December 2014, Issue 76

Gene Therapy:
The Next Frontier in Managing Exudative AMD

Irene Rusu, MD

Szilárd Kiss, MD

Weill Cornell Medical College, New York/Presbyterian Hospital, New York, New York

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents have revolutionized the treatment of neovascular age-related macular degeneration (AMD). With relatively frequent intravitreal anti-VEGF injections, patients can now expect to maintain and even improve visual function. However, the burden, on both the patient and the health care system, of these anti-VEGF injections is significant. Indeed, several recent studies suggest that patients treated with anti-VEGF therapy are monitored less frequently and receive significantly fewer injections in clinical practice compared with patients in major clinical trials.^1,2 These less frequent dosing and follow-up strategies may, in turn, lead to inferior visual acuity results in the real world setting. As such, an intense area of AMD research has focused on sustained delivery of anti-VEGF agents. One approach to continuous delivery of anti-VEGF agents is that of ocular gene therapy.

In many ways, the eye is ideally suited for gene therapy: it is a relatively small organ that is immune privileged and has well-defined and well-characterized diseases (e.g. AMD) that benefit from prolonged therapy. The concept of gene therapy lies in delivering a non-pathologic viral vector that carries a payload of genetic information (e.g. RNA or DNA) encoding a therapeutic protein. Once that vector delivers its payload to a specific cell, the machinery inside the cell transcribes the genetic information and produces the therapeutic molecule at a constant rate for an indefinite amount of time. Theoretically, a single injection with gene therapy could replace the multitude of anti-VEGF injections for the treatment of AMD.

Our group hypothesized that a single intravitreal administration of adeno-associated virus (AAV) vector expressing bevacizumab (Avastin, Genentech/Roche) would result in persistent intraocular expression of bevacizumab and suppress VEGF-induced neovascularization. We constructed an AAV rhesus serotype rh.10 vector to deliver bevacizumab (AAVrh.10BevMab)³ and demonstrated that a single administration of AAVrh.10BevMab provides long-term suppression of ocular neovascularization in a mouse model of AMD. Non-human primate studies with AAVrh.10BevMab are currently in progress; over 2 years following a single intravitreal injection with AAVrh.10BevMab, bevacizumab can still be detected in the vitreous of non-human primates.

While bevacizumab gene therapy is likely several years away, safety, tolerability and efficacy data from phase 1 clinical trials were reported recently for two other gene therapy approaches for the treatment of AMD. Avalanche Biotechnologies in Menlo Park, CA is developing AVA-101, an AAV2 vector that contains a gene encoding sFLT-1, a naturally occurring anti-VEGF protein with high natural binding affinity to VEGF. When administered in a subretinal fashion, the vector is expressed by the host retinal cells to produce sFLT-1 protein which inhibits the formation of new blood vessels and reduces vascular permeability by binding and blocking VEGF activity. In a recently reported phase 1 study presented at the 2014 ASRS Meeting, AVA-101 was reported to be well-tolerated with no significant vector-related or procedure-associated safety concerns.⁴ Patients who received AVA-101 gained or maintained vision with minimal or no need for rescue treatment at one year. Patients, all of whom were treated with numerous anti-VEGF injections prior to enrollment, were treated with AVA-101 and needed only a mean of 0.33 injections out of 12 rescue opportunities. In the 8 treated patients, out of a total of 72 rescue injection opportunities, only 2 injections were required. AVA-101 is currently being studied in a phase 2a trial with results expected in mid-2015.

Genzyme Corporation in Cambridge, Massachusetts has developed a novel, chimeric anti-VEGF molecule, sFLT01, delivered by intravitreal injection of an AAV2 vector (AAV2-sFLT01). The transgene product of AAV2-sFLT01 is a hybrid molecule comprised of domain 2 of Flt-1 (VEGF-R1) linked to a human immunoglobulin G1 (IgG1) heavy chain Fc fragment. The molecule forms a forced homodimer that binds with high affinity to VEGF. At the 2014 Retina Society meeting, it was reported that, in a phase 1 dose escalation study, intravitreally injected AAV2-sFLT01 is safe and well tolerated.⁵ Biological activity was noted in 4 of 11 “expected responders” as defined by the study investigators. Although the response rate with AAV2-sFLT01 was significantly less than that noted with AVA-101, both phase 1 studies reinforce the clinical feasibility of a gene therapy approach for the long-term treatment of exudative AMD.

Available data suggest that gene therapy for the long-term treatment of exudative AMD is possible. The encouraging results from two recently presented phase 1 trials need to be followed up with longer-term safety, tolerability and efficacy studies.

References:
1. Kiss S, Liu Y, Brown J, Holekamp NM, Almony A, Campbell J, Kowalski JW. Clinical monitoring of patients with age-related macular degeneration treated with intravitreal bevacizumab or ranibizumab. Ophthalmic Surg Lasers Imaging Retina. 2014 Jul-Aug;45(4):285-91.
2. Holekamp NM, Liu Y, Yeh WS, Chia Y, Kiss S, Almony A, Kowalski JW. Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration. Am J Ophthalmol. 2014 Apr;157(4):825-833.
3. Mao Y, Kiss S, Boyer JL, Hackett NR, Qiu J, Carbone A, Mezey JG, Kaminsky SM, D'Amico DJ, Crystal RG. Persistent suppression of ocular neovascularization with intravitreal administration of AAVrh.10 coding for bevacizumab. Hum Gene Ther. 2011 Dec;22(12):1525-35.
4. Jeffrey S. Heier. Gene Therapy for Exudative AMD: One-Year Results of Phase 1 Clinical Trial with rAAV.sFLT-1. Presented at the 2014 Annual Meeting of the American Society of Retinal Specialists, San Diego, CA.
5. Jeffrey S. Heier. Preliminary Results of Phase I Study with AAV2-sFLT01 as Gene Therapy for Treatment of Exudative AMD. Presented at the 2014 Annual Meeting of The Retina Society, Philadelphia, PA.

Dr. Kiss is a consultant for Allergan, Genentech, Regeneron, and Avalanche and receives research funding from Genzyme, Genentech, Regeneron, and Allergan.