Intellect Neurosciences Inc. (fka ILNS)

[montanus]

About Age Related Macular Degeneration and CONJUMAB platform technology

AMD is the third most important cause of blindness in the world and the leading cause of blindness in higher income countries with ageing populations.
AMD is a disease affecting the central area of the retina (macula) at the back of the eye. In the early stages of the disease lipid material accumulates in deposits underneath the retinal pigment epithelium. These deposits are known as drusen, and can be seen as pale yellow spots on the retina. The pigment of the retinal pigment epithelium may become disturbed, with areas of hyperpigmentation and hypopigmentation. In the later stages of the disease, the retinal pigment epithelium may atrophy completely. This loss can occur in small focal areas or can be widespread (geographic atrophy). In some cases, new blood vessels grow under the retinal pigment epithelium and occasionally into the subretinal space (exudative or neovascular AMD). Haemorrhage can occur which often results in increased scarring of the retina. The early stages of the disease are in general asymptomatic. In the later stages there may be considerable distortion within the central visual field leading to a complete loss of central visual function.

Approximately 5% of blindness globally is due to AMD(1). It is estimated that globally 196 million (95% credible interval 140—261) people will have AMD in 2020, increasing to 288 million in 2040 (205—399)(2).

The major risk factors for AMD are age, genetic factors and tobacco smoking. Considerable research has focussed on the role of diet, light exposure and association with cardiovascular disease and its risk factors, however, the effects of these risk factors are less certain.

Treatment of AMD has been revolutionised by the use of anti-vascular endothelial growth factor agents that bind to vascular endothelial growth factor or their receptors and slow down the growth of new blood vessels. These interventions are delivered by injection into the eye. However, they are only applicable for the neovascular form of the disease. Currently there is no effective treatment for geographic atrophy. There is some evidence that antioxidant vitamin supplements may slow down the progression of AMD to late stage disease and visual loss.
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1. Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. The British journal of ophthalmology. 2012 May;96(5):614-8. PubMed PMID: 22133988.
2. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng C-Y, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet Global Health. 2014;2(2):e106-e16.
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List of Cochrane reviews on AMD
Treatments that are effective

Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration
Photodynamic therapy for neovascular age-related macular degeneration
Laser photocoagulation for neovascular age-related macular degeneration (effective in slowing down progression of vision loss but no longer in general use)
Treatments that are probably not effective or where effectiveness is currently uncertain

Antiangiogenic therapy with interferon alfa for neovascular age-related macular degeneration
Macular translocation for neovascular age-related macular degeneration
Surgical implantation of steroids with antiangiogenic characteristics for treating neovascular age-related macular degeneration
Submacular surgery for choroidal neovascularisation secondary to age-related macular degeneration
Statins for age-related macular degeneration
Ginkgo biloba extract for age-related macular degeneration
Laser treatment of drusen to prevent progression to advanced age-related macular degeneration
Radiotherapy for neovascular age-related macular degeneration
Complement inhibitors for age-related macular degeneration
Nutritional interventions

Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration
Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration
Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration
Related reviews

Reading aids for adults with low vision
Surgery for cataracts in people with age-related macular degeneration
Links to key websites
The Royal College of Ophthalmologists: http://www.rcophth.ac.uk
NICE website: http://www.nice.org.uk
National Eye Institute: http://www.nei.nih.gov
Journal of American Medical Association: http://jama.jamanetwork.com
AMD Alliance international www.amdalliance.org
Macular Society www.macularsociety.org
RNIB www.rnib.org.uk
Cochrane Eyes and Vision group www.cochraneeyes.org
(IAPB acknowledges Jennifer Evans, Co Coordinating Editor of the Cochrane Eyes and Vision Group and Tanya Moutray, January 2014)

http://www.iapb.org/vision-2020/what-is-avoidable-blindness/age-related



CONJUMAB:

I am excited about the potential of our CONJUMAB antibody drug conjugate platform and the therapeutic potential of the lead program, CONJUMAB-A, for treatment of age-related macular degeneration (AMD). CONJUMAB is designed to empower chaperone-like monoclonal antibodies with cytoprotective properties for treatment of various forms of amyloidosis and other types of proteinopathies in which irregular accumulation of abnormally folded proteins causes oxidative stress and inflammation, resulting in irreversible damage and death of cells. This relates to many different diseases, including diseases of the eye (AMD, glaucoma, diabetic retinopathy), brain diseases (Alzheimer's disease, Parkinson's disease (PD), Huntington's disease, motor neuron disease (ALS) and Creutzfeld Jacob disease (CJD)) and peripheral diseases (multiple myeloma, systemic amyloidosis, familial serum amyloid neuropathies and isolated atrial amyloidosis). Numerous proteins, including, amyloid beta (Aß), tau protein, huntingtin protein, superoxide dismutase, prion and transthryetin, become abnormally folded, making them potential targets for the CONJUMAB approach.

Our lead program, CONJUMAB-A, offers an important advantage to the Aß antibodies currently in clinical development for both AD and AMD by several large pharmaceutical companies. This is because those antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, crenzeumab, RN6G and GSK33766A) are designed for a single purpose, namely to clear Aß, while none act on the important secondary neurotoxic mechanisms, such as oxidative stress that causes most of the damage from Aß. By contrast, CONJUMAB-A is empowered with a potent antioxidant. An important step in establishing proof-of-principle was the initial data generated through our collaboration with iNovacia to evaluate compounds synthesized by Lonza for Intellect. The data demonstrated the conjugation of the antioxidant molecule to an amino acid does not reduce its antioxidant activity. Pending adequate financial resources, these studies, which are almost complete, will allow us to select a drug candidate to take into development, providing the trigger for us to move forward with LONZA into an expanded manufacturing project, bringing us closer to the submission of an Investigational New Drug application.

In principle, our approach could be applied to improve many different types of antibodies, such as those that previously disappointed in clinical trials. However, currently we are focused on optimizing CONJUMAB-A using our own humanized antibody IN-N01, which targets the N-terminus of Aß. We believe IN-N01 to be superior to bapineuzumab because of its reduced potential to cause inflammation that results from our reengineering into an IgG4 class antibody.

Among several potential indications, we have decided to focus on AMD since both AMD and AD share several similarities, while the eye offers less challenge for delivering the drug. Indeed, physicians routinely perform injections into the eye cavity. Moreover, AMD is the leading cause of blindness in people over the age of 55, most of who respond poorly or not at all to existing therapies. While the relatively recent introduction of anti-vascular endothelial growth factor agents, such as intravitreal bevacizumab and ranibizumab, appear to have improved the prognosis for patients with wet AMD, preclinical studies have raised a potential red flag on anti-VEGF therapies, suggesting that increasingly aggressive use in eye disease could trigger side effects and potentially cause long-term damage. Moreover, no one has been able to develop an effective treatment for dry AMD, which is a significantly larger population, as it is the precursor to wet AMD.

Ample evidence has established oxidative stress as an important contributor in the pathogenesis of AMD and several studies have indicated antioxidant molecules can help reduce damage to the retina. Various Aß-lowering and Aß-neuroprotective strategies have demonstrated the ability to protect against damage in various models of retinal degeneration, including Aß-specific antibodies. Two such antibodies, GSK933766A and RN6Gare being tested in Phase 2 AMD trials having demonstrated an ability to reduce damage to RPE cells in animal models following systemic administration. These data lead us to believe CONJUMAB-A has the potential to become a strong leader in the field based on its combined properties to remove Aß and reduce oxidative stress when delivered in high concentrations directly to the eye.

https://globenewswire.com/news-release/2013/02/13/523315/10021734/en/Intellect-Neurosciences-Issues-Letter-to-Shareholders.html

Conjumab may increase the efficiency of solanezumab through linking with the melatonin (OX2) molecule (empower the mab to use the drug @ higher dose) or may help drugs like ponezumab with their anti inflammation properties which is a major issue in several potential drugs.

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