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