WCCT Global is a leader in both early and late stage Drug Development for increased intraocular pressure and Glaucoma
Glaucoma is characterized by the slow, progressive degeneration of retinal ganglion cells (RGCs) and optic nerve axons. The disease affects over 66 million people worldwide, causing bilateral blindness in 10% of the cases reported.
The most common form of the disease is primary open angle glaucoma (POAG), with a prevalence ranging from 0.58% in Asian Americans and as high as 6.7% in African Americans. African-Americans have a greater prevalence of the disease, contributed by optic nerve damage occurring at an earlier age, incurring more severe damage than other ethnic groups and experiencing less surgical repair successes. There are several recognized risk factors for glaucoma, such as an increased intraocular pressure (IOP), aging, family history, high myopia, systemic hypertension, cardiovascular disease, migraine headaches, peripheral vasospasm and prior nerve damage. The visual damage incurred from glaucoma is considered irreversible. However, it can be treated if diagnosed at an early enough stage. Since blindness is ultimately induced by the loss of visual field caused by neuronal cell death, understanding the pathology that leads to increased IOP, and subsequently to neuronal cell death, is crucial to the development of effective treatments.
WCCT Global’s Ophthalmology Center of Excellence which includes more than 12 leading Principal and sub Investigators in this cutting edge field works with sponsors in both early development and late stage research to offer strategies that more rapidly demonstrate the pharmacologic actions of the novel targets being tested. Because WCCT Global has access to healthy volunteers of diverse ethnic lineage and patients with increased IOP and Glaucoma, they work with sponsors to rapidly get the information necessary to launch a Global Development Program months ahead of the classic development paradigms hence providing a strategic advantage to those served.
In order to meet the needs of this highly specialized therapeutic area an in-depth understanding of the pathology and disease state is required:
Primary Open Angle Glaucoma is typically diagnosed by the presence of the “classical triad”:
- characteristic pattern of visual field defects
- morphological loss of optic disk substance
- increased IOP
Increased IOP of greater than 21 mm Hg (mean adult of 15-16 mm Hg) is not required for diagnosis. It has been traditionally theorized that patients with POAG typically exhibit increased resistance to the outflow of aqueous humor through the trabecular meshwork, which results in an increase in IOP and subsequent cell death from compression of the optic nerve axons.
As with many medical conditions, no single gene has been linked to the expression of POAG. As with many other chronic medical conditions, it seems to be determined by the interactions of multiple genes which may either increase or decrease the risk of glaucoma. In contrast, other forms of glaucoma, including congenital glaucoma and Reiger syndrome, can be mapped to specific genes leading to deformation of the anterior chamber of the eye.
DEVELOPING CONCEPTS OF PATHOLOGY
Since Glaucoma is a disorder caused by progressive nerve damage, many of the classic mechanisms of nerve damage associated with other progressive neurodegenerative disorders have been studied in the pursuit of the potential “route-cause” of Glaucoma. However, to date, no single mechanism stands out .
The following table presents the potential biochemical or cellular mechanisms under review.
|Neuronal Mechanism||Experimental Evidence||Experimental Outcome|
|Glutamate Receptor Activation||Ophthalmic glutamate levels are elevated in glaucoma||Retinal Ganglion cell Apoptosis|
|NMDA / NonNMDA inotropic Receptor Activation||Intracellular Calcium concentration increased||Retinal Ganglion Cell death|
|Nitric-Oxide (NO) neurotoxicity||Nitric-oxide Synthetase-2 found in astrocytes of damaged regions of the retina||Neurotoxicity|
|Disrupted transport of neurotropic factors (regulate growth, differentiation and death of neurons)||transport disrupted by increased IOP||Retinal Ganglion Cell apoptosis|
|NeuroInflammation||Association of glaucoma with many autoimmune diseases (Type 1 Diabetes, autoimmune thyroid disease & Rheumatoid Arthritis)||Neuronal Apoptosis|
|Neuroprotection (T-Cell integrity)||Susceptibility to neuronal damage from increased IOP is immune dependent||Retinal Ganglion Cell death induced in absence of T-Cells|
CURRENT TREATMENT OPTIONS
The goal of treating glaucoma lies primarily on preventing or delaying the loss of visual field. Since neuronal cell death is irreversible, no cure is available once the visual field is lost. However, since IOP is the primary risk factor causing the loss of RGCs, the strategies of treatment mostly involve lowering IOP. Other important factors such as cost, convenience and safety should also be considered. Current treatments for glaucoma include medication, laser use and surgery.
Pharmacologic treatments of ocular hypertension and glaucoma, to date, have focused on inhibiting the inflow of aqueous humor, enhancing the outflow of aqueous humor, protecting the optic nerves (more recently) and manipulating the osmotic pressure between plasma and the eyes.
α2 adrenoreceptor agonists and β1 receptor antagonists lower IOP by inhibiting the inflow of aqueous humor to the eye. Timolol, which is the most prescribed drug, and betaxolol, which has the fewest systemic side effects, are both β1 receptor blockers. A third type of drug that inhibits the inflow of humor is carbonic anhydrase inhibitors, such as acetazolamide and dorzolamide. Such drugs are often formulated together as in Cosopt (dorzolamide hydrochloride and timolol maleate).
Another method of reducing IOP is by enhancing the outflow of humor from the eyes through the use of muscarinic acetylcholine receptor agonists. This mechanism is indirect, but involves a muscarinic acetylcholine receptor (M3)-mediated contraction of the ciliary muscle. The contraction causes the widening of the spaces in the trabecular meshwork. The newest class of drugs using this strategy is the prostaglandin F2α derivatives which enhance the uveoscleral outflow. Bimatoprost falls under this category and is considered the most effective anti-glaucoma drug.
Laser and Surgery
A secondary choice of treatment of glaucoma is the use of laser therapy. The primary strategy involves “burning” holes in various areas within the eyes including the ciliary and the pigmented trabecular meshwork cells. The benefits include being noninvasive, needing less patient compliance and lowering the possibility of infection or bleeding. The IOP of most patients can decrease about 20-30%, but the treatment effect wears off 5-10% every year. In combination with timolol, the two year IOP lowering success rate is 70%, compared with the laser alone (44%) and timolol alone (30%).
A common form of surgery is trabeculectomy, which creates a guarded channel allowing aqueous humor to flow from the anterior chamber inside the eye to sub-Tenon’s and subconjunctival space. The benefits of surgery include stabilizing IOP and bypassing the requirements for strict patient adherence and continuous drug costs. Surgery is considered as the last resort because failure of surgery can result in immediate blindness due to complications such as choroidal effusion, hypotonic maculopathy, suprachoroidal hemorrhage and optic nerve snuffing.
FUTURE TREATMENT OPTIONS
Based on new knowledge gained from research on the pathology of neuronal apoptosis, there are several forms of new treatments. Many of these treatments focus on neuroprotection through anti-apoptosis of retinal ganglion cells.
|NMDA receptor antagonist||memantine|
|NOS inhibition||aminoguanidine, Ginko bilboa extract|
|Calcium Channel Blockade||flunarizine|
|caspase-3 inhibition||ciliary neurotrophic factor, BIRC-4, minocycline|
|Heat Shock Factor-1 (HSF-1) mediation||geranylgeranylacetone|
|PI-3 kinase/AKT pathway||erythropoietin|
The staff at WCCT Global has extensive experience working with in the development of treatments for increased IOP and Glaucoma.
WCCT Global has successfully carried out numerous healthy volunteer safety and tolerance trials as both an investigational site and a CRO managing an early development & proof of concept (PoC) studies at several sites. WCCT Global has studied both topical and systemic agents and has also been a Phase II/III investigational site for 2 of the new compounds in development. WCCT Global leverages their knowledge and experience in this therapeutic area to strategically help their clients.
As the industry looks to get more data from phase 1 trials, there is an increasing interest to include patient populations in the phase 1 program. WCCT Global, during the protocol development phase, would help sponsors design an integrated SAD/MAD in healthy volunteers intercolated with SAD/MAD proof of concept in treatment naïve patients with increased IOP/Glaucoma. Such an integrative design enables the sponsor to collect safety, tolerance and exposure-response information efficiently and enables go/no-go development decisions to be reached much sooner than before.
Additionally, WCCT Global is strategically based in a densely populated area of 8 million people found throughout the Southern California region and thus has access to a diverse set of patient populations. Therefore, WCCT Global is able to recruit treatment naïve subjects within timelines that sponsor’s need by utilizing their proprietary advertising strategy.