Can you provide an overview of the unmet medical need Ocugen is pursuing in ophthalmology?

Ophthalmology represents a huge unmet medical need particularly in the many diseases affecting the back of the retina. A treatment for many of these diseases are either nonexistent or there is a significant population of non-responders to available therapies, representing a large, underserved population. For example, dry age-related macular degeneration, which leads to irreversible blindness due to degeneration of the retina, has no available treatment and an estimated US patient population of 9 to ten million. For other retinal diseases, such as Retinitis Pigmentosa or Leber Congenital Amaurosis, there are no available treatments. We focus on these areas because we can help a large population of patients who do not have access to any treatments.

What compelled Ocugen to take on COVID-19 vaccine development?

The analogy I favor is, if you are a soldier in a war, you do not want to sit on the sidelines. In the COVID space, irrespective of who you are, if you have the expertise and network, you need to contribute your skills to overcome this pandemic. We looked into the US landscape and noticed that all of the vaccines are based only on the spike protein. I have had a longstanding relationship with Bharat Biotech, and one of the vaccines they developed, which was funded by the Gates Foundation, is their rotavirus vaccine. It has done extremely well globally, and to date Bharat has developed over 16 vaccines, dosing billions of people. The COVID-19 vaccine, known as COVAXIN® is developed in collaboration with the Indian Council of Medical Research, which is equivalent to the NIH in the US. This whole-virion vaccine works by taking the virus, growing it, inactivating it chemically, like the polio virus, and add adjuvants. The inactivated virus is a proven technology platform that has been used for several licensed vaccines including influenza, polio, rabies, JEV, etc. and has historically demonstrated acceptable safety and efficacy in children and adults.

There are three components of the vaccine: one is safety, the second is efficacy, and everyone is focusing on these two. However, the most important is immunogenicity. You need to have very good neutralizing antibodies when you get the vaccine, so you block the infection, and eventually it tapers off. Cellular mediated responses are critical for memory. Therefore, if you are faced with infection in the future, memory triggers the immune response and activates B cells and neutralizing antibodies. 

We are pursuing submission of a biologics license application (BLA) for COVAXIN. We are in discussions with the FDA to understand the additional information required to support a BLA submission and anticipate that data from an additional clinical trial will be required to support the submission. We feel that a differentiated vaccine like COVAXIN is a critical tool to include in our national arsenal given its potential to address the SARS-CoV-2 variants, including the delta variant, and given the unknowns about what will be needed to protect US population in the long term.

How are you managing manufacturing challenges?

Bharat has launched 16 vaccines, and their platform is similar to what they have used to make polio virus vaccines for many years but securing US-based manufacturing capability was a critical step as we prepare to submit our regulatory submissions to the FDA and Health Canada. We have selected Jubilant HollisterStier of Spokane, Washington as our manufacturing partner for COVAXIN to prepare for potential commercial manufacturing of COVAXIN for the US and Canadian markets. Based on Bharat Biotech’s strong track record of developing and commercializing vaccines globally and Jubilant’s proven track record in manufacturing, we are well-prepared to transition US manufacturing of COVAXIN to our new manufacturing partner. 

How is Ocugen’s Modifier Gene Therapy platform a unique approach in ophthalmology?

If you look at Retinitis Pigmentosa, there are about 150 defective genes capable of causing the disease. That means some of the genes may have multiple mutations. Luxturna is the only product approved using a traditional gene therapy platform. It targets the RPE 65 gene. This is only one gene and covers 1,000 patients in the US out of 100,000. That took 8-10 years to develop. If you take that approach, it is almost impossible to develop 150 products to cover all of the gene mutations. Most of these patients become legally blind by the time they are in their mid-40s. There is a significant unmet need, and desperation from the patients’ perspective to treat this disease.

Ocugen’s modifier gene therapy platform represents a breakthrough innovation designed to address multiple diseases with one product. This novel approach targets nuclear hormone genes (NHRs), which regulate multiple functions within the retina. NHRs are higher up in the regulatory pathway where you have different functional networks in the retina, which are responsible for cell development, inflammation, all the way to cell survival. By targeting a functioning nuclear gene like an NR2E3, it upregulates all the functional networks associated gene expressions, resets homeostasis, and restores normal cell function.

Based on our modifier gene therapy platform, we received four orphan designations from FDA and orphan medicinal product designation for the treatment of both Retinitis Pigmentosa and Leber Congenital Amaurosis from the European Commission. Five different animal models, with a single subretinal injection, showed significant rescue from multiple endpoints we measured. People often ask if you give a broad therapy like this, will it cause any off-target effects? The answer is no. According to a review of the histology and immunochemistry, everything looked normal, and it appeared to be safe demonstrating the power of this platform.