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312 III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

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19.1.2Pharmacological Approach and Current Clinical Studies

19.1.2.1 Protein Kinase C Inhibitors

A. Girach, D.S. Fong

317

III 19

Core Messages

Protein kinase C (PKC) is a family of intracellular serine/threonine kinases that are involved in cellular signaling processes

Elevated glucose levels lead to the generation of advanced glycation end products via the polyop pathway and finally to the de novo synthesis of diacylglycerol (DAG), resulting in upregulation of tissue-specific isoforms of DAG

A tissue specific PKC- inhibitor is ruboxistaurin (LY333531)

Preclinical studies have demonstrated an inhibition of vascular endothelial growth factor (VEGF)-induced permeability

19.1.2.1.1 Introduction

The World Health Organization (WHO) estimates that 171 million persons are currently affected and 366 million will be affected with diabetes mellitus by the year 2030 [20]. Diabetic retinopathy is present in about 40 % of diabetic patients 40 years and older [10]. After 20 years of diabetes, almost every patient has some form of retinopathy. After 30 years of diabetes, proliferative diabetic retinopathy is present in 70 % of people with Type 1 diabetes [14]. One mechanism in the pathophysiology of diabetic retinopathy is the activation of protein kinase C (PKC).

19.1.2.1.2Protein Kinase C Family of Isoenzymes

Intracellular kinases are enzymes that add phosphate groups to cellular proteins. There are two main types of intracellular kinases: Tyrosine kinases are enzymes that phosphorylate proteins at tyrosine sites. Serine/threonine kinases are enzymes that phosphorylate proteins at serine/threonine sites. PKC is a serine/threonine kinase that is distributed throughout the body and is known to play an important part in a variety of cellular signaling processes (Table 19.1.2.1.1).

Several phase III studies have been performed demonstrating that there is a dose dependent statistically significant reduction in the rate of moderate visual loss

Ruboxistaurin had a statistically significant impact on diabetic macular edema (DME) progression. Ruboxistaurin as given orally has been well tolerated in clinical trials and has shown benefit in prevention of vision loss in patients with non-proliferative diabetic retinopathy

Table 19.1.2.1.1. Protein kinase C involvement in multiple cellular/vascular processes [6]

Ion channel gating

Permeability

Receptor function

Cytoskeletal structure

Proliferation

Apoptosis

Cell division

Transcription

The PKCs are a family of structurally and functionally related proteins derived from alternative splicing of single mRNA transcripts. There are currently at least 13 known isoenzymes of the PKC family. These can be divided into conventional, novel and atypical types, based on their degree of calcium and phospholipid dependency (Table 19.1.2.1.2). Certain PKC isoforms are expressed preferentially in different tissues of the body. The vascular, retinal and renal tissues express PKC-I and PKC-II more so than other isoenzymes. In particular, the retina is known to preferentially express the PKC-I, PKC- II and PKC- [15]. One other characteristic of PKC is that their activity has been shown to correlate with increasing plasma glucose concentration (Fig. 19.1.2.1.1).

318

19 III

III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

Table 19.1.2.1.2. PKC isoforms

Conventional		Novel	Atypical

	I
	II
		μ
Calcium		Calcium	Calcium
	dependent	independent	independent
Phospholipid			Phospholipid
	dependent		independent

MembranePKCactivity	150
MembranePKCactivity	-1-1(pmol.min.mgprotein)
	100
	50
	0
	0	10	20	30

Plasma glucose (mmol/l)

Fig. 19.1.2.1.1. Linear regression between membrane monocyte PKC activity and fasting plasma glucose. Data points represent the pooled experimental observations in 19 patients with diabetes (white circles) and 14 control subjects (black circles) (r2 = 0.4008, p = 0.0001). [5]

19.1.2.1.3PKC Activation and Diabetic Retinopathy

Hyperglycemia from diabetes is associated with increased incidence and progression of diabetic retinopathy [11]. These elevated levels of glucose lead to an increased flux through the polyol pathway, the

generation of advanced glycation endproducts and the generation of reactive oxygen species. Hyperglycemia stimulates a de novo synthesis of diacylglycerol (DAG), which cause an upregulation of tissuespecific isoforms of PKC, leading to translocation of these isoforms from the cytosol to the membrane. This translocation to the membrane form of PKC then causes a cascade of events (Table 19.1.2.1.1), which ultimately lead to the development of diabetic complications (Fig. 19.1.2.1.2). In addition, upregulation of PKC also leads to stimulation of vascular endothelial growth factor (VEGF) expression. Increased VEGF can in turn increase activation of PKC [1, 21].

In animal models, Suzuma and colleagues [16] looked at transgenic mice which overexpressed PKC- in the endothelium of their vasculature, and found an increased level of neovascularization in response to ischemia. Conversely, in mice expressing dominant negative PKC- , they found a markedly diminished neovascularization response to the same ischemic insult. In addition to its role in neovascularization, PKC- overexpression also leads to increased endothelial permeability, a factor in diabetic macu-

lar edema (DME) [13].

19.1.2.1.4 PKC- Inhibitor – Ruboxistaurin

The role of PKC in the pathophysiology of diabetic retinopathy suggests that inhibition of the PKC- enzyme, by a specific PKC-inhibitor, might prevent or reduce the risk of diabetic retinopathy. After extensive screening, ruboxistaurin (LY333531) was discovered in 1994. Ruboxistaurin is a bisindolylmaleimide compound that is an orally administered PKC- specific inhibitor (Fig. 19.1.2.1.3), that has high levels of I and II isoform-specific inhibitor activity (Table 19.1.2.1.3). Preclinical studies of ruboxistaurin have shown activity in diabetic retinopathy (DR).

Diabetes

Hyperglycemia

AGEDAGROS

PKC β Activation

VEGF

Retinal Microvascular Damage

Vascular Leakage

Capillary Nonperfusion

Hypoxia

Proliferative

Impaired Visual

Diabetic Macular Edema

Retinopathy

Function

(Neovascularization)

Fig. 19.1.2.1.2. Metabolic pathway of diabetes induced impaired visual function. AGE advanced glycation endproducts, DAG diacylglycerol, ROS reactive oxygen species, PKC protein kinase C, VEGF vascular endothelial growth factor

19.1.2.1 Protein Kinase C Inhibitors 319

O N O

N	N
	CH3
Fig. 19.1.2.1.3. Chemical structure	O
Fig. 19.1.2.1.3. Chemical structure	N
of ruboxistaurin (LY333531)	CH3

Table 19.1.2.1.3. Kinase selectivity of ruboxistaurin (LY333531). (Adapted from [9])

Kinase		IC50 (nM)
PKC-		360
PKC-	I	4.7
PKC-	II	5.9
PKC-		300
PKC-		250
PKC-		600
PKC-		> 100,000
PKC-		52
PKA		> 100,000
Ca calmodulin		6,200
Casein kinase		> 100,000
Src-tyrosine kinase		> 100,000
Rat brain PKC		3,200

PKC protein kinase C

19.1.2.1.4.1 Pre-clinical

Experimental studies carried out by Ishii et al. confirmed elevated levels of PKC activity in streptozotocin induced diabetic rats when compared to normal rats. This elevation of retinal PKC activity was reduced to near normal levels by oral administration of ruboxistaurin. In addition, Ishii et al. monitored mean retinal circulation time (MRCT) and found an abnormally high MRCT in diabetic rats that could be normalized with treatment of oral ruboxistaurin. Aiello et al. showed that ruboxistaurin could block VEGF-induced increased vascular permeability in rats [1]. In another model, histological evaluation of the retinal distribution of intravenously injected 70 kDa lysine-conjugat- ed fluorescein dextran was performed. Rats received intravitreal injection of vehicle alone in one eye and ruboxistaurin, a selective PKCinhibitor (LY333531), (10 nmol/l) in the contralateral eye, followed by intravitreal injection of VEGF (0.5 nmol/l final) in both eyes. VEGF-treated eyes demonstrated diffuse fluorescein staining throughout the retinal tissue, while combined treatment with VEGF and ruboxistaurin demonstrated significantly less fluorescein leakage to near normal levels (Fig. 19.1.2.1.4). In a porcine model of neovascularization of the retina, following retinal vascular occlusion, treatment with oral ruboxistaurin resulted in a significant reduction in neovascularization over 3 months [7].

III 19

Fig. 19.1.2.1.4. Ruboxistaurin blockade of VEGF-induced increased retinal vascular permeability. VEGF vascular endothelial growth factor, RBX ruboxistaurin. [1]

19.1.2.1.4.2 Clinical

Ruboxistaurin has been studied in clinical trials; the key ones relevant for ophthalmology are summarized below:

Endothelial dysfunction and ruboxistaurin

Hyperglycemia is associated with endothelial dysfunction, and alters the endothelial-depen- dent vasodilatory response to acetylcholine. To study this effect, forearm blood flow was measured in response to increasing arterial infusions of endothelial-dependent vasodilator methacholine under hyperglycemic conditions. In a placebo controlled, double masked crossover study in healthy volunteers, inhibition by ruboxistaurin led to an increase in forearm blood flow and prevented the reduction in the nitric oxide mediated vasodilation induced by a hyperglycemic state [3].

Phase 1b study

Ocular, systemic safety and pharmacodynamic effects of ruboxistaurin were studied in a placebo controlled, double-masked, randomized 28 day study of ruboxistaurin (8 mg twice per day,

16 mg per day, or 16 mg twice per day) or placebo in 29 patients with diabetes. These patients had either no or mild non-proliferative diabetic retinopathy. The results showed that oral ruboxistaurin was well tolerated and there were no clinically relevant safety concerns. Interestingly, there was a dose-dependent reduction in mean retinal circulation time with ruboxistaurin, when compared to placebo, p = 0.046 (Fig. 19.1.2.1.5) [2]. Similar results were obtained with retinal blood flow. This pivotal study demonstrated, for

320 III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

19 III

	80
	80	Placebo


(%)		8 mg
		8 mg
	60	16 mg
progressionof	40	32 mg
		32 mg



Probability

	20





	0		Log rank p value = 0.54
	0		Log rank p value = 0.54

Fig. 19.1.2.1.5. Impact of ruboxistaurin on mean retinal circulation time. *p < 0.05 (placebo vs 32 mg/day). RCT mean retinal circulation time, non-diabetic (historical controls) = 0. RBX ruboxistaurin. (Adapted from [2])

the first time, that a pharmacodynamic impact of ruboxistaurin could be seen as early as 28 days in these patients with diabetes, that the 32 mg dose seemed to be the most efficacious dose and confirmed the animal findings on mean retinal circulation time found by Ishii et al. [8].

19.1.2.1.5 PKC-DRS Trial

The PKC-Diabetic Retinopathy Study was a phase 3 multicenter, double-masked, randomized, placebo controlled trial of 252 patients, randomized to either placebo, 8 mg, 16 mg or 32 mg ruboxistaurin given orally once per day. The trial duration was 3 years and used the primary endpoint of either a 3-step progression of diabetic retinopathy (DR) on 7-field color stereo fundus photography or occurrence of panretinal photocoagulation (PRP).

Eligible patients had one eye with at least moderately severe non-proliferative DR (NPDR), equivalent to Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy grading scale 47b–53e, without prior PRP, and a best-corrected visual acuity (VA) of at least 45 letters on the ETDRS visual acuity chart (Snellen equivalent = 20/125). Any level of DME was allowed at baseline, as was prior focal/grid photocoagulation.

At baseline, the four groups were well matched and there were no statistically or clinically significant differences, except that the 16 mg group had a higher mean body mass index. There was no statistically or clinically significant difference between the groups in their ophthalmic characteristics. The baseline mean best-corrected VA was 80 letters (Snellen equivalent = 20/25) for the placebo group and this was well matched compared to the ruboxistaurin groups.

After 3 years of follow-up, the primary endpoint of DR progression or PRP did not reveal any benefit

0	6	12	18	24	30	36	42
			Months

Fig. 19.1.2.1.6. Primary endpoint: time to progression of retinopathy or PRP [18]

	50
	50				Placebo


	40				8 mg
					16 mg
(%)	30				32 mg
ofMVL	30
	20


Probability
	10
	10
	0

				Log rank p-value: 32 mg vs. placebo: 0.038
				Log rank p-value: 32 mg vs. placebo: 0.038


	0	6	12			18		24	30	36	42
							Months

Fig. 19.1.2.1.7. PKC-DRS Trial. Secondary endpoint: occurrence of moderate visual loss. [18]

for any of the ruboxistaurin treated groups (Fig. 19.1.2.1.6).

However, an interesting finding from the PKCDRS trial was noted in the pre-determined secondary endpoint of time to occurrence to moderate visual loss (15 or more letter loss on ETDRS VA chart). There was a statistically significant reduction in the event rate to moderate visual loss in the 32 mg ruboxistaurin arm when compared to placebo, in a pairwise comparison (Fig. 19.1.2.1.7).

19.1.2.1.6 PKC-DMES (MBBK) Trial

The PKC-Diabetic Macular Edema Study was a phase 3 multicenter, double-masked, randomized, parallel, placebo controlled trial involving 686 patients, randomized to either placebo or 4 mg, 16 mg, or 32 mg ruboxistaurin given orally once per day. The trial duration was 3 years. The primary endpoint was a composite endpoint: progression of DME to within 100 μm from the center of the macula on 7-

19.1.2.1 Protein Kinase C Inhibitors 321

field color stereo fundus photography (as graded by a reading center) or occurrence of focal/grid photocoagulation.

Patients’ study eyes had to have: DME between 300 and 3,000 μm from the center of macula at baseline, mild or moderately severe NPDR, equivalent to ETDRS retinopathy grading scale 20 – 47a, without prior PRP or focal/grid laser photocoagulation, and a best-corrected VA of at least 75 letters on the ETDRS VA chart (Snellen equivalent = 20/32). At baseline, the four groups were well matched for their medical and ophthalmic characteristics with no clinically relevant differences between them.

Surprisingly, there were no statistically significant differences between any of the ruboxistaurin treated group and placebo for the primary endpoint of progression of DME to a sight-threatening stage or application of focal/grid laser photocoagulation (Fig. 19.1.2.1.8). However, there seemed to be an imbalance in the site-to-site application and reasons for application of focal/grid laser photocoagulation. When the secondary endpoint of progression of DME alone (without the laser photocoagulation

Probability of progression %

Pl acebo 4 mg RBX

16 mg RBX

32 mg RBX

Log rank p-value: 32 mg RBX vs. Placebo: 0.14

Time (months)

Fig. 19.1.2.1.8. PKC-DMES Trial. Primary endpoint: progression of DME to sight-threatening stage or focal/grid laser photocoagulation. [17]

Probability of progression %

Placebo 4 mg RBX

16 mg RBX

32 mg RBX

Log-rank p-value 32mg vs. placebo = 0.054

Time (months)

Fig. 19.1.2.1.9. PKC-DMES Trial. Secondary endpoint: progression of DME to sight-threatening stage. [17]

component) was examined, there was a reduction in the progression of DME, towards a sight-threatening stage (within 100 μm from center of macula), by the 32 mg ruboxistaurin group, when compared to placebo (Fig. 19.1.2.1.9).

19.1.2.1.7 PKC-DRS2 (MBCM) Trial		III 19
The PKC-Diabetic Retinopathy Study 2	trial was	III 19
The PKC-Diabetic Retinopathy Study 2	trial was
started while the PKC-DRS and PKC-DMES studies
were ongoing, and was initially set up to mimic the
PKC-DRS trial. The original primary endpoint of the
PKC-DRS2 trial was progression of DR or PRP treat-
ment, but when the moderate vision loss results from
PKC-DRS trial were known, and given that a vision
loss endpoint would be a better outcome measure,
the primary endpoint of the PKC-DRS2 trial was
changed to sustained moderate vision loss, without
any unmasking of this trial.
The PKC-DRS2 trial was a phase 3 multicenter, dou-
ble-masked, randomized, parallel, placebo controlled
trial involving 685 patients, randomized to either pla-
cebo or 32 mg ruboxistaurin given orally once per day.
The trial was 3 years in duration. The new primary
endpoint was sustained moderate vision loss (SMVL)
at 3 years. SMVL was defined as moderate vision loss
( 15 letter loss on ETDRS VA chart) sustained for
6 months at the end of the trial, or the last 6 months
of study participation if a patient discontinued early.
Patients needed to have at least one eye eligible
with: moderately severe-very severe NPDR, equiva-
lent to ETDRS retinopathy grading scale 47a–53e,
without prior PRP, and a best-corrected VA of at least
45 letters on the ETDRS VA chart (Snellen equivalent
= 20/125). Any level of DME was allowed at baseline,
as was prior focal/grid photocoagulation.
At baseline, there were no statistically or clinically
significant differences noted between the placebo
and 32 mg ruboxistaurin groups, with the mean
baseline best-corrected VA of 77 ETDRS chart letters
in both groups (Snellen equivalent 20/32).
The primary endpoint of SMVL occurred in 9.1 %
of placebo patients, as compared to 5.5 % of 32 mg
ruboxistaurin patients. This equated to a 40 % risk
reduction in vision loss, in addition to standard of
care, by ruboxistaurin, and this was statistically sig-
nificant (p = 0.034) [19].
Other secondary endpoint results indicate:
Mean VA at 3 years was statistically significantly
lower in the ruboxistaurin group compared to
placebo eyes (p = 0.012).
In a categorical analysis of baseline-to-endpoint
change, 2.4 % of placebo eyes gained	15 letters

as compared to 4.9 % of ruboxistaurin eyes (p = 0.027).

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