Article Date: 11/1/2011

Is the 0.5-mg Lucentis Dose Best?
SUBSPECIALTY NEWS

Is the 0.5-mg Lucentis Dose Best?

Studies: No vision improvement with 2-mg dosing.

■ Twelve-month data from Genentech's four-arm 1,098-patient HARBOR trial indicates that a 2-mg dose, delivered either monthly or PRN, is not quite as effective as the approved 0.5-mg dose delivered monthly in improving vision.

The results, released at the recent AAO meeting, showed the 0.5-mg dose of Lucentis delivered monthly was the most effective dosage, providing a mean improvement in VA from baseline of 10.1 letters. The 2-mg dose given monthly demonstrated a mean improvement of 9.2 letters, while 0.5-mg PRN showed a mean gain of 8.2 letters and 2-mg PRN provided a mean gain of 8.6 letters.

None of the four arms achieved their superiority or non-inferiority benchmarks.

In the READ3 trial using Lucentis for DME, new six-month results showed little difference in effectiveness between 0.5-mg and 2-mg dosing. Visual acuity and central retinal thickness changes were maintained to the one-year evaluation, said Quan Nguyen, MD, of the Wilmer Eye Institute, though patients receiving the 2-mg dose on average required 1.3 fewer injections at one year.

In the READ3 study, the primary endpoint at six months was the mean

change in the visual acuity; the secondary endpoint was the change in retinal thickness. All patients received six injections of the drug until month 6; from months 6 to 24, patients can receive additional treatment on an asneeded basis if the central retinal thickness exceeds 250 µm.

Dr. Nguyen reported that at six months the 2-mg group had a mean increase of 7.5 letters of visual acuity, and the 0.5-mg group had a mean increase of 8.7 letters. Both groups also had a rapid and sustained decrease in the retinal thickness from baseline to month 6.

siRNA Drugs May Harm the Retina

Dr. Ambati warns of concerns with a new drug class.

■ According to new studies by University of Kentucky researchers, an emerging pharmaceutical platform used in treating a variety of diseases may produce unintended and undesirable effects on eye function. The paper, “Short-interfering RNAs Induce Retinal Degeneration via TLR3 and IRF3,” appeared in a recent online edition of the journal Molecular Therapy.

“Short-interfering RNA (siRNA) technology has been regarded as one of the most exciting emerging platforms for new pharmaceuticals,” said Jayakrishna Ambati, MD, PhD, professor of physiology, and professor and vice chair of ophthalmology and visual sciences at UK.

To this point, siRNA drugs have been the subject of clinical trials past and present for a variety of disorders including: cancers, viral respiratory infections, hypercholesterolemia, macular degeneration, diabetic retinopathy and glaucoma. Major obstacles to realizing the therapeutic potential of siRNAs include delivery of the drug into cells and a generic suppression of blood vessel growth through immune activation, as shown by a 2008 paper from the Ambati group in the journal Nature.

“We now show a new undesirable effect of siRNAs that are 21 nucleotides or longer in length: these siRNAs, regardless of their sequence or target, can cause retinal toxicity,” asserts Dr. Ambati.

By activating a new immune pathway consisting of the molecules TLR3 and IRF3, the Ambati team contends that these siRNAs damage the retinal pigmented epithelium.

“Damage to the RPE cells by siRNAs can also lead to secondary damage to the rods and cones, which are light-sensing cells in the retina,” said Dr. Ambati.

The scientists' findings indicate that caution should be applied when designing or using siRNAs intended for either direct application to the eye, or intended for use in a way that may allow the drug to access the eye.

“Another novel aspect of this research is that the RPE degeneration caused by siRNAs resembles the pathology seen in geographic atrophy due to advanced AMD,” continued Dr. Ambati. “As there are few models of geographic atrophy, which affects millions of people worldwide, this paper provides an important advance for research in developing new treatments for this disease.”

Because the research shows that siRNAs shorter than 21 nucleotides in length can evade the TLR3-IRF3 offtarget immune response, it may be possible to achieve therapeutic effects without retinal damage by designing shorter siRNAs, the University of Kentucky researchers concluded.

A Look at the 2011 PAT Survey Results

Samantha Stahl, Assistant Editor

■ The 2011 Preferences and Trends (PAT) Survey indicated particular focus on anti-VEGF treatment and a continuing shift towards vitrectomy for retinal detachments.

The 2011 data was generously provided by the American Society of Retinal Specialists and the survey's editor, J. Michael Jumper, MD. The ASRS received responses from more than 380 members.

Unsurprisingly, a hot topic this year pertained to the one-year results of the CATT study. “It was interesting to note that 60% of respondents continue to use a ‘treat and extend’ protocol when following their patients with wet AMD, compared to 32% who follow monthly and treat when active,” says Dr. Jumper.

When asked of their current management of a 70-year-old patient with a subfoveal CNV lesion size 1 disc area, 20/100 vision, 70.63% of respondents said they treated with Lucentis, while 26.94% preferred Avastin.

In another survey question, 73.24% reported that regardless of the CATT study results, they continue using the same neovascular AMD treatment on existing patients they were using prior to the trial, whereas 7.3% of respondents switched from Lucentis to Avastin. 15.57% continued using Avastin exclusively, 3.16% continued using Lucentis exclusively and less than 1% switched from Avastin to Lucentis.

Respondents were divided on whether or not they believe that the United States government should expand the CATT study to compare Lucentis and Avastin for diabetic macular edema — 53% of those polled said yes, 46% said no — and edema from retinal vein occlusion, with 46% saying yes and 53% no.

Bilateral simultaneous anti-VEGF injections for wet AMD have grown in popularity as more retina specialists gain experience with the treatment and an increased number of patients require bilateral treatment. While only 27% of respondents in 2008 said they perform bilateral simultaneous anti-VEGF injections, this year's survey saw a huge jump up to 55% of respondents.

The survey revealed that 61% of respondents prescribe prophylactic topical antibiotics after intravitreal anti-VEGF injection. “It will be interesting to follow this trend given recent data to suggest that this practice may lead to bacterial resistance,” says Dr. Jumper. Only 27% of those polled said they use prophylactic topical antibiotic drops or ointment prior to injections.

Now that retina specialists have several years of experience with anti-VEGF agents, he notes an interesting question on the use of AREDS vitamins for a patient with bilateral wet AMD, good vision, and perifoveal pigment atrophy. Despite lack of evidence that the formulation is helpful for wet AMD, 75% of respondents reported that they would continue recommending use of AREDS. “This suggests that we are now seeing vision loss from dry AMD in patients with well-controlled wet AMD,” says Dr. Jumper.

Answers were mixed concerning the percentage of retinal detachment cases that use a scleral buckle, with 21.56% reporting placing in 0-10% of cases, 23.65% in 11-20% of cases, 17.07% in 21-40% of cases, 11.08% in 41-60% of cases and 25.75% in more than 60%. Less than 1% said they never place a scleral buckle.

“Regarding the management of retinal detachment, there has been a shift away from scleral buckling alone and toward vitrectomy over the past several years. We have repeated a question regarding the management of a phakic, inferior detachment,” notes Dr. Jumper.

The survey asked, “For a 65-year-old phakic RD, -3.00 myope, 1 ½ clock-hour size flap tear at 6:00 anterior to equator, 45% detached, macula-on, fellow eye pseudophakic, I usually recommend: Scleral buckle, vitrectomy, vitrectomy with buckle or pneumatic retinopexy.” In 2004, 72% said they would treat with scleral buckle alone. This year, only 42% treated with a buckle alone. While in 2004 only 7% of respondents would have repaired the phakic, inferior detachment with vitrectomy, the number has gone up to 27% this year. The combined use of scleral buckle and vitrectomy increased from 20% in 2004 to 30% this year. RP

IN BRIEF

Early data on new DME therapy. Allegro Ophthalmics, announced promising results from a small phase 1 study using integrin peptide therapy to treat DME. The study focused on determining safety and initial efficacy of this new class of treatment in an open-label, single-dose study. All 15 of the enrolled patients had end-stage DME, with visual acuity of 20/100 or worse. Many of these patients were refractory to current treatment options and exhibited the onset of diabetic retinopathy.

Results presented at the recent AAO annual meeting showed that eight of the 15 patients in the trial demonstrated three to five lines of BCVA improvement after 90 days, and a definitive improvement in OCT central macula thickness. Those patients who did not respond to treatment did not experience any disease progression during the trial. Additionally, the clinical benefit lasted until the end of the trial, equating to 90 days of treatment.

Integrin peptide therapy is an emerging new class of treatment for vascular eye diseases. Based on a small molecule discovered by Allegro Ophthalmics' founders in collaboration with CalTech, ALG-1001 works upstream from current anti-VEGF treatments by binding to multiple integrin-receptor sites and affecting multiple angiogenic pathways.

Imagen has funding and management team. Imagen Biotech secured up to $40 million in Series A financing from SV Life Sciences, Novo Ventures and Fidelity Biosciences to pursue the identification and development of new treatments for blinding diseases with high unmet medical needs, including dry AMD.

Matthew Feinsod, MD, formerly at Eyetech Pharmaceuticals and currently a medical officer in the FDA's Ophthalmology Division, will lead these efforts as Chief Medical Officer for Imagen. David Guyer, MD, former founder and CEO of Eyetech Pharmaceuticals and current partner at SV Life Sciences, will serve as the Executive Chairman of Imagen. Scott Cousins, MD, professor of Ophthalmology and Director of the Duke Center for Macular Diseases, is Chief Scientific Officer.

Imagen says it is actively screening a variety of promising compounds using rigorous criteria for scientific merit and commercial opportunity. “We continue to seek collaborations worldwide with companies, researchers, and institutions that have identified new pathways and/or compounds that might lead to a treatment for sight-threatening diseases with unmet needs, whether prevalent or rare,” says Dr. Feinsod.

Potential treatment for Usher Syndrome advances. Oxford BioMedica announced that the FDA has approved its Investigational New Drug application for the phase 1/2a clinical development of UshStat, a novel gene-based treatment for Usher syndrome type 1B.

The open-label, dose-escalation study will enroll up to 18 patients at the Oregon Health and Science University's Casey Eye Institute. The study will evaluate three dose levels for safety, tolerability and aspects of biological activity and is expected to be initiated by the end of 2011.

Usher syndrome is caused by a mutation of the gene encoding myosin VIIA (MY07A), which leads to progressive retinitis pigmentosa combined with a congenital hearing defect. UshStat technology delivers a corrected version of the MYO7A gene to address the vision loss associated with the disease.

On the basis of preclinical data, it is anticipated that a single application of UshStat to the retina could provide long-term or potentially permanent stabilization of vision. There are currently no approved treatments available for Usher syndrome type 1B.

Eylea has positive one-year-data in CRVO. Patients with DME secondary to CRVO who received asneeded injections of Regeneron's anti-VEGF therapy Eylea on average at one year were able to retain almost all of the vision gains they had achieved during the first six months of treatment.

Going from monthly 2-mg dosing of Eylea to PRN dosing, patients' median vision went from 17.3 letters to 16.2 letters, with 55% retaining gains of three lines or more. Patients who received sham injections lost visual acuity.


ERRATUM

The article "Microincision Vitrectomy Surgery for Diabetic Retinopathy" (October 2011) did not provide an up-to-date financial disclosure for Yusuke Oshima, MD, PhD. The correct statement is as follows: “Dr. Oshima receives lecture fees and travel support from Alcon Laboratories, Carl Zeiss Meditec, DORC International, Santen Japan and Senju Japan when he addresses their sponsored seminars, and consultant fees from Alcon and Topcon Medical Systems, but he has no proprietary interests or royalties from any companies in relation to any products mentioned in this article.”


Retinal Physician, Issue: November 2011