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Posts tagged ‘AMD’

Due to the pressure of other commitments, I only had the pleasure of attending the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) for two days, but one of my key take home messages from the meeting is how we can use the eye as a window into the brain.  This is particularly relevant to Alzheimer’s research.

ARVO researchers at a lunchtime workshop that I attended asked the question of what can we learn from shared disease mechanisms in age-related macular degeneration (AMD), Alzheimer’s Disease (AD) and Glaucoma to devise therapies of the future?

What I learnt in the introduction by Nicholas Bazan from LSU Health Sciences is that both AD and AMD are both multifactorial, genetically complex, progressive, late-onset neurodegenerative conditions.  Common features include:

  1. Age-related neurodegeneration
  2. Amyloid precursor protein mis-processing
  3. Non-resolving inflammatory response
  4. Selective apoptotic cell death

Researchers in the workshop presented early experimental findings.

Catherine Bowes Rickman from Duke presented data that showed anti-amyloid immunotherapy blocks retinal pigment epithelium (RPE) damage and visual function defects in an AMD-like mouse model.  Interesting questions were raised as to whether mouse Aß aggregates differently to human, so is this a good model?

Adriana Di Polo from the University of Montreal discussed Glaucoma and AD: common neurodegenerative pathways and therapeutic targets. It was interesting to note that high rates of visual abnormalities, including glaucoma, have been reported in AD patients, but causality has not been established. Neuronal loss in both glaucoma and alzheimer’s disease occurs via common cell death processes including altered metabolism of Amyloid Precursor Protein (APP) and Aß.

What Di Polo highlighted in her talk was the potential to use therapies effective in one disease to treat the other e.g. galantamine is approved for treatment of mild to moderate AD symptoms.  Because it crosses the retinal-brain barrier and has high bioavailability, she presented results using this in an animal model of glaucoma.

Her conclusion was that “therapeutic modalities that promote neuroprotection in AD may be useful in glaucoma and vice versa.”

The third speaker of this fascinating workshop was Ian Trounce from Melbourne, who challenged the Amyloid theory of AD. His hypothesis was that sAPPα may trigger oxidative stress in mitochondria and be the problem. He discussed the increasing acceptance/overlap in pathologies between Parkinson’s and AD.  He presented data that sAPPα overexpression protects retinal ganglion cells (RGC) from rotenone via PI3K-AKT activation.

Critical feedback on the three presentations was provided by Guy Eakin of the American Health Assistance Foundation (AHAF) and Imre Lengyel from UCL.

As Dr Lengyel succinctly notes in his UCL Institute of Ophthalmology bio:

“It appears that the development of age related macular degeneration (AMD) and Alzheimer’s disease (AD) share similar histopathology, vascular risk factors and genetic predisposition. In addition, the development of AMD appears to use similar or identical steps on the cellular and molecular levels to AD: vascular damage, oxidative stress, inflammation, extracellular protein and peptide degradation or deposition, and the role for lipids and trace elements (especially zinc) in the degenerative process are amongst the many common features. Furthermore, amyloid beta peptides are an integral part of drusen (the hallmark lesion in AMD) and their formation might be similar to plaque formation in AD.”

I applaud ARVO for looking at how the eye can be used as a window into the brain. It raises the intriguing prospect that research on AMD may not only help understand the cause of AD, but that the eye may serve as an experimental model for future new treatments. Collaboration between Opthalmology and Alzheimer’s researchers is something I expect and hope we will see more of.


This afternoon at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting in Fort Lauderdale saw the long-awaited briefing on the National Eye Institute Lucentis v Avastin comparative effectiveness trial in AMD.

I wrote in a previous post about the CATT results published in the New England Journal of Medicine.

I also tweeted from the briefing, but must add the disclaimer that live tweeting is tough and none of my tweets should be relied upon for accuracy.

What did I learn from the briefing (aside from the fact that ARVO’s technology vendors have real challenges in not being able to light a room properly, set up wifi and get a projector to work):

  • The CATT study was set-up before anyone knew what the price for Lucentis was.
  • No mention was made in the briefing today about comparative cost – but isn’t that what everyone thinks this study is about?
  • No mention was made of how you balance the cost benefits against the trade-off of the higher risk of serious adverse events that was seen.
  • When asked what they would give to a relative, most of the panel answering Q&A “punted” and said they would discuss the data with the patient, and try and get them to make an informed decision.
  • Only Dan Martin from Cleveland Clinic stuck his neck out and said if the patient asked him to make the choice of what to take, he would use Avastin over Lucentis – this statement clearly resonated with the audience (he received a big round of applause)
  • Two year data is already available and some of it was shown today, with no difference in death rate at 2 years between Lucentis or Avastin. The two year data will be published this time next year.
  • The study was not adequately powered to look at the serious adverse events (SAE), which means the statistically significant difference in SAEs may never be truly understood.

Overall, my impression from the briefing is that Lucentis is not identical to Avastin, although functionally the benefits from both appear broadly comparable with no statistical significance between them in terms of visual acuity gains. No mention was made of when you might use one drug over the other (if at all).

Lucentis did have some benefits over Avastin such as a lower retinal thickness at one year compared to the other three treatment groups, which was statistically significant. Both drugs produced an immediate and substantial decrease in retinal fluid, but more eyes were completely dry with Lucentis.

My thoughts are that the debate over Lucentis v Avastin is like the difference between a brand versus a generic, they are similar in terms of efficacy but not identical. While that’s perhaps an over-simplification given that in this case one drug is FDA approved and the other is not, those who want a brand and can afford it will buy a brand, while others may prefer the “generic” for cost reasons.

Will the Lucentis v Avastin decision be any different? If you can afford Lucentis through your insurance you may choose to take that, otherwise Avastin is another option for AMD.  Weighing cost versus slightly higher risk of SAE’s (for which there’s no adequate explanation showing causality) is how I would approach this decision.

It was interesting to note that the follow-up will continue and two year results will be published this time next year. They may shed further light on the serious adverse event differences, but I suspect that given the way the study is powered, this issue may not be resolved any further.

My overall take is that there is nothing compelling in the data to suggest that any ophthalmologist that is using bevacizumab off-label will switch patients to ranibizumab. Off-label Avastin use in wet AMD received an official NEI endorsement from the CATT study and will continue.

Equally those who are happy with Lucentis will not switch to Avastin on the back of this study, given that the Lucentis data appeared slightly better in places.  The controversy will no doubt continue and other studies comparing Lucentis v Avastin will add further insight.


Breaking news:

The New England Journal of Medicine have just published online the results of the Comparison of Age-related macular degeneration treatment trial (CATT) comparing the efficacy of FDA approved ranibizumab (Lucentis) to off-label bevacizumab (Avastin); a trial that has important commercial importance given the comparative costs of an intravitreal injection of around $1950 (Lucentis) vs. $50 (Avastin).

Key Study Results

Based on 1208 patients randomly assigned in the single-blind noninferiority trial, primary outcome was mean change in visual acuity between baseline and 1 year. This was equivalent between the two drugs.

Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively.

Secondary outcome measures included the incidence of ocular and systemic side effects, the results show some similarities and differences:

Rates of death, myocardial infarction and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20).

The proportion of patients with serious adverse events (primarily hospitalization) was higher with bevacizumab than with ranibizumab (24.1% vs 19%)

The conclusion of the study is that:

At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered to the same schedule”

However, here is the potential ‘get out’ for Genentech:

Differences in rates of serious adverse events require further study.

The investigators note that the difference in serious adverse events may be due to:

“chance, imbalances in baseline health status that were not included in the medical history or multivariate models, or a true difference in risk.”

i.e. they don’t know.

What the results from the CATT study mean is that Avastin and Lucentis are similar, but different. That is not a surprising result given that they originate from the same anti-VEGF monoclonal antibody.  However, they are not identical.

Clearly, if I were a patient, the additional 5% risk of serious adverse events would have to be weighed against the cost benefits. For those who are uninsured or unable to afford Lucentis, receiving Avastin may be an informed decision worth taking.  As the investigators note:

One of the many factors that contribute to the selection of a drug for a patient is cost.  A single dose of ranibizumab costs 40 times as much as a single dose of bevacizumab.  This cost differential has important economic implications when extrapolated to the more than 250,000 patients who are treated for neovascular AMD annually in the United States.

I look forward to hearing the animated discussion of these results at the ARVO annual meeting in Fort Lauderdale on Sunday.

ResearchBlogging.orgThe CATT Research Group (2011). Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration New England Journal of Medicine DOI: 10.1056/NEJMoa1102673

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This weekend I will be at the annual meeting of The Association for Research in Vision and Ophthalmology (ARVO) in Fort Lauderdale.

I’m excited about attending because earlier in my career I worked at Alcon Laboratories on European IDE clinical trials for three novel intra-ocular lenses.

ARVO is the ophthalmology equivalent of AACR and is where scientists involved in drug, device research meet to discuss new findings and early stage research.

The title of meeting is “Visionary Genomics.”  After listening to the plenary session at the recent AACR annual meeting by Lynda Chin on how insights from cancer genomics are translating into personalized medicine, I’m looking forward to seeing the impact of genomics on vision research.

Sunday’s ARVO/Alcon keynote presentation is from Roderick McInnes who is the Canada Research Chair in Neurogenetics at McGill University in Montreal.

A presentation that is already generating some advance interest is Sunday’s presentation of the results from the Comparison of Age Related Macular Degeneration Treatments Trials (CATT).

Age related macular degeneration (AMD) is the leading cause of vision loss in those over 65 in the United States, with over 7 million people estimated to be at risk.  Once you have AMD in one eye, you have a 43% risk of developing it in the other eye over a  five year period, a scary statistic!

The first CATT clinical trial is between bevacizumab (Avastin®) and ranibizumab (Lucentis®), both similar anti-VEGF inhibitors that are derived from the same monoclonal antibody.  It will be interesting to see whether the data supports the current practice of off-label use of bevacizumab given its lower cost compared to ranibizumab.

The findings from this data will also potentially impact aflibercept (VEGF-Trap) that is being co-developed by Bayer and Regeneron.  In February, Regeneron submitted a biologics license application (BLA) to the FDA for the use of VEGF-Trap in wet AMD.

The initial results from the aflibercept phase III AMD trial announced late last year showed a non-inferiority to ranibizumab.  If aflibercept is approved and comes to market in 2012, depending on the CATT results, it may have to compete on price against off-label bevacizumab in AMD.  Whether a more convenient injection once every two months for VEGF-Trap (compared to monthly for Lucentis) is sufficient to justify a price premium, it will be interesting to watch the market dynamics in this space.

You can find more about the meeting on the ARVO conference website and they have also put up a blog for the meeting.   The theme of my blog posts over the next few days will be ophthalmology related, and I expect to be live tweeting from ARVO 2011 on Sunday and Monday.  I’ll also be aggregating tweets from the meeting (hashtag #ARVO11) on this blog.


Human eye cross-sectional view. Courtesy NIH N...Image via Wikipedia

VEGF Trap-Eye is a formulation of VEGF Trap (aflibercept) and is an anti-angiogenic agent that can be injected into the eye to stop the proliferation of blood vessels. Regeneron (REGN) are co-developing it with Bayer (BAY) and it is currently in clinical trials for the treatment of wet Age-Related Macular Degeneration (AMD), Diabetic Macular Edema (DME) and Central Retinal Vein Occlusion (CRVO).

Phase II DME clinical trial results presented at the
Angiogenesis 2010 meeting in Miami showed the primary endpoint of a
statistically significant increase in visual acuity over 24 weeks compared to
the standard of care (laser treatment) was met.

There are high levels of vascular endothelial growth factor (VEGF) associated with DME, so the news that VEGF Trap-Eye has biological activity in this disease is positive.What makes this data promising is the fact that DME is the leading cause of blindness in adults under 50 and there are 370,000 Americans with clinically significant DME with 95,000 new cases a year.

The ability to treat DME by an eye injection, rather than use an expensive laser will make it easier to treat the disease. It will be interesting to see what how the cost of treatment with VEGF Trap-Eye compares to laser therapy procedures, should the agent make it to market.

The recent pricing issue faced by Genentech with its VEGF inhibitors Lucentis
(eye indications) and Avastin (oncologic indications) are also relevant because
Regeneron are developing VEGF-Trap in cancer with it’s partner sanofi-aventis
(a client).

For VEGF Trap-Eye, Regeneron retains all U.S. marketing
rights, while Bayer has rights to market ex-US in return for a 50/50 profit
share with Regeneron.The results so far look promising and aflibercept looks like an interesting agent well worth watching as the development moves forward.

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