The First Ophthalmic Innovation Summit

Earlier this year, two venture capitalists, Emmett Cunningham of Clarus Ventures and Bill Link of Versant Ventures, came up with the idea to hold a meeting prior to this year’s AAO Meeting, to enable start up and other small and early-stage ophthalmic companies to present new innovations that they were working on to a group of “angels” and other potential investors, key ophthalmic industry leaders, and other interested parties. Thus was born the first Ophthalmic Innovation Summit (OIS). The day-long event was held at the Palace Hotel in San Francisco on October 22nd, co-chaired by the above mentioned venture capitalists.

Over 400 attendees listened to 10 minute presentations from 25 early stage and small companies, including twelve ophthalmic device companies, and thirteen working on ophthalmic pharmaceutical products to battle various disease states.

The device companies presenting included:

-- AcuFocus, Inc. – (a corneal inlay) Jim Socks, SVP Clinical & Regulatory Affairs
-- ReVision Optics, Inc. – (the Presby corneal inlay) J. Randy Alexander, President & CEO
– PowerVision, Inc. – (a fluid-filled accommodating IOL) Barry Cheskin, President & CEO
– NuLens Ltd. – (an accommodating IOL) Ori Gal, CEO
– LenSx Lasers, Inc. – (femtosecond laser for cataracts) Ron Kurtz, MD, President & CEO
– VisionCare Ophthalmic Technologies, Inc. – (implantable telescope for AMD) Allen Hill, President & CEO
– WaveTec Vision – ( wavefront aberrometer) Tom Berryman, President & CEO
– Ocular Therapeutix, Inc. – (hydrogel bandage lens) Amar Sawhney, PhD, President & CEO
– OptiMedica Corporation – (pattern-scan laser for retina, and a femtosecond laser for cataracts) Mark Forchette, President & CEO
– NeoVista, Inc. – (Epi-Rad 90 brachytherapy for AMD) John Hendrick, President & CEO
– Oraya Therapeutics – (IRay X-ray therapy for AMD) Jim Taylor, President & CEO
– Second Sight Medical Products, Inc. – (retinal prosthesis) Rob Greenberg, MD, PhD & CEO

[Editor’s note: I have written extensively on NeoVista and its Epi-Rad 90 treatment for AMD. Please see the links at the end of this posting. I have also just written a comprehensive report on the Oraya IRay X-ray treatment for AMD. That link is also included at the end of this posting.]

The pharmaceutical companies presenting included:

– MacuSight – (pharma for AMD) David Weber, PhD, President & CEO
– Ophthotech Corporation – (pharma for AMD) Samir Patel, MD, President & CEO
– Taligen Therapeutics – (pharma for inflammatory disease) Abbie Celniker, PhD, CEO
– Eyetech Inc. – (Macugen for AMD) Michael Atieh, Executive Chairman*
– NeuroTech – (pharma for AMD) Ted Danse, President & CEO
– Aerie Pharmaceuticals, Inc. –(pharma for glaucoma) Tom van Haarlem, MD, President & CEO
– Panoptica, Inc. – (seeking early-stage ophthalmic drugs) Paul Chaney, President & CEO
– SARCode Corporation – (pharma for inflammatory disease) Tom Gadek, PhD, CEO
– Lux Biosciences, Inc. – (dry eye/uveitis) Ulrich Grau, PhD, President & CEO
– Applied Genetic Technologies Corporation (AGTC) – (gene therapy) Sue Washer, CEO
– ESBATech – (Alcon - biotech) Dominik Escher, PhD, CEO
– Sirion Therapeutics – (anti-inflam/uveitis, GA in AMD)Barry Butler, President & CEO
– iCo Therapeutics – (antisense for diabetic & macular edema) Andrew Rae, MBA, President & CEO

[Editor's Note: Some of the above presentations have been put online. Follow the links of the highlighted companies to see their presentations. In addition, some of the other presentations -- mentioned below -- are also shown online. Again, follow the highlighted text to see the presentations.]

In addition to the company presentations, industry leaders participated in panel discussions on topics ranging from views of the private and public sectors, financing of ophthalmic device and pharmaceutical companies, what established ophthalmic companies are seeking in smaller companies, and regulatory issues (ophthalmic devices, ophthalmic drugs).

Executives from larger companies weighed in with criteria that, for them, makes a new idea worthy of investment. These included proof of concept in animal studies as well as some characteristics that will distinguish the drug or device from competitors’ products. None of the individual investors in the audience thought that a slow economy was a bad time, per se, to make investments, and, in fact, several commented that putting assets on the table now will enhance their potential returns when capital starts flowing again.

As a wrap up to the meeting, two prominent ophthalmic practitioners, Richard Lindstrom and Mark Blumenkranz took a look at what the next five years might hold in the posterior segment (Blumenkranz) and the anterior segment (Lindstrom).

Dr. Lindstrom said that glaucoma surgeries may become a safe and more effective first-line alternative to medical management in patients who are regularly non-adherent with, or whose disease is refractory to, topical therapies. He also suggested that efforts to prevent cataractogenesis and presbyopia may someday preempt efforts to treat them.

Dr. Blumenkranz said that ophthalmologists are learning what oncologists discovered years ago – combination therapy is often superior to monotherapy. He also noted that virtually all retinal diseases conform to one of four avenues of pathogenesis, and that all four of those are in some part VEGF-dependent.

With the success of this first meeting, Dr. Cunningham hopes to make the OIS an annual event.


Prior to the meeting, Dr. Cunningham sat down with Jim Stommen, the recently retired editor of Medical Device Daily, to discuss both the upcoming OIS meeting and issues related to ophthalmic device and drug development. Here, presented with permission of The Healthcare Syndicate, a website devoted to healthcare information for the venture capital community, is the full interview:

EYE ON INNOVATION – AN INTERVIEW WITH: DR. EMMETT CUNNINGHAM, OPHTHALMOLOGIST AND VENTURE CAPITALIST

Dr. Emmett Cunningham is a Partner at Clarus Ventures. He will be Co-Chairing the upcoming Ophthalmology Innovation Summit scheduled for October 22nd at San Francisco’s Palace Hotel along with Dr. Bill Link of Versant Ventures. Prior to Clarus, Dr. Cunningham was senior vice president, medical strategy, at Eyetech Pharmaceuticals, where he helped build and lead the development and commercialization of Macugen, the first pharmacotherapy for age-related macular degeneration (AMD). Prior to Eyetech, he was at Pfizer. Dr. Cunningham is an ophthalmologist, an internationally recognized specialist in infectious and inflammatory eye disease, and an Adjunct Clinical Professor of ophthalmology at Stanford University.

Dr. Cunningham discussed both the upcoming Ophthalmology Innovation Summit and issues related to ophthalmic drug and device development with Jim Stommen, recently retired editor of Medical Device Daily.

HS: What are the key marketplace challenges for firms – and their investors – operating in the ophthalmic space?

Cunningham: The ophthalmic space has become relatively crowded in the past 5 years, which means there are more people and companies chasing the same end-points and indications. That’s a good thing for the patients who need new and improved treatments, but it makes investing a little more challenging because it’s harder to predict what the competitive landscape will look like 5 to 10 years down the road. In addition, the cost of running clinical trials continues to rise, and trials take more time enrolling. Perhaps the biggest challenge, however, is the overall financial environment. Investors, including venture investors, have responded to recent changes by becoming less willing to take on risk. For those companies developing drugs, many investors want to see randomized Phase II data. Similarly, for commercial-stage companies, many investors like to see enough of a sales ramp to be able to predict profitability. This has effectively left some companies “stranded” between financings.

HS: Aside from the format for trials and trial approvals, etc., are there any specific regulatory issues that apply broadly within the ophthalmic pharma space?

Cunningham: There are lots of very nuanced regulatory issues in the space. Really, ophthalmology has four big indications: wet AMD, dry AMD, diabetic macular edema/diabetic retinopathy, and glaucoma/neuroprotection. Everyone would agree that these each have the potential to be billion-dollar-plus markets. The next-largest indication is dry eye, which currently is about a $500 million-sized market in the U.S., but could be much larger once drugs with improved efficacy are available.

If you look at AMD, the first drug approved was Eyetech’s Macugen. It had modest efficacy, but was clearly more efficacious than placebo or the standard of care at the time. Next to come along, about a year later, was Lucentis, which had much greater efficacy. And by greater efficacy, if you looked at the primary endpoint response range, Macugen was in the 70% range and Lucentis was above 90%. So once you have a therapy that has a 90% efficacy rate, however you define that, it becomes very challenging to develop a drug that’s superior. So from the perspective, of having a very effective drug on the market, it’s harder to develop new drugs in the wet AMD space.

Dry AMD also is a very large market, but no one to date has developed a drug for it, so the regulatory and clinical development issues are still to be worked out. There are trials underway, and people are very enthusiastic about them, but until it actually happens, it’s unknown territory.

Dry eye has also historically been a very difficult indication. Allergan has Restasis approved for dry eye, but no other company has been able to get a drug approved for that indication. My guess is that it is difficult because the pathogenesis is complex – most companies go after things that are anti-inflammatory, or that increase tear production, but inflammation on the one hand and tar production on the other each contribute only partially to the pathogenesis of dry eye, so targeting either mechanism might be treating only part of the disease.

It’s a lot easier to develop a drug for glaucoma, where you have a very clear endpoint of pressure reduction, but because we have so many drugs available for pressure reduction, the hurdle has been raised to where the absolute pressure reduction for any given agent needs to be pretty pronounced. The hot area right now appears to be the so-called ROCK inhibitors, and a few companies are looking at those, but to be real winners in this space, they have to have good tolerability and compelling efficacy.

The are lots of other indications, such as infectious conjunctivitis, allergic conjunctivitis, etc., that are much smaller markets.

HS: Are those smaller markets worth getting involved with?

Cunningham: Yes and no. There are certain costs of developing a drug, no matter how big the market is, so if the market doesn’t justify those costs, then people don’t do it. They might do it as a second indication once it’s gotten approval for a lead indication, but they typically don’t bet the ranch on small indications.

HS: The agenda for your upcoming conference addresses the development of both device and drug solutions. Are there more opportunities for innovation, especially by smaller companies, on the device side?

Cunningham: Some problems are more amenable to devices, such as optical problems – those problems that have to do with focusing the image on the retina. One example is reversing presbyopia with accommodating intraocular lenses, currently pursued by Visigen, NuLens, and PowerVision. On the instrument side, WaveTec has a device that is used for accurately measuring the refractive area of the eye at the time of surgery to try to help improve placement of intraocular lenses, among other things. Devices also play a role in glaucoma management, particularly for patients who fail medical therapy. Examples would be Glaukos and Transcend, among others. There are lots of other examples, but generally I would say there’s considerable activity in both devices and drugs in ophthalmology.

HS: We have talked quite a bit about AMD, so I’m wondering where we’re headed with Lucentis, which has the huge market penetration, and then Avastin, which has made strides on an off-label basis.

Cunningham: Just by way of history, it’s not that long ago that we had no good therapies for neovascular AMD. I have friends who are retinal specialists who say, frankly, that practicing in that era was depressing, because patients would come in, they would have had a huge vision loss in one eye and oftentimes both eyes, and the physicians would have nothing to do except hold their hands and try to get them through it. So this whole era of anti-VEGF therapy has truly been a revolution in therapy for what is the leading cause of blindness in the developed world. Lucentis is a phenomenal drug. Genentech really outdid itself. Their commercial issue, however, is that Lucentis is basically an enhanced fragment of Avastin. So, once the Lucentis data came out, but when there was still a year or so until approval, people had the idea to compound Avastin and inject it into the eye, and experience with Avastin and Lucentis over the past 4 years has led many to assume that the two drugs have equivalent efficacy. To address this point directly, there’s an ongoing trial, called CATT, that is designed to rigorously compare the relative efficacy of Lucentis vs. Avastin for neovascular AMD. If Avastin is shown to be non-inferior, many assume that Lucentis sales will drop dramatically.

So now you have two very good drugs that are available for AMD – Lucentis and Avastin. You also have Macugen and lasers – specifically photodynamic therapy and thermal laser therapy. The first question, therefore, has to be, what is the unmet need? I think it’s clear that there’s a proportion of patients who don’t respond very well to intraocular VEGF inhibitors. Maybe it’s 20%, maybe it’s 30%. It depends on who you talk to. Maybe it’s only 10%. But it’s in that range. In addition, even those who respond to anti-VEGF agents find it difficult to tolerate these injections every month or two. They tend to be older patients, many have to be brought to the office by family members, the eye has to be prepared in a sterile fashion -- just as though they were going to undergo surgery, and then the injection is given.

I think a big movement in the space now is trying to find novel targets that can either supplement the efficacy of Lucentis or Avastin, which is a high hurdle because they have up to a 90% response rate, or treat those who are not responsive to Lucentis/Avastin. One such agent is the aptameric PDGF inhibitor being developed by OphthoTech. Others include a raft of complement inhibitors being developed for wet and dry AMD. The other thing that people are looking at is getting agents into a sustained-release format so that injections might only be every three months or six months instead of every month or two, to save the patient burden and the physician burden, because these injections have become so frequent that doctors are spending a significant portion of their time just doing injections. That’s the two big pushes in the AMD area right now.

HS: Two device-based approaches being studied as possible solutions for AMD involve the use of ionizing radiation delivered via systems developed by NeoVista and Oraya Therapeutics, both of which will present at the Summit. How would you characterize their progress?

Cunningham: If you had asked me five years ago whether I thought radiation would work, I would have said no. I would have said no because there had been trials that had looked at various radiation therapies for AMD, and they had basically failed. What NeoVista and Oraya would tell you, I believe, is that the radiation in those earlier trials was external radiation, and so wasn’t very focused. NeoVista actually puts the radioactive device very, very close to the retina and Oraya gives a finely focused external beam. I haven’t seen all the data for NeoVista -- and I think Oraya’s device is fairly early in development -- but the data that I have seen looks very intriguing.

HS: The laser refractive surgery (LASIK) segment has been dramatically impacted by the overall economic decline, but within that space, one intriguing segment is that of premium intraocular lenses. How is the market going for P-IOLs? Are some patients and practitioners taking a “wait and see” approach toward whatever improvements are forthcoming in what is a first-generation product market?

Cunningham: Premium IOLs have been much less affected than refractive surgery. The reasons are probably multiple and complex, but at base I think older retirees have more discretionary funds and tend to be more willing to spend the money for optimal vision.

HS: An intriguing area on the device side of ophthalmic therapy lies in the femtosecond laser technology for cataract removal that is under development by LenSx, another company slated to present at the Summit. Does this have the potential to be a “disruptive” technology in the space?

Cunningham: They’re early in their innovation curve, but the technology looks very impressive. If they’re able to do what they plan to be able to do, I think it could be disruptive.

HS: You talked a little earlier about glaucoma, and obviously you have surgical approaches, but there are some other innovative approaches that look to me making inroads because of the falloff in patient compliance on the drug side. Docs often talk about the difficult time they have keeping their patients compliant in use of drugs for glaucoma.

Cunningham: A few points: A) Glaucoma is very, very common; B) many patients are to a greater or lesser extent non-compliant; and C) many patients – perhaps up to 50% -- need more than one drug, which speaks both to how refractory the disease can be and, as mentioned, the issue with compliance. For all those reasons, new therapies are always welcome, and it could be another drop with a novel mechanism of action, that had the potential to be additive to current drops, another drop that was just so effective that it could supplant what is out there, or a device that could either supplant some of those patients who are on multiple drops or treat some of those downright treatment failures who don’t respond to any number of drops. For all of those reasons, glaucoma still is a very attractive space.

HS: Could you talk about the current funding environment in the ophthalmic space?

Cunningham: I don’t know if it’s the end of the beginning or the beginning of the end, as Churchill said, but I think people are beginning to see the light at the end of the tunnel. That said, credit and investments are still tight, and since the third quarter of last year, people have just been much more circumspect about their investments. I’d like to think that over time, things would get back to where they were a couple of years ago, which is to say staged investors willing to help shepherd these companies from inception through exit.

HS: What do you hope to accomplish with this new Ophthalmology Innovation Summit?

Cunningham: I’ve thought for some time now that it would be great to have a venue that would bring together early-stage companies, investors and the larger, later-stage public companies to facilitate the development and delivery of new drugs and devices to improve therapies for vision-threatening disorders. We also welcome entrepreneurs, physicians and vision scientists who are interested in company building and the process of developing ophthalmic drugs and devices. As you look at the agenda, I think you’ll agree that it really is a “who’s who” in the ophthalmology space, from the large companies, to the most promising private companies, to the VCs who invest in this space. Our hope is that this will be the first of what becomes an annual tradition.


References:

The Ophthalmic Innovation Symposium Agenda

An Overview of the OIS Meeting of October 22, 2009
Academy Alive – email from the AAO to its members for October 23, 2009.

Eye on Innovation Interview
The Healthcare Syndicate


Links to Previous Postings:

NeoVista Writeups:

NeoVista Epi-retinal Strontium 90 Treatment for Wet AMD (2-14-07)

NeoVista Epi-retinal Strontium 90 Treatment for AMD Update (7-10-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2 (11-19-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3 (10-1-08)


Oraya Writeup:

Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report

Avastin/Lucentis Update 35: The CMS Does the Full Monty on Code Q2024 for Avastin!

According to an email received yesterday by Jack Mitchell of the Senate Committee on Aging, “Effective immediately, CMS is no longer going to recognize code Q2024 for payment of non-outpatient hospital claims. Practitioners are directed to return to their previous reporting practice for small intraocular doses of Bevacizumab (Avastin®) furnished prior to October 1, 2009.”

“The Medicare claims processing contractors will post the following information on their websites within 5 days to inform providers of this policy: “Effective immediately, the Centers for Medicare & Medicaid Services (CMS) no longer recognizes Healthcare Common Procedure Coding System (HCPCS) Code Q2024 Bevacizumab (Avastin®) for payment of non-outpatient hospital claims. Practitioners shall return to their previous reporting practice for small intraocular doses of Bevacizumab (Avastin®) furnished prior to October 1, 2009. HCPCS Code Q2024 will be deleted as of January 1, 2010, and, therefore, it will be removed from the Average Sales Price (ASP) pricing file effective with the January 2010 Release.”

In addition, the Medicare contractors have been instructed to reprocess any claims from physicians for Avastin administered in their offices that were paid based on the Q2024 code if requested by the physician.

In plain English, this reverses the prior reversal and the policy goes back to the original policy in effect before the reduction in reimbursement took place. Good news for both retinal physicians using Avastin and for patients and Medicare!


According to a spokesperson for the AAO, Dr. William L. Rich, the AAO's Medical Director for Health Policy, "The AAO, all three retinal societies, Congress and our patients are all very thankful for this reversal. It benefits patients, doctors, and taxpayers."

Oraya IRay In-office Stereotactic X-ray Treatment for AMD: A First Report

Another new company with a treatment for wet AMD has come out of “stealth mode”, and presented information on how it’s system works and the results of it’s initial clinical trials. Here is an in-depth presentation of the Oraya IRay radiotherapy system.

Introduction

Over the past few years, several drug-based treatments have been suggested and tried to prevent visual loss due to neovascular age-related macular degeneration. Two anti-VEGF drugs, Avastin and Lucentis are now available to prevent significant vision loss in a majority of wet-AMD patients who are treated. However, it appears that repeated intravascular injections over an indefinite time period are required to keep the disease at bay.

One promising approach to reducing the number of injections needed is the synergistic use of radiation in conjunction with intravascular injections, to prevent the proliferation of vascular tissue and to induce visual acuity gains.

The idea of using radiation as a treatment modality for wet AMD has been around for years, but its use has been limited due to the potential damage that can be done to sensitive tissue within the eye without localization of the radiation beam and treatment area. Two companies now claim to have systems that achieve that aim.

The NeoVista Epi-Rad 90 System

The first of the two new therapy systems is the NeoVista Epi-Rad 90, which involves delivery of a target dose of 24 Gy of beta radiation to the center of the choroid neovascularization (CNV) following a partial vitrectomy for placing the strontium 90 tip close to the choroid. Several controlled clinical trials with this system are currently underway to determine if the combined use of radiation therapy and anti-VEGF injections can result in AMD control with fewer injections, compared to drug use alone.

(For more on the NeoVista Epi-Rad 90 system and the clinical trials underway, please see my four reports already posted on this site – links noted at the end of this writeup.)

The Oraya IRay System

Now, a second, office-based system has been proposed and is in early stages of testing. This is the Oraya IRay system, that uses a table-top source of low-energy X-ray beams, directed through the sclera onto the macula to treat CNV secondary to AMD. Unlike the NeoVista system, the Oraya IRay system delivers three doses of highly localized low energy X-ray radiation to the macula non-invasively, using a robotic positioning system, targeting algorithm and a device, I-Guide, for eye stabilization and motion detection. This office-based procedure can be performed in about 10-20 minutes, under a topical anesthetic. The IRay device delivers three beams of up to 8 Gy each through three different locations on the sclera (roughly at 7 o’clock, 6 o’clock and 5 o’clock), delivering up to 24 Gy to a single spot on the macula.

The unique method of delivering the three beams of radiation to the macula was chosen to avoid other sensitive eye structures such as the lens and optic nerve. In addition, the angle of the beam path minimizes collateral damage to radiosensitive structures, while enabling the delivery of the appropriate dosage of radiation (24 Gy) to the choroidal neovascularization that was found clinically useful in the NeoVista studies.

Details of the System

The IRay system consists of three parts: the robotically-controlled X-ray generation and eye imaging workstation (Figs. 1-3); the I-Guide, which is coupled to the patient’s eye via suction, and aligns and optically connects the eye to the X-ray generator (Figs. 5, 6); and the adjoining shielded operator workstation (Figs.3, 4).

To minimize the effects of eye motion during therapy, the I-Guide is used, which consists of a contact lens coupled to the eye with syringe-generated suction, and attached to a central post. The post is mounted to a stabilizer bar via a ball joint. The purpose of the I-Guide is to steady the eye and act as a target for the imaging system to monitor the eye’s position and gaze angle. During treatment, the automated positioning software continuously evaluates the deviation of the eye from nominal. Motion of the eye already is substantially reduced by the I-Guide and is monitored in real-time using a two-camera imaging system. When necessary, the beam is automatically gated off by an algorithm that incorporates time as well as displacement, allowing brief eye excursions while still maintaining effective targeting. The I-Guide is designed with a breakaway feature that allows emergency exit of the patient from the system.

Targeting is achieved on the basis of a calculated position of the fovea, as determined by the simple geometric relationship of the center of the I-Guide lens to the back of the eye. Oraya determined its targeting algorithm based on extensive pre-clinical studies, mathematical modeling of the eye, and subsequent developmental work. Pre-procedure fundus imaging, obtained via spectral-domain OCT, is used to verify targeting and ensure that patients with “outlier” fundus anatomy are identified.

In performing the procedure, the operator, after protecting the lower lid with a specially designed self-retaining retractor, places the I-Guide on the anesthetized eye. The patient’s head is secured in a chin rest/head restraint, which incorporates a radiation shield.

The operator at the shielded operator workstation obtains a visual lock on the eye and applies the appropriate X-ray dose to the three designated spots on the sclera. The three 3.5 mm collimated X-ray beams are sequentially and automatically delivered to converge onto a single 4 mm target spot on the fovea (Figs. 7-11).

This office-based, low-voltage (100 keV) X-ray radiation therapy is a 10-20 minute procedure with no appreciable external shielding required. For patients, the exposure is comparable to the radiation received in getting an X-ray of the head and neck. For operators, the radiation exposure would be equivalent to ~0.14 mrem/hour or one-quarter of the radiation from a transcontinental airline flight. Each patient would get just one lifetime dose, not repeated exposures. Even though doctors might experiment, after FDA approval, with pulse or repeat dosing at some interval, Oraya is not studying repeat dosing at this time.


The following illustrations show the elements of the system:


Figure 1. The Table-top X-ray Generator System




Figure 2. The 3-Part System Platform




Figure 3. The I-Ray System



Figure 4. The I-Ray System (showing operator station and shielding)




Figure 5. The I-Guide Assembly




Figure 6. The I-Guide in Position




Figure 7. The Robotic System and Spot Distribution




Figure 8. Spot Positioning on the Sclera




Figure 9. The X-Ray Beam Size on Sclera and Macula




Figure 10. X-Ray Beam Distribution within the Eye and Brain




Figure 11. X-Ray Beam Intensity on Fovea

Clinical Trials

Phase I (CLH001)

There are three clinical trials planned. The Phase I Trial (CLH001) has been initiated and is fully recruited with over 60 patients to having been treated at either 16 or 24 Gy.

The Phase I trial is a pilot study to evaluate the safety and tolerability of the IRay stereotactic, radiosurgery system in patients with Choroidal Neovascularization (CNV) secondary to AMD. The study aims to determine safety, preliminary efficacy, and dose evaluation.

The study includes two cohorts: those without previous treatment and those previously treated with anti-VEGF therapy requiring additional treatment due to persistent or recurring disease activity.

Monthly retreatment with additional anti-VEGF drug, if needed, is based on any of the following criteria:

– Increase of >100 microns central subfield thickness using SD-OCT
– Evidence of new macula hemorrhage on clinical exam
– New area of classic CNV on FA
– ≥10 EDTRS letter decrease in BCVA vs. previous visual acuity score, with associated fluid on SD-OCT

The initial results, on 28 patients with up to a year followup, treated in Mexico City, were presented by Dr. Peter Kaiser of the Cleveland Clinic Foundation at the Retina Sub-Specialty pre-meeting held prior to the main 2009 AAO Meeting. Dr. Kaiser reported on patients treated with 16 Gy of radiation plus Lucentis (following two monthly injections) in 15 anti-VEGF-naïve patients and in 13 prior Avastin or Lucentis patients (who had had on average 2.9 injections prior to entry into the study).

There were no device-related serious adverse events and no evidence of radiation-related abnormalities, but there were a few device related adverse events, all superficial keratopathy − which Dr. Kaiser attributed mostly to placement of the I-Guide. These superficial events required no intervention by the physician.

The efficacy results are shown in Figures 12, 13 and 14 below:

Figure 12. CLH001 Efficacy Results after 12 months



Figure 13. CLH001 Efficacy Results for Treatment Naive and Previously Treated Patients


Figure 14. Loss or Gain in Letters


The results of this feasibility study, while meant to evaluate primarily safety and tolerability of the IRay therapy, demonstrated a number of encouraging efficacy signals, including substantial preservation and gain of vision in both the treatment-naïve and previously treated cohorts, as well as low numbers of required anti-VEGF retreatment injections. The rate of the anti-VEGF retreatment injections (following the two mandatory “baseline” doses) was found to be only 0.9 per patient over 10 months, and ~56% of patients needed no additional anti-VEGF injections, while still demonstrating visual acuity preservation and gain at least comparable to that seen in other studies, such as MARINA and PrONTO, with much greater injection burdens.

(For a refresher on the MARINA, PrONTO – and ANCHOR studies, please see my NeoVista Update report of July 11, 2007, linked at the end of this report.)

Anti-VEGF retreatments, as described by Dr. Kaiser, are shown in the following graph:


Figure 15. Anti-VEGF Retreatments

Dr. Kaiser concluded that IRay extends the durability of Lucentis, reduces the number of injections, and appears safe and effective.

The company concluded that its non-invasively delivered, ionizing radiation in combination with Lucentis appears to:

– Extend the durability effect
– Limit the number of anti-VEGF injections
– Work in both treatment n ive and previously treated patients, and,
– Be safe and well tolerated

Phase II Clinical Trial (CLH002)

Oraya expects to enroll the first patients in a multi-center, randomized, masked, sham-controlled European trial before the end of the year, using a 16 Gy dose. (The company continues to evaluate the possibility of adding a higher-dose treatment arm.) It is expected that 8-10 sites in Europe will participate.

Phase III Pivotal (CLH003)

This larger randomized, masked, sham-controlled study is expected to initiate in mid-2010 and plans to enroll approximately 450 patients in 15-20 sites in both the U.S. and Europe


Questions and Answers

During the recent 2009 AAO Meeting in San Francisco, CEO of Oraya, Jim Taylor, was interviewed by Lynne Peterson of Trends-in-Medicine. She asked him the following questions:

Asked about the long-term safety of IRay, Taylor said, “I’d be the last person to say we have absolute certainty we know the outcome (with IRay). The comfort comes from the ample data and research from ocular oncology and from some early work done in radiotherapy for AMD that suggest the incidence of radiation retinopathy is low. Years of study in ocular oncology have given comfort that the doses here (are safe). We know that AMD has an inflammatory component to it, and we know that AMD causes scarring and building of lesions in the eye that don’t respond to anti-VEGF therapy. We also know that radiation is anti-vascularization and antifibrotic as well. Lastly, we know that if you combine an anti-VEGF agent with radiation, you get a synergistic effect”.

Taylor explained that radiation works best on concentrated lesions in an atmosphere of oxygenation. So, stopping leaking capillaries with an anti-VEGF, tends to make the center of the lesion more robust, and a better target for radiotherapy. Oraya has worked with radiation and oncology researchers and experts around the world to determine the dose and the approach. The science looks good. And the radiation is not delivered through the cornea but through the sclera. Taylor said one advantage of IRay over NeoVista’s therapy is that IRay is robotically delivered while NeoVista has a hand-held system. “We have a robot that is a wonderfully designed sniper, shooting low energy in tightly collimated beams with 3 beams going through the sclera at separate points, all converging at the same point on the fovea”. The IRay goal is to deliver either 16 Gy or 24 Gy to a spot centered on the fovea covering approximately 6 mm in diameter.

The three elements of IRay that Taylor highlighted were:

1. Robotic positioning.

2. Continuous tracking and management of eye motion with the I-Guide.

3. Collimation of the beam.

Does IRay make financial sense for retina specialists? Probably, if CMS reimburses for it. There would be an initial machine cost plus a per-procedure disposable cost. Taylor believes the procedure will be cost-effective because it should reduce both diagnostic testing and anti-VEGF injections. IRay is not currently being tested in dry AMD, but that might be an area for research in the future, as drusen formation has been demonstrated to have an inflammatory component which may be amenable to radiotherapy.



References:

1. Office-based External Beam Radiation Therapy for Age-related Macula Degeneration; Hsu, Jason and Regillo, Carl; Retinal Physician, September 2009.

2. Stereotactic Radiotherapy for AMD; Taylor, James; Ophthalmology Innovation Summit, October 2009.

3. Motion Management for a Novel Ophthalmic Stereotactic Radiosurgical Device; Chell, E. et al; AAPM, July 2009.

4. 2009 AAO Meeting; Peterson, Lynne and Woods, Diane; Trends-in-Medicine, November 2009. (Subscribers, only, contact Trends-in-Medicine)


Links to the NeoVista Writeups:

NeoVista Epi-retinal Strontium 90 Treatment for Wet AMD (2-14-07)

NeoVista Epi-retinal Strontium 90 Treatment for AMD Update (7-11-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 2 (11-19-07)

NeoVista Epi-Retinal Strontium 90 Treatment for AMD: Update 3 (10-1-08)

Avastin/Lucentis Update 34: More on the Comparative Studies

In my constant search for new information about AMD treatments, I happened across a blog devoted to all things retina: The Retina Blog. In one posting, following the recent AAO Meeting, author David Khorram reported on Dan Martins talk during the Retina SubSpecialty Day Meetings. Apparently, the Academy sent out an email on its Academy Live network describing Dan’s talk in more detail than I had received.

Anyway, The Retina Blog had the up-to-date details on both the CATT Study and most of the other head-to-head studies – although, news about the Spanish study appears to be missing.

Here, thanks to David Khorram, is the latest information on the comparative studies.


Head-to-head Lucentis vs. Avastin Trials
10-25-09
The Retina Blog – David Khorram, MD

This bit of news just came in from the annual meeting of the American Academy of Ophthalmology, which is being held right now in San Francisco. There is a lot happening in terms of these two drugs. The results will be important, both clinically and economically. Lucentis costs $2,000 per dose. Avastin costs less than 10% per dose. Both drugs are made by Genentech — that’s a whole different story. Here is a list of the current clinical trials as described in the article from the “Academy Live” email of Friday October, 23, 2009, a service of the American Academy of Ophthalmology.

Bevacizumab vs. ranibizumab: Initial results expected in 2011

Bevacizumab (Avastin) and ranibizumab (Lucentis) are competing in a hefty schedule of six head-to-head randomized clinical trials directly comparing their use in AMD patients, said Daniel F. Martin, MD. This year, researchers hope to complete enrollment in the studies, which compare varying doses and treatment schedules of the drugs. Initial study results are expected to be available in early 2011, according to Dr. Martin.

Here’s the status of each of the studies:

* The NEI-sponsored CATT (Comparison of AMD Treatments Trial) study began enrolling an estimated 1,200 wet AMD patients at 44 sites in the United States in February 2008. The four-arm study comparing bevacizumab and ranibizumab on fixed and variable schedules is proceeding well, according to Dr. Martin, with one-year results targeted for 2011.

[Editors Note: According to Dr. Martin, enrollment is expected to be completed by the end of November, at which time enrollment will be closed. For more on the CATT Study, see my CATT Study Update 10.]

* In April 2008, researchers in the United Kingdom began enrolling an anticipated 600 patients at 17 sites in the IVAN (Inhibit VEGF in Age-related choroidal Neovascularization) study. This four-armed study compares monthly bevacizumab 1.25 mg and ranibizumab 0.5 mg injections given over two years with three monthly injections followed by PRN dosing.

* The four-site German VIBERA study started enrolling 360 AMD patients in 2008 to receive three monthly bevacizumab 2.0 mg or ranibizumab 0.5 mg injections and additional injections as needed.

* The Austrian MANTA study began assigning an anticipated 320 AMD patients in June 2008 to three monthly bevacizumab or ranibizumab injections, with additional treatment as needed.

* Researchers in Norway began enrolling an anticipated 450 patients in the 12-site LUCAS study in March. Subjects receive bevacizumab 1.25 mg or ranibizumab 0.5 mg monthly as needed until dry, with intervals between doses decreasing over time.

* French investigators opened enrollment this fall in the 600-patient, 20-site GEFAL study. Subjects are randomized to receive three initial monthly injections of one of the two drugs.

[See my Update 25 for more on the French study.]

David Khorram, MD is the co-founder of Marianas Eye Institute, and the medical director of the Center for Advanced Diabetic Eye Care. A US-trained Board Certified ophthalmologist, he is listed in "Guide to America's Top Ophthalmologists."

Avastin/Lucentis Update 33: The Wording of the CMS Order for Repricing of Avastin

The following note was received this morning by my contact in Senator Kohl’s office, from the director of CMS’ Office of Legislation, along with the wording, shown below, taken from the Federal Register of October 30th.


From the Office of Legislation of CMS:

“The excerpt from the CY 2010 hospital outpatient PPS final rule follows below. I have also attached the relevant page (page 615) from the copy of the rule that went on display at the Federal Register on Friday afternoon.

As requested, I am also checking with our program experts to see if we have any flexibility regarding the timing of this coding change (i.e., whether it can be applied retroactively or whether it can go into effect before January 1). If you have any questions, please let me know. “


From page 615 of the Federal Register, October 30, 2009:

We note that HCPCS code Q2024 (Injection, bevacizumab, 0.25 mg) was implemented effective October 2009 and represents a different dosage descriptor for the same drug described by HCPCS code J9035 (Injection, bevacizumab, 10 mg). Further, HCPCS code Q2024 has been replaced with HCPCS code C9257 (Injection, bevacizumab, 0.25 mg) effective January 1, 2010. In accordance with our CY 2010 policy to make a single packaging determination for a single drug, we are applying the methodology described above to bevacizumab and are assigning the applicable bevacizumab HCPCS codes the same packaging status for CY 2010. HCPCS codes C9257 and J9035 are included in Table 35 below.


In what I read from this in plain English, the reimbursement for the 0.25 mg dosage of Avastin, used in treating AMD, will revert on January 1st to the reimbursement in place before the change over on October 1st, or about $50.00, which I believe is what it was before the change.

Further, both CMS and Senator Kohl’s office, along with several ophthalmic organizations (AAO, ASRS, among others), continue to look into/request that the change in policy be implemented before January 1st.