Newer drugs in Glaucoma Mangement

1. Newer Drugs in
Glaucoma Management
Dr. Shylesh Dabke
Aravind Eye Hospital
Tirunelveli

2. Introduction
▪ Glaucoma is comprised of a group of progressive degenerative diseases
characterized by a specific pattern of axonal death.
▪ Our current first line therapies are often inadequate. Both the Collaborative
Initial Glaucoma Treatment Study and the Ocular Hypertension Treatment
Study, found that more than one single class of medications is needed for
the majority of patients.
▪ Adherence is a major limiting factor in taking medications, and an increase in
ophthalmic medications decreases adherence.

3. Therapies last longer
Constant medication instillation
Adherence & IOP lowering
Risk of visual impairment and blindness

4. ▪ Goals for development of these new drug formulations should be to have a
favourable adverse event profile that minimizes obvious ocular or systemic
toxicities.
▪ Pilocarpine was the first drug introduced in 1877 for treatment of glaucoma.
▪ Twenty years have passed since the development of the last drug class in
glaucoma: Latanoprost (Xalatan), the first prostaglandin analogue, in 1996.
▪ One new class of topical IOP-lowering therapy is available to patients in
Japan, the first in almost two decades.

5. ▪ In the period from the late 1990–2010, while there were additional new
chemical entities, fixed dose combinations, and formulation improvements,
there were no new classes of ocular hypotensive medications approved
worldwide.
▪ Multiple drugs with novel mechanisms of action, new formulations, and new
delivery mechanisms are currently in development.

6. Why new drugs?
▪ Neural damage irreversible – need for neuroprotective agents
▪ Patients with asthma, bradycardia, allergy to sulfa drugs or topical
brimonidine – not much options left other than Sx
▪ Need for preservative free drugs
• Benzalkonium – punctate / ulcerative keratopathy
• Thiomersal – hypersensitivity
▪ Drugs for newer drug delivery systems

8. Innovative Hypotensive Drugs
▪ With the greater comprehension of processes involved in aqueous humor
production, innovative ocular hypotensive drugs, with specific molecular targets,
have been developed and are currently under evaluation in several clinical trials
- ROCK inhibitors - Cannabinoids
- A1 receptors agonists - Local calcium channel blockers
- BkCa ionic channel modulators - Latrunculinic derivates

9. RHO-kinase associated protein inhibitors
(ROCK inhibitors)

10. Transmembrane
receptors and their
ligands
RHO-GTPase
ROCK
Myosin light chain (MLC)
phosphorylation
cytoskeletal changes,
cell motility, and smooth
muscle contraction
Trabecular meshwork
cells possess smooth
muscle-like properties
Influence aqueous humor outflow facility
RHO-dependent transduction pathway

11. RHO-kinase associated protein inhibitors
(ROCK inhibitors)

12. ▪ May provide beneficial effects in terms of prevention of scarring tissue
formation after filtration surgery, neuro-protection, axonal regeneration and
regulation of ocular blood-flow.

13. Adenosine receptors agonists

14. A1 receptor
Secretion of matrix
metalloproteinase-2
Digestion of type IV
collagen
Removes protein from TM
Lowering outflow
resistance
Reducing intraocular
pressure

15. Adenosine receptors agonists

16. BkCa ionic channel modulators
▪ Another possibility of pharmacological approach is represented by enhancing
the levels of nitrogen monoxide(NO), whose release in trabecular environment
activates ion channels to provoke relaxation of smooth muscle cells.
▪ Latanoprostene bunod: a nitric oxide donor and prostaglandin analogue

18. SiRNAs
▪ Blocks the b2-adrenergic receptor via specific gene silencing. Specifically targets
ADRB2 and thus the ciliary body’s production of aqueous humor.
▪ Bamosiran (SYL040012) (Sylentis S.A., Tres Cantos, Madrid, Spain)
▪ It has been shown to reduce IOP in preclinical studies.
▪ Phase I studies demonstrated a tolerable safety profile and the drug was only
present in ocular tissues, thereby potentially eliminating safety issues.
▪ Actual values of IOP-lowering have not been reported.

19. Cannabinoids
▪ There is a large amount of experimental data showing the IOP reduction
properties of cannabinoids.
▪ The cannabinoid receptor 1 (CB1) was detected in the trabecular meshwork
and ciliated epithelium, supporting the role of their agonists in reducing IOP.
▪ No new clinical progress has been made in glaucoma with respect to
marijuana.

20. Local calcium channel blockers
▪ Local administration of calcium channel blockers, such as verapamil, was
associated with ocular outflow enhancement in animal models and humans
but their use is limited by systemic effects including severe bradycardia and
blood hypotension.

21. Latrunculinic Derivates
▪ Macrolides that can inhibit actine polymerization—have provided a greater
trabecular meshwork activity through actine cytoskeleton disruption.
▪ Animal models and post-mortem analysis, after topic or intracameral
administration.
▪ Phase I study, showing a significant IOP reduction in treated eyes (Rasmussen
et al., 2014).

22. ▪ Other molecules are currently under development or preclinical evaluation
acting by increasing trabecular outflow or delaying its production.
▪ Examples of these drugs:
- Angiotensin II receptor antagonists
- 5- hydroxytryptamine receptor 2 (5- HT2) agonists
- Anecortave acetate
A steroid agonist that seems to counter ocular hypertension by inhibiting
plasminogen activator inhibitor-1, although precise mechanism of action is
still unclear.
Retaane, Alcon Research - AMD

23. Excitotoxicity, Oxidative Stress, Mitochondrial
Dysfunction & Neuroprotection
▪ In recent years, an important focus on oxidative stress and mitochondrial
dysfunction as a cause of glaucomatous neurodegeneration has been carried
out.
▪ It is assumed that the concentration of free oxygen radicals and other cell
death mediators (TNF, etc.) increases during inflammatory responses as a
result of ischemic insults during events, such as ocular hypertension.

24. ▪ Thus, the limiting the oxidative stress could be an effective mean in order to
obtain a form of neuroprotection and reduce ischemia-related damage.
▪ Antioxidant/antiapoptotic agents(In mouse models, effective in RGC
protection)
- Alpha-luminol
- Ginkgo biloba extracts
- Resveratrol
- Stanniocalcine-1
- Alpha-lipoic acid
▪ Molecules that have been evaluated in human subjects with neuroprotective
intent in glaucoma are
- Memantine (receptor antagonist for NMDA glutamatergic)
- Brimonidine (an alpha2-adrenergic agonist).

25. ▪ Memantine, by blocking the exocytotoxic process mediated by glutamate, has
proven useful in preventing the loss of RGC in animal models.
▪ New pharmacological approaches in neuroprotection for glaucoma and other
optic neuropathies are currently in development.
▪ Further studies are needed in order to determine with greater certainty
whether neuroprotective agents can bring benefits in terms of cell
survival/progression of disease in patients with glaucoma.

26. Neurotrophic Growth Factors
▪ Neurotrophic factors, including CNTF, BDNF, neuronal growth factor (NGF),
and the glial cell line-derived neurotrophic factor (GDNF) are produced by
cells within the retina.
▪ In fact, intrinsic growth factors do not seem to be sufficient in maintaining
the viability of RGC in conditions of chronic disease, but exogenous
neurotrophic factors may be administered in several different modes.

27. ▪ For example, intravitreal injections of 5 micrograms of BDNF and 2
micrograms of CNTF have reduced the death of RGC in animal models by 8
and 22% respectively after 1 month (Ko et al., 2000, 2001; Ji et al., 2004).
▪ It is reported that topical administration of NGF four times a day for 7 weeks
increases the density of ganglion cells by 37% (Lambiase et al., 2009).
▪ It should be noted that this treatment, while showing functional improvements
detected with ERG, VEP and HFA, it was still carried out on a limited number of
patients and in the absence of a control group, thus raising doubts about its
real efficacy.

28. ▪ Long-term studies on the ganglion cells have unfortunately shown that
beneficial effects of neurotrophic factors are temporary, slowing but not
preventing cell death.
▪ The administration of neurotrophic factors can be maintained in time by
making advantage of slow release devices implantation.

29. Gene Therapy
▪ Approach to elevate endogenous retinal production of neurotrophic factors shows
promising preclinical results in many retinal neurodegenerative disorders, including
glaucoma.
▪ An innovative method by which neurotrophic factors can be given is the use of viral
vectors that integrate within the target cells, increasing the endogenous production
of neurotrophic factors in the retina.
▪ While proving to be effective and well tolerated in animal and experimental
glaucoma models, the effects of this method have been transient, probably due to
short duration of viral vectors gene expression.

30. ▪ Alternative non-viral vectors may become useful also for gene therapy in glaucoma,
since they avoid the adverse effects usually associated with viral vectors.
▪ Noninvasive topical ocular gene delivery was effectively carried out in a mouse
model using eye drops of poly (ethylene oxide)-poly (propylene oxide) poly (ethylene
oxide) (PEOPPO-PEO) polymeric micelles.
▪ A peptidomimetic ligand developed to improve the survival of RGC in glaucoma is
represented by a TrkA receptor agonist.
▪ TrkA has provided a significant and sustained survival in experimental models of
glaucoma.

31. STEM CELL THERAPY
▪ In recent years, stem cells have been the subject of great attention as a potential
source of cell replacement in diseases that lead to blindness, such as glaucoma.
▪ Despite the growing understanding of ocular stem cells biology and properties, their
clinical application seems still uncertain.
▪ Several studies have shown that retinal precursor cells extracted from embryonic
retina of animal models have been successfully transplanted into the subretinal
space of mice.
▪ Despite the promise, the low numbers of integrating cells hinder a real functional
recovery in the transplanted eyes, even if some restoration of vision was observed.

32. ▪ Autologous mesenchymal stem cells (MSCs) derived from human bone
marrow could represent a further source of stem cells for regenerative
purposes given their greater ease of extraction and their ability to migrate
to retina and optic nerve head (ONH) after intravitreal injection in murine
models.

33. FINAL CONSIDERATIONS
▪ In recent years, great strides have been made in the research of glaucoma
treatment. Newer strategies will get better results with fewer side effects and
invasiveness.
▪ The study of alternative pharmacological approaches gives great hopes
regarding neuro-protection and cell therapy. Til date, however, the practical
use is still limited to clinical trials, because coherent results, showing clear
efficacy in visual field defects prevention and retinal neuronal cell death
decrease, are not available yet.
▪ Great efforts have been made regarding animal and cellular research, and the
results appear encouraging.