Gene therapies hold promise for treating blindness
Gene therapies for ocular disorders are close to becoming a reality, with a number of firms testing new treatments, according to Dr Jay Duker, co-founder of Hemera Biosciences. His firm is carrying out the first human trials of HMR59, a gene therapy for advanced dry age-related macular degeneration, with results set to be available in the coming months. Additionally, Spark Therapeutics recently completed a phase 3 clinical trial of its product Luxturna, which aims to treat inherited retinal disease.

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Genetic therapies offer new pathways for ophthalmic disorders

Biotechnology companies such as Hemera Biosciences, Spark Therapeutics and AGTC have several ophthalmic treatments in the clinical pipeline.

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Genetic therapies for ophthalmic disorders such as inherited retinal dystrophies are moving forward in the field and taking steps toward becoming a clinical reality.

The future of gene therapy in retinal disease is a bright one, with many gene therapy companies offering exciting possibilities, Jay S. Duker, MD, a co-founder of Hemera Biosciences, a privately held biotech company, told Ocular Surgery News.

“Gene therapy is being tested in many organ systems, but the retina is one of the best organs in the body to consider gene therapy for several reasons. First, the eye is relatively isolated from an immunologic view. This makes inflammation less of an issue. Second, the ordered topography of the retina is an advantage. Third, the eye volume is such that relatively small amounts of material are needed to treat an eye. Finally, we have many tests of structure and function that are safe and easy to perform in the office to determine the effectiveness of the gene therapy,” he said.

Therapies in the pipeline

Hemera Biosciences is developing anti-complement therapies delivered via gene therapy. Its lead product, HMR59, is an AAV2-based gene therapy designed to be injected intravitreally into the eye in an office setting to treat advanced dry age-related macular degeneration, according to Duker, an OSN Retina/Vitreous Board Member. This is the first gene therapy for dry AMD ever tested in humans.

Jay S. Duker

The therapy induces intraocular cells to produce a solubilized form of a naturally occurring protein blocker of membrane attack complex, “the final step in the complement cascade,” he said.

“The phase 1b dose-escalating trial of HMR59 in eyes with severe geographic atrophy from dry age-related macular degeneration is fully enrolled. Initial safety results should be available this fall or early winter. A phase 2 multicenter placebo-controlled trial of HMR59 is in the advanced planning stages,” Duker said.

Duker also noted that Spark Therapeutics is anticipated to receive FDA approval for Luxturna (voretigene neparvovec), a gene therapy treatment of confirmed biallelic RPE65-mediated inherited retinal disease.

Katherine A. High, MD, co-founder, chief scientific officer and president of Spark Therapeutics, told Ocular Surgery News that Luxturna has completed a phase 3 clinical trial. The therapy began a phase 1 clinical trial in 2007, she said, before the creation of Spark Therapeutics in 2013.

The gene therapy was developed when High was the director of the Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia (CHOP). Because the hospital was not in the business of licensing products, a decision had to be made for the future of Luxturna, she said.

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“We considered a number of options, including partnering with a biotech or a pharmaceutical company, but most had very little experience with gene therapies. This was an ultra-rare indication, and sometimes ultra-rare indications can be lost in the shuffle of a big company. After a lot of deliberation, we made the decision to spin out an independent company from our unit at CHOP. The unit employed about 80 people; when we spun out, we took a number of those people and added a number of other individuals. The company, even though it was formed in 2013, had a running start. When it was formed, we had an asset in phase 3. That’s unusual,” High said.

Targeting inherited retinal dystrophies

Spark Therapeutics has two additional ocular gene therapies in the pipeline. High said SPK-7001 has been advanced to an open-label, dose-escalated phase 1/2 trial to assess the safety and preliminary efficacy of subretinal administration for choroideremia. The company is also investigating a preclinical gene therapy for the treatment of Leber’s hereditary optic neuropathy.

“Gene therapy has a great deal to offer in the area of inherited retinal dystrophies. This has been a target tissue that has really not been amenable, for example, for repeated protein administrations. It hasn’t been amenable for small molecule therapy, either. So, I think that presents a niche for gene therapy. It’s interesting to me because vision is one of the most complex mechanisms in the body, with over 250 genes involved. Of course, most of these don’t have treatments, and so I believe we should be able to leverage the work that we’ve done in RPE65 and take advantage of the lessons learned to shorten clinical development timelines,” High said.

Since its creation, Spark Therapeutics has secured $1 billion in financing to support the growth of its clinical programs and platforms, according to the company website.

Bright future

Applied Genetic Technologies Corporation (AGTC), a publicly traded company developing gene therapies for rare lung and eye diseases, also has several therapies in clinical trials. One, a phase 1/2 trial, will evaluate the safety and efficacy of recombinant adeno-associated virus vector expressing retinoschisin for the treatment of X-linked retinoschisis, according to the company.

According to a company investor presentation given in August, AGTC reported it had $148.7 million in cash and investments as of March 31 and $135 million to $140 million expected at the fiscal year end on June 30. This will allow the company to complete enrollment and analysis for the phase 1/2 trials of X-linked retinoschisis and achromatopsia.

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Gene therapy for ophthalmic disorders is bright, and the future offers some exciting advancements for retinal diseases, Duker said.

“As mentioned, we should have an FDA-approved gene therapy for one form of inherited retinal dystrophy soon. Other corrections of mutations will follow. Drug delivery via gene therapy will not be too far behind. The future will include more retinotrophic viral vectors, allowing for better gene delivery, as well as some non-viral vectors,” he said. – by Robert Linnehan

References:

Our scientific programs and platforms. Spark Therapeutics. http://sparktx.com/scientific-platform-programs/. Accessed Sept. 12, 2017.

Products. Applied Genetic Technologies Corporation. https://www.agtc.com/products. Accessed Sept. 14, 2017.

Russell S, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)31868-8.

Safety and efficacy of rAAV-hRS1 in patients with X-linked retinoschisis (XLRS). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02416622. Updated Aug. 31, 2017. Accessed Sept. 13, 2017.

Treatment of advanced dry age related macular degeneration with AAVCAGsCD59. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03144999. Updated May 16, 2017. Accessed Sept. 13, 2017.

Visionary Science for Life Changing Cures 2017. Applied Genetic Technologies Corporation. http://files.shareholder.com/downloads/AMDA-2H6BI7/5243637568x0x954037/4044D075-C3ED-483E-9DCC-466D012B14A7/AGTC_Summer_2017_Investor_Presentation.pdf. Published Aug. 15, 2017. Accessed Sept. 14, 2017.

For more information:

Jay S. Duker, MD, can be reached at New England Eye Center, 800 Washington St., Box 450, Boston, MA 02111-1533; email: jduker@tuftsmedicalcenter.org.

Katherine A. High, MD, can be reached at Spark Therapeutics, 3737 Market St., Suite 1300, Philadelphia, PA 19104; email: kathy.high@sparktx.com.

Disclosures: Duker reports he is a co-founder of Hemera Biosciences. High reports she is co-founder, chief scientific officer and president of Spark Therapeutics.