New anti-inflammatory drug for rheumatoid arthritis
Submitting InstitutionUniversity of Aberdeen
Unit of AssessmentBiological Sciences
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Immunology
Summary of the impact
The University of Aberdeen's discovery of a novel drug for the treatment
of rheumatoid arthritis and
related inflammatory/autoimmune disorders has brought substantial
industrial investment in
research and development. The new drug is expected to enter clinical
trials shortly and has the
potential to transform the way rheumatoid arthritis is currently treated,
as few patients currently
have access to the expensive biological agents which dominate existing
therapy. Aberdeen has
commercialised its research into a university spin-out company and
subsequently licensed the
programme to a UK drug-development company, Modern Biosciences plc. The
created and protected UK expertise and jobs.
The specific impacts on commerce have been: substantial industrial
investment in research and
development, job creation and protection within UK industry,
commercialisation of a new product
via a licencing deal, and academic consultancy in industry.
Rheumatoid Arthritis (RA) is a chronic, progressive and disabling
condition affecting 165 million
people worldwide. Along with other common immune disorders such as
inflammatory bowel disease, RA has proved difficult to treat because of
the high cost of available
therapies, to which more than 80 per cent of patients are not given
Research carried out at the University of Aberdeen has provided evidence
drugs may be just as effective as expensive biological agents in treating
autoimmune disease. The
research grew out of work begun in 1999, sponsored by the company Nicox on
HCT1026 (a nitric oxide-generating derivative of an anti-inflammatory drug
related to ibuprofen)
developed to treat pain associated with osteoarthritis, without causing
stomach ulcers. This was a
natural area for Aberdeen to explore as it is a recognized world-leader in
musculoskeletal research. Observations suggested that the drug in question
also prevented bone
loss. Dr Iain Greig, Senior Research Fellow at Aberdeen's Institute of
Medical Sciences and now
Head of Operations at the Kosterlitz Centre for Therapeutics there, joined
the University in 1998
and became involved in this research in 2000 when it was clear there was
with Aberdeen's bone research. The medicinal chemistry Greig provided
helped lead to the
discovery of a number of highly potent novel compounds that had
therapeutic potential for the
prevention of bone loss [1 to 3] and [b].
As part of a project team that also included Professor Stuart Ralston and
Dr Rob van`t Hof — both of
whom moved to Edinburgh University in 2005 — Greig embarked on a drug
programme aimed at taking these compounds into the clinic for the
treatment of osteoporosis.
Fundamental studies on the mode of action of these compounds led to the
discovery that the drugs
acted at a point shared between the pathways involved in activating the
cells that cause bone loss
and the activation of the immune system found in rheumatoid arthritis. The
team then re-focused
their efforts in this direction, generating compounds, biphenylketones [4,
5] and [c, e, i] and
biphenylsulfonamides  and [d], which act by a novel mechanism,
targeting a previously
unexplored factor in the signalling pathway that regulates immune cells
. Precise details have
not been revealed because of commercial sensitivities surrounding what
would be a first-in-class
drug. A further series of compounds, triarylsulfonamides  [f], were
developed which met the
stringent requirements of the pharmaceutical industry prior to licensing.
Greig and the University of Aberdeen created the spin-out company OsteoRx
Ltd and licensed
these compounds to Modern Biosciences, which embarked on a development
programme in 2008.
Under this licence agreement, Greig initially continued to provide
medicinal chemistry support at
Aberdeen. Utilizing the expertise and insight he had built up during many
years of working on the
project, he discovered two further compound classes whilst trying to
resolve a potential
toxicological liability and a metabolic liability. Both liabilities were
successfully replaced with other
chemical moieties. The medicinal chemistry was then transferred to a
number of providers, mostly
conducted by a UK company, Peakdale Molecular, with guidance from Greig.
References to the research
 van `t Hof RJ, Idris AI, Ridge SA, Dunford J, Greig IR and Ralston SH
(2004). Identification of
biphenylcarboxylic acid derivatives as a novel class of bone resorption
inhibitors. J. Bone Miner.
Res., 19, 1651-1660. Paper detailing the discovery of an
entirely new class of therapeutic agents
against a novel biological target, and demonstration of anti-resorptive
properties in a model for
post-menopausal bone loss.
 Idris AI, van 't Hof RJ, Greig IR, Ridge SA, Ross RA, Ralston SH.
(2005). Regulation of bone
mass, bone loss and osteoclast activity by the cannabinoid CB1 receptor. Nat.
Med., 11, 774-779.
Highly cited paper (146 citations) showing the first evidence of a role
for the cannabinoid system in
regulation of bone metabolism, and potential for targeting this in the
treatment of osteoporosis.
 Greig IR, Idris AI, Ralston SH and van `t Hof RJ. (2006). Development
and characterization of
biphenyl sulfonamides as novel inhibitors of bone resorption. J. Med.
Chem., 49, 6487-7492.
Paper showing the development, quantitative structure activity
relationship (SAR: a highly-accurate
mathematical model for predicting potency) and anti-resorptive
properties of the first highly potent
and metabolically-stable compounds against the target described in ref
 Idris AI, Greig IR, Bassonga-Landao E, Ralston SH and van `t Hof RJ.
(2009). Identification of
novel biphenyl carboxylic acid derivatives as novel antiresorptive agents
which do not impair PTH
induced bone formation. Endocrinology, 150, 5-13. Paper
demonstrating that these compounds
not only prevented bone loss, but that the effect was additive with
agents encouraging bone gain,
giving additional increases in bone density over that possible with
 Greig IR, Coste E, Ralston SH and van 't Hof RJ. (2010). Discovery of
biphenylketones as dual
modulators of inflammation and bone loss. Bioorg. Med. Chem. Lett.,
20, 5548-5551. Paper
showing the development, SAR, anti-inflammatory and anti-resorptive
properties (in models for
rheumatoid arthritis and post-menopausal bone loss) of the first small
molecule compounds with
the potential to treat both rheumatoid arthritis and associated bone
 Greig IR, Coste E, Ralston SH and van 't Hof RJ (2013). Development
of triarylsulfonamides as
novel anti-inflammatory agents. Bioorg. Med. Chem. Lett., 23,
816-820. Paper showing the
development, structure activity relationship (SAR) and anti-inflammatory
properties (in a model for
rheumatoid arthritis) of the compounds which facilitated
commercialisation and were taken forward
into pre-clinical development.
Key grant funding associated with the research
• Technology Strategy Board, Biomedical Catalyst (2012-2015),
£1,562,595, matched with approximately £1,200,000 from IP Group plc [a]
• Modern Biosciences: Novel Anti-inflammatory agents, Greig IR,
(2007-2011), direct income
£54,130, total investment in project to date >£2 million, (outsourced
in vivo studies,
pharmacokinetics, synthetic chemistry and patent fees; not including other
costs such as
company overhead costs of £500k pa, a major proportion of which can be
attributed to this
• NESTech (Scottish Universities Challenge Fund): Novel Bone
Resorption Inhibitors; Greig
IR and E. Rattray, (2006-2008), £198,768
• Arthritis Research Campaign: Small molecule inhibitors of TNF
signalling as novel anti-rheumatic
agents; van `t Hof RJ, Ralston SH, Greig IR and Idris AI, (2005-2007),
• Scottish Enterprise, Proof of Concept,RSE Enterprise Fellowship
(Greig) and Proof of
Concept Follow on: Novel Bone Resorption Inhibitors, Greig IR, van
`t Hof RJ, Ralston SH
and E. Rattray, (2002-2006), £285,869
Details of the impact
The research at the University of Aberdeen has given the pharmaceutical
industry a new paradigm
for the treatment of rheumatoid arthritis and other inflammatory /
autoimmune disorders. The
research identified a completely novel mechanism of action and biological
target for the treatment
of RA, which is now being translated into the next generation of drugs for
fighting the disease.
Compounds being taken forward to clinical trials were designed and
synthesised at Aberdeen,
which has received commercial investment in further research and
development via a spin-out
company and a licensing deal. UK jobs have been created and protected, and
academics with the
relevant expertise have taken on new consultative roles in industry.
A licensing and co-development deal was reached in 2007 with Modern
Biosciences [a], a drug
development company which sources late-stage discovery projects from
academia and start-up
companies, conducts early proof-of-principle clinical studies and
out-licenses the resulting
programmes to the pharmaceutical and biotechnology industries. The deal
has brought potential
investment into the research of nearly £5 million, which will take the
programme to a point of filing
an Investigational New Drug application, after which additional funds will
be sought to take a
candidate drug into Phase 1 and 2a studies, designed to prove safety and
These trials are expected to begin within a year, but tangible patient
benefits may still be several
years away. Precedent deal values for products at a similar stage of
development (Phase 2a) have
reached as much as $600 million and the market worth for this product is
estimated at over £5
billion [a]. Of course, the uncertainty of the market for new
pharmaceutical products means that it
is difficult to make precise predictions about either the financial
returns or the likely timescale of
The funding the research has attracted includes over £2 million from
Modern Biosciences for the
programme itself, with a further £1.6 million from the government-backed
award [a], which was launched in 2011 with the aim of boosting growth in
the UK life sciences
sector. This award is to be matched by IP Group plc, a UK intellectual
property company which
aims to develop technology innovations in partnership with university
research departments and
which is MBS' lead investor. Separately, the research brought in direct
grant funding of £600,000
to Aberdeen University, enabling further drug discovery projects.
In terms of jobs created, this has meant six full-time posts, and a
further four expected over the
next two years, at a UK medicinal chemistry contract research
organisation, Peakdale Molecular
[a]. It is particularly encouraging that such expertise has been protected
from the general trend
towards outsourcing work to lower cost overseas organisations. Greig was
taken on as an
intellectual property consultant by Modern Biosciences, a role which
involved writing patents. He
has continued to write [g - i] and manage a portfolio of 8 published
patents [b - i], of which all have
been granted, and two further recent filings. Greig was also taken on as a
consultant by Modern Biosciences, initially providing hands-on synthesis
at Aberdeen (most of [g]
and much of [h]) and then more recently advising on drug design, with
synthesis conducted by
contract research organizations [a].
Commercial sensitivities on the part of Aberdeen's industry partners have
precluded media or other
public engagement about the potential patient benefits of the research.
Claimed impact as defined by REF: Industry has invested in research
and development; a new
product has been commercialised by the University of Aberdeen, via
spin-out and a licensing deal;
UK jobs have been created and protected; skilled people have taken up a
specialist role (via
academic consultancy) in industry; and a new process (in terms of a new
paradigm for the
treatment of rheumatoid arthritis) has been taken up by industry.
Sources to corroborate the impact
[a] Testimonial from Chief Executive Officer at Modern Biosciences. This
describes the importance
of research performed at Aberdeen for project development, investment and
number of jobs
Details of the TSB Grant can be found at the following site, searching
[b] Ralston SH, Greig IR, van `t Hof RJ and Armour KJ. Alkane diol
derivatives as therapeutic
agents for the treatment of bone conditions. Patent: WO03/037321 (2001).
Granted US 29-06-10.
Covers compounds shown in .
[c] Ralston SH, Greig IR, Mohamed AI and van `t Hof RJ. Ketones and
reduced ketones as
therapeutic agents for the treatment of bone conditions. Patent:
WO2004/098582 (2003). Granted
US 11-08-09. Covers compounds shown in [4 and 5].
[d] Ralston SH, Greig IR, Mohamed AI and van `t Hof RJ. Alkyl aryl
sulfonamides as therapeutic
agents for the treatment of bone conditions. Patent: WO2005118528 (2004).
Granted US 21-06-09.
Covers the compounds described in .
[e] Greig IR, Ralston SH and van `t Hof RJ.
related compounds and their use as therapeutic agents. Patent US2008221220
14-07-09. Covers a small subset of compounds shown in 
[f] Greig IR, Ralston SH and van `t Hof RJ. Biphenyl-4-yl-sulfonic acid
arylamides and their use
as therapeutic agents. Patent WO2008/114022 (2007). Granted US 03-09-13.
compounds shown in .
[g] Greig IR, Clase JA, Fisher R, Sheridan RM, Smith A, Tozer MJ and
Tuffnell AR and van `t Hof
RJ. Aryl-phenyl-sulfonamide-cycloalkyl compounds and their use, Patent:
(2008). Granted 07-05-13. Covers compounds being taken forward into
[h] Greig IR, Clase JA, Fisher R, Sheridan RM, Smith A, Tozer MJ,
Tuffnell AR and van `t Hof RJ.
Aryl-phenyl-sulfonamide-phenylene compounds and their use. Patent:
Granted 26-06-12. Covers compounds currently being developed as backups.
[i] Ralston SH, Greig IR, Mohamed AI and van `t Hof RJ. Ketones and
reduced ketones as
therapeutic agents for the treatment of bone conditions. US Divisional:
Granted 06-10-09. Covers the use of compounds shown in .
The above patent references are given to corroborate the impact. For
simplicity, only dates of US
grants are given as examples. Details of other territories in which these
are being prosecuted,
including European States and Japan, can be found on the European Patent
The costs associated with filing and prosecuting patent
applications can only be borne where there is substantial value in the
project; to have a portfolio of
8 international patents is a very significant financial commitment. All of
the patent applications
have been granted or allowed, demonstrating that the research had novelty,
utility and inventive