Article Date: 9/1/2005

SUBSPECIALTY NEWS
Inside Genentech's Lucentis Strategy

The company had no experience in ophthalmic drugs, but has moved its wet AMD treatment ahead quickly.
BY JERRY HELZNER, SENIOR EDITOR

When biotech giant Genentech was developing its groundbreaking colorectal cancer drug bevacizumab (Avastin), which last year became the first antiangiogenic agent approved by the FDA, company researchers came to believe that an anti-VEGF therapy could also be effective against wet AMD.

"We think of drugs in terms of targets," Charles Johnson, MB, ChB, the South African-trained vice president of biotherapeutics for Genentech told Retinal Physician. "We started to think about diseases in which VEGF could play a role and AMD is definitely one of those diseases."

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

"We noted that antiangiogenic agents were also effective in reducing the edema around 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 for developing a treatment for wet AMD."

Thus, from a modified fragment of the Avastin molecule, ranibizumab (first known as RhuFab and then Lucentis) was created in a Genentech research laboratory.

This article will examine Genentech's strategic "game plan" in initiating a range of complementary clinical studies which, taken overall, have been instrumental in expediting the process to prove the safety and efficacy of Lucentis as a treatment for all forms of wet AMD.

MAKING KEY DECISIONS

Despite Genentech's lack of previous experience with ophthalmic therapies, once the company decided to move ahead with a development program for Lucentis its research managers acted decisively.

"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," says Dr. Johnson. "One of the ways we try to accomplish this is through local delivery of the drug through an intravitreal injection."

Designing the initial clinical studies for Lucentis called for other critical decisions.

"A key part of Genentech's mission is to discover and develop biotherapeutics that address major unmet medical needs," says Dr. Johnson. "Because verteporfin (Visudyne) was already an approved therapy for predominantly classic wet AMD, we felt our best path to approval was to initiate a clinical trial for Lucentis against the occult and minimally classic forms of the disease."

Dr. Johnson says that at the time the phase 1 Lucentis clinical trials were initiated in late 1999, Genentech researchers tended to believe that different therapies might be needed to treat different forms of wet AMD.

"Then, we felt we were on firmer ground going after occult and minimally classic," he notes. "Now, we believe that Lucentis may be effective in treating all forms of wet AMD."

When Lucentis showed great promise in its phase 1 trials for safety and efficacy, Genentech researchers made another major decision that helped greatly to speed up the development process. They jumped directly from phase 1 to large-scale, pivotal phase 3 clinical studies.

"We were new to ophthalmology, but we have a robust program and have been able to move very fast," says Dr. Johnson.

THE DATA ARE IMPRESSIVE

The phase 3 MARINA trial, involving 716 patients, is Genentech's key study in the company's attempt to gain FDA approval for Lucentis in the treatment of occult and minimally classic wet AMD. These forms of the disease encompass approximately 80% of all wet AMD cases.

It is the recently released data from the MARINA trial, showing that 95% of patients given the drug maintained or improved vision after 1 year, with an average gain of 7 letters on an ETDRS chart, that has impressed the ophthalmic community and moved Lucentis to the head of the list of promising wet AMD drugs. The two other approved therapies for wet AMD, Visudyne and pegaptanib sodium (Macugen) are able to delay or halt disease progression but have not shown to be able to improve vision.

The new MARINA data were presented in July during the 23rd Annual Meeting of the American Society of Retina Specialists (ASRS) in Montreal, Canada.

"These data are very compelling because, for the first time, we have a potential treatment which has been shown to improve vision in a significant number of patients with wet AMD as opposed to just slowing progression of vision loss," said Joan W. Miller, MD, retina specialist at the Massachusetts Eye and Ear Infirmary, who presented the data.

An analysis of the 1-year data showed that adverse events were similar to those seen in earlier trials of Lucentis. Common side effects occurring more frequently in the Lucentis arms than in the control group were mild to moderate, and included conjunctival hemorrhage, eye pain, and vitreous floaters. Serious ocular adverse events occurring more frequently in Lucentis-treated patients were uncommon (<1%) and included uveitis and endophthalmitis.

Another large-scale, pivotal phase 3 study, called ANCHOR, is currently under way, with 1-year data expected to be released later this year. The goal of this study is to compare 2 different doses of Lucentis against Visudyne in the treatment of predominantly classic wet AMD.

Thus, between the MARINA and ANCHOR studies, Genentech's goal is to present enough favorable data to the FDA to gain approval for Lucentis in the treatment of the occult, minimally classic, and predominantly classic forms of wet AMD. Genentech is working closely with the FDA to obtain approval and make the drug available to patients as quickly as possible. It is possible that the FDA could approve Lucentis by the middle of next year.

A hint as to what the ANCHOR study might show can be found in recent 1-year data from the phase 1 and 2 FOCUS study, in which patients with predominantly classic wet AMD received both Visudyne and Lucentis or Visudyne and a sham injection. In the FOCUS study, the average patient receiving both Visudyne and Lucentis showed a significant improvement in visual acuity, while the average patient in a control group receiving Visudyne and sham showed a decrease in visual acuity at 12 months.

In addition to meeting the study's primary efficacy endpoint of maintaining vision in patients with wet AMD, secondary endpoint results show there was a 13-letter difference in mean change in visual acuity from study entry between the 2 treatment groups as measured by the ETDRS eye chart. At 12 months, patients treated with Lucentis and PDT gained an average of 5 letters in visual acuity compared to study entry, while those in the control group lost an average of 8 letters. Twenty-four percent (25/105) of patients treated with Lucentis in combination with PDT vs. 5% (3/56) of patients treated with PDT alone improved vision by 15 letters or more compared to study entry.

Genentech has also embarked on a phase 3b study called PIER, which will attempt to determine if Lucentis can maintain its level of effectiveness on a less-frequent dosing schedule.

"We hope that PIER will demonstrate that less-frequent dosing does not mean a lesser benefit," says Dr. Johnson. "No one likes a needle in the eye, so less-frequent dosing would create a better safety profile for Lucentis."

ADVANCING LUCENTIS

Genentech's partner for Lucentis outside of the United States, Canada, and Mexico is Novartis. The results of the phase 3 studies will be used to obtain approvals in markets outside of North America. To this end, Novartis has been enrolling patients for the ANCHOR study at sites in Europe and Australia. However, Lucentis will almost certainly be approved in the United States before it is approved in the European Union.

Flemming Ornskov, MD, president of Novartis Ophthalmics, said that in addition to its ongoing international development efforts for the drug, Novartis is about to start an additional Lucentis trial in Europe that will relate to a number of clinically relevant questions, including frequency of dosing.

"The Lucentis data coming from the MARINA and FOCUS trials have been highly impressive," says Dr. Ornskov. "The significant improvement in vision achieved overall represents the first major step forward in developing a wet AMD treatment with proven clinical efficacy. I give Genentech high marks for running a phenomenal program and for their openness with the retinal community."

Novartis Ophthalmics, in a partnership with QLT Inc., also markets Visudyne, which until now has been the cornerstone wet AMD therapy. Dr. Ornskov sees a future for Visudyne in combination therapies and for patients who find Visudyne a more convenient and less invasive treatment.

"Visudyne has a very good response rate and is highly effective in fast-sealing of the lesion," notes Dr. Ornskov. "Though Lucentis will be used as monotherapy in many patients, there may be other patients who will gain added benefits from a combination therapy. We are currently exploring further opportunities for using Visudyne as a combination therapy."

INVESTIGATOR-SPONSORED STUDIES

In addition to the clinical trials it has initiated on its own, Genentech is providing free drugs and some funding to several small investigator-sponsored studies of Lucentis. Genentech welcomes these studies because they add to the knowledge of the mechanism of action of the drug.

"These investigator-sponsored studies are useful to us," says Dr. Johnson. "The more research that's conducted, the better we understand such aspects of the drug as speed of onset. However, I don't think these types of studies are going to change our basic thinking about how and why Lucentis works."

One such investigator-sponsored study is called the PrONTO Study. The 2-year, 40-patient study was initiated in 2004 by Philip Rosenfeld, MD, PhD, of the Bascom Palmer Eye Institute in Miami and called for 3 monthly injections of Lucentis for patients with all types of lesions. The purpose of PrONTO is to determine, through optical coherence tomography (OCT), how quickly visual acuity improves and central retinal thickness (CRT) decreases following Lucentis therapy.

Anne Fung, MD, a retina fellow at Bascom Palmer, reported that Lucentis reduced CRT by an average of approximately 50 μm by day 1.

"We knew Lucentis worked fast in reducing retinal edema, but we didn't know how fast," says Dr. Fung. "The results were more impressive than we had hoped."

Dr. Fung says the average patient in the PrONTO study demonstrated a statistically significant improvement in vision (about 7 letters) by day 14, and improved a bit more to 8.5 letters by day 90. This improvement was found across all types of lesions.

"Our data are similar to other Lucentis studies and are supportive of the MARINA findings," says Dr. Fung.

Once the immediate goals of achieving approval for Lucentis as a treatment for wet AMD is met, Genentech researchers will initiate studies designed to extend the range of indications for the drug.

Dr. Johnson told Retinal Physician that diabetic macular edema (DME), central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) are also potential targets for Lucentis. Novartis Ophthalmics expects to play a role in conducting the clinical trials for these additional indications.

"There are clearly other opportunities for us to pursue with Lucentis," Dr. Johnson says. "The ophthalmology community should know that Genentech is committed to meeting unmet needs in the area of ophthalmic drugs."

 

Key Clinical Studies for Lucentis

Genentech says its clinical trials are designed to provide physicians with clinically meaningful information about how Lucentis works in subsets of patients, as a monotherapy and in combination with Visudyne. The following are key, complementary studies initiated by Genentech:

FOCUS phase 1 and 2

The FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) trial is a phase 1 and 2 randomized, single-masked study evaluating the safety, tolerability, and efficacy of Lucentis in combination with PDT in 162 patients with predominantly classic wet AMD. In this study, patients were randomized 2:1 to receive PDT followed by either 0.5 mg injections of Lucentis or sham injections for 23 months. The FOCUS study is being conducted at 25 sites in the United States.

MARINA pivotal phase 3

MARINA (Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab (formerly, RhuFab) In the treatment of Neovascular AMD) is a phase 3 study of 716 patients in the United States with minimally classic or occult wet AMD who were randomized 2:1 to receive intravitreal Lucentis injections or a control regimen. The control regimen consisted of a sham injection, meaning the treating physician prepares and anesthetizes the patient's eye but does not perform an injection. Patients treated with Lucentis were further randomized to receive either a 0.3 mg or 0.5 mg dose of Lucentis once a month for 2 years. Data from the first year of this study were announced at the 23rd Annual Meeting of the American Society of Retina Specialists in July 2005.

ANCHOR pivotal phase 3

ANCHOR (ANti-VEGF Antibody for the Treatment of Predominantly Classic CHORoidal Neovascularization in AMD) is a randomized, multicenter, double-masked, active treatment-controlled, phase 3 study comparing 2 different doses of Lucentis to verteporfin photodynamic therapy (Visudyne) in 423 patients with predominantly classic wet AMD. The trial is ongoing in the United States, Europe, and Australia in patients with predominantly classic wet AMD. Top-line data from this study are anticipated in Q4 2005.

PIER phase 3b

PIER, (a phase 3b, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to AMD) is a study comparing 1 of 2 doses of Lucentis to sham injections in 184 patients in the United States with wet AMD. In this trial, Lucentis is administered once per month for the first 3 doses followed thereafter by doses once every 3 months for a total of 2 years of treatment. Top-line data from this study are anticipated in Q1 2006.

HORIZON

HORIZON is a clinical trial that is an extension study available to patients enrolled in the MARINA, ANCHOR, and FOCUS studies (regardless of treatment arm). All patients in HORIZON will receive Lucentis. For information on any Genentech-initiated study, contact Genentech, South San Francisco, CA.

Investigator-Sponsored Study: PrONTO

PrONTO (Prospective OCT imaging of patients with Neovascular AMD Treated with IntraOcular Lucentis) The PrONTO study, which began in August of 2004, is being sponsored by Bascom Palmer Eye Institute and Genentech, Inc.PrONTO's goal is to determine how quickly visual acuity improves and the central retinal thickness decreases following Lucentis therapy using OCT and then, after 3 monthly doses determine the durability of the treatment response with intermittent therapy offered only if needed based on OCT findings Design is a prospective, open-label, uncontrolled, clinical study Inclusion criteria are neovascular AMD; subfoveal CNV; all lesion types; recent disease progression, central retinal thickness at least 300 μm; multiple visits required � 6 visits each month for the first 3 months, then visits once a month for a total of 2 years.

Information: Maria Esquiabro, (305) 326-6508; Dr. Philip Rosenfeld, (305) 326-6148. This study is fully enrolled and not accepting new patients.

IN BRIEF

Leaked Lucentis data. According to a Seattle Times report, some investigators involved in the pivotal phase 3 trials of Lucentis for wet AMD were paid an average of $300 to $500 an hour by Wall Street firms to provide insights on the drug's safety and effectiveness. The revelations brought an immediate call from Sen. Charles Grassley (R-Iowa) for the Securities and Exchange Commission to look into the practice.

The newspaper reported that the investment firm Citigroup Smith Barney talked to 26 ophthalmologists, many of whom were involved in the clinical trials for both Lucentis and its key competitor, the recently approved AMD therapy Macugen.

"The doctors were able to give Smith Barney valuable comparative information," the article asserted.

Smith Barney then summarized the information it had gathered on Lucentis in a report to investors on May 5 of this year, predicting that 97% of patients given Lucentis would have stable or improved vision. When the drug's developer, Genentech, released results of its phase 3 MARINA study of Lucentis on May 23, the article states that Smith Barney's numbers "were almost exactly on the money." The news caused a sharp drop in Eyetech shares.

The phase 3 results (which were similar to the publicly available phase 1 and 2 results released in 2003) indicated that 95% of Lucentis patients had stable or improved vision. Investigators who spoke to Wall Street firms say they provided only their general impressions of Lucentis and did not violate confidentiality.

Macugen 2-year data. Eyetech Pharmaceuticals recently presented 2-year data related to its phase 2 and 3 VISION trial for Macugen.

Eighty-eight percent (1053/1190) of subjects who received at least 1 treatment continued into year 2, and were rerandomized. In the combined analyses, 89% (941/1053) of subjects rerandomized at week 54 were assessed at Week 102. Over 2 years, the mean number of treatments for all subjects rerandomized to therapy was 15.7 of a possible 17 injections (92%). From baseline to week 102, subjects who received Macugen 0.3 mg for 2 years demonstrated a relative preservation of visual acuity when compared with sham. Patients treated with Macugen 0.3 mg for a second year showed a mean loss of 9.4 letters of vision, compared to a loss of 17.0 letters for sham, demonstrating a relative treatment effect of 45% (P<=0.05). Fewer subjects who continued a second year of Macugen 0.3 mg lost 3 lines or more of vision: 59% of the 0.3 mg arm (78/133) lost <15 letters versus 45% (48/107) of subjects receiving sham (P<0.05).

When comparing subjects receiving 1 year of Macugen to those who received 2 years of Macugen, Eyetech said the second year of therapy afforded additional protection from vision loss. Sixty-seven percent more occurrences of a 3-line loss of vision were noted in patients receiving but 1 year of therapy compared to those receiving 2 years of therapy (35 occurrences in the 1-year group versus 21 occurrences in the 2-year group; P<=0.05). During year 2, no new systemic safety concerns or ocular safety issues emerged and the incidence of endophthalmitis decreased.

Compared with both 1 year of therapy followed by 1 year of usual care, or 2 years of usual care, a 2-year treatment regimen of Macugen provided sustained therapeutic benefit and better visual outcome at week 102. The favorable safety profile continued with a second year of Macugen treatment, and the risk of endophthalmitis, albeit small, was modifiable with attention to injection technique.

New leader for Iridex. Iridex Corporation has announced that its board of directors has appointed Barry G. Caldwell, 54, as its new president and CEO, succeeding Theodore A. Boutacoff, 58, who had served in the post since 1989. As announced earlier this year, Boutacoff has been elected chairman of the board of Iridex. Caldwell has also been elected to serve on the board.

Iridex is a leading provider of semiconductor-based laser systems for ophthalmology and dermatology markets.

Eyetech to be bought by OSI. Eyetech Pharmaceuticals, the developer of the FDA-approved drug Macugen for wet AMD, has agreed to be acquired by OSI Pharmaceuticals for about $935 million in cash and OSI stock. The deal is valued at about $20 for each share of Eyetech, $15 of it in cash..

This is OSI's first venture into ophthalmic drugs. Until now, OSI has focused on treatments for cancer and diabetes. Its flagship drug is Tarceva, which is FDA-approved for advanced non-small cell lung cancer.

 



Retinal Physician, Issue: September 2005