Genentech: A Powerful New Foe of AMD
The biotech giant is using its work in anti-VEGF as a springboard into ophthalmology.
BY JERRY HELZNER, SENIOR EDITOR

It's extremely rare for a company to be so identified with the industry that it helped to create that its name becomes almost synonymous with the industry itself. A few that come immediately to mind are RCA with broadcasting, IBM with computers, Texas Instruments with semiconductors, and Genentech with biotechnology.

Of all these corporate giants, Genentech probably most deserves the title of "pioneer." From its founding in 1976, Genentech immediately showed it intended to break away from the accepted concepts of how a drug development company should conduct research, and instead created an entirely new drug discovery process. While traditional pharmaceutical companies combined small organic molecules with enzymes and cell receptors in the hopes of making a "hit" that would lead to a new drug, the genetic engineering practiced by Genentech allowed company scientists to produce large amounts of proteins, hormones and other therapeutic agents through cloning.

Throughout its 28-year history, Genentech has been responsible for many "firsts" in the biotechnology industry, including perfecting the production of genetically engineered therapies such as insulin, human growth hormone and clot-busting drugs that have saved the lives of countless heart attack and stroke victims. A considerable number of the currently approved biotechnology products originated from -- or are based on -- Genentech science. Genentech manufactures and commercializes multiple biotechnology products directly in the United States and licenses several additional products to other companies.

In 1989, Genentech took the first step that eventually led the company into the ophthalmic arena. In that year, Genentech discovered vascular endothelial growth factor (VEGF), a protein that plays a critical role in the formation of new blood vessels.

Research into VEGF and how it's involved in both tumor growth and retinal disease has become an increasingly important initiative for Genentech in recent years, and has led the company into new areas of oncologic and ophthalmic drug development.

In this article, I'll examine the entry of Genentech into the ophthalmic drug arena and the progress of its wet AMD treatment, ranibizumab (Lucentis), from inception through to current Phase III clinical trials.

From Oncology to Ophthalmics

Since 1996, Genentech has been led by Chairman and CEO Arthur D. Levinson, Ph.D. Levinson, now 54, has been described as an imaginative thinker with broad technical interests. He originally joined the company in 1980 as a senior scientist and in a decade rose to the position of head of research.

A self-described "science geek," Dr. Levinson is a backyard astronomer who taught his son and daughter about the structure of DNA using Lego blocks. Dr. Levinson is by nature more at home in a research lab than in the executive suite. However, under his leadership Genentech has flourished, receiving several important drug approvals.

"Art understands the heart of this business," said one Genentech board member.

Under Dr. Levinson's leadership, Genentech has probably been best known for its work in oncology, especially with the 1997 approval of Rituxan for certain forms of non-Hodgkins lymphoma, the 1998 approval of Herceptin for metastatic breast cancer, and the approval this year of the breakthrough antiangiogenic Avastin for colorectal cancer. One of the company's goals is to become number one in U.S. oncology sales by 2010.

Rituxan has become Genentech's biggest-selling drug, generating almost $1.5 billion in revenue in 2003, with continuing strong growth in sales this year. Herceptin had sales of $425 million last year.

Avastin is the first approved therapy designed to attack the VEGF protein and inhibit angiogenesis, the process by which new blood vessels develop. Many industry observers expect Avastin to eventually account for more than $1 billion in annual sales.

Attacking Wet AMD

"While our work on Avastin didn't directly lead us into the ophthalmic area of drug development, the stimulus for our interest in developing a treatment for wet AMD was definitely our research in VEGF," says Charles Johnson, M.B., Ch.B., the South Africa-born vice president of clinical biotherapeutics for Genentech. "We think of drugs in terms of targets. We started to think about the diseases in which VEGF could play a role and AMD is definitely one of those diseases."

Dr. Johnson says that a key part of Genentech's mission is to discover and develop biotherapeutics that address major unmet medical needs.

"Loss of vision in elderly people is as debilitating as anything you can imagine," says Dr. Johnson. "We felt it was important for us to pursue an AMD treatment."

One factor that gave Genentech researchers hope that they were on to a potentially promising treatment for wet AMD was the results they obtained when they used anti-VEGF (antiangiogenic) compounds to attempt to shut down the blood vessels supplying cancerous tumors.

"We noticed that antiangiogenic agents were also effective in reducing the edema in tumors, which tend to be spongy," says Dr. Johnson. "This was a corroborating factor in our thinking that this mechanism was probably going to be useful in our approach to developing a treatment for wet AMD."

Though antiangiogenics hold great promise for both oncologic and ophthalmic indications, Genentech researchers were also aware that VEGF has an important purpose in the body, especially in developing collateral blood vessels that help in cardiovascular circulation.

"It's not a good thing to generally suppress VEGF in people who don't have tumors," says Dr. Johnson. "In developing a treatment for wet AMD, we had to create an antiangiogenic agent that was potent enough to attack the disease, but not so potent as to cause systemic problems. One of the ways we try to accomplish this is through local delivery of the drug through an intravitreal injection."

In the clinical trials in which patients have been injected with Lucentis, the interval between injections has until now been 4 weeks.

"We now have evidence that we might be able to give the injection every 3 months and still have good results," says Dr. Johnson. "It's something we're looking into that would be a benefit to patients. And, looking ahead, we'll continue to work on alternate ways to deliver the drug."

Lucentis has Competition

Lucentis, on which Genentech is partnering with Novartis outside of the United States, is one of three new treatments in late-stage clinical trials for wet AMD that have drawn great interest from the ophthalmology community. Genentech describes Lucentis as a humanized antibody fragment that's designed to bind to and inhibit the action of VEGF, preventing vessel growth and leakage. Genentech says Lucentis is designed to bind to all five isoforms of VEGF, providing it with greater potential to inhibit VEGF.

The other wet AMD treatments that are far along in the approval process are the Eyetech/Pfizer antiangiogenic pegaptanib sodium (Macugen), which is generally expected to receive FDA approval late this year, and Alcon's angiostatic cortisene, anecortave acetate (Retaane 15mg) which could be approved as early as next year.

In a Phase Ib/II clinical trial, 97.5% of 40 patients with various forms of wet AMD who received monthly injections of Lucentis had stable or improved vision after 210 days, with 45% of those improving by 3 lines or more on an ETDRS chart.

Genentech is currently conducting two Phase III clinical studies of Lucentis. The first trial, called MARINA, is a randomized, multicenter, double-masked, sham-injection controlled study evaluating the safety and efficacy of two different doses of Lucentis in approximately 716 patients with minimally classic or occult wet AMD.

This trial completed enrollment in 2003, and initial results are expected in the first half of 2005.

The second trial, called ANCHOR, is a randomized, double-masked, multicenter, active treatment-controlled study comparing two different doses (300g and 500g) of Lucentis to verteporfin photodynamic therapy (Visudyne) in approximately 426 patients with predominantly classic AMD. This study continues to enroll patients.

Looking Ahead

To many observers, the entry of Genentech into the ophthalmic arena indicates the growing interest of major pharmaceutical and biotech companies in finding treatments for eye diseases that are sure to become more prevalent as the huge baby boomer generation ages.

"We're not known as an ophthalmology company, but ophthalmologists should know that we're very careful thinkers about what we do in taking a comprehensive approach to developing new therapies," says Dr. Johnson. "We take great pains to understand the pathology of diseases and make very focused decisions. For example, in our current Phase III clinical trials for Lucentis, we've divided the patient population into subgroups. By doing this, we hope to answer some very specific questions about how Lucentis works in these subpopulations. We also have a history of working very closely with specialists, and we've spent a great deal of time meeting with ophthalmology thought leaders."

Dr. Johnson says Genentech's future participation in ophthalmology largely rests on the success of the Lucentis trials.

"Dependent of the success of these trials, we may go into other ophthalmic indications," concludes Dr. Johnson. "This could be a very important molecule long-term for Genentech."

Genentech at a Glance

History: Genentech was founded in 1976 by young venture capitalist Robert A. Swanson and biochemist Herbert W. Boyer, Ph.D. It was Dr. Boyer's pioneering work in the early 1970s in a new scientific field called recombinant DNA technology that had captured Swanson's interest. Swanson's belief in the commercial potential of this new science was so compelling that the two men formed Genentech at their first meeting, thus creating the first biotechnology company and starting an entirely new industry. In the 1970s, Genentech produced the first recombinant protein and was able to clone the gene for human insulin, which led to the approval of the first recombinant protein therapy. In the 1980s, Genentech received approval for Protropin growth hormone, the first product manufactured and marketed by a biotechnology company. In that same decade, the company received approval for the clot-busting drug Activase and also discovered vascular endothelial growth factor (VEGF), a protein that plays a critical role in angiogenesis, or the formation of new blood vessels. In recent years, Genentech has received approvals for several important new drugs for the treatment of different types of cancers, asthma and plaque psoriasis. The company currently has more than 30 promising compounds in its developmental pipeline. Company Mission: To be the leading biotechnology company, using human genetic information to discover, develop, manufacture and commercialize biotherapeutics that address significant unmet medical needs. Key Goals: In 1999, Genentech set several key goals that it hoped to achieve by 2005. Among these goals are 25% average annual non-GAAP growth in earnings per share; five new products or indications approved; five significant products in late-stage clinical trials, and $500 million in new revenue from strategic alliances or acquisitions. The company is confident that it can meet or exceed the first three of these goals, while conceding that attaining the final goal may take longer than it had originally anticipated. Key Products: Rituxan for the treatment of certain forms of non-Hodgkin's lymphoma; Herceptin for patients with certain types of metastatic breast cancer; Avastin for use in combination with chemotherapy for metastatic colorectal cancer; Xolair for treatment of moderate-to-severe persistent asthma in adults and adolescents; Raptiva for the treatment of moderate-to-severe plaque psoriasis in adults 18 or over who are candidates for systemic therapy or phototherapy; TNKase, a single-dose clot-busting agent for the treatment of acute myocardial infarction; and Activase, a tissue-plasminogen activator to dissolve blood clots in patients experiencing acute myocardial infarction, acute massive pulmonary embolism or acute ischemic stroke. Must be administered within 3 hours of symptom onset. Development Pipeline: (products currently in clinical trials): Among the more than 30 compounds in Genentech's pipeline are Tarceva for refractory lung cancer and pancreatic cancer; Lucentis for wet AMD; Veletri for acute heart failure; Omnitarg for breast, lung, ovarian and prostate cancer; and Nutropin for adult growth hormone deficiency. Sales: Approximately $3.3 billion in 2003, with non-GAAP diluted earnings of $0.60 a share adjusted for a recent 2-for-1 stock split. For the first 6 months of 2004, Genentech recorded revenue of more than $2 billion and set a goal of non-GAAP 2004 earnings of $0.75 to 0.80 a share. R&D Spending: Genentech reinvested approximately 22% of its 2003 revenues into R&D, significantly more than the pharmaceutical industry average. Headquarters: South San Francisco, Calif. Employees: About 7,000, more than 20% with advanced degrees CEO: Arthur D. Levinson, Ph.D. Stock Listed: New York Stock Exchange (symbol DNA) Recent Stock Price Range: $45 to $55