Boehringer Ingelheim Animal Health The feline chronic kidney disease (CKD) segment
First to Know information package Part 1
March 2013
Introduction Cats have an innate predisposition for certain chronic conditions, such as CKD, hypertension, hyperthyroidism and osteoarthritis. Combined evidence, based on peer reviewed publications and in-depth market research, suggest that up to 10% of the general cat population and as much as 35% of geriatric cats suffer from CKD. Unfortunately, CKD is often diagnosed in later stages of disease as overt clinical signs only become apparent once more than 66% of kidney function is lost.1 The limited treatment options currently available don’t typically deliver
Boehringer Ingelheim Animal Health, a leading provider of innovative veterinary pharmaceuticals, is proud to offer a new alternative in the medical management of feline chronic kidney disease (CKD). Soon, Semintra®, the first veterinary registered angiotensin receptor blocker (ARB) for the reduction of proteinuria associated with CKD in cats will be introduced in Europe after having received a unanimous positive opinion from the European Medicines Agency in 2012.
the prompt or dramatic clinical improvement desired in these cases. In addition, the administration of chronic medication presents a challenge for both cat and owner. These factors have contributed to a feeling of discouragement among veterinarians and owners treating cats with CKD. Studies have shown a significant correlation between proteinuria and survival in cats with CKD, even at low protein concentrations.2 The risk of mortality increases with severity of proteinuria, making proteinuria one of the most important prognostic factors for CKD progression.3
With this first part of the Semintra® information package, we are providing you with some background market research on feline CKD and some first scientific details about this groundbreaking new product. Further information will follow in the coming months regarding pharmacodynamics, pharmacokinetics, and the excellent safety profile of this new molecule.
We look forward to offering you a state-of-the-art solution for the management of proteinuric cats suffering from CKD. By addressing the current therapeutic challenges and supporting treatment compliance in cats with CKD, we hope to enable you to improve the future of your feline patients and their owners.
2
Market research
3
Market research – Feline CKD Current market research confirms that CKD is a common condition in cats, accounting for approximately 13 visits per practice per month, including 4 newly diagnosed cases.4
Table 1 Average number of feline CKD patients, previously or newly diagnosed, seen by veterinarians per month in the UK, Germany and France.4
Average number of CKD patients per month
15
13
10
Existing cases
10 5
9 4
7 3
New cases Cats with CKD often remain undiagnosed and untreated until later stages of disease when clinical signs become apparent to owners.5 Once clinical signs of CKD are present, 66-75% of the functional nephrons have been destroyed.1 Although robust published data on prevalence are lacking, peer reviewed articles have suggested that approximately 3% of the general cat population and up
to 35% of older cats have CKD. Current market research data increase these values up to 10% for the general cat population and approx. 50% for cats 12 years and older.6 Indeed, earlier and improved recognition of CKD may provide further evidence that this disease has a significantly higher prevalence than currently suspected.
Table 2 Suspicion of CKD is generally first aroused in veterinarians (%) for the following reasons in the United Kingdom, France, Germany, and the Netherlands.7
Suspicion of CKD upon...
UK
FR
D
NL
Clinical signs: vomiting, lethargy, inappetence, PU/PD
70%
70%
70%
90%
17%
8%
3%
3%
12%
22%
27%
7%
Most cases identified with blood tests done for other reasons like pre-anaesthesia screening “I screen all cats over 8 yrs of age for CKD”
4
Market Research – Feline CKD Table 3 Average percentage of cats initially presented and diagnosed with CKD are found in the following stages (early, mid, and late stage) of disease in Germany France and the UK.4
70 Germany 60
France UK
50
Stage of disease at initial presentation
40
% 30 20 10
Mid
Early
Late
Stage of CKD
Table 4 Average percentage of cats treated by veterinarians with pharmaceuticals for CKD in France, Germany, the UK and the USA.8
90 80 70 60
%
Proportion of CKD cats treated with a pharmaceutical
50 40 30 20 10 0 France
Germany
UK
USA
5
Market research - Feline CKD A poll of practicing small animal and feline exclusive veterinarians identified the following most frequently mentioned unmet needs when evaluating their current treatment options for feline CKD.7
UNMET NEEDS
E A S I E R T O A D M I N I S T E R M E D I C AT I O N
L I Q U I D F O R M U L AT I O N
M O R E I M M E D I AT E , V I S I B L E E F F I C A C Y
L E S S F R E Q U E N T A D M I N I S T R AT I O N
RELIABLE EFFICACY
G R E AT E R E F F E C T O N H Y P E R T E N S I O N
8
Angiotensin Receptor Blockers ARBs
9
Angiotensin Receptor Blockers (ARBs), also known as angiotensin II receptor (type AT1) antagonists, or sartans, are a class of antihypertensive drugs used extensively in human medicine. Boehringer Ingelheim Animal Health will soon introduce the first ARB for use in veterinary medicine as a novel solution for the management of feline chronic kidney disease. This drug class derives clinical benefits by its targeted action on the renin-angiotensin-aldosterone system (RAAS) [See Fig A]. Renin, an enzyme released by the kidneys, converts inactive circulating angiotensinogen, secreted by the liver, into angiotensin I. Angiotensin I is then converted by angiotensin converting enzyme (ACE) in the lung and kidney to angiotensin II, which is the active peptide hormone capable of binding and activating angiotensin receptors in the effector tissues. Fig. A: The production and physiological actions of angiotensin II
Renin-angiotensin-aldosterone-system Liver
Decrease in renal perfusion (juxtaglomerular apparatus)
Angiotensinogen Legend
Renin Secretion from an organ
Kidney
Angiotensin I
Stimulatory signal Inhibitory signal
Surface of pulmonary and renal endothelium: ACE
Lungs
Reaction Active transport
Angiotensin II
Kidney
Passive transport
Pituitary gland: posterior lobe
Collecting duct: H20 absorption
H20
Arteriolar vasoconstriction. Increase in blood pressure
ADH secretion
Tubular Na+ CI- reabsorption and K+ excretion. H20 retention Adrenal gland: cortex
Arteriole
H20 CI
-
K Na +
+
Sympathetic Activity
Aldosterone secretion
Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases.
10
ARBs block the last step of the renin-angiotensin pathway [Fig B.], and thereby, inhibit the harmful effects of angiotensin II in a target specific manor, as opposed to the non-specific action of angiotensin-converting enzyme inhibitors (ACE inhibitors).9
Fig. B ARB direct targeting of Angiotensin II type 1 receptor
ANGIOTENSINOGEN
RENIN
In specifically binding the angiotensin II type-1 (AT1) receptor, ARBs block AT1 receptor activation by angiotensin II, preventing such undesirable effects as:9,10,11, • • • • •
ANGIOTENSIN I
ACE
vasoconstriction aldosterone release sodium & water retention sympathetic nervous system activation release of pro-fibrotic inflammatory mediators and
ANGIOTENSIN II
• glomerular hypertrophy ARBs
AT1 receptors are predominantly found in the heart, adrenal glands, brain, liver and kidneys where they mediate regulation of blood pressure, as well as fluid and electrolyte balance. ARBs have little to no affinity for the angiotensin II type-2 (AT2) receptor, thus preserving the beneficial effects mediated by AT2 receptor activation, such as: 9,10,11 • • • • •
vasodilation sodium and water excretion tissue regeneration apoptosis and inhibition of inappropriate cell growth
AT2 receptors are found in the heart, adrenal glands, uterus, ovaries, kidneys and brain, and counterbalance the effects of angiotensin II on blood pressure and renal function mediated by AT1 receptors.9
AT 1 R E C E P T O R
AT 2 R E C E P T O R
The direct target selectivity of ARBs allows them to maintain optimal efficacy over time, unlike ACE inhibitors, which can decrease in efficacy of angiotensin II reduction with chronic use due to “ACE-escape.”13 Normally, angiotensin I is converted to angiotensin II by means of angiotensin-converting enzyme (ACE), however, other pathways also exist.
11
Fig. C “ACE-escape” Alternative pathways to ACE in the production of Angiotensin II in the RAAS
LIVER
ANGIOTENSINOGEN
RENIN
KIDNEY
INCREASED BLOOD PRESSURE
N E G AT I V E FEEDBACK
ANGIOTENSIN I
BRADYKININ SODIUM RETENTION
ACE Escape alternative pathways ( t - P A , To n i n , Chymase & Cathepsin G)
ACE INACTIVE FRAGMENTS
ALDOSTERONE
AT 1 R E C E P T O R S I N ADRENAL GLAND
ANGIOTENSIN II
AT 1 R E C E P T O R S I N BLOOD VESSELS
VA S O C O N S T R I C T I O N
These alternate pathways generate increased amounts of angiotensin II observed with chronic ACE-inhibitor use. This “ACE-escape” explains the phenomenon of gradually increasing tissue and plasma levels of angiotensin II observed in patients chronically treated with ACE-inhibitors. Table 7 depicts such an example of “ACE-escape” in a long-term study of 9 patients. Plasma ACE activity remained reduced during months of treatment, however, although plasma angiotensin II had fallen to low levels 4 hours post drug administration, it tended to increase with time.
12
Despite ACE inhibition, angiotensin II levels increased over other escape pathways. In the 6th month, levels were no different from control 12 hours after drug administration.13
Table 7 Long-term results in nine patients treated 4-6 months with an ACE inhibitor, MK 421, 20 mg13
Escape of Angiotensin II despite ACE inhibition 100 80
Plasma ACE (nmoL/mL/min)
60 40 20 0
30
Plasma Ang II (pg/mL)
20 10 0 Placebo
4h
24h
1
2
3
Hospital
4
5
6
Months *P