AMD Update 3 Current Studies for Treating Macular Degeneration

In its upcoming February 25th issue, Ocular Surgery News presents a table of ongoing clinical trials for treating age-related macular degeneration. I have reproduced the table below.

For more information on any of these, or the 186 current open trials for treating age-related macualar degeneration, please go to Clinical Trials.gov. By using the “Refine Search” tab, and putting in the name of any of the trials listed in the table into the search box, you should be able to gain more information about each.


(By right-clicking on the table image and opening in a new tab or window, a larger more readable version will appear.)

CATT Study Update 8 The Story Behind The CATT Study

As any of you who have read this Journal know, I began writing about Avastin on January 31, 2006, after starting this online Journal the month before. I had read the first reports about this new drug in a report from the Retina Society Meeting held in July 2005, and then the first reports out of that year’s AAO Meeting. You can read my comments in my writeup, Avastin: A New Hope for Treating AMD.

Since that time I have written about Avastin vs. Lucentis 24 additional times, and about the CATT Study a previous 7 times. When I inquired earlier this month about the status of the CATT Study, Maureen Maguire was kind enough to send me a copy of the article she and Drs. Martin and Fine had submitted to Retina Times for publication in its Fall 2008 issue. I requested permission from both the editor of Retina Times and the three authors to reprint their story in my Journal to allow for wider publication than just the membership of the American Society of Retina Specialists (ASRS). I thank all involved for their cooperation in this effort.

Re-printed with permission of the authors and the American Society of Retina Specialists (ASRS). This article appears in the Fall 2008 Issue of Retina Times, the official publication of the ASRS, and is accessible by members only. For information about the ASRS, please go to www.asrs.org.


Comparison of AMD Treatments Trials (CATT): Lucentis – Avastin Trial

Daniel F. Martin MD, Maureen G. Maguire PhD, and Stuart L Fine MD

Drs. Daniel Martin (Emory University) and Stuart Fine (University of Pennsylvania) are Co-Study Chairs for the CATT Study, while Dr. Maureen Maguire (Director of the Coordinating Center at University of Pennsylvania) is the CATT Study Director.

Published in the Fall 2008 issue of Retina Times

Just over 3 years ago, two major events dramatically transformed the treatment of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). On July 17, 2005, the results of the MARINA trial comparing ranibizumab (Lucentis®) to placebo for the treatment of minimally classic and occult CNV were presented at the annual meeting of American Society of Retina Specialists meeting in Montreal. Patients assigned to ranibizumab were not only much more likely to maintain visual acuity (VA), but also had improvement in VA in unprecedented numbers. A few moments later, Philip Rosenfeld, MD, PhD presented a paper on the beneficial short-term effect of intravitreal injection of bevacizumab (Avastin®) in a single patient with neovascular AMD.

These events set off an explosion of controversy and debate on topics ranging from the penetration of molecules of different molecular weights through the retina to the ethics of off-label use of an untested agent when a well-studied, highly efficacious, and relatively safe drug was available, albeit at a very high price. By June 30, 2006 when the Food and Drug Administration approved ranibizumab for treatment of neovascular AMD, the data from additional Genentech randomized trials had provided strong evidence that ranibizumab’s efficacy and safety extended to a wide spectrum of neovascular lesions. In addition, substantial information on the pharmacokinetics, safety, and changes in vision after treatment with bevacizumab had accumulated, and the use of bevacizumab had become fully entrenched in many vitreoretinal practices.

The time was ripe for a head-to-head comparison to establish the relative efficacy and safety of these two drugs and to determine whether treating less than monthly with either drug could provide the same beneficial results on vision as the monthly injections. Led by investigators at Emory, University of Pennsylvania, and Duke, grant applications were submitted in January 2006 and received expedited peer review. In October 2006, the National Eye Institute approved funding for the Comparison of AMD Treatments Trials (CATT) – Lucentis-Avastin Trial.

Once funded, the major task that remained was to secure funding for the cost of ranibizumab and bevacizumab. The NEI grant covered the cost of purchasing, repackaging, and distributing Avastin. However, the $25 million drug cost for ranibizumab was not covered. This was anticipated and the CATT leadership had begun discussions with CMS early in the development of the trial design. The Centers for Medicare and Medicare Services (CMS) already were paying for ranibizumab for patients with neovascular AMD and the vast majority of affected patients were Medicare beneficiaries. The 2000 Clinton Initiative made it clear that routine care for patients in a clinical trial was covered by Medicare. Ranibizumab was already part of routine care and therefore it was logical to assume that it too would be covered. It was also expected that the potential cost savings to CMS from this study would serve as strong motivation for collaboration. This was acknowledged by CMS leaders early on, but the statutory authority of CMS to assist in the study was limited. The CATT leadership was told that to fully achieve the funding and masking that we requested would require “an act of Congress.” In addition, some concern was raised as to whether ranibizumab could indeed be covered in the trial by the existing Medicare Clinical Trial Policy.

Four months later (November 2006), the CATT leadership learned at an Institute of Medicine forum, where they had been asked to present these study related issues, that CMS lawyers had narrowly interpreted existing Medicare Clinical Trials Policy as forbidding the use of CMS funds for payment for ranibizumab within CATT. Despite alternative interpretations by officials in other branches of the National Institutes of Health and many Medicare carriers, the central CMS lawyers viewed the FDA-approved ranibizumab as investigational within CATT and not eligible for reimbursement. Over the next 14 months, the CATT leadership engaged in a steady stream of efforts to secure payment for ranibizumab for patients in the trial. Their efforts resulted in four important policy changes and clarifications that will be a lasting legacy of the CATT:

1) Drug Coverage: On July 9, 2007, the Revised Medicare Clinical Trial Policy was published. This policy change, driven in part by the CATT, and specifically stated that CMS could in fact pay for a drug (ranibizumab) in a clinical trial if that drug was otherwise available to Medicare beneficiaries outside of the study.

2) Masking: Over a six month period, CMS staff worked closely with the CATT to develop an AMD Demonstration Project that would have facilitated payment and masking of the study drugs. The project addressed many problems of billing for and maintaining masking of a drug when the injecting physician has no knowledge of the identity of the drug. In May, 2007 the AMD Demonstration Project was approved by CMS. However, it was not granted final approval by the Office of General Counsel (OGC). Although the Demonstration Project never became operational, it significantly stimulated discussion on these issues and contributed to the development of a National Public Forum on the Impact of Payment Policy on Clinical Trials hosted by CMS in September 2007 at which time issues raised by the CATT were presented. In addition, it is anticipated that the project may serve as a blueprint for payment of drug and patient care costs in a future NIH-sponsored trials.

3) Co-Pays: The issue of who can legally pay for a co-pay was clarified. The only entity that can legally pay a Medicare co-pay is another federal entity. As such, the NEI can pay a co-pay in the CATT and have committed funds to do so.

4) “Act of Congress”: The recent Medicare bill that rescinded the 10.6% fee cut also contained an amendment that granted to the Secretary of DHHS the authority to develop alternative payment mechanisms for items and services provided in an NIH sponsored trial if these mechanisms will enhance the scientific integrity (masking of drug) of the trial. This is the authority that the CATT needed from the very beginning. This amendment was proposed by the CATT leadership and introduced as part of a bill through the offices of Senator Herb Kohl (Democrat, Wisconsin). The bill passed on July 15, 2008.

By the end of this long process, the initial goal of providing study drug to CATT patients with no out-of-pocket expense was achieved. Lucentis is billed to CMS and 80% is covered as per the Revised Medicare Policy. Supplemental insurance policies will cover the remainder of the cost. In cases where the patient has no supplemental policy (estimated at 15% or less of patients), the NEI can legally pay the co-pay. While the Congressional amendment to the Medicare bill is too late to benefit the CATT directly, the leadership of the study was determined to prevent these delays from ever happening again and to clear the way for other comparative clinical trials that will follow.

In February, 2008, the first patients were enrolled in the CATT and by the end of July, more than 250 had enrolled. (Editor’s Note: As of October 10th, more than 400 patients are now enrolled.) Eligibility criteria for the trial are broad. Patients must have previously untreated CNV with the lesion or sequelae of the lesion (eg, blood, retinal pigment epithelium detachment, fluid) under the center of the fovea. While lesion composition (ie, classic or occult CNV) is assessed by the CATT Photograph Reading Center, there are no eligibility criteria related to lesion composition. Visual acuity must be between 20/25 and 20/320, inclusive.

Patients are assigned through randomization with equal probability to one of four groups for treatment during the first year (see below). The doses are 0.5 mg {0.05 ml} for ranibizumab and 1.25 mg {0.05 ml} for bevacizumab.

• Ranibizumab on a fixed schedule of every 4 weeks

• Bevacizumab on a fixed schedule of every 4 weeks

• Ranibizumab on variable schedule dosing; i.e., after initial treatment, monthly evaluation for treatment based on signs of lesion activity

• Bevacizumab on variable schedule dosing; i.e., after initial treatment, monthly evaluation for treatment based on signs of lesion activity
  

Formatech, Inc, an aseptic manufacturing and fill facility, repackages commercially available bevacizumab into smaller vials for use in CATT. Ranibizumab is supplied through the conventional supply mechanism for each clinic. Syringes are filled with study drug by the clinic coordinator or another person in the center and presented to the CATT ophthalmologist for injection. The CATT ophthalmologist and vision examiners are masked to the identity of the study drug.

Retreatment decisions in the two variable (as needed) dosing arms of the study are driven primarily by findings on the OCT. If any subretinal, intraretinal, or sub-RPE fluid is apparent on any of the 6 slow map scans, the eye is treated. If there is no fluid on OCT, but there are other signs of active CNV, the eye is treated. These signs include new subretinal or intraretinal hemorrhage, persistent subretinal or intraretinal hemorrhage, decreased visual acuity relative to the last visit without another explanation, increased lesion size on fluorescein angiography relative to the last angiogram, or leakage on fluorescein angiography. Fluorescein angiography is required at specific visits and may be used in deciding whether treatment is warranted. Fluorescein angiography may be obtained at other visits to aid in the decision on whether treatment should be applied.

The primary outcome measure is change in visual acuity. Secondary outcome measures include number of treatments, retinal thickness at the fovea, adverse events, and cost. At the 12-month visit, patients in the fixed schedule groups will be randomly assigned continue on the fixed schedule for a second year or to receive treatment according to the guidelines for variable schedule dosing. A total of 1200 patients will be enrolled and followed through two years.

The basic questions of the relative efficacy of ranibizumab and bevacizumab remain unanswered. All retinal specialists are eager to identify ways to decrease the frequency of injection. However, there is still no convincing data on whether any of the various approaches to decreasing treatment frequency provide the same level of visual acuity benefit as monthly dosing. The CATT will provide answers to these important questions, but the timing of those answers is entirely dependent on the rate of enrollment. More than 200 retina specialists are participating through more than 40 clinical centers (see http://www.nei.nih.gov/CATT or http://clinicaltrials.gov/ct2/show/NCT00593450 for a list of participating centers). The retina community and all patients with AMD will benefit from the results of CATT. There has never been a better time to consider referring a new neovascular AMD patient to a CATT clinical center for enrollment.

Stem Cells in Ophthalmology Update 27 ACT Interim Clinical Results Are Outstanding

Having treated 36 patients in two clinical trials for Stargardt’s Macular Dystrophy (SMD - 24 patients to date) and for dry Age-Related Macular Degeneration (AMD - 12 patients to date), Advanced Cell Technology reported the interim results obtained with 18 of these patients (9 in each trial) in the US-based studies. Both trials (NCT01345006 - Stargardt’s, and NCT01344993 - AMD) began in July 2011, giving the company up to three-year’s data for the earliest patients, and a median of 22 months followup for all. The interim results were reported in The Lancet, published online October 14, 2014 in: “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies”.

An additional Stargardt’s trial, being conducted at two clinics in the United Kingdom, with 12 patients enrolled (NCT01469832), along with 3 of the 4 patients treated in each of two trials with better vision candidates, as part of the two clinical trials in the publication (Phase IIa), were not included in The Lancet results.

As noted by Paul K. Wotton, Ph.D., President and Chief Executive Officer of Advanced Cell Technology, "These study results represent an important milestone and strengthen our leadership position in regenerative ophthalmology. We would like to thank the patients for their willingness to participate in these studies. Our findings underscore the potential to repair or replace tissues damaged from diseases. We plan to initiate comprehensive Phase 2 clinical trials for the treatment of both AMD and SMD, two disease states where there is currently no effective treatment."

Editors Note: As announced on October 15th by the company, the Phase II dry AMD clinical trial (50 Patients) will start during the 1st Half of 2015 and is expected to be completed in the middle of 2016, taking place at 10 Trial Sites across North America. The Phase II SMD clinical trial (100 patients) will start during the 4th Quarter of this year or by the end of the year. It will take 18-24 months to complete, taking place at 30 sites across North America and Europe.

Robert Lanza, M.D., Chief Scientific Officer of ACT and co-senior author of the paper, commented, "Diseases affecting the eye are attractive first-in-man applications for this type of investigational therapy due to the immune-privileged nature of the eye. Despite the degenerative nature of these diseases, the vision of 10 of 18 patients showed measurable improvement at the six month follow up, after transplantation of the RPE cells. Furthermore, the cells have been well tolerated for a median period of 22 months with two of the patients treated more than three years ago. We are pleased that there have been no serious safety issues attributable to the cells observed in any of the patients."

Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute, principal investigator and co-lead author of the publication said, "The data published in The Lancet support the potential safety and biological activity of stem cell-derived retinal tissue. Once again, surgical access to the subretinal space has proven safe. However, for the first time in humans, terminally differentiated stem cell progeny seem to survive, and do so without safety signals. Combined with the functional signals observed, these data suggest that this regenerative strategy should move forward. This is a hopeful and exciting time for ophthalmology and regenerative medicine."

These two studies provide the first evidence of the mid- to long-term safety, survival, and potential biologic activity of pluripotent stem cell progeny into humans with any disease. In addition to showing no adverse safety issues related to the transplanted tissue, anatomic evidence confirmed successful engraftment of the RPE cells, which included increased pigmentation at the level of the RPE layer after transplantation in 13 of 18 patients.

There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. Thirteen (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt’s macular dystrophy.

Figure 3: Change from baseline in best-corrected visual acuity in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B) Median change in best-corrected visual acuity was expressed as number of letters read on the Early Treatment of Diabetic Retinopathy Study visual acuity chart in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B). Red lines show treated eyes and blue lines show untreated eyes of patients during the first year after transplantation of the cells derived from human embryonic stem cells. Green lines show the difference between the treated and untreated eyes. Patients who underwent cataract surgery after transplantation are not included in the graph. There was a significant difference in the letters read in transplanted eyes of patients with age-related macular degeneration versus non-transplanted controls at 12 months (median 14 letters vs –1 letter; p=0·0117). There was an increase in letters read in transplanted eyes of patients with Stargardt’s macular dystrophy versus non-transplanted controls at 12 months (median 12 letters vs two letters, although the sample size was too small to allow reliable calculation of the Wilcoxon signed-rank test).

The SMD and dry AMD trials are prospective, open-label studies designed to evaluate the safety and tolerability of human embryonic stem cell (hESC)-derived RPE cells following sub-retinal transplantation into patients at 12 months, the studies' primary endpoint. Three dose cohorts were treated for each condition in an ascending dosage format (50,000 cells, 100,000 cells, and 150,000 cells). Both the SMD and dry AMD patients had subretinal transplantation of fully-differentiated RPE cells derived from hESCs.

Dr. Anthony Atala, a surgeon and director of the Wake Forest Institute for Regenerative Medicine at Wake Forest University in an accompanying commentary in The Lancet said:

"It really does show for the very first time that patients can, in fact, benefit from the therapy.

That allows you to say, 'OK, now that these cells have been used for patients who have blindness, maybe we can also use these cells for many other conditions as well, including heart disease, lung disease and other medical conditions.' "

Human embryonic stem cells have the ability to become any kind of cell in the body. So scientists have been hoping the cells could be used to treat many diseases, including Alzheimer's, diabetes and paralysis. But the study is the first human embryonic stem cell trial approved by the Food and Drug Administration that has produced any results.

"It is really a very important paper."

The co-authors of the study summarized their interpretation of their results in this way:

“The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that human-embryonic-stem-cell-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.”

My takeaway from reading The Lancet article (and several of the accompanying writeups about the study) is, the use of RPE derived from embryonic stem cells is safe and efficacious, particularly in the eye. But most of all, this important study shows that Advanced Cell Technology is able to safely stop the progression of to-date untreatable dry AMD and SMD retinal diseases (17 of 18 patients) and to improve the vision in those who have lost considerable sight (10 of 18 patients).

Finally, the two clinical trials that are reported on in The Lancet, were done on patients with nothing to lose (with vision no better than 20/400), whereas patients in the Phase IIa study, still in progress, have vision no worse than 20/100. It is anticipated that even better results will be shown with this better vision group.

References:

1. ACT Announces Positive Results from Two Clinical Trials Published in The Lancet Using Differentiated Stem Cell-Derived Retinal Pigment Epithelium (RPE) Cells for the Treatment of Macular Degeneration, ACT Press Release, October 14, 2014

2. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies, Schwartz, SD, Lanza R, et al, The Lancet, Online, October 14, 2014.

Other Resources:

Encouraging New Paper on ACT Stem Cell-Based Trial for Macular Degeneration, Paul Knoepfler, Knoepfler Lab Stem Cell Blog, October 14, 2014

Embryonic Stem Cells Restore Vision In Preliminary Human Test, Rob Stein, NPR Health Blog, October 14, 2014

Disclosure: As of September 17, 2014, I own a small number of shares of the company’s stock.

AMD Update 11 Potential Breakthrough Drug Delivery System for AMD

Earlier last week, I was reading a report on Dr. Robert Langer’s keynote address from the recent ARVO meeting held in Ft. Lauderdale, FL, “The Future of Regenerative Medicine in Ophthalmology”, and thought that his idea of a prototype microchip or polymer implant, that contained pockets or drug reservoirs that could be selectively controlled or opened by a patient’s physician, in this case the individual pocket or drug reservoir opened by the application of a focused laser beam, could really be useful in treating AMD. Instead of monthly injections of anti-VEGF agents, a single implant containing multiple doses could be implanted and each dose activated by a simple ophthalmic laser beam upon need.

Then, lo and behold, last Friday morning I received a news release from a company called On Demand Therapeutics, Inc., which, it turns out, holds the rights from Dr. Langer’s laboratory at MIT and spin-off companies, to develop just such a device. John Santini is the president of the new company. He is the co-founder and former president of MicroCHIPs, a company founded by Santini and Dr. Langer in 1999, to develop proprietary reservoir arrays that are used to store and protect chemical sensors or potent drugs within the body for long periods of time, based on the research and inventions derived from Dr. Langer’s MIT laboratories.

A Little History

In 1976, Dr. Langer and Judah Folkman, MD, a pioneer in anti-angiogenic research, devised a polymer material that released an angiogenic inhibitor. The agent thwarted neovascularization and stunted the growth of tumors in rabbit corneas. The research bore fruit when the U.S. Food and Drug Administration approved the anti-VEGF agents Macugen (pegaptanib sodium solution, Eyetech/Pfizer) in 2004 and Lucentis (ranibizumab, Genentech) in 2006.

Santini, a former graduate assistant of Robert Langer, founded MicroCHIPS along with Langer and MIT colleague Michael Cima in 1999. He led the firm for 11 years, through several funding rounds, including a recent round resulting in nearly $16.5 million raised that took the total to $70 million.

Santini has now moved on to head up On Demand Therapeutics Inc., a San Francisco-based MicroCHIPS spinout.

The Problem and a Possible Solution

In his ARVO address, Dr. Langer said the researchers' main dilemma in developing a drug release reservoir was designing polymers that could elute large bioactive molecules. Porous polymers enable timed and controlled elution of almost any bioactive molecule, regardless of its size. "These pores are large enough so that molecules, even of millions of molecular weight, can get through," according to Dr. Langer.

Newer technologies show promise. For example, a prototype microchip device comprises tiny pockets or drug reservoirs. The application of an electrode dissolves a gold coating on the chip, allowing the drug agent to elute in a timed and controlled way. Such devices are being developed by MicroCHIPS for the treatment of severe osteoporosis through the delivery of an anabolic bone-building hormone, and also for continuous glucose monitoring for people with diabetes.

Dr. Langer said that the chip (or drug reservoirs) may also have applications in retinal drug delivery.

A physician-controlled retinal drug delivery technology would involve an implant with sealed drug reservoirs. The targeted application of an ophthalmic laser to open one or more of the wells to allow the release of the respective drug into the eye, could constitute a breakthrough, said Dr. Langer.

On Demand Therapeutics, Inc. (ODTx)

ODTx was formed in May 2009 as a unique joint venture between MicroCHIPS, a developer of intelligent implant systems, and InterWest Partners, a leading diversified venture capital firm. ODTx leverages the intellectual property and technical expertise of MicroCHIPS combined with the ophthalmic domain expertise and financial resources of InterWest. The company has an exclusive, worldwide license to 60 issued patents and numerous pending applications related to ophthalmic on-demand drug delivery and related technologies.

The ODTx device is a biocompatible, non-resorbable injectable rod, comprised of multiple discrete reservoirs designed to release, on demand, specific drugs in clinically optimized doses. (See Figure 1.) Each reservoir can safely store small or large molecule drugs in the eye until release is initiated using a standard ophthalmic laser during a simple, routine, office-based procedure. (See Figure 2.)

Figure 1. The Drug Reservoir Implant 

Figure 2. Initiation of Drug Release

Typical retinal drug delivery procedures, such as for treating CNV (choirodal neovascularizaion, or “wet” AMD) require monthly intravitreal needle injections. Current implantable devices are largely focused on steroids and/or deliver sustained release formulations which have no mechanism for control of dosing, leading to significant side effects such as glaucoma or cataracts. In contrast, once the ODTx device is implanted during an in-office procedure, the ophthalmologist can control drug delivery by focusing a laser beam on one of the multiple sealed reservoirs.

Administering a laser pulse creates a micro-opening in the device that releases the drug into the eye. Unactivated reservoirs remain intact until those doses are indicated. There is no need for monthly injections and the patient is easily maintained through regular follow-up visits and subsequent non-invasive laser activation procedures.

Current Status of the Development

Multi-reservoir devices have been fabricated and used in three in vivo feasibility studies. These studies demonstrated the implantation procedure, that the devices were well tolerated, and that both small and large molecule drugs could be released on demand when their reservoirs were opened by an ophthalmic laser. The company is now considering various opportunities, including venture investment and corporate deals with pharmaceutical and medical device companies, to quickly move products utilizing this innovative drug delivery platform into the clinic.

Some Questions......

In thinking about this innovative approach to providing on-demand drugs to the retina, I came up with a series of questions that will have to be answered before this invention can be comercialized and brought to market.

Here are my questions – and I’m sure there are others – I look forward to your comments.

1. What size will the drug reservoir have to be to contain the equivalent of five or so 0.5 mg doses of, say, Avastin?

2. As “floaters” (small strands of clumped vitreous) can become annoying, what effect on vision would the reservoir have? Would it be implanted in the retina, or free floating? Would it be “visible” just sitting in the back of the eye?

3. Would a small puncture of an individual cell allow all of the drug contained within that cell to release, to become available to the retina?

4. How will the company distinguish between full and empty cells – perhaps by coloring the solutions?

5. Finally, how long will it take to answer all of the questions and obtain FDA marketing clearance?

My guess is a minimum of three to five years.

NeoVista Epi Retinal Strontium 90 Treatment for AMD Update 3

During the 2008 Retina Society Meeting, held last weekend, NeoVista, Inc. provided eighteen-month data from its Phase II feasability study of the company’s novel beta radiation epi-retinal therapy for the treatment of the wet form of age-related macular degeneration (AMD). The long-term data from the study, which was initiated to test the safety and efficacy of their therapy when used in conjunction with Avastin (bevacizumab), showed a marked advancement in mean visual acuity results at month 18, while only a limited number of patients required additional injections of Avastin.

The data were presented at the Retina Society Meeting by Nelson R. Sabates, MD, Professor and Chairman, Department of Ophthalmology, University of Missouri-Kansas City (UMKC) School of Medicine and the lead investigator in NeoVista's ongoing Phase III study, CABERNET (CNV Secondary to AMD Treated with BEta RadiatioN Epiretinal Therapy).

"The data released demonstrate that NeoVista's concomitant approach has the potential to offer patients a less frequent treatment option that is just as effective, if not more effective, than the current standard of care," said Dr. Sabates. "It's highly encouraging to continually see patient outcomes improving as the study progresses."

"We're very delighted with the latest data from our Phase II study, as not only did the visual acuity improve in our patients over the long-term, but very few patients received additional injections as well," said John N. Hendrick, President and CEO of NeoVista. "The ultimate pledge of this therapy continues to be demonstrated as the long-term data hold promise in minimizing the treatment burden both for patients and physicians, not to mention the overall financial burden for the healthcare system."

NeoVista's revolutionary therapy applies a targeted dose of beta radiation to the leaking blood vessels that affect central vision; concomitantly, two injections of an anti-vascular endothelial growth factor (anti-VEGF) agent are delivered to maximize the acute therapeutic response. Preliminary data show that NeoVista's targeted radiation therapy can be safe for both the patient and the physician, and may be able to restore the patient's vision. The current standard of care for wet AMD requires persistent injections of anti-VEGF drugs for an indefinite period.

The ongoing multicenter feasibility study enrolled 34 trial participants (with a mean age of 72 years) from June 2006 to April 2007 at two centers in Brazil and one in Mexico. These patients, with predominantly classic, minimally classic, or occult (with no classic) choroidal neovascularization (CNV), received a single 24 Gy treatment of NeoVista's epiretinal brachytherapy in combination with two intravitreal injections of Avastin, one dose prior to or at the time of radiation delivery and another one month later, depending on which arm of the trial the patient was enrolled in. Additional therapy was delivered based upon the investigator's evaluation of disease activity.

Analysis of 18-month follow-up on the first 25 trial participants to reach that milestone, as shown in Graph 1 below, shows a mean improvement in visual acuity of 10.7 letters using the Early Treatment Diabetic Retinopathy Study (ETDRS) test; 96 percent of patients lost 15 letters or fewer, 76 percent gained some letters, 44 percent gained 15 or more letters, and 8 percent gained 30 or more letters. Of particular interest, 68 percent of the patients in the study did not require additional injections of Avastin throughout the 18-month period and the average number of additional injections within this subset was only 2.4 injections by month 18.


Graph 1

The visual acuity data after 18 months compares favorably with the results reported after 12 months, as shown in Graph 2 below. (This graph compares the Epi-Rad treatment without Avastin (purple color), with Epi-Rad plus Avastin (blue color) and the Marina (green) and Anchor (red) studies, which both used Lucentis.)

Graph 2

For more information on the NeoVista Epi-Retinal treatment, and for further information on the Marina and Anchor Studies, see my three earlier reports on NeoVista, posted November 19, 2007; July 11, 2007; and February 14, 2007.

Most of the limited number of adverse events were related to the vitrectomy procedure (retinal tear, retinal detachment, subretinal hemorrhage, and vitreous hemorrhage), rather than the epiretinal brachytherapy. To date, no instances of radiation toxicity have been reported by the Doheny reading center.

In contrast to other forms of radiation therapy for wet AMD, NeoVista's approach delivers the peak dose of energy directly to the lesion without damaging the normal retinal vasculature. Utilizing strontium 90, the focused energy is delivered to a target area up to 3 mm in depth and up to 5.4 mm in diameter. Importantly for patients, the systemic exposure to radiation is minimal, as the effective dose to the entire body from NeoVista's epiretinal device is less than that from a typical chest x-ray.

With the continued promise of these Phase II trial results, NeoVista continues to enroll patients in the company's pivotal trial, CABERNET. CABERNET is a multicenter, randomized, controlled study that will enroll 450 subjects at 45 sites worldwide, evaluating the safety and efficacy of NeoVista's epiretinal brachytherapy delivered concomitantly with the FDA-approved anti-VEGF therapy Lucentis (ranibizumab) versus Lucentis alone.

CATT Study Update 3 Avastin vs Lucentis – To Get Underway by Year’s End!

The following information was provided to me from the recent CATT Study training meeting held in Philadelphia.

(Please note the addended updates below.)

Patient enrollment for the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT Study) is set to begin before the end of the year, with enlistment beginning on December 1st.

The study will enroll about 1,200 patients with newly diagnosed wet AMD, randomly assigned to one of four treatment groups:

(Group1) Lucentis with four-week dosing, and after one year, re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings;

(Group 2) Avastin with four-week dosing, and after one year, re-randomization to Avastin every four weeks or variable dosing as required based on diagnostic findings;

(Group 3) Lucentis on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity; and

(Group 4) Avastin on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity.

The regimens are based upon the fact that Avastin is generally given on a variable basis and Lucentis has only been formally tested in a fixed regimen. The main objective will be changes in visual acuity, with secondary objectives including change in lesion size, fluid found in optical coherence tomography and cost, which the study chairman, Dr. Dan Martin of Emory University emphasized is not the sole purpose of the study.

The study will follow patients for two years and will take about four years to complete. One year follow-up data will be reported in late 2009. The study will be conducted in 47 centers in the US.

NEI/NIH is emphasizing that this is more than just a cost study, and that the primary goals are to better understand the safety and efficacy of intravitreal Avastin and to develop better dosing/re-treatment guidelines for both Avastin and Lucentis.

The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) is a set of multicenter, randomized clinical trials of treatments for neovascular age-related macular degeneration (AMD), the leading cause of blindness in the United States. The Lucentis-Avastin comparison trial is supported by the National Eye Institute (NEI) of the National Institute of Health (NIH).

I expect to have a list of participating centers, hopefully with contact information, by the end of this week and will attempt to put it online. If it becomes available from the University of Pennsylvania website, I will link to that source.

Update:

I now have the CATT clinical site information on 46 of the 47 sites that are believed to be interested in participating in the clinical trial. I have been asked not to publish the names until the contracts with Upenn have been signed. I plan to honor that request.

However, anyone wishing to know the names of the clinics in their state that will be recruiting patients for the study can email me (iarons(at)erols.com – or the link at the side of this page) and I will be happy to cut and paste and supply you with the names of local clinics. Just mention the state that you are interested in.

As soon as Upenn gives me the OK, I will publish the information – or link to their site if they put it online.

I have also learned, as of 10/20/07, that the CATT Study will not be effected by the recent decision by Genentech to cut off the supply of Avastin to compounding pharmacies.

UPenn will act as the compounding pharmacy and will supply the doses of Avastin needed for the study to the 47 participating clinics.

Avedro Update Company Completes U S Phase III Study of Microwave Treatment for Progressive Keratoconus and Ectasia after Refractive Surgery

I have been following the progress of Avedro since I first learned about the formation of the company back in May 2009 (The Rebirth of Thermal Keratoplasty). I then wrote about the company a second time in February 2010 (Avedro Keraflex: Microwaves for Reshaping the Cornea).

Now the company has announced completion of the one-year follow up visits of patients enrolled in its two multi-center Phase III clinical studies, although, not releasing the data as yet, which is undergoing timely analysis.

When the analysis is completed, I will bring you the results.

Multi-Center US Phase III Studies for the Treatment of Progressive Keratoconus and Ectasia Following Refractive Surgery

Avedro, Inc. announced the completion of all one-year follow-up visits for patients enrolled in its two multi-center Phase III studies evaluating the safety and efficacy of corneal collagen cross-linking for the treatment of progressive keratoconus and ectasia following refractive surgery.

Keratoconus is a degenerative disease of the eye and is the leading cause of corneal transplants in the US today. Ectasia following refractive surgery is a complication following various types of surgery, including LASIK. Outside the US, Cross-linking has been deemed safe and effective and is approved for use in treating keratoconus and ectasia post-refractive surgery.

For more information about both clinical trials please see:
for ecstasia - http://clinicaltrials.gov/ct2/show/NCT00674661
for progressive keratoconus - http://clinicaltrials.gov/ct2/show/NCT00647699

Dr. Peter Hersh, a leading refractive surgeon and Medical Monitor for Avedro's clinical trial stated, "Avedro's efforts to make this clinically important treatment available to US patients is applauded by all US ophthalmologists who today lack any approved therapeutic treatment to halt the progression of these sight threatening conditions."

"I am extremely pleased that we have reached this important stage in the US clinical trials and our team is working diligently to accomplish a timely analysis of data," said David Muller, CEO of Avedro. "Outside the US, cross-linking has become the standard of care for treating weak and ectactic corneas. It is our hope to bring this technology to the US in the near future."

The company is also the sponsor of another clinical trial using its Keraflex KXL technique, which  is expected to get underway in August 2011, Safety and Efficacy of the KXL System With Riboflavin 0.1% Ophthalmic Solution for Corneal Collagen Cross-Linking in Eyes With Keratoconus -  http://clinicaltrials.gov/ct2/show/NCT01344187
 

The purpose of this study is to compare the efficacy of two treatment regimens for corneal collagen cross-linking for the treatment of keratoconus. The treatment is designed to help improve or slow the progression of keratoconus. The study treatment involves using an eyedrop containing riboflavin, also known as vitamin B2. Riboflavin increases your eye's sensitivity to light. The riboflavin eyedrops are placed in your affected eye at two-minute intervals for 10 minutes and then your affected cornea is exposed to ultraviolet light (UVA) from the KXL System (the UV light machine) for another 2 or 3 minute period, depending upon which treatment group subjects are assigned to. Subjects will be followed for twelve months to evaluate the safety and efficacy of the treatment.

Avastin Lucentis Update 15 The Brits Join in on the Fight

Apparently, British doctors are joining the fight against the high price of Lucentis and have called for a comparative study with Avastin, similar to the one about to begin in the U.S., funded by NEI/NIH. I just came across this newspaper article written a little over a month ago in The Guardian.

Please see the addendum added at the end of this article for an important update.


NHS doctors challenge high drugs prices

Sarah Boseley, health editor, The Guardian
Monday July 30, 2007

British doctors are to rebel against high prices set by pharmaceutical companies for their products by giving patients a cheap but unlicensed drug that prevents blindness, the Guardian has learned.

Unable to afford to treat all those losing their sight with a licensed and extremely expensive drug, Lucentis, some primary care trusts are giving NHS doctors the green light to use tiny shots of a similar drug, Avastin, which is marketed for bowel cancer, but costs a fraction of the price. Avastin is widely used for eye complaints in the United States.

A call from the former health secretary, Patricia Hewitt, for Avastin's manufacturer to put the drug through trials for wet age-related macular degeneration went unheeded. Now the NHS is funding a groundbreaking trial which will compare Avastin directly with Lucentis. Both drugs are manufactured by Genentech.

The moves represent the first real challenge in this country to high prices set by drug companies. There is growing unease at the cost of new drugs and high prices have led to the banning or rationing of some medicines in the NHS by the National Institute for Health and Clinical Excellence (Nice). The companies say they need billions of dollars in sales to recoup their research and development costs, but critics accuse them of profiteering.

Meanwhile, in the developing world, unaffordably high drug prices have brought the pharmaceutical industry into disrepute, forced their prices down and led to successful campaigns to allow generic copycat companies to sell cheap versions of drugs.

Around 26,000 people develop wet age-related macular degeneration (AMD) every year - a condition that can make them blind within months. Lucentis can save and even improve their vision - but Genentech, the manufacturers, and Novartis, who market it in the UK, have set the price so high - at £761.20 per injection - that Nice has said it should only be used in the 20% worst cases and then only when patients have already lost the sight of one eye.

Appalled at the implications, a number of ophthalmic surgeons in the UK are now offering treatment with Avastin, a very similar but bigger molecule also made by Genentech but licensed for bowel cancer. One bowel cancer phial can be split into many tiny doses suitable for injection into the eyes, costing as little as £10 a shot. In spite of the absence of trials or a licence, the use of Avastin has spread through the US and there is now data on more than 7,000 patients. It has also been used by some private clinics in the UK.

In the Greater Manchester area, public health directors of PCTs have taken the unprecedented decision to offer patients Avastin on the NHS. "We think as many people as possible should be treated for wet AMD. To afford it we need to use Avastin," said Peter Elton, director of public health for Bury, who is leading on the issue for the Greater Manchester area. "If you have only got one eye affected, the other eye might get something else the next year. By the time you come to treat the wet eye, it has gone too far. We think that is not ethically acceptable."

He and his colleagues are happy with the evidence amassed so far and he points out that Medicare, the state-funded healthcare service in the US, is using Avastin in 48 out of 50 states.

Moorfields eye hospital in London, the most famous in the country, is also exploring a scheme to use Avastin on the NHS. But the stakes are so high for the NHS that it is taking the unprecedented step of funding a trial which will directly compare the use of Avastin and Lucentis in wet AMD.


Further investigation has uncovered an additional information source on this story. PharmaTimes World News has published the “story behind the story”, providing further background about the reasons behind the push by British ophthalmologists to avoid the use of Lucentis and push for the approval to use Avastin in treating their AMD patients. For the complete story, follow this link.

Gene Therapy in Ophthalmology Update 17 Hemera Biosciences Obtains Initial Funding

In December 2011, following that year’s AAO Meeting, I wrote about Hemera Biosciences and its complement regulation therapy via the use of gene therapy to prevent membrane attack complex (MAC), the final stage of the complement cascade that is implicated in both dry and wet AMD. (Gene Therapy in Ophthalmology Update 5: A Complement-Based Gene Therapy for AMD)

I am now happy to report that Hemera has obtained initial funding, along with the issuance of a US Patent and can now begin manufacturing its drug, soluble CD59 (protectin), perform animal toxicology and initiate a phase 1 clinical study.

To review, HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death. 

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles.

The primary focus for the company will be preventing the conversion of the dry form of AMD from progressing into the wet form, however, they think that there's a role for HMR59 in treating the dry form (drusen and GA) as well as wet (neovascular) AMD.

Here is the company’s news release:

Hemera Biosciences Raises $3.75 Million; Patent Issued for TreatingAge-related Macular Degeneration

BOSTON, MA (March 15, 2013)  Hemera Biosciences announced its Series A financing of $3.75 million and issuance of US Patent 8,324,182 B2 on December 4, 2012, for treating age-related macular degeneration (AMD) with a human protein, soluble CD59 -- otherwise known as protectin.

“Human genetic studies and preclinical research have shown that alterations in complement – a significant driver of inflammation -- play a key role in the development of both wet and dry AMD,” said Adam Rogers, MD, one of the founders of Hemera. 

Preclinical studies done in the laboratory of Rajendra Kumar-Singh, PhD, another Hemera founder, have shown that intravitreal injection of an adeno-associated virus  that expresses soluble CD59, in an animal model, prevents the development of choroidal neovascularization. Choroidal neovascularization is the leading cause of  severe vision loss due to the wet form of AMD.

“Membrane attack complex (MAC) formation is the last step in the complement inflammation pathway.  Soluble CD59 when expressed in our animal models using gene therapy, prevents the development of MAC, death of retinal pigment epithelial cells and prevents abnormal blood vessel development in the eye.  Use of gene therapy to express soluble CD59 allows for long term treatment for this chronic blinding disease,” said Dr. Kumar Singh.

With the $3.75 million of financing raised in this initial round of funding, Hemera expects to have sufficient resources to manufacture the drug, perform animal toxicology studies and initiate a phase 1 study.

The founders and management team include Elias Reichel, MD, Jay Duker, MD, Rajendra Kumar-Singh PhD , and Adam Rogers, MD who all are on faculty at Tufts University School of Medicine.

About Hemera

Hemera Biosciences, founded in 2010, is a private company headquartered in Boston, Massachusetts that focuses on developing and commercializing gene therapy for age-related macular degeneration and other ocular conditions.

Hemera is developing its proprietary soluble CD59 gene therapy technology as a treatment for age-related macular degeneration for both the dry and wet forms of the disease.  The company’s lead program is the first and only complement therapy that directly targets MAC.  Hemera was started by some of the world’s leading experts in AMD and gene therapy.

AMD Update 2 Investigative Therapies Discussed at the 2008 AAO Meeting

In June of this year, Dave Harmon of Market Scope, reporting on the 2008 ARVO meeting, published a graphic describing AMD Cases in the U.S. by Type and Stage. I reproduced that table in this Journal.

Now, Harmon and his Market Scope team have reported on the latest information about retinal therapies from the 2008 American Academy of Ophthalmology (AAO) meeting held in Atlanta, in the December issue of Ophthalmic Market Perspectives.

In the Retina Subspecialty Meeting, held just prior to the main AAO meeting, Carmen Puliafito called treatment aimed at arresting the progression of geographic atrophy, “the new Holy Grail of macular degeneration therapy.” He reported on one of several new therapies for treating dry AMD.

Dru Thomas of Market Scope has put together the following two tables of new therapies for both dry and wet AMD. They are presented with permission of Market Scope. (For more information from the AAO meeting or for obtaining Ophthalmic Market Perspectives, please contact Market Scope directly.)

Stem Cells in Ophthalmology Update 14 Current Stem Cell Clinical Trials

Thanks to new friend, Alexey Bersenev, and his stem cell blog, Hematopoiesis, I have been able to add several companies and medical institutions to my list of those involved in ophthalmic clinical trials using stem cells. Alexey recently posted a blog entry, Cell therapy clinical trials in 2011, describing his efforts to put together a list of entities undertaking stem cell clinical trials. He came up with a total of 151 clinical trials underway, of which eight were in ophthalmology.

I am able to add one that he missed, giving a total of nine clinical trials underway (and another about to start). The new list, showing the trials by ophthalmic application, are presented in the accompanying table.

Anyone wishing a pdf file of the table can get it by sending me an email request.

Avastin Lucentis Update 17 The Controversy Heats Up Once Again

This writeup was posted on the WSJ Health Blog earlier this afternoon. Isn’t it interesting about the timing – just as the CATT Study comparing the two drugs is set to begin the day after Genentech cuts off supply of Avastin to compounding pharmacies.

Genentech Restricting Avastin Sales To Curb Eye Use

Posted by Jacob Goldstein
WSJ Health Blog
October 11, 2007, 2:39 pm

The toughest competitor for Genentech’s eye drug Lucentis has been Avastin, a Genentech cancer drug.

Today, though, Genentech said it wouldn’t let wholesalers sell Avastin to compounding pharmacies, which have been taking Avastin out of vials and putting it into pre-packaged syringes for eye treatment.

Avastin isn’t approved for use in the eyes, but it’s very similar to Lucentis, which the FDA cleared last year to treat an eye disease called wet macular degeneration. Some doctors substitute Avastin for Lucentis because a dose of the cancer medicine used for the eye disease is a lot cheaper. Avastin used that way costs about $40 a month compared with $2,000 a month for Lucentis. (Physicians are free to prescribe drugs for unapproved uses.)

In a letter explaining the decision (see below), Genentech pointed out that Lucentis was developed expressly for use in the eyes, and that the FDA has expressed safety concerns over the re-packaging of Avastin.

In the first six months of this year, U.S. sales of Avastin were $1.1 billion, and Lucentis sales were $420 million.

Avastin, which is sold through wholesalers, will still be available to hospital pharmacies and directly to doctors after the company ends sales to compounding pharmacies at the end of next month.

But Anne Fung, a San Francisco ophthalmologist, said she worries that some doctors, unable to buy the drug from compounding pharmacies, may do the re-packaging work themselves without the proper safety equipment. “This move is taking it out of a regulated environment into an unregulated environment,” she told the Health Blog. That could increase the risk of contamination and serious eye infections.

Fung, who said Avastin and Lucentis are split roughly 50-50 among macular degeneration patients, said she would likely try to get Avastin from a hospital pharmacy, which might charge her more than the compounding pharmacy.

Genentech spokeswoman Dawn Kalmar pointed out that most wet macular degeneration patients are covered by Medicare, and said the company helps connect patients who can’t cover their copay (which can be $400 a month for Lucentis) with charities that help with payment.


Here is a copy of the Genentech letter:


Letter to Physicians

October 11th, 2007

Dear Retinal Community Member:

On behalf of Genentech, manufacturer of Avastin® (bevacizumab), I am writing to inform you of a change to the distribution of this product. Like all of Genentech's FDA-approved oncology products, Avastin is distributed directly to physicians and hospital pharmacies through authorized wholesale distributors. Genentech has also permitted compounding pharmacies to purchase Avastin from authorized wholesale distributors. As of November 30, 2007, Genentech will no longer allow compounding pharmacies to purchase this product directly from wholesale distributors. This change does not otherwise impact the distribution of Avastin nor will it remove Avastin from the marketplace or otherwise limit a physician's prescribing choice. Physicians can still order Avastin directly from authorized wholesale distributors.

Avastin is an infused medication approved by the U.S. Food and Drug Administration (FDA) for use in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum and in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC).

Despite the availability of LUCENTIS® (ranibizumab injection), an FDA-approved treatment for neovascular (wet) age-related macular degeneration (AMD), some ophthalmologists are using Avastin for the unapproved treatment of this and other ocular indications. Avastin is not FDA-approved for ocular uses and is not manufactured to meet U.S. Pharmacopoeia (USP) ophthalmic standards. This change will not go into effect until November 30, 2007 to allow for physicians and compounding pharmacies to adjust to this change in distribution.

A series of events have contributed to our decision to make this change to our distribution of Avastin. Most important among these events is the FDA approval and broad availability of Lucentis for patients with wet AMD. Subsequent to the approval of Lucentis, the FDA raised concerns related to the sterility and repackaging of Avastin for ocular use in a Warning Letter to a compounding pharmacy and, separately, during a routine FDA inspection of our South San Francisco manufacturing facility, concerns were raised by inspectors related to the ongoing ocular use of Avastin because it is not designed, manufactured or approved for this use. In addition, we note that Avastin has not undergone any formal, randomized, controlled clinical trials for ocular use.

We recognize this change may require some adjustment on your part and are acknowledging this by notifying you seven weeks prior to the change taking effect. In addition, I would like to reiterate Genentech's commitment to patient access to our approved products. We have always believed that no eligible patient should go without one of our approved medicines due to financial barriers alone. As such, we have invested in a dedicated support services organization to assist with providing patients access to our medicines. Specific to Lucentis, we offer The LUCENTIS Commitment™, a comprehensive support program dedicated to facilitating timely reimbursement. If you or your patients have any questions related to our access and reimbursement services, please contact us toll-free at 1-866-724-9394.

Should you have questions or comments about this distribution change, I encourage you to contact us at physicianquestions@gene.com. We will do our best to respond to your inquiry by the end of the next business day. Thank you for your patience and understanding as we move forward with implementing this change.

Sincerely,

Susan Desmond-Hellmann, M.D.,M.P.H.
President, Product Development
Genentech, Inc.