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Posts from the ‘Ophthalmology’ category

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.

 

Today in the plenary session of the 102nd Annual Meeting of the American Association for Cancer Research (AACR), Lynda Chin from Dana-Farber Cancer Institute in Boston provided an excellent overview of the challenges and opportunities of translating insights from cancer genomics into personalized medicine that will benefit patients.

I unequivocally recommend listening to the webcast of the plenary when it is posted on the AACR website.

As Dr Chin stated at the start of her presentation, “cancer is fundamentally a disease of the genome.”  The goal of all cancer research is to make progress with prevention, detection and cure.

In the plenary presentation she highlighted some of the successes that have come from understanding the genome e.g. the knowledge of BRAF mutation in melanoma led to the identification of a target and development of a new drug in 8 years.  In addition to the development of novel therapeutics, genomics research has helped companies reposition drugs and she highlighted crizotinib as an example (move from C-Met to ALK inhibition in NSCLC).

These successes have “motivated researchers” according to Chin.  However, it is transformative new technology such as the next generation of sequencing technology that has heralded “a new era of cancer genomics.”  Massively parallel sequencing enables comprehensive genome characterization.

Not only has innovative new sequencing technology increased the throughput, but it has dramatically decreased the costs.  As Dr Chin noted, some have questioned whether cancer genomics is worth it?  She outlined some of the recent successes, such as BAP1 in ocular melanoma (see my previous post on this) as examples of its value.

Challenges remain such as the management of the vast amount of data that genome sequencing produces.  Data management, processing and storage remain issues, as does the need to develop a reference human genome against which a patient’s tumor profile could be compared.

And even when you find a mutation, the challenge is to separate the “drivers” from the “passengers.” This according to Chin requires a “robust statistical framework”.

Cancer signaling is not linear, but is a highly interconnected and redundant network, so it remains a big task to translate genomics into personalized medicine.  According to Dr Chin using mice as models to bridge the gap between sequencing and man may be the way forward in translating cancer genomics into personalized medicine.

I would like to thank Victor Pikov, a neurophysiologist and biomedical engineer at Huntington Medical Research Institutes (HMRI) for drawing my attention to his NeurotechZone Blog that has a really fascinating post on the manufacturing of the next generation of artificial retina, the Argus™ 111, by the Lawrence Livermore National Laboratory (LLNL).

If you have an interest in this area, then Victor is also co-chair of 3rd International Conference on Neuroprosthetic Devices (ICNPD-2011) to be held in Sydney from November 25-26, 2011. Further information can be found on NeuroTechZone.

Second Sight Medical Products recently obtained a CE mark and European Market Approval for the Argus™ II system that incorporates 60 electrodes into the retinal prosthesis.

However the next generation of artificial retina, the Argus™ III is already in development.  It has 200 electrodes – a quantum leap forwards.  It’s hard not believe that an array that is four times as densely packed with sensors, will not provide improved vision.

Second Sight will no doubt be planning clinical trials for Argus™ III and it sounds like it will provide a further leap forward in the technology to restore some sense of vision to patients who have lost their sight through age-related macular degeneration (AMD) or retinitis pigmentosa (RP).

I have taken the liberty of embedding below, the excellent YouTube video that Lawrence Livermore National Laboratory (LLNL) have produced about their manufacturing of the Argus™ III artificial retina. It is well worth watching!

 

I wrote last week about Second Sight’s European Marketing Approval for the Argus II “artificial retina”.  What this news also stands for is the success of collaboration as a route to innovation.

The Artificial Retina Project (“Restoring Sight through Science”) through which Argus II was developed is a collaborative effort between six United States Department of Energy (DOE) research institutions, 4 universities and private industry.

Each offers unique scientific knowledge and specialist expertise, without which it is unlikely the project (that is continuing with the development of a more advanced Argus III artificial retina) would have been successful.

I’ve listed the collaborators below and as recorded on the DOE website, what they bring to the Artificial Retina Project.

DOE National Labs:

  • Argonne National Laboratory – Performs packaging and hermetic-seal research to protect the prosthetic device from the salty eye environment, using their R&D 100 award-winning ultrananocrystalline diamond technology.
  • Lawrence Livermore National Laboratory (LLNL) – Uses microfabrication technology to develop thin, flexible neural electrode arrays that conform to the retina’s curved shape. LLNL also uses advanced packaging technology and system-level integration to interconnect the electronics package and the thin-film electrode array.
  • Oak Ridge National Laboratory – Measures the effect of increasing the number of electrodes on the quality of the electrical signals used to stimulate the surviving neural cells in the retina.
  • Sandia National Laboratories – Develops microelectromechanical (MEMS) devices and high-voltage subsystems for advanced implant designs. These include microtools, electronics packaging, and application-specific integrated circuits (ASICs) to allow high-density interconnects and electrode arrays.
  • Brookhaven National Laboratory – Performs neuroscience imaging studies of the Model 1 retinal prosthesis.

Universities:

  • Doheny Eye Institute at the University of Southern California – Provides medical direction and performs preclinical and clinical testing of the electrode array implants. Leads the Artificial Retina Project.
  • University of California, Santa Cruz – Performs bidirectional telemetry for wireless communication and chip design for stimulating the electrode array.
  • North Carolina State University – Performs electromagnetic and thermal modeling of the device to help determine how much energy can be used to stimulate the remaining nondiseased cells.
  • California Institute of Technology – Performs real-time image processing of miniature camera output and provides optimization of visual perception.

In October 2004, Second Sight Medical Products and the DOE signed a Co-Operative Research and Development Agreement (CRADA) in which the above institutions agreed to share intellectual property and royalties from their research, with Second Sight chosen to be the commercial partner.  As part of the CRADA, Second Sight obtained a limited, exclusive license to the inventions developed during the DOE Retinal Prosthesis Project.

You can find more information about the history of this fascinating project on the Artificial Retina Project website, that also has links to several patient stories from around the world.

The Artificial Retina Project is a case study on the success of collaboration.  Whether such an ambitious project that was funded by the US Government would ever have taken place in the private sector is the question that comes to my mind?  Would a private company have been able to harness the intellectual power of 10 research institutions in this way?

If not, then do governments have a role to play in biomedical innovation by drawing partners together so that advances in basic research can be applied to new products, whether they be new drugs or novel devices?

And if you agree that governments do have a role to play what should be the extent of government funding?  In the case of artificial retina, the DOE has funded this since 1999, with its contribution rising from $500K to $7M per year. Those numbers may also be direct costs, and not reflect the cost of investments in buildings, research facilities etc.

I’d be interested in any thoughts you would like to share on this.

Detecting a door or a window may not be a big deal for all of us with normal vision, but for those who lose their sight, e.g. through retinitis pigmentosa (RP), a new “artificial retina” now provides hope of a better quality of life.

The Argus™ II Retinal Prosthesis System from California based company Second Sight, has just received CE marking.  This innovative device can now be sold and marketed within Europe, but it remains investigational in the United States. It is the first such device to be approved.

While this blog is mainly focused on the biotechnology industry, I’m very interested in innovation and bringing novel products to market. I also have a personal interest in the ophthalmology market.  Earlier in my career, I spent three years at Alcon working with leading European ophthalmologists on intra-ocular lens clinical trials, including the IDE registration trial for AcrySof®.

In the same way that a cochlear implant does not restore hearing, the “artificial retina” or so-called “bionic eye” from Second Sight is not intended to restore vision, instead it artificially provides electrical signals that it is hoped the brain can learn to interpret as shapes.

The “artificial retina” has three parts, a small video camera worn in a pair of glasses that captures visual images.  This transmits the electronic images to a video processing unit worn by the patient.  Data is then transmitted wirelessly to an implant that is located on top of the retina.

The array of electrodes resting on the retina stimulates those rods and cones that remain functional to generate electrical impulses that are then transmitted down the optic nerve to the brain.  Patients learn to interpret the patterns of light that are generated, and in the process gain some sense of visual perception that improves their daily life.

In an interview broadcast on French radio station, RTL one of the four French patients in the clinical trial, Thierry, talks about how this retinal stimulation device has improved his autonomy and quality of life.

When faced with blindness, any progress is noteworthy and it will be interesting to see the extent to which this technology can be further developed.  I expect that more clinical trial data will be forthcoming at the annual meeting of ARVO (Association for Research in Vision and Ophthalmology) in May.

Update August 23, 2012:  FDA Panel to review whether to recommend of approval of Argus II artificial retina in the United States

The FDA Ophthalmic Devices Panel will review on September 28, 2012 the Humanitarian Device Exemption (HDE) market approval application by Second Sight for its Argus II Retinal Prosthesis System with an indication for patients with severe to profound retinitis pigmentosa (RP) who have bare or no light perception in both eyes.

What is a Humanitarian Device Exemption? 

“An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.”  U.S. Food & Drug Administration

Given the lower standard required for a HDE, and the fact that Second Sight obtained a CE mark in Europe, it would be hard to believe the FDA advisory panel will not recommend approval in a patient population that are effectively blind.

However, the FDA guidance also notes that an approval of an HDE, while allowing marketing of the device, does require it’s use to be at facilities where an institutional review board (IRB) has approved the use of the device. If approved for sale in the US, the market for Second Sight will be limited as a result to academic and hospital settings that have an IRB able to provide the necessary oversight and review.

“An approved HDE authorizes marketing of the HUD. However, an HUD may only be used in facilities that have established a local institutional review board (IRB) to supervise clinical testing of devices and after an IRB has approved the use of the device to treat or diagnose the specific disease. The labeling for an HUD must state that the device is an humanitarian use device and that, although the device is authorized by Federal Law, the effectiveness of the device for the specific indication has not been demonstrated.”

For those interested in more information, background material on the HDE application will be available on the FDA website no later than 2 days prior to the September 28 meeting of the Ophthalmic Devices Panel of the Medical Devices Advisory Committee.

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The December 17, 2010 issue of “Science” has the catchy of title of “Insights of the Decade”, one of which is an article by Jennifer Couzin-Frankel, “Inflammation Bares a Dark Side”, that describes the ubiquitous role of inflammation. She concluded that:

“Mediating inflammation in chronic diseases is a new frontier, its success is still uncertain.”

Inflammation has been shown to play an important role in multiple chronic illnesses such as cancer, and in type 2 diabetes it promotes insulin resistance and the death of pancreatic beta cells.  In 2007, Marc Donath and colleagues published a landmark study in the New England Journal of Medicine where he used the drug anakinra, in patients with type 2 diabetes, to block interleukin-1 (IL-1), a cytokine that mediates the inflammatory response. The conclusion of the paper was that:

“The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation.”

The finding that diabetes patients whose inflammatory response was blocked did better, has led several companies to work on drug development in this area.

One of these is the biotechnology company, Xoma, whose stocked jumped 200% in the week before Christmas.  Although there was no press release or announcement of any company news, it looks like investors decided to take a gamble that the phase 2 trial results for Xoma 052 in type 2 diabetes will be positive.  As often happens, the wisdom of the crowd, led to others joining the share buying frenzy.

Source: Google Finance.

Xoma had previously announced on November 4, 2010 (emphasis added) that accrual was complete in the Phase 2a trial of XOMA 052 in subjects with Type 2 diabetes:

“This randomized, placebo-controlled trial, in which 74 patients were enrolled, is designed to evaluate extended biologic activity and safety of XOMA 052. Outcomes will include diabetes measures such as hemoglobin A1c, or HbA1c, and fasting blood glucose, or FBG, and C-reactive protein, or hsCRP, a biomarker of inflammation associated with cardiovascular risk. Interim results from the first three months of treatment in this six month trial are expected to be announced in the first half of January 2011.

Enrollment completed in Phase 2b trial of XOMA 052 in patients with Type 2 diabetes. This randomized, placebo-controlled dose-ranging trial enrolled 420 patients and is designed to further evaluate the safety and efficacy of XOMA 052 dosed once monthly compared to placebo. The results will include data on measurements of HbA1c, FBG and hsCRP. Top line results are expected to be announced in the first quarter of 2011.”

XOMA 052 is a high affinity monoclonal antibody that targets the inhibition of IL-1 beta.  Its ultra-high affinity allows for monthly dosing and lower dose levels which supports patient compliance in chronic diseases. Positive phase 2 results for XOMA 052 in Behcet’s Uveitis was presented in November to the American College of Rheumatology.

According to the November 2010 Xoma Corporate Presentation, the overall market size for diabetes is $22B, of which the IL-1 share is $7B, raising the possibility that XOMA 052 could be a blockbuster if shown to be safe and effective.

Source: Xoma November 2010 Corporate Presentation

Whether these numbers are realistic or ‘pie-in-the-sky’ dreams remains to be seen and we will have to wait and see what happens with future study readouts.

Note: Additional information on the deal with Servier can be found here.

Update March 18th 2014 by @maverickny

FDA awarded Xoma and Servier orphan drug designation for XOMA 052 (gevokizumab) for the treatment of pyoderma gangrenosum (PG), a rare disease that induces painful skin ulcers.  Standard therapy involving corticosteroids or cyclosporin are effective in approx. half of patients, but for those that relapse this new approach may offer new treatment options.

The two companies previously signed development and financial agreements including a 2011 agreement to commercialize XOMA 052, an anti-inflammatory drug candidate and another in 2013 to start the Proof-of-Concept (POC) clinical program to study gevokizumab.

Earlier this month, Xoma provided an update on its gevokizumab development program:

“Based on results from the Company’s Phase 2 program in patients with erosive osteoarthritis of the hand (EOA), XOMA does not intend to launch pivotal development for the broad EOA indication. The Company will conduct a review of the full dataset to determine if there is a segment of the patient population that best responds to gevokizumab therapy prior to initiating any potential additional clinical studies in this indication.”

The phase 3 program for gevokizumab in patients with pyoderma gangrenosum thus looks to be the best shot they have with this agent at present.

Update August 28th 2017 by @maverickny

Novartis have acquired the rights to Xoma’s gevokizumab following the phase 3 failure 18 months ago. The company is paying $31 million (€26 million) upfront for the distressed assets relating to the anti-IL-1 beta allosteric monoclonal antibody.

The company have previously garnered FDA approval for Ilaris in two subtypes of the rare auto-inflammatory diseases cryopyrin-associated periodic syndromes in 2009. A large trial in at-risk cardiovascular disease patients with high levels of chronic inflammation also began enrolling patients.

Data presented recently suggest Novartis has succeeded in demonstrating an anti-inflammatory drug can cut the risk of major cardiovascular events so if the company can make the commercial case for Ilaris, its big bet on cardiovascular disease may pay off. Where gevokizumab fits in with the anti-inflammatory portfolio isn’t yet clear.

Update January 7th 2019 by @maverickny

Things are becoming more interesting on the gevokizumab (now VPM087) front.

Novartis have just opened a phase 1 trial exploring the impact of adding gevokizumab to standard of care anti-cancer therapies for metastatic colorectal, gastroesophageal, and renal cancers with different arms for 1/2/3 line therapies.

Initial data are expected year end 2022, so it will be a while before we see what happens in terms of the study readout.

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Uveal melanoma is a common cancer of the eye that involves the iris, ciliary body and choroid.  It is a disease that hits 2000 people per year in the United States and is common in those over 50.  Standard treatment involves removal of the eye or radiotherapy. There is an unmet need for systemic drug therapy.

Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been found in many skin melanomas.  In 80% of the cases, a single point mutation in exon 15 (T1799A) has been shown to occur.  Some new agents in development such as PLX4032, ipilumumab, GSK2118436 have shown promise in advanced skin melanoma, but research suggests that BRAF may not be the key to Uveal melanoma.

Henriquez et al, in a paper published in Investigative Ophthalmology & Visual Science showed that the T1799A BRAF mutation was only present in 9 of 19 iris melanoma tissue samples, but only in one case of uveal melanoma, suggesting differences in the genetic and clinical differences between the two.

Recently, two papers have been published that provide new insight into this intraocular cancer. In the December 2, 2010 issue of the New England Journal of Medicine, Van Raamsdonk et al, found mutations of either the GNAQ or GNA11 gene to be present in 83% of uveal melanomas that were sequenced (n=713).

Harbour et al, in the December 3, 2010 issue of Science reported findings of a frequent mutation of BAP1 in metastasizing uveal melanomas. They found that in 26 of 31 (84%) of uveal melanoma tumors they examined, there was a mutation of BAP1, the gene encoding BRCA1 associated protein 1 (BAP1) on chromose 3p21.1. The results published in Science, “implicate loss of BAP1 in uveal melanoma metastasis and suggest that BAP1 pathway may be a valuable therapeutic target.”

The data suggests that there may be multiple pathways involved in uveal melanoma.  It is promising to see translational medicine in action, with scientists seeking to understand the molecular basis of a disease so that targeted therapies can be developed.  Uveal melanoma only strikes a relatively small number of patients, but if a highly effective drug can be developed, this could be a market opportunity worth pursuing.

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