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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com 

SPECIAL REPORT #27

Age Related Macular Degeneration.

Age Related Macular Degeneration (AMD) is the major cause of irreversible central vision loss.  AMD is characterized by a progressive degeneration of the central zone of the retina: the macula. The fovea, located near the centre of the macula, is mainly composed of cone photoreceptors and permits a detailed, high acuity vision required for reading and face recognition. AMD is a complex, highly heritable, multifactorial disease caused by the interplay of age, genetic and environmental risk factors, such as smoking, obesity as well as excessive light. About 50 genetic factors have been linked to AMD. Two of these variants are responsible for most of the inherited risk of AMD. They are common alleles in the European population (10% allele frequency each) and significantly associated with early and late AMD where their allele frequency is 30% for each of the variant.

The initial phase of AMD is asymptomatic and most subjects will never develop a symptomatic phase. The intermediate phase consists in diminishing rod cell function and therefore impaired vision in a darker environment. During this stage subjects often notice deformation of straight lines triggered by accumulation of debris deposits under the retina, known as drusen, which are clearly visible by a specialised diagnosis of the back of the eye.

Approximately 50 % of patients with early/intermediate AMD will develop debilitating late AMD. There are two types of severe late AMD. An atrophic or “dry” form which progresses slowly and destroys the central vision and the “wet” form where new vessels are formed in the choroid and/or retina, the neovascular form. The frequencies of the two forms are roughly equivalent.

The VEGF approaches

Since 2006, anti-angiogenic agents, which had first been developed to treat various cancers, have drastically changed the outcome of the “wet” form of disease.

Three drugs, which all inhibit the neovascularisation process in blocking the Vascular Epithelial Growth Factor (VEGF) pathway have been approved worldwide: Avastin or bevacizumab (Roche-Genentech), Lucentis or ranibizumab (Novartis) and Eylea or aflibercept (Bayer and Regeneron).) The three agents are delivered through a rather stressful intravitreal injection (IVI) and have to be repeated several times depending on the severity of the disease. In some rare cases, a single injection is sufficient to stop the progression of the disease for years . In the more severe cases, a monthly injection is required for at least one year.

A series of other anti-VEGF products are currently being investigated in clinical settings. Beovu (brolucizumab) Novartis’ own successor of Lucentis has been approved in 70 countries, including the US, EU, UK, Japan and Australia, but a recent study showed unexpected high degrees of vasculitis and ocular venous occlusions. Roche’s fricimab – a bispecific antibody which targets angiopoetin-2 and VEGF-A – has received marketing authorisation application in Europe and in the US, in July 2021. Allergan, now AbbVie’s abicipar – a DARPIN therapeutics – has received a complete negative response letter from the US FDA in August and has returned its rights to Molecular Partners based in Switzerland. Opthea’s (Melbourne, Australia) OPT 3022, a dual VEGF-C /VEFG-D Trap completes the short list of the most advanced follow-up drugs in AMD. On October 22, the FDA has approved Genentech’s Susvimo, a port delivery system with a customized formulation of ranibizumab. The difficulty for Genentech with this device, is to convince patients to accept having surgery to have an implant the size of a grain of rice placed under the eye lid. The refillable eye implant is the first of its kind and requests refilling every six months in contrast to the monthly IVI of Lucentis.

Other approaches

Apellis, a biotechnology company based in Waltham, USA, is developing drugs that target the complement C3, a target which has been linked to the emergence of AMD. Pegcetacoplan, which binds and inhibits complement protein C3, already been approved for the treatment of paroxysmal nocturnal haemoglobinuria, will be assessed, in 2022, in a phase 3 trial for the treatment of intermediate AMD.

High-temperature requirement A1 (HTRA1), a serine protease secreted by a number of tissues, including retinal pigment epithelium (RPE), has also been associated with increased risk of AMD. Scientists at Genentech have developed HTR2163, a novel antigen-binding fragment (Fab) directed against HTRA1 to test the therapeutic hypothesis that an abnormal serine protease activity is involved in the progression of AMD. The phase 1 study has been completed and reported in the June issue of the American Journal of Ophthalmology.

Photodynamic therapy is also being used in particular patients by some ophthalmologists.

There are currently no drugs available for the treatment of intermediate and atrophic AMD, in spite of numerous efforts in the field focussing on anti-inflammatory agents, neuroprotective agents, agents that modulate the visual cycles, treatments that restore choroidal blood flow, gene therapy and even pluripotent stem cells. In 2019, Novartis announced a collaboration with Microsoft to explore the use of artificial intelligence to open new avenues in AMD.

Institut de la Vision

Recent progress made by Dr. Florian Sennlaub and his team, at the Institut de la Vision in Paris, is opening a new frontier in the field. They have shown that all forms of AMD are invariably associated with an accumulation of mononuclear phagocytes (MP) in the subretinal space, a family of cells that include inflammatory and resident macrophages. (Progress in Retinal and Eye Research, 2017). In the healthy eye, the photoreceptor layer does not contain macrophages. Photoreceptors are particularly sensitive to cytokines and oxidative species produced by macrophages to destroy microbial organisms. In AMD mononuclear macrophages invade the photoreceptor layer and induce photoreceptor degeneration. The team led by Sennlaub has discovered that the main genetic variants linked with AMD render macrophages resistant to a rapid elimination from the photoreceptor layer and thus promotes their accumulation and photoreceptor degeneration, which triggers further MP recruitment, the beginning of a “vicious circle”. This mild chronic inflammation induces the degeneration of the healthy photoreceptors. It may seem surprising that variants associated with AMD elicit an exaggerated inflammatory response, but it is probably precisely for this reason that these variants were selected in human evolution: the stronger inflammation of people carrying these variants might have helped neutralize microbes and survive infections. Over the generations these variants have become more and more common. Sennlaub is currently studying the effect of environmental AMD-risk factors on MP accumulation in AMD. But his most exciting hypothesis lies in the observation that pharmacological intervention, which inhibits the accumulation and unfavourable action of macrophages on the retina, has a beneficial effect on the occurrence of AMD. The team has identified several biological targets of interest which are thoroughly assessed, in various preclinical models. Amongst them, the interaction of Thrombospondin-1 (TSP-1) with CD47 mediated subretinal macrophage elimination has triggered renewed interest. This promising work might lead to treatment of atrophic or “dry” AMD.

For many years we have been advocating that the study of retinal (highly specialised neurons) degeneration, such as in AMD, could also help understand the pathogenic mechanisms of other degenerative brain diseases.

Important Figures

AMD is currently affecting 200 million subjects in the world.

AMD will affect close to 300 million subjects by 2040.

AMD is the first cause of visual handicap in subjects above 50 years of age.

AMD’s first symptoms appear at around 65 years of age.

AMD early or severe forms are occurring in 25 to 30% of patients aged 75 years and above.

Market

The global AMD treatment market was valued at $7.775 billion in 2020 and is expected to reach $12.85 billion by 2026 with an estimated Compound Annual Growth Rate (CAGR) of 7.4% during the forecast period, in spite of the potential emergence of biosimilars. North America holds around 44% of the global market. The COVID-19 outbreak had a significant negative impact on the 2020 sales mainly because of a massive decrease of attendance at scheduled clinic visits for intravitreal injections. The current market is highly consolidated with four companies: Bayer, Novartis, Regeneron and Roche. Other companies active in the field are: AbbVie, Alimera Sciences, Bausch Health Companies, Neurotech, Opthea, Ophthotech, Pfizer, Sam Chun Dan Pharma and Stem Cells.

Pricing of Lucentis and Eylea varies between $600-800 in Europe for a single monthly dose and up to $2,000 in the United States. Lucentis, Eylea and Avastin account for close to 99% of the market share in the western world. Off label use of Avastin (bevacizumab) is quite popular in several countries, although Genentech never filed the drug in this indication. Sales for Lucentis and Eylea pegged around $7 billion in 2020. Both Lucentis (ranibizumab) and Eylea (aflibercept) will have to compete with the launch of emerging biosimilar drugs as soon as 2022. In September 2021, the US FDA has approved Byooviz or SB11, a ranibizumab biosimilar from Genentech, as the first ever ophthalmology biosimilar.  The product was developed by Samsung Bioepis and will be commercialised by Biogen at an undisclosed price in June 2022. Japanese biopharmaceutical companies Gene Techno Science and Kishi Kasei announced in December 2019, an agreement to co-develop an Eylea (aflibercept) biosimilar for Japan. The agreement also involves Fuso Pharmaceuticals which had been developing a new high yield aflibercept cell line. This agreement followed news that Samsung Biopeis has extended its agreement with Biogen for the commercialisation of SB15, its own aflibercept biosimilar.

This article was prepared with the input and an interview with Dr Picaud and Dr. Sennlaug from the Institut de la Vision.

Paris December 17, 2021

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