SUBSPECIALTY NEWS
Researchers See Promise in VEGF Trap
AMD Treatment Attracts Potential Partners.
JERRY HELZNER, SENIOR EDITOR
The recent approval of Genentech's Lucentis appeared to settle the issue of which
drug would serve as the primary therapy for the treatment of wet AMD, at least for
the foreseeable future. But in recent weeks a potential rival has stirred excitement
based on highly promising results from a small phase 1 trial.
Interestingly,
the drug that has created this new interest is a familiar name — VEGF Trap.
Regeneron Pharmaceuticals has spent a decade developing VEGF Trap.
However, the progress of this therapy through clinical trials was interrupted when
Regeneron changed the method of delivery from intravenous to intravitreal injection.
The change was made to negate the possibility of systemic side effects that antiangiogenic
agents are known to cause when delivered intravenously. In addition, a partnership
with Aventis on VEGF Trap for AMD was sidetracked when Aventis was taken over by
Sanofi and the entire Sanofi-Aventis drug development portfolio was re-evaluated.
"We are currently developing VEGF Trap for AMD on our own," says
George Yancopolous, MD, Regeneron's chief scientific officer. "However, we have
recently been approached by several companies that are showing an interest in partnering
with us on VEGF Trap."
Regeneron recently completed a 6-week phase 1 trial on VEGF
Trap in which patients demonstrated a mean improvement in BCVA of 13.5 letters,
with some patients gaining 15 or more letters. These results are comparable to data
from Lucentis trials. Regeneron has now initiated a 150-patient, 12-week phase 2
trial. Dr. Yancopolous anticipates that if all goes well in phase 2, a phase 3 trial
could start early next year.
Though
VEGF Trap is still at least 3 years away from possible approval as a treatment for
wet AMD, its mechanism of action is intriguing. The drug creates a decoy receptor
that "fools" VEGF into binding with the decoy and then converts into a harmless
soluble complex. Hence, the name VEGF Trap.
"VEGF Trap has potential advantages in that it binds VEGF at a
far higher rate than Lucentis, it probably can be safely given in much higher doses
than Lucentis, and its effects may be longer-lasting than Lucentis," says Dr. Yancopolous.
"Of course, these theories will have to be proven in the upcoming clinical trials
but we have already safely given a 4 mg dose of VEGF Trap to patients, which is
8 times higher than the approved Lucentis dose."
Peter Campochiaro, MD, a retina specialist at the Wilmer Eye Institute
of Johns Hopkins University, served as an investigator in the VEGF Trap phase 1
trial and is also participating in the phase 2. He calls VEGF Trap "a very good
VEGF antagonist, just as Lucentis is a very good VEGF antagonist."
Dr. Campochiaro says the ability of VEGF Trap to bind to VEGF
A, B and C and placental growth factor with high affinity (Lucentis binds only VEGF
A) gives the drug "theoretical advantages" that will have to be proven through the
clinical trials process.
"Being able to bind to VEGF with higher affinity can be an advantage
if it prolongs the duration of the effect," says Dr. Campochiaro. "And being able
to bind with placental growth factor could also be an advantage because placental
growth factor may play a significant role in ocular diseases. The ability to give
a higher dose is another theoretical advantage that will have to be tested in the
trials."
Jeffrey S. Heier, MD, vitreoretinal specialist at Ophthalmic Consultants
of Boston, recently became a member of the Regeneron Scientific Advisory Board.
He finds VEGF Trap to be "one of the more interesting compounds currently under
investigation." He is essentially in agreement with Dr. Campochiaro in pointing
out the specific "theoretical advantages" of VEGF Trap but also notes that "there
remains a great deal of work to appropriately gauge this compound's role in the
treatment of AMD."
Regeneron has followed a path similar to Genentech in that the
company has been developing antiangiogenic agents for both solid tumors and wet
AMD. Regeneron also has another major drug development program that involves a treatment
called IL-1 for inflammatory diseases. All of Regeneron's key drug candidates are
currently in clinical trials.
IN BRIEF
■ Alcon partners with Eli Lilly. Eli Lilly and Company and Alcon, Inc. said they have
signed a long-term agreement to co-promote ruboxistaurin mesylate (Arxxant) in the
United States and Puerto Rico. Arxxant is an investigational oral drug for the treatment
of moderate to severe nonproliferative diabetic retinopathy. The FDA recently gave
Arxxant an "approvable letter" requiring that Lilly furnish additional clinical
data, which could come from an ongoing study or from a new trial. The co-promotion
agreement is dependent on FDA approval of the drug.
"We believe combining the respective expertise of Lilly and
Alcon will allow us to maximize the value of this potential new therapy for patients,
physicians and our shareholders," says Khoso Baluch, vice president, U.S. diabetes
business unit, Lilly. "Alcon will lead the promotional efforts to the eyecare community,
increasing awareness of the benefits that Arxxant could provide if approved as the
first oral medication to reduce the risk of vision loss associated with diabetic
retinopathy."
■ New Lucentis study planned. Retina specialists from Wills Eye Hospital in Philadelphia
plan to begin a study to determine whether wet AMD patients who failed Avastin or
Macugen can benefit by being switched to Lucentis. Richard S. Kaiser, MD, is serving
as principal investigator for this Genentech-sponsored study.
■ Panel rejects IMT. An FDA advisory panel voted 10 to 3 not to approve the
Implantable Miniature Telescope (IMT), a device designed to improve the sight of
end-stage AMD patients. Though the IMT produced significant average gains in visual
acuity in a large phase 2/3 clinical trial, panel members cited safety issues as
the reason for not approving the device. The FDA can accept or reject the panel's
recommendation. The IMT was developed by Vision Care Ophthalmic Technologies, located
in Saratoga, Calif.
■ Visudyne sales drop. QLT Inc. reported global sales of its Visudyne therapy for
wet AMD of $95.3 million for the quarter ended June 30. This represents a decrease
of 26.1% compared to sales in the second quarter of 2005 and a 10.7% decline compared
to the first quarter of 2006. Visudyne sales in the United States for the June quarter
were approximately $18.9 million, representing 20% of total worldwide sales for
the quarter.
The drop is largely attributable to the use of Avastin off-label
and Macugen to treat wet AMD.
■ B&L licenses retinal patents. SurModics, Inc., a provider of surface modification
and drug-delivery technologies, said it has granted Bausch & Lomb an exclusive
license to patents relating to the use of Genistein in the treatment and prevention
of retinal diseases. Technology relating to the use of Genistein was among the technologies
acquired by SurModics in connection with the acquisition of InnoRx in 2005. InnoRx
had licensed patents covering inventions made by InnoRx founder and retinal surgeon
Eugene de Juan, Jr., MD.
SurModics
says Genistein is a soy isoflavone with strong anti-oxidant and anti-VEGF activity
that has been shown to reduce retinal vascular leakage in diabetic animals. It is
seen as a potential treatment for diabetic macular edema.
■ Medicare physician fees. CMS has proposed a cut of 5.1% across-the-board in payments
for physician services provided by doctors under Medicare. The cut will take effect
on Jan. 1, 2007 unless Congress takes action to roll it back. In recent years, Congress
has rolled back proposed cuts in physicians' fees on 2 occasions.
CMS said the cut was required because spending on doctors'
services was increasing faster than expected, and faster than the annual goals set
by a statutory formula.
■
New laser treatment. Lumenis Ltd., a global developer, manufacturer, and seller
of laser and light-based devices for a variety of applications, said it has received
exclusive worldwide licensing rights for SRT, a new laser therapy for selectively
treating retinal diseases.
Lumenis notes that while conventional laser treatments can be
effective in slowing down the progression of disease, they seldom restore or improve
visual acuity in the area treated due to the non-discriminating nature of the laser
burn. In contrast, Lumenis says SRT is a novel technology that selectively targets
and confines the treatment to specific cells at the back of the retina. Because
there is little heat generated, the surrounding photoreceptors are left undamaged.
■ Allergan
grant program. Allergan, Inc. has created the Allergan Horizon Grant Program, through
which Allergan plans to contribute $1 million over 2 years. The program was established
to provide awards to academic medical institutions to support fellows seeking to
develop careers in academic medicine. These awards will fund fellowship programs
that conduct clinical research in the diagnosis or pharmacological treatment of
glaucoma, corneal, and retinal diseases. Grant applications should be submitted
by the department chair, division chief or fellowship director of the academic institution
and must be received by Allergan Medical Affairs, 2525 Dupont Drive, Irvine, Calif
92612, no later than Sept. 30, 2006.
■ Preserved Kenalog warning. A recent alarming increase in reported cases of sterile endophthalmitis associated with the intravitreal injection of preserved Kenalog
is causing concern to retinal specialists.
Some doctors who have experienced almost no endophthalmitis
from intravitreal preserved Kenalog injections in past years are now reporting rates
as high as 15%. Bristol-Myers Squibb, the maker of the drug, says that there have
been no changes in its manufacturing procedures. The company is conducting tests
and has requested additional information from doctors
For now, doctors are advised to use preservative-free triamcinolone
from a compounding pharmacy.
OSI Cuts Back Eyecare
Research
Company Cites
Declining Macugen Sales.
JERRY
HELZNER, SENIOR EDITOR
With sales of its wet AMD drug Macugen expected to continue to fall in the face
of strong competition from off-label use of Genentech's Avastin and recently approved
Lucentis, OSI Pharmaceuticals has responded to the realities of the marketplace
and suspended or curtailed some of its eyecare research. The company said there
is no guarantee that suspended research efforts will resume.
However, the company will go forward with its recently announced
phase 4 LEVEL study to determine Macugen's effectiveness as a maintenance therapy
for wet AMD after initial treatment with one of the Genentech drugs. OSI will also
continue to fund research for Macugen in diabetic retinopathy and central retinal
vein occlusion.
In connection with the suspension/curtailment of research, the
company has taken a $319 million goodwill impairment charge, which amounts to more
than $5 for each outstanding share of OSI. The charge represents the value OSI had
placed on the future stream of eyecare products arising from the research capabilities
of Macugen developer Eyetech, which OSI acquired in 2005. OSI said that it believes
the long-term value of the Macugen franchise itself had not been impaired and would
not be written down.
OSI CEO Colin Goddard, PhD, had hinted in recent months that a
continuing decline in Macugen sales would cause the company to re-evaluate its financial
commitment to eye care. In the 3 months ending June 30, U.S. sales of Macugen amounted
to $36.7 million, compared to $50.5 million in the first 3 months of the year, a
quarter-over-quarter decline of more than 25%. Analysts have been persistent in
questioning Dr. Goddard about the company's plans for continuing to fund its slumping
eyecare business, as OSI has promising franchises in both oncology and diabetes.
OSI shocked Wall Street last year when it paid more than $650
million in cash and stock to acquire Eyetech. OSI shares dropped sharply when news
of the planned acquisition was first announced as investors recognized that Lucentis,
then in late-stage clinical trials, had already demonstrated a major efficacy advantage
over Macugen.
Dr. Goddard had recently put forward several strategies designed
to revive Macugen sales. He has advocated the drug as part of a "1-2 punch" in treating
AMD, with Macugen serving as a maintenance therapy after initial treatment with
Avastin or Lucentis. He also emphasized Macugen's excellent safety profile and its
effectiveness when used in the early stages of wet AMD.
Some studies have confirmed that these approaches are valid. However,
OSI's promotion of these strategies has not thus far been enough to overcome the
greater efficacy offered by Avastin and Lucentis.
The key LEVEL trial using Macugen for maintenance will continue.
"Next-Generation" Wet AMD Drug?
Lpath
Developing Drug with Multiple Mechanisms.
JOHN
PARKINSON, ASSOCIATE EDITOR
In the 6 years since the start of the 21st century, major advances have been made
in the treatment of wet AMD. Now, a startup company, Lpath Inc., is developing a
drug that it says is potentially part of a platform of "next-generation" antiangiogenesis
drugs.
This small, publicly traded San Diego-based company has developed
Sphingomab — a drug indicated for the treatment of wet AMD. Specifically, the
drug targets sphingosine-1-phosphate (S1P), a bioactive lipid, which has been
found to contribute to tumor angiogenesis. Sphingomab is the first monoclonal antibody
to be synthesized against a lipid target.
Ophthalmologist Glenn L. Stoller, MD, heads Lpath's ocular division
and says the drug not only targets angiogenesis, but also inhibits scar formation
and combats inflammation. Dr. Stoller adds that these multiple mechanisms —
if proven efficacious in humans — would differentiate Sphingomab from any existing
wet AMD drugs on the market or in development, including Lucentis.
However, Dr. Stoller notes that any comparison between these 2
drugs would be premature at this point.
Dr. Stoller joined the company earlier this year because he was
excited about the science behind Sphingomab. "Bioactive lipids are unexplored targets
in ophthalmology and S1P appears to play an important role in many of the processes
that lead to AMD-related vision loss," he says. "Inhibiting S1P via Sphingomab appears
to be a promising novel approach toward treating exudative AMD."
While Lpath is in early development with its drug for wet AMD
— the company hopes to begin a phase 1 clinical trial in the middle part of
2007 — enthusiasm and expectations are high. "There's room for other players
in the field. I don't think innovation for treating AMD ends with the introduction
of Lucentis," says Dr. Stoller. "My
personal goal is to bring another valuable
therapeutic drug to our patients."
Sphingomab
was developed by Roger Sabbadini, PhD, chief scientific officer and founder of Lpath.
Initially, Dr. Sabbadini was targeting cardiovascular disease with this monoclonal
antibody, but later found that it may be efficacious for certain cancers and ocular
diseases. The company has given this biotech platform a brand name called ImmuneY2,
which can be defined as a series of technologies that, when combined, create antibodies
against bioactive lipids.
Also, in the company pipeline is another ImmuneY2-based drug referred
to as Lpathomab. This drug will target cancer and does not have any ocular indications,
according to the company.
Overall, the company's goal is to get through the clinical trials
with its ImmuneY2 platform drugs and bring them to market for multiple indications.
"We hope to develop a series of compounds that will demonstrate
both safety and efficacy in humans in a wide range of indications," explains Scott
Pancoast, president and chief executive officer. "With Sphingomab, this certainly
seems the case because it has shown in animals and preclinical studies efficacy
in different types of cancer, in AMD, and in post-myocardial infarction." Sphingomab
may also someday be indicated for other ocular indications, including diabetic retinopathy,
PVR, and modulation of post trabeculectomy scarring.
Looking to the longer term and assuming the company does get drugs
to market, Pancoast would be open to options, including creating a separate subsidiary
for the ocular division or a buyout.
Venture capital for the company was initially provided by Western
States Investment Group and additional financing has come from Johnson & Johnson
and Biogen Idec, as well as approximately 100 private investors. Lpath is also attempting
to secure Small Business Innovation Research (SBIR) grants from the federal government.
Retinal Physician, Issue: September 2006