Jeff Willis, MD, PhD is a Senior Medical Director and retina specialist at Genentech. He talks to Lu Rahman about some of the company’s work developing medicine for eye disease and offers insight into the ophthalmology field today.
Genentech is committed to advancing science and developing effective and innovative medicines for patients with serious eye diseases like geographic atrophy (GA). “We have a number of ongoing ocular programs that we believe will help us better understand the biology behind ophthalmic diseases and develop better treatment options for patients,” says Jeff Willis, Senior Medical Director.
“We are currently investigating RG6147, an anti-HtrA1 monoclonal antibody Fab fragment, in the Ph II GALLEGO study for GA. HtrA1 is a trimeric serine protease expressed by retinal pigment epithelium and horizontal cells in the retina. Blocking HtrA1 may delay progression of GA. We also have a new molecular entity RG6312 in a Phase I study for GA,” he reveals.
The company is also investing in platform technologies beyond currently available treatments like fragment antigen-binding (Fab) antibodies. “Specifically, we are looking for tools that allow us to not only expand the efficacy window through both new mechanisms of action or novel targets, but also seek to increase the duration of clinical effect,” he explains.
Genentech is also advancing diagnostic imaging technologies to yield data that will help identify patients who will respond better to certain treatments or who may need more treatment. “By using computational methods such as deep learning to analyse patient data, we hope to inform better clinical trial and therapeutic design. This information will provide a deeper understanding of the biology of each disease, allowing early intervention and preventing the loss of visual function,” says Willis.
Many of Genentech’s past studies, including work on lampalizumab have generated large amounts of data that have allowed it to better understand diseases like GA. “We’re now hoping to utilise these data for end-to-end deep learning so we can predict disease progression, find the right patients, and conduct better and faster studies, which gets us answers and solutions more quickly,” Willis explains. “For example, we’re evaluating the possibility of using the lampalizumab dataset to develop algorithms that can predict lesion growth for GA. If this is successful, it will hopefully lead to more streamlined GA trials in the future.”
Outside of the clinic the company is investing in novel imaging technologies that may reveal more about retinal biology and mechanisms of disparate retinal treatments. “Additionally, we are collaborating with investigators to collect biomarker data, including aqueous humour samples, so that we can better understand disease biology. This may ultimately provide us with insights into how to best deliver various therapies and optimise patient outcomes.”
Willis explains that the company is also looking to conduct more work in the natural history of retinal disease, hopefully to continue efforts like MACUSTAR to better understand earlier diseases like intermediate age-related macular degeneration (AMD). “Our ambition is to understand earlier endpoints that predict eventual progression to irreversible blindness, so that we can potentially develop treatments that prevent the development of these events. This will allow us to better characterise populations at risk for loss of visual function and hone-in on technologies that are more sensitive and specific in tracking these patients. Ultimately, being able to determine before an interventional study is started, who is at risk and who needs therapy, will inform clinical practice,” he adds.
Like any field, this one is not without challenges. “The first is how we identify which individuals are at risk for faster disease progression so we can also shift focus to disease prevention rather than waiting for a person’s disease to get worse. As we mentioned earlier, we are developing multiple technologies to address disease progression and to determine what new medicines or modalities are most appropriate for each individual,” Willis says.
Another challenge is the durability of existing and future medicines. “Developing a medicine that requires fewer injections over time will not only make it easier for patients and healthcare providers but will improve compliance and improve treatment outcomes in the real world. At Genentech, we are addressing ways to develop medicines and technologies that will allow patients to receive their medicines less frequently,” he adds.
From a research standpoint, Willis says finding translatable animal models for diseases like age-related macular degeneration disease (AMD) is a challenge and requires the industry to invest in lengthy and expensive clinical studies. “From a target perspective, the field has seen tremendous clinical success in blocking (vascular endothelial growth factor) VEGF in AMD. While anti-VEGF therapies have benefited most patients, not all achieve the outcomes we’d like to see. We believe that exploring other targets, modalities and combination therapies will help these other patients, and having better pre-clinical tools could help us accelerate clinical testing,” he says.
Running proof of concept clinical studies in ophthalmology is challenging due to the large size and cost. “For example, there is significant heterogeneity in the GA population, which makes it challenging to identify which patients should be treated and which patients will get worse. We have done work to improve some of the challenges facing these clinical studies. Much of this involves leveraging clinical datasets from failed efforts (eg. CHROMA and SPECTRI) to better randomise and control our studies such that they can be designed with greater efficiency and power. We also use patient derived clinical samples to dive into disease biology using genetics and proteomics to inform research efforts as we look for better therapeutic targets,” he explains.
Looking ahead, Willis sees areas where breakthroughs could exist. “Instead of waiting for a patient’s disease to progress before treating them, we believe there is opportunity to identify patients at higher risk and treat them before they lose significant vision.” Genentech is also pursuing regenerative therapy that aims to restore function in the eye. “We see regenerative medicine as another approach that, combined with therapeutic intervention, can help people at various stages of disease and address unmet needs for diseases like GA,” he adds.
The company is also invested in understanding GA and other diseases that cause vision loss. “We are excited that important clinical results will be shared in the next few years for GA in particular. These results will advance our understanding of disease biology and will allow us to develop better interventions to help us understand whether a single agent or combination approach is more appropriate for a given disease or individual.”
Of course, the Covid-19 pandemic has impacted this sector, like others. Willis explains: “Our commitment is always to our patients and their safety. Patients are counting on us to develop therapies that will help improve their lives.
“With many sites closed due to the pandemic, some of our early stage clinical trials were impacted due to interruptions in patient treatment, resulting in missing data. As we learned more about the disease, we worked closely with our sites to help mitigate some of the concerns and challenges.
“Additionally, patients in our early stage trials were concerned about potential Covid-19 exposure, negatively impacting enrolment for certain diseases, and making it challenging to collect data from existing trial patients. Many ophthalmology visits can’t be shifted to virtual visits so we needed to adapt in different ways: we provided transportation to sites, had weekend clinics, and created hour-blocks at sites specifically for trial patients. By shortening our patient visits we had to prioritise study assessments and this meant that we may have missed data points for future analysis. To overcome future in-person limitations we’re looking into how we can leverage telemedicine and other technologies.”
And the outlook for the ophthalmic sector? Willis states: “Globally, we have an aging population, and expect the need for conditions such as wet AMD will only increase in the coming decades. In addition, the number of people with diabetes who are at risk for diabetic eye disease is expected to increase — according to the National Eye Institute, the number of people in the US with diabetic retinopathy is predicted to double from 7.7 million to 14.6 million by 2050. In looking at these trends, we continue to explore and develop new ways of treating these and other eye disorders.” But, he adds, we also need to find ways to increase patient access.
Volume 23, Issue 1 – Winter 2021/22
About the author
Jeff Willis, MD, PhD is a Senior Medical Director and retina specialist. At Genentech, he was the diabetic macular edema (DME) indication lead for the Phase III Yosemite and Rhine trials for faricimab (2017-2019) and the clinical lead for the overall Port Delivery System (PDS) with ranibizumab (2020-2021). Willis now leads Genentech’s early development programs in Geographic Atrophy.