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Wednesday 17 October, 2018

Pharming Group N.v.

Pharming Reports Positive Data From First


    Primary Endpoint was met, with rhC1INH treatment reducing neutrophil
gelatinase-associated lipocalin (NGAL), a widely recognized marker of acute 
renal damage 

    Pharming Group N.V. ("Pharming" or "the Company") (Euronext Amsterdam: 
PHARM) today
announced positive results from a Phase II investigator-initiated study of 
RUCONEST(R)
(recombinant human C1 esterase inhibitor, or "rhC1INH") in a double-blind,
placebo-controlled clinical trial in patients at risk of nephropathy resulting 
from
contrast-enhanced examinations.

    The study was led by Dr. Michael Osthoff at the University Hospital Basel, 
Basel,
Switzerland.  75 eligible patients with known moderate to severe renal function
impairment
were given either 50 units per kg (up to 4200 units) of RUCONEST(R) (n=37) or 
placebo
(n=38) immediately prior to treatment with standard-of care contrast medium as 
part of an
elective coronary angiography with or without a percutaneous coronary 
intervention ("PCI"),
 and then a second identical treatment four hours after the intervention .

    In the overall study, RUCONEST(R) showed a statistically-significant effect
(p= 0.038)
in reducing the rise in urinary Neutrophil Gelatinase-Associated Lipocalin 
(NGAL), the
primary endpoint for the study and a generally recognized early marker of acute
renal
injury, in patients with diagnosed renal function impairment undergoing 
interventions
enhanced with standard contrast media such as PCIs.

    The results were especially clear in the sub-group of patients (n=30) 
undergoing PCI.
The intent-to-treat analysis in this group showed that patients on RUCONEST(R) 
had a
median increase in peak urinary NGAL concentration within 48 hours of 1.8 ng/ml
compared
with an increase of 26.2 ng/ml in the placebo arm (p=0.04). This corresponds to
a clear
difference in the median percentage change in the peak urinary NGAL level within
48 hours
of 11.3% in the RUCONEST(R) arm and 205.2% in the placebo arm (p=0.001).

    The overall assessment of the study also showed trends that patients 
undergoing more
invasive interventions and procedures requiring higher volumes of contrast 
medium
experienced a stronger benefit from the RUCONEST(R) treatment.

    The treatment also showed an excellent safety profile comparable to the 
placebo group
- a particularly significant observation considering the high-risk patient group
included
in the study (average age approximately 77 years, with multiple comorbidities 
and impaired
kidney function)

    This data therefore supports additional clinical investigations for the use
of rhC1INH
in a new indication where there is significant unmet medical need.

    A secondary endpoint measured was Troponin T, a marker of cardiovascular 
damage caused
by the examination or intervention itself, but this did not show a meaningful 
difference
in the overall study population: the power of the study and the variety of 
interventions
applied were not suitable to perform an appropriate evaluation.

    Following these positive results, Pharming will continue discussions with 
Dr. Osthoff
and other experts in this area with the aim to perform further clinical 
development to
establish the efficacy and efficiency of RUCONEST(R) treatment in the patient 
group likely
to experience the greatest benefit.  Dr. Osthoff will be publishing the full 
results of
his study in due course.

    Dr Michael Osthoff, Basel University Hospital Basel, Basel, Switzerland and
Primary
Investigator, said: 

    "We are very pleased that we were able to provide an early proof-of-concept
that
dosing RUCONEST(R) ahead and following contrast enhanced investigations and 
interventions,
particularly in those patients that have to undergo PCI, may limit subsequent 
damage to
these patients' kidneys. We believe that these positive results merit further 
clinical
investigations and confirmation in a larger trial, and we are very keen to 
continue the
collaboration with Pharming."

    Dr Bruno Giannetti, Chief Operations Officer of Pharming, said: 

    "Reaching a significant difference already in a small number of patients in
this
well-run exploratory trial gives a surprisingly clear positive signal in what 
could become
a large new indication for RUCONEST(R).

    "Furthermore, invasive interventions requiring contrast medium applications,
like PCI,
are known to cause damage to organs like the kidney and the brain through small
thromboembolic events triggering complement cascade activation. RUCONEST(R) is a
recombinant form of the most important element of the body's own complement 
activation
braking system.  NGAL is a sensitive indicator to detect and assess this 
combined damage
in this particular situation. These results therefore also provide important 
predictive
information on the potential protective effects of RUCONEST(R) in a number of 
other
indications like pre-eclampsia or reperfusion injuries, in which complement 
activation is
thought to play an important role."

    As planned, Pharming has filed for regulatory approval in the Netherlands 
and shortly
also in Australia to begin the first clinical study of RUCONEST(R) in 
pre-eclampsia.

    About Contrast-induced Acute Kidney Injury ("CI-AKI") 

    Acute kidney injury (AKI) affects 13-18% of all patients admitted to 
hospital in
developed countries.  The estimated general incidence of CI-AKI is 
approximately 7%. Its
incidence may increase to >50% in the presence of risk factors such as 
chronic kidney
disease, diabetes mellitus and nephrotoxic drugs[1].  

    These estimates apply to over 38 million contrast-enhanced investigations in
the USA
alone, and around the same number in the rest of the world.  In practice, the 
vast
majority of the patients affected are those with existing kidney impairment, 
which is
estimated variously at between 13%-21% of the total.  This implies a potential
maximum
addressable market size of several million patients in each of those main 
markets.

    About Contrast-induced Nephropathy 

    Contrast-induced nephropathy (CIN) is a very serious form of AKI, a 
complication of
angiographic procedures resulting from the administration of contrast media. It
is the
third most common cause of hospital-acquired acute renal injury and represents 
about 12%
of the cases. CIN is defined as an elevation of serum creatinine of at least 25%
or
greater than or equal to0.5 mg/dl (44 mumol/l) from baseline within 48 h. The 
incidence of
CIN varies between 0 and 24% depending on a patient's risk factors. It is 
generally a
transient and reversible form of acute renal failure. However, the development 
of CIN is
associated with longer hospital stays and an increased morbidity and mortality,
in
addition to a higher financial cost. A meta-analysis that included 40 studies 
found a 6%
incidence of CIN after contrast-enhanced computed tomography (CT) scans, 9% 
after
peripheral angiography and 4% after intravenous pyelography. The incidence of 
CIN is low
in patients with normal renal function (0-5%).  However, several prospective 
controlled
trials reported an incidence of 12-27% in patients with pre-existing renal 
impairment.
Furthermore, in one study, an incidence as high as 50% was reported in patients
with
diabetic nephropathy undergoing coronary angiography in spite of the use of 
low-osmolar
contrast media and adequate hydration. Notably, up to 15% of those patients 
required
dialysis.[2]  

    The best care available today still results in very serious consequences for
some
patients (with 6%-11% proceeding to dialysis or worse outcomes depending on the
medium
used and their level of renal performance prior to the scan, according to 
various studies),
 although this is improving slowly as new less-damaging contrast media are 
introduced.

    About NGAL 

    NGAL (neutrophil gelatinase-associated lipocalin, also known as lipocalin-2
and as
siderocalin) is a protein involved in innate immunity
[https://en.wikipedia.org/wiki/Innate_immunity ] responses.  It is expressed in
neutrophils [https://en.wikipedia.org/wiki/Neutrophils ] and in low levels in 
the kidney
[https://en.wikipedia.org/wiki/Kidney ], prostate 
[https://en.wikipedia.org/wiki/Prostate ]
, and epithelia of the respiratory [https://en.wikipedia.org/wiki/Respiratory ]
and
alimentary tracts [https://en.wikipedia.org/wiki/Alimentary_tract ], including 
the renal
tubules. Renal expression of NGAL is dramatically increased in kidney injury 
from a
variety of causes, and NGAL is released primarily into both urine but also 
plasma. NGAL
levels rise very quickly after the event triggering kidney difficulty, making 
NGAL an
early and sensitive biomarker of kidney injury. Both plasma and urine NGAL 
concentrations
correlated highly with serum creatinine concentrations. Kidney biopsies in these
patients
showed intense accumulation of immuno-reactive NGAL in 50 % of the cortical 
tubules. These
results identified NGAL as a widespread and sensitive response to established 
AKI in
humans[3]. Specifically, the predictive utility of NGAL for AKI in CIN has been
confirmed
in a recent meta-analysis[4].

    About Pharming Group N.V. 

    Pharming is a specialty pharmaceutical company developing innovative 
products for the
safe, effective treatment of rare diseases and unmet medical needs. Pharming's 
lead
product, RUCONEST(R) (conestat alfa) is a recombinant human C1 esterase 
inhibitor approved
for the treatment of acute Hereditary Angioedema ("HAE") attacks in patients in
Europe,
the US, Israel and South Korea. The product is available on a named-patient 
basis in other
territories where it has not yet obtained marketing authorization.

    1. Source: Contrast Medium-Induced Acute Kidney Injury
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478328 ]: Umar Sadat, Ammara 
Usman,
Jonathan R. Boyle, Paul D. Hayes, Richard J. Solomon. Cardiorenal Med. 2015 Jun;
5(3):
219-228.

    2. Source: Contrast-induced Nephropathy
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969626 ]:  Nazar M. A. Mohammed,
Ahmed
Mahfouz, Katafan Achkar, Ihsan M. Rafie, Rachel Hajar. Heart Views. 2013 
Jul-Sep; 14(3):
106-116.

    3. Neutrophil gelatinase-associated lipocalin (NGAL): A new marker of kidney
disease
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528839 ]: Prasad Devarajan, Scand
J Clin
Lab Invest Suppl. 2008; 241: 89-94.  

    4. Neutrophil Gelatinase-Associated Lipocalin in the prediction of 
Contrast-Induced
Nephropathy, a systemic review and meta-analysis: Tong j, Li H, Zhang H et al, J
Cardiovasc Pharmacol 2015; 66: 239-45.

    RUCONEST(R) is distributed by Pharming in Austria, France, Germany, 
Luxembourg, the
Netherlands, the United Kingdom and the United States of America. Pharming holds
commercialisation rights in Algeria, Andorra, Bahrain, Belgium, Ireland, Jordan,
Kuwait,
Lebanon, Morocco, Oman, Portugal, Qatar, Syria, Spain, Switzerland, Tunisia, 
United Arab
Emirates and Yemen. In some of these countries distribution is made in 
association with
the HAEi Global Access Program (GAP).

    RUCONEST(R) is distributed by Swedish Orphan Biovitrum AB (publ) (SS: SOBI)
in the
other EU countries, and in Azerbaijan, Belarus, Georgia, Iceland, Kazakhstan,
Liechtenstein, Norway, Russia, Serbia and Ukraine.

    RUCONEST(R) is distributed in Argentina, Colombia, Costa Rica, the Dominican
Republic,
Panama, and Venezuela by Cytobioteck, in South Korea by HyupJin Corporation and
in Israel
by Kamada.

    RUCONEST(R) is also being examined for approval for the treatment of HAE in
young
children (2-13 years of age) and evaluated for various additional follow-on 
indications.

    Pharming's technology platform includes a unique, GMP-compliant, validated 
process for
the production of pure recombinant human proteins that has proven capable of 
producing
industrial quantities of high quality recombinant human proteins in a more 
economical and
less immunogenetic way compared with current cell-line based methods. Leads for
enzyme
replacement therapy ("ERT") for Pompe and Fabry's diseases are being optimized 
at present,
with additional programs not involving ERT also being explored at an early stage
at
present.

    Pharming has a long-term partnership with the China State Institute of 
Pharmaceutical
Industry ("CSIPI"), a Sinopharm company, for joint global development of new 
products,
starting with recombinant human Factor VIII for the treatment of Haemophilia A.
Pre-clinical development and manufacturing will take place to global standards 
at CSIPI
and are funded by CSIPI. Clinical development will be shared between the 
partners with
each partner taking the costs for their territories under the partnership.

    Additional information is available on the Pharming website:
http://www.pharming.com

    Forward-looking Statements 

    This press release of Pharming Group N.V. and its subsidiaries ("Pharming",
the
"Company" or the "Group") may contain forward-looking statements including 
without
limitation those regarding Pharming's financial projections, market 
expectations,
developments, partnerships, plans, strategies and capital expenditures. 

    The Company cautions that such forward-looking statements may involve 
certain risks
and uncertainties, and actual results may differ. Risks and uncertainties 
include without
limitation the effect of competitive, political and economic factors, legal 
claims, the
Company's ability to protect intellectual property, fluctuations in exchange and
interest
rates, changes in taxation laws or rates, changes in legislation or accountancy
practices
and the Company's ability to identify, develop and successfully commercialise 
new products,
 markets or technologies. 

    As a result, the Company's actual performance, position and financial 
results and
statements may differ materially from the plans, goals and expectations set 
forth in such
forward-looking statements. The Company assumes no obligation to update any
forward-looking statements or information, which should be taken as of their 
respective
dates of issue, unless required by laws or regulations. 

    For further public information, contact
Sijmen de Vries, CEO: T: +31-71-524-7400
Dr Bruno Giannetti: T: +31-71-524-7170

    FTI Consulting 

    Julia Phillips/ Victoria Foster Mitchell, T: +44-203-727-1136
LifeSpring Life Sciences Communication, Amsterdam, The Netherlands 
Leon Melens, Tel: +31-6-53-81-64-27

        PRN NLD



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