Establishment of Photopharmica Ltd. to exploit novel photosensitising dyes as photoactivatable antibacterial therapeutics
Submitting InstitutionUniversity of Leeds
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology, Microbiology
Medical and Health Sciences: Clinical Sciences
Summary of the impact
Leeds researchers discovered a novel class of tissue penetrating,
light-activated dyes that were selectively and rapidly taken up by
bacteria. Based on the dyes' promising antimicrobial activity, the
University of Leeds span-out Photopharmica Ltd. Further research at Leeds
has progressed the development of a targeted antimicrobial for chronic
wound infections. Photopharmica has raised £11.5M in external investment,
around £6.0M of which has been deployed since 2009 to support a 57 patient
phase IIb clinical trial. The results, which showed substantially reduced
loads of all bacterial species, led to a further £250K investment in 2012
to support Photopharmica's strategy to bring an antimicrobial drug to the
A new class of bioactive photosensitising dyes
In the mid-1990s, an interdisciplinary research collaboration at the
University of Leeds between the groups of Professor John Griffiths
(Department of Colour Chemistry then School of Chemistry) and Professor
Stan Brown (Department of Biochemistry at the time) led to the discovery
of novel photosensitising dyes that were capable of generating singlet
oxygen efficiently with (red) light of a wavelength needed for good tissue
Recognising the potential of these dyes in photodynamic therapy (PDT),
the researchers received substantial grants from Yorkshire Cancer Research
from 1998 (£3.5M, including a programme grant). PDT requires the
combination of light and a photosensitiser drug to achieve a therapeutic
effect; the mechanism involves absorption of light by the photosensitiser,
activation of molecular oxygen by the excited photosensitiser, and damage
by the resulting highly reactive singlet oxygen leading to cell death. The
need for a light source ensures that the process can be targeted precisely
to the site of disease. This funding supported research by Griffiths and
his colleagues to develop synthetic methods for the systematic preparation
of water-soluble photosensitising dyes including phenothiaziniums(1) and
phthalocyanines (2,3) In parallel with these synthetic studies, between
1996 and 2001, Brown's research group carried out experiments to evaluate
the cellular uptake and in vitro photodynamic activity of these
compounds for potential applications as anticancer or antimicrobial
The collaborative team demonstrated the value of the novel
photosensitisers as photoactivatable antimicrobial agents, and optimised
their activity. Bacteria can be classified into two broad groups - Gram
positive and Gram negative bacteria - and dangerous pathogens are found in
both classes. Although it was well known that some photosensitising dyes
were active against Gram positive bacteria, none had previously been found
active against Gram negative bacteria. The novel photosensitisers are
active against Gram negative bacteria, Gram positive bacteria (including
antibiotic resistant bacteria such as methicillin-resistant Staphylococcus
Aureus, MRSA) and fungi. Research conducted at Leeds showed that
both Gram positive and Gram negative bacteria could be killed provided
that the photosensitiser was cationic (4). Through a process of systematic
structural modification, with parallel in vitro and in vivo
screening, detailed structure-activity relationships were established.
Specific phenothiaziniums, with far superior antibacterial activities
compared to other known photosensitisers, were discovered, including the
subsequent candidate agent PPA904 (5). A crucial advantage of these
compounds, which made them suitable for treating infected tissue, was
their highly selective uptake by bacteria compared to mammalian cells.
This intellectual property was transferred to the University spin-out
company Photopharmica Limited and followed up by a range of national and
regional applications. Photopharmica was established in 2001 to continue
the clinical development of the candidate agent PPA904. The class of
photosensitising dyes were patent protected worldwide through a patent
cooperation treaty (PCT) application (5), with Brown and O'Grady as named
Phase IIa clinical trial
The first clinical trial, funded by Photopharmica, focused on the
treatment of chronic infected leg and foot ulcers; it took place in 2004
under the `DDX' (`Doctors and Dentists Exemption') rules which allowed
clinicians to use the experimental therapy on a named patient basis. This
DDX study involved nine patients, and led to regulatory approval of a
Phase IIa clinical trial. The Phase IIa clinical trial, involving 32
patients from three centres (16 with chronic leg ulcers and 16 with
diabetic foot ulcers), was led by Professor Lesley Rhodes (University of
Manchester) and was undertaken in 2005-2007. Clinicians from Dundee,
Manchester and Leeds carried out the clinical work with support from both
Griffiths and Brown. This trial demonstrated a significant reduction of
bacterial load in patients (6).
Department of Colour Chemistry/School of Chemistry
Griffiths (Lecturer 1969-81, Senior Lecturer 1981-99, Professor 1999-2004,
Research Professor (part time) 2004-12)
Stephen Gorman (2001-8), Russell
Cox (1998-2000), Jack Schofield (1992-2004) (Research Fellows)
Department of Biochemistry/Faculty of Biological Sciences
Professor Stan Brown (Professor of Biochemistry 1971-2009)
(1995-2010), Simon Wood (1991-1996), Kirste Mellish (1998-2003), Denise
(1998-1999) (Research Fellows), Andrea Bell (Technician 1998-2002,
Research Fellow 2002-10)
Andrew Minnock (1991-1995), Cassandra O'Grady
(2000-3) (PhD students)
Key research grants and funding
i. "Programme grant", Yorkshire Cancer Research, PI: Prof. S. Brown,
ii. "Photodynamic therapy", Yorkshire Cancer Research, PI: Prof. S.
Brown, 1998-2005, £500k.
iii. "Lasers for photodynamic therapy", Yorkshire Cancer Research, PI:
Prof. S. Brown, 1998-2003, £150k.
iv. Yorkshire Cancer Research, PI: Prof. S. Brown, 1998-2005, £500k.
v. Yorkshire Cancer Research, PI: Prof. S. Brown, 2002-2006, £230k.
Grants from Yorkshire Cancer Research are awarded following extensive peer
review on a competitive basis, provided the proposed research meets
stringent quality criteria.
References to the research
1. S.A. Gorman, A. L. Bell, J. Griffiths, D. Roberts, S.B. Brown, The
synthesis and properties of unsymmetrical 3,7-diaminophenothiazin-5-ium
iodide salts: Potential photosensitisers for photodynamic therapy, Dyes
and Pigments 2006, 71, 153-160. (10 citations; Source:
2. D J Ball, S Mayhew, S R Wood, J Griffiths, D I Vernon and S B Brown, A
comparative study of the cellular uptake and photodynamic efficacy of
three novel zinc phthalocyanines of differing charge, Photochemistry
and Photobiology, 1999, 69, 390-396. (51 citations; Source:
Scopus, 24/10/13) http://dx.doi.org/10.1111/j.1751-1097.1999.tb03303.x
4. A. Minnock, D.I. Vernon, J. Schofield, J. Griffiths, J. H. Parish and
S. B. Brown., Photoinactivation of bacteria. Use of a cationic
water-soluble zinc phthalocyanine to photoinactivate both Gram-negative
and Gram-positive bacteria, J. Photochem. Photobiol. (B) 1996, 32,159-164.
(206 citations; Source: Scopus, 24/10/13) http://dx.doi.org/10.1016/1011-1344(95)07148-2
5. S. B. Brown and C. C. O'Grady, Biologically active methylene blue
derivatives, International PCT application WO02096896. This application
established a filing date in all contracting states and was followed up by
the filing and granting of national and regional patents (see
corroborative evidence A).
6. S. Morley, J. Griffiths, G. Philips, H. Moseley, C. O'Grady, K.
Mellish, C. L. Lankester, B. Faris, R. J. Young, S. B. Brown and L. E.
Rhodes, Phase IIa randomized, placebo-controlled study of antimicrobial
photodynamic therapy in bacterially colonized, chronic leg ulcers and
diabetic foot ulcers: a new approach to antimicrobial therapy, Brit.
J. Dermatol. 2013, DOI: 10.1111/bjd.12098. (0 citations; Source:
All papers are in internationally-leading peer-reviewed journals and are
hence ≥2*, but references 2-4 are particularly highlighted by the UoA to
demonstrate the quality of the underpinning research.
Details of the impact
Context - a large market
Chronic wounds such as infected leg ulcers represent a significant burden
to patients and to healthcare systems throughout the world. A study in Nursing
Times (Nursing Times 2008, 104, 44- 45) describes the
impact of chronic wounds on a representative healthcare system:
approximately 200,000 patients in the UK have a chronic wound and the cost
of caring for these patients is conservatively estimated at £2.3-3.1
billion per year i.e. around 3% of total NHS expenditure. The cost of
treating those patients with venous ulceration, mostly in primary care and
through community nursing services, is over £168-198 million per year.
Pain and odour can affect quality of life, and these common symptoms are
frequently associated with poor sleep, loss of mobility and social
As described in Section 2, the candidate photodynamic therapeutic PPA904
stems from the discovery and initial evaluations of the new class of
photosensitising dye by Brown, Griffiths and colleagues. Subsequent
studies by the Leeds team revealed that these dyes have properties which
made them suitable for photodynamic therapy (PDT). The candidate agent
PPA904 was identified as part of targeted chemical modifications led by
Griffiths and laboratory antimicrobial screening studies led by Brown (5).
The intellectual property generated by the two research groups was
transferred to the spin-out Photopharmica for further development in 2001.
Patents have been granted in all major territories in the world,
all of which are current and are owned by Photopharmica, covering the
application of specific phenothiazinium photosensitisers in photodynamic
Commercial impact - job creation
Photopharmica successfully raised £11.5M of external investment from IP
Group PLC and others to support its research and development programme,
£6.25M million of which has been deployed since 2008 (E,F) (see below).
Some of these funds have supported further research and development of
PPA904 and other candidate photosensitisers by researchers at the
University of Leeds (outlined in Section 2).
The establishment of Photopharmica as a viable spin-out company
has also created jobs. Since 2008, Photopharmica has employed on
average 8 employees according to the needs of its R&D cycle, and
additional personnel have been employed at contract research organisations
providing services to support its clinical trials (F).
Health benefits - reducing infectious bacteria
Between 2009 and 2011, Photopharmica deployed around £6.0M to fund a Phase
IIb trial of antimicrobial photodynamic therapy involving PPA904 in the
treatment of chronic leg ulcers. Thus, a new drug was trialled with
patients. This trial involved 11 leading UK institutes and recruited
57 patients at seven sites across the UK (G).
The trial showed that subjects receiving weekly PPA904 treatment (with
light activation) showed a statistically greater reduction in the total
load of bacteria in the wound compared to placebo and light. Crucially,
significantly fewer PPA904-treated patients (compared to placebo)
experienced post-treatment bacterial load levels above the recognised
clinical threshold for prevention of wound healing. Significantly fewer
PPA904-treated patients experienced very high post-treatment bacterial
load levels, suggesting that PPA904 may reduce the risk of acquiring an
infection. All bacterial species, including MRSA, were substantially and
significantly reduced (H).
The trial reported that the treatment was well tolerated and no safety
concerns were raised by the independent Data Safety Monitoring Board.
Analysis of wound area and quality of life scores showed that the
treatment had no adverse effect on either (H).
Commenting on this trial, the Head of Wound Healing at Cardiff University
Medical School, Chief Investigator on the trial and Editor-in-Chief of
International Wound Journal commented: "In 30 years in the wound
healing field, I have never seen a topical treatment with efficacy
anywhere near that which Photopharmica has demonstrated. Very few
significant advances have been made in this field over the last decade;
I believe the Photopharmica technology is the disruptive change needed."
Following these promising Phase IIb clinical trial results, in December
2012, Photopharmica raised a further £250K in external investment to
source an acquisition and/or co-development partner to help bring a novel
photodynamic antimicrobial to market (E,F).
Sources to corroborate the impact
A. The international PCT application WO02096896 (S. B. Brown, C. C.
O'Grady, J. Griffiths, K. J. Mellish, R. G. Tunstall, D. J. H. Roberts and
D. I. Vernon, "Biologically Active Methylene Blue Derivatives")
established a filing date (30.5.2002) in all contracting states. It was
followed up by a range of regional and national applications, including
the following granted patents: (a) AU2002256784 (Austrailia; filed
30.5.2002, granted 12.7.2007); (b) AU2007221946 (Australia; filed
11.10.2007, granted 1.4.2010; (c) CA2448303 (Canada; filed 25.11.2003,
granted 13.7.2010); (d) CN100491362 (China; filed: 30.5.2002, granted
27.5.2009); (e) EP1392666 (Europe; filed 30.5.2002, granted 28.2.2007);
(f) HK1063788 (Hong Kong; filed 1.9.2004, granted 29.6.2007); (g)
JP4554198 (Japan; filed 30.5.2002, granted 29.9.2010); (h) KR100957260
(Korea; filed 15.1.2009, granted 12.5.2010); (i) NO324321 (Norway; filed
28.11.2003, granted 24.9.2007); (j) NZ529682 (New Zealand; filed
24.11.2003, granted 13.7.2006); (k) US7915254 (US; filed 4.4.2008, granted
29.3.2011); (l) US7855197 (US; filed 28.6.2008, granted 21.12.2010); (m)
US8188074 (US; filed 12.5.2008, granted 29.5.2012); (n) US7732439 (US;
filed 10.7.2008, granted 10.5.2010); (o) US7371744 (US; filed 26.11.2003,
granted 13.5.2006); (p) ZA200309215 (South Africa; filed 26.11.2003,
B. The international PCT application WO2006032848 (J. Griffiths, S. A.
Gorman and A. L. Bell, "Photosensitisers and Their Uses") established a
filing date (14.9.2005) in all contracting states. It was followed up by a
range of regional and national applications, including the granted patent
US7407948 (US; filed 20.3.2007, granted 5.8.2005), which are currently
C. The international PCT application WO0224226 (S. B. Brown, A. L. Bell,
J. Griffiths and J. Schofield, "Photosensitisers") established a filing
date (21.9.2001) in all contracting states. It was followed up by a range
of regional and national applications, including the following granted
patents: (a) AU2001287915 (Australia; filed 21.9.2001, granted
24.11.2005); (b) CA2423252 (Canada; filed 20.3.2003, granted 20.1.2009);
(c) EP1320383 (Europe; filed 21.9.2001, granted 13.6.2007); (d) US7276494
(US; filed 21.3.2003, granted 2.10.2007).
D. The international PCT application WO2006032847 (S. B. Brown and C. C.
O'Grady, "Wound Healing") established a filing date (14.9.2005) in all
contracting states. It was followed up by a range of regional and national
applications, including the following granted patents: (a) EP1797053
(Europe; filed 15.9.2005, granted 3.11.2010); (b) JP5118967 (Japan; filed
14.9.2005, granted 16.1.2013); (c) US7407953 (US; filed 20.3.2007, granted
E. Statement, Business Development Manager, IP Group PLC, 1st
F. Statement, Senior Programme Manager, Photopharmica Ltd, 1st
G. "Clinical Trial to Investigate Treatment With Photodynamic Therapy to
Reduce Levels of Bacteria in Leg Ulcers", ClinicalTrials.gov identifier:
H. Statement, Chief Investigator, Phase IIb clinical trial; Director,
Institute for Translation, Innovation, Methodology and Engagement,
University of Cardiff; and Head, Wound Healing Research Unit, Dept. of
Dermatology and Wound Healing, Univ of Cardiff, 29th January
I. Press releases: (a) http://www.photopharmica.com/latest_news.htm
(accessed 4.12.12); and (b) http://www.ipgroupplc.com/media-centre/ip-group-news/2011/2011-10-05