FDA: Arxxant Requires Another Trial
Lilly Intends to Appeal the Decision.
Eli Lilly and Company said it has decided to appeal a request by the FDA for an
additional, 3-year, phase 3 clinical trial for ruboxistaurin mesylate (Arxxant).
Arxxant has been considered a highly promising drug because, if approved, it would
be the first oral treatment for moderate-to-severe nonproliferative diabetic retinopathy
FDA said it wants additional efficacy data before it will consider approving Arxxant
for DR. Lilly believes that such a trial would require up to 5 years to complete.
The new request from the FDA follows Lilly's August announcement that it had received
an "approvable" letter from the FDA.
At the time Lilly received the approvable letter, the company
was hopeful that it could avoid a new trial by providing the additional clinical
data from 2 ongoing phase 3 clinical trials. Lilly has already signed a long-term
agreement to co-promote Arxxant with Alcon. However, the agreement is contingent
upon FDA approval of the drug.
"We are certainly disappointed with this communication from the
FDA. Diabetic retinopathy is a significant unmet medical need to which we have devoted
more than a decade of clinical research with no guarantee of approval," said John
Lechleiter, PhD, president and chief operating officer of Eli Lilly and Company.
"We still believe that ruboxistaurin has potential as a treatment for diabetic eye
disease and are exploring the feasibility of further development of this molecule,"
clinical trials for Arxxant will continue while Lilly evaluates its options for
further development of the drug.
Arxxant is a specific protein kinase C beta (PKC) inhibitor and
is the first of a new class of compounds being investigated for the treatment of
DR, diabetic peripheral neuropathy, and diabetic nephropathy. PKC is a signaling
enzyme in the body and overactivation has been linked to the underlying process
of microvascular damage caused by diabetes. While tight blood sugar control lowers
the risk of diabetic microvascular damage, there are currently no oral medications
approved in the United States to treat DR. According to the World Health Organization
and the American Diabetes Association, DR is the leading cause of vision loss in
adults 20 to 74 years old in industrialized countries.
Lilly had previously said that pooled data from 2, 3-year phase
3 trials involving 813 patients showed that 32 mg of Arxxant daily reduced the risk
of sustained moderate vision loss by 41% when compared to placebo in patients with
moderate-to-severe nonproliferative DR. Vision loss occurred in only 6.1% of patients
treated with Arxxant compared to 10.2% of patients treated with a placebo. Vision
loss was defined as a 3-line loss on the eye chart that was sustained for at least
Investigators found that Arxxant was generally well tolerated
and had an overall adverse event profile, as well as a serious adverse event profile,
similar to placebo.
Arxxant was submitted to the FDA in February 2006 and subsequently
was granted priority review. The August approvable letter from the FDA requested
additional efficacy data to support the clinical evidence presented by Lilly in
its New Drug Application (NDA). The latest announcement results from ongoing communication
between Lilly and the FDA to determine if the additional evidence could come from
ongoing trials or if a new trial would be required.
At this time, Lilly does not intend to withdraw the NDA, because
withdrawal would require restarting the review process, should Lilly ultimately
move forward with development of Arxxant.
Avastin vs Lucentis
Study Gets OK
Fund 2-Year Trial.
A head-to-head study comparing the efficacy and safety of 2 Genentech drugs, Lucentis
and Avastin, as treatments for wet AMD now has the financial support of the National
Institutes of Health (NIH). There have been many calls for such a study due to the
fact that Lucentis costs approximately $1,950 an injection and Avastin can be given
for less than $100 an injection.
The National Eye Institute, part of the NIH, will finance the
study. The trial is expected to cost approximately $16 million and involve up to
to 1200 patients, who are expected to be divided into 4 groups.
NIH sources said 1 group would be given Lucentis injections every
4 weeks. A second group would receive Avastin every 4 weeks. The other 2 groups
would get either Lucentis or Avastin on an as-needed basis, with retreatements determined
by OCT measurements. In the recently completed PrONTO study, the use of OCT measurements
to determine retreatment resulted in most patients requiring approximately 5 to
6 injections per year. Patients will be followed for 2 years.
Before Lucentis won US regulatory approval in June, numerous retina
specialists began using Avastin to treat wet AMD because it has a similar molecular
structure to Lucentis and could be used off-label as an intravitreal injection.
Avastin is an FDA-approved systemic colorectal cancer treatment. Since Lucentis
was approved, many doctors have switched to that drug, particularly for patients
with good insurance coverage.
In related news, Genentech said that Lucentis sales in the quarter
ended Sep. 30 far exceeded analysts' forecasts. Lucentis, which is rapidly being
adopted as a first-line treatment for wet AMD, had sales of $153 million, while
Wall Street was looking for $35 to $45 million.
Will Share in Development Costs.
Bayer HealthCare and Regeneron Pharmaceuticals, Inc. announced that the companies
have entered into a collaboration agreement for the global development, and commercialization
outside the United States, of VEGF Trap for the treatment of eye disease by local
administration, specifically intravitreal injection. VEGF Trap, currently in phase
1 and 2 clinical trials, is a protein that binds to or "traps" vascular endothelial
growth factor (VEGF) and blocks its activity. VEGF is thought to play a critical
role in certain eye diseases, particularly the wet form of AMD.
Regeneron, which has been developing the drug, will retain all
rights to the commercialization of VEGF Trap within the United States.
Retinal Physician reported in its September/October issue
that Regeneron was in active talks with potential partners for VEGF Trap. This interest
intensified following the report of highly promising phase 1 trial results for VEGF
Trap and positive comments from leading retina specialists.
Under the agreement, Bayer and Regeneron will collaborate on the
development of VEGF Trap through an integrated global plan that encompasses wet
AMD, diabetic eye diseases, and other eye diseases and disorders. The companies
will jointly commercialize VEGF Trap-Eye outside the United States and will share
equally in profits from ex-US sales. Regeneron will retain 100% of all profits from
Bayer will make an upfront payment of $75 million to Regeneron
and the 2 companies will share the global development costs, expected to total more
than $250 million over the next several years.
Phase 2 Data on AMD Drug
and Duration of Response Are Encouraging.
Acuity Pharmaceuticals, a clinical stage ophthalmic pharmaceutical company, has
announced positive results from its phase 2 CARE trial for bevasiranib sodium (formerly
Cand5), Acuity's lead compound for the treatment of wet AMD. Bevasiranib is a first-in-class
small interfering RNA (siRNA) therapeutic designed to silence the genes that produce
vascular endothelial growth factor (VEGF).
The CARE study was a randomized, double-masked trial that included
3 dose levels of bevasiranib tested in 129 patients with wet AMD at 28 sites nationwide.
The study focused on patients with serious disease, classic or active minimally
classic AMD, including those patients who had failed previous treatments.
Acuity reports that all doses were well tolerated and most adverse
events mild and related to the administration (intravitreal injection) procedure.
There were no systemic adverse events observed. In 2 separate bevasiranib clinical
trials, there was no systemic bevasiranib exposure in patients.
"Bevasiranib is a promising new agent that has now demonstrated
encouraging potential in this first large-scale study in wet AMD patients with aggressive
disease," said Lawrence Singerman, MD, founder and executive secretary of the Macula
Society, clinical professor of ophthalmology at Case University, and a principal
investigator for the study at its Cleveland site. "Bevasiranib's excellent safety
profile, its demonstrated ability to inhibit the growth of choroidal neovascular
lesions, and its potential for prolonged duration of effect warrant proceeding to
Visudyne sales drop. Global sales of QLT's Visudyne therapy for wet AMD totaled
$75.1 million for the quarter ended Sept. 30. This represents a decrease of 39.3%
over sales in the third quarter of 2005 and a 21.2% decline compared to the second
quarter of 2006. Visudyne sales in the United States for the quarter were approximately
$11.0 million, compared to $18.9 million for the June quarter.
"The decline in Visudyne sales has been more rapid than anticipated
and as a result we are lowering our 2006 annual Visudyne sales range from the previous
range of $370 million to $385 million, to a new range of $340 million to $355 million,"
said Bob Butchofsky, president and CEO of QLT Inc. "Forecasting product sales in
a market undergoing the kind of significant transformation that we see in age-related
macular degeneration is very difficult and we are disappointed at having to reduce
our annual guidance. However, we continue to believe that Visudyne will remain an
important part of treatment regimen for AMD and that combination therapy with Visudyne
is the future for AMD treatment."
PASCAL data. Julia Haller, MD, professor of ophthalmology at Wilmer Eye Institute
of Johns Hopkins Medical Center, has presented new data demonstrating that the Pascal
photocoagulator from OptiMedica, Inc., offers substantial advantages compared to
conventional photocoagulation. These advantages include increased speed, precision,
and patient tolerance.
In a presentation titled, "Initial Clinical Experience with a
Patterned Scanning Laser (PASCAL) for the Treatment of Retinal Diseases," Dr. Haller
reported on a pilot study of 10 eyes comparing Pascal photocoagulation to conventional
photocoagulation. Patients were treated for proliferative diabetic retinopathy and
diabetic macular edema at Wilmer Eye Institute. The study demonstrated increased
uniformity and precision of spot placement, substantially reduced treatment time,
and considerably improved patient tolerance in the treatment of proliferative diabetic
retinopathy with Pascal photocoagulation.
Dr. Haller also discussed the collective experience of Pascal
laser photocoagulation treatments conducted at 5 leading research institutions.
"We have now treated more than 1,200 patients and our experience has shown that
the Pascal system performs as well as conventional single-spot delivery lasers in
terms of efficacy and lack of complications, but far better in terms of physician
and patient acceptance" she said.
Retinal Physician, Issue: November 2006