickenpox and shingles. This work was
unprecedented, the first ever report in either open literature or patents
regarding the antiviral action of the BCNAs. Indeed, only the H- and
Me-substituted parent compounds had previously been reported at all, and
they had been shown to be inactive in a range of biological assays.
The molecules synthesised in McGuigan's BCNA research programme
represented completely new chemical entities. The initial `hit molecule'
was about 250-times more powerful in vitro than the first-line
drugs against VZV, acyclovir and its valyl ester (Valtrex) [3.1].
Subsequent work to generate second generation aryl BCNAs revealed in 2000
that the lead candidate, Cf1743, was the most potent inhibitor of VZV ever
reported [3.2]. Cf1743 was roughly 10,000-times more active
than acyclovir in vitro; with detectable activity in assays at
concentrations below 1 nM. This molecule is currently one of the most
potent antivirals against any human pathogenic virus.
Cardiff University took the lead to exploit the potent anti-VZV BCNA
agents and licensed the patents to Fermavir Pharmaceuticals in August
2005. By 2005 Cardiff had committed over $250K in patent costs on the BCNA
family, a sum matched by an upfront payment by Fermavir. Fermavir
Pharmaceuticals was a New York based spinout specifically formed to
exploit the BCNA family. Fermavir was listed on NASDAQ in October 2005
with a market capitalisation at that time of $24M solely on the basis of
the Cardiff/Rega BCNA assets. Working with Fermavir, the Cardiff/Rega team
researched and developed FV-100 as a novel orally bioavailable pro-drug of
Cf1743 [3.3]. This R&D was highly collaborative with
McGuigan (Cardiff) carrying out drug design and synthesis, Balzarini
(Rega) performing the antiviral assay and various contract research
organisations (sponsored by the commercial partner) undertaking
pre-clinical regulatory work. Pre-clinical research and development on
FV-100 was completed in 2007, and the agent entered Phase I clinical study
Over 56 journal publications have arisen from the Cardiff BCNAs/VZV
research from the McGuigan lab (1999-2011). The lead references [3.1]
and [3.2] have each been cited over 120 times. Comprehensive
reviews were published in 2002 [3.4] and 2009 [3.5].
In addition, 45 patent international filings have been made at various
stages of the work [3.6].
References to the research
[3.1] McGuigan, C., Yarnold, C.J., Jones, G., Velázquez,
S., Barucki, H., Brancale, A., Andrei, G., Snoeck, R., De
Clercq, E. and Balzarini, J. Potent and selective inhibition of
varicella-zoster virus (VZV) by nucleoside analogues with an unusual
bicyclic base. J. Med. Chem. (1999) 42: 4479-4484. http://dx.doi.org/10.1021/jm990346o
[3.2] McGuigan, C., Barucki, H., Blewett, S., Carangio, A.,
Erichsen, J.T., Andrei, G., Snoeck, R., De Clercq, E. and Balzarini, J.
Highly potent and selective inhibition of varicella-zoster virus by
bicyclic furo pyrimidine nucleosides bearing an aryl side chain. J. Med.
Chem. (2000) 43: 4993-4997. http://dx.doi.org/10.1021/jm000210m
[3.3] McGuigan, C., Pathirana, R.N., Migliore, M., Adak, R.,
Luoni, G., Jones, A.T., Diez-Torrubia, A., Camarasa, M-J.,
Velazquez, S., Henson, G., Verbeken, E., Sienaert, R., Naesens, L.,
Snoeck, R., Andrei, G. and Balzarini, J. Preclinical development of
bicyclic nucleoside analogues as potent and selective inhibitors of
varicella zoster virus. J. Antimicrobial Chemotherapy (2007) 60:
(cited 30 times)
[3.4] Balzarini, J. and McGuigan, C. Bicyclic pyrimidine
nucleoside analogues (BCNAs) as highly selective and potent inhibitors of
varicella-zoster virus replication. J. Antimicrobial Chemotherapy (2002)
[3.5] Balzarini, J. and McGuigan, C. FV-100 as a new approach for
the possible treatment of varicella-zoster virus infection. J.
Antimicrobial Chemotherapy (2009) 64: 671-73.
The research work described above was supported in part by MRC grants
(total £157,000, 1996-2003) and by commercial grants from Fermavir
(£64,000, 2005-2008) and Inhibitex (part of an overall £1.27 million
investment into Cardiff laboratories, 2007-2013) with McGuigan serving as
PI on all grants. For example:
• McGuigan, C. (PI and sole investigator). The discovery of new
anti-herpetic agents. 2001-2003. MRC. £116K.
• McGuigan, C. (PI and sole investigator). Design, synthesis and
evaluation of novel antiviral nucleosides. 2005-2008. Fermavir Research
Details of the impact
The BCNA anti-VZV (shingles) research of McGuigan has underpinned
significant commercial impact during the assessment period with the
creation of wealth and highly skilled jobs within the biotechnology
sector; overseas industry has invested heavily in this novel technology.
Through the development of a potent anti-VZV agent the research is poised
to deliver near to market patient benefits; efficacy and safety in
patients has been demonstrated.
Although shingles involves a short-term acute phase it frequently has a
long and very painful recovery period. This post herpetic neuralgia (PHN)
phase will affect ca. 25% of patients who will still have shingles pain 90
days after infection. Indeed, shingles is not ideally treated with the
current first-line therapy of acyclovir or its prodrug Valtrex which
require high doses to be administered several times daily (e.g. acyclovir
800mg, 5 times daily). The initial clinical data for FV-100 shows it to
have superior efficacy for managing PHN which is one of the most
significant unmet needs in shingles treatment[5.1]. There are
approximately 1 million patients presenting with shingles p.a. in
USA/Europe with an estimated pharmaceutical market size ca. $750M p.a.
Clinical development and commercial impact
The discovery of the potent anti-VZV activity of BCNAs by McGuigan along
with his laboratory's contributions in the collaborative development of
Cf1743 and its counterpart pro-drug FV-100, have led to the successful
progress of a novel first-in-class potent anti-VZV agent through phase
I/II human clinical trials.
The effective collaborative research partnership between Cardiff/Rega and
Fermavir, and the promising outcomes of FV-100 in pre-clinical studies[5.2]
led the US pharmaceutical company Inhibitex Inc. to acquire Fermavir in
2007 [5.3] in a deal worth over $19 million[5.4].
Since FV-100 was Fermavir's only drug candidate asset, this places a
direct market valuation on the FV-100 candidate at that time. During the
assessment period itself Inhibitex invested research funding (ca. £280K
2008-12) to the McGuigan laboratories to support the FV-100 clinical
research programme [5.4]. In 2008 Inhibitex launched phase 1
safety/pharmacokinetic clinical trials in 50 healthy
volunteers. This work was followed by a major (ca. $10M) 350-patient
double-blind randomised study in shingles patients[5.4].
Two-thirds of patients received FV-100 at two doses. FV-100 was proven to
be a safe and effective therapeutic for VZV shingles at about one-tenth of
the dose and one-third of the dosing frequency of the current standard of
care (Valtrex). At 400mg once a day the incidence of PHN was reduced from
20% (Valtrex, 1g, 3 times a day) to 12%[5.1]. The use of
analgesics, including opiates, was also significantly reduced in the
FV-100 group. The continued success of FV-100 in Phase I and II clinical
studies (including a double-blind randomised study, see above) contributed
to the acquisition of Inhibitex by Bristol-Myers Squibb (BMS) [5.4,5.5].
Inhibitex's only other major asset was also designed in Cardiff's
laboratories, INX-189, a phase II anti-viral agent against the hepatitis C
virus. Based upon the positive outcome of the clinical trials FV-100 was
acquired from BMS (2012) for an undisclosed fee by Synergy Pharmaceuticals
(New York)[5.6], a NASDAQ listed company (currently valued at
$400M) with plans for a FV-100 registration trial for 2014 [5.7].
The development of anti-VZV BCNAs, including Cf1743 and FV-100, has been
driven by major financial investment from the commercial pharmaceutical
sector, creating wealth (realised through the three acquisition deals
related to FV-100 assets, see above) and highly skilled jobs in Cardiff
The Cardiff research funded by the MRC and Industry has led to the
commercial adoption of a new class of anti-VZV agent. Investment has been
significant and major multi-$M clinical trials have been undertaken.
Industry has been enhanced by this project, and we claim significant
commercial impact, and emerging health impact. FV-100 is poised for phase
III registration trials and represents the most potent agent currently
known versus VZV shingles, but human efficacy is already proven.
Sources to corroborate the impact
[5.1] Statement from physician and key opinion leader (University of
Alabama at Birmingham and USA Government advisor on in viral disease).
Perspective on current VZV (shingles) management and the place of FV-100
as an anti-VZV therapeutic.
[5.2] Contact - CEO, Biovitas, New York and former founder of Fermavir.
Corroboration of the effective research partnership between Cardiff/Rega
and Fermavir leading to acquisition of Fermavir by Inhibitex Inc., GA,
[5.3] Business Wire Press release: Inhibitex acquisition of Fermavir and
recognises the discovery of FV-100 in the Cardiff laboratory of McGuigan.
[5.4] Statement from former CEO Fermavir and former Senior VP Research
Inhibitex (now retired).
Corroboration of FV-100 as the only drug candidate asset in Fermavir at
the time of acquisition by Inhibitex (at $19 million) and thus
establishing the value of the FV-100 asset at the start of the assessment
period. Inhibitex's strategy of continued funding to the McGuigan
laboratories to support the development of FV-100. The positive outcomes
of the FV-100 clinical trials.
[5.5] Business Wire Press release: Acquisition of Inhibitex by
Bristol-Myers Squibb (BMS) for $2.5 billion with clear mention of FV-100
as one of the two drug candidates in Inhibitex at the time. The other
being INX-189, another Cardiff-McGuigan discovered drug.
[5.6] Synergy Pharmaceuticals Press Release: Acquisition of FV-100 from
BMS. The success of FV-100 in Phase II clinical studies and the companies
forward plans for the agent.
[5.7] Statement from President and CEO Synergy Pharmaceuticals.
Corroboration of how the positive outcomes of the FV-100 clinical trials
led to the acquisition of FV-100 by Synergy Pharmaceuticals. The
incorporation of a new company ContraVir to specifically develop FV-100
and plans for its registration trials in 2014.
All documents, testimony and webpages saved as PDFs are available from
the HEI on request.