For people diagnosed with ocular melanomas, the only effective treatment for many years has been radiation therapy which destroys sight in the affected eye. This was Melody Burchett’s experience when she was diagnosed with a type of ocular melanoma in December 2010 after going in for what was supposed to be a routine screening for new eyeglasses. But the range of possible treatment options for patients could soon change thanks to a new therapy from Aura Biosciences that has successfully passed through Phase II testing.
Aura recently presented the final results from Phase II testing of bel-sar, a first-line treatment of early-stage choroidal melanoma, a subset of ocular melanomas that affect the inner eyes (also called uveal melanomas). Choroidal melanoma is a rare and aggressive cancer that is both vision- and life-threatening. Treatment with radiation causes over 85% irreversible vision loss and other severe comorbidities
Rather than radiation, Aura’s approach uses virus-drug conjugates (VDCs) that are activated by light to target tumors. Elisabet de los Pinos, PhD, Aura’s CEO, explained the technology during an interview with GEN. She became interested in VDCs after working in a virology laboratory at the National Institutes of Health. After spinning out Aura Biosciences, she and her team chose to focus first on choroidal melanoma to test the effectiveness of using VDCs to treat various types of tumors. They plan to target other kinds of cancers in the future and already have a project focused on bladder cancer in the works.
Aura’s VDCs consist of an empty HPV capsid, a virus-like particle that binds selectively to heparin sulfate proteoglycans on tumor cells. Capsids are coated with a novel photosensitizer—part of a class of drugs that form reactive oxygen species when activated by infrared light. Once the VDC therapy binds to the tumor cells, the tumors are briefly exposed to a light source to activate the photosensitizer. The reactive oxygen species damage the tumor cell membranes leading to cell death. Sensing the damage, the body’s immune system is also activated and mobilizes immune cells to further target and destroy the tumor.
Multiple safety studies conducted prior to launching clinical trials showed that the VDCs bind selectively to tumor cells and that there is no damage to healthy retina cells, de los Pinos said. “That’s critical because we didn’t want the retina to be damaged since it’s such a critical structure for vision.” Patients undergo three cycles of treatment over nine days with no radiation required. And importantly, Aura’s results suggest that the treatment is curative if tumors are diagnosed and treated.
“It’s an exciting milestone for the company and for patients,” de los Pinos said. Being able to precisely target and eliminate the tumors while preserving patients’ vision makes this “one of the best example[s] of a targeted therapy.”
A successful trial
Aura’s Phase II study of bel-sar was an open-label, ascending single and repeat dose escalation trial designed to evaluate the safety and tolerability of bel-sar as well as to assess the preliminary efficacy to patients of taking up to three cycles of bel-sar treatment with one or two laser applications per treatment. The company presented the results at the Retina Society Annual Meeting held in Lisbon, Portugal.
The Phase II trial, which had about 20 patients enrolled, included both single and multiple ascending dose cohorts. About 80% of patients who received the treatment were categorized as high-risk for vision loss with tumors located close to the fovea or optical disc. Aura also assessed the size of patients’ tumors to select patients with small but actively growing tumors, de los Pinos said. Patients with tumors up to 2.5 mm are typically considered early-stage cases. All patients were monitored closely over 12 months to assess tumor control, visual acuity preservation, and tumor growth rate.
In terms of preserving visual acuity, bel-sar was effective in 90% of patients who received three cycles of the therapy. Bel-sar therapy also achieved an 80% tumor control rate among patients who received three cycles of therapy. For the 80% of patients that responded to bel-sar, the data showed a statistically significant reduction in tumor growth rate compared to each patient’s documented growth rate at study entry. Patients had an average tumor growth rate of 0.02 mm/year after joining the trial, according to the results.
Bel-sar also proved to have a favorable safety profile. Patients did not show any dose-limiting toxicities nor did they show treatment-related serious adverse events, significant adverse events, or systemic adverse events. Any treatment-related adverse events that did occur were most mild and easily resolved. Researchers also reported no treatment-related posterior inflammation, with no vitritis, choroiditis, retinitis, retinal pigment epithelium changes, or vasculitis in patients. There was some anterior chamber inflammation present in about 18% of patients, but it was mild, usually self-limited, and required no or short-duration topical-only steroid treatment. Patients also indicated that the treatment was painless.
The next step is to put the treatment through its paces in a larger pool of patients as part of a Phase III trial. At the same time, Aura is exploring the potential of using VDCs to target blender tumors. They already have collected some preclinical data but the project is still in its early stages. “The bladder responds well to immune modulating agents, [and we] have the power of a direct targeted [therapy] plus immune stimulation,” de los Pinos said. “There’s not much I can tell you until we present the data, but there’s a lot of excitement.”
Connecting patients to trials
Since her diagnosis, Burchett has worked to bring awareness to ocular melanomas and to connect patients to resources, clinical trials, and other forms of support. She founded A Cure in Sight (ACIS), a patient advocacy organization for the ocular melanoma community in 2013, and serves as its president. The organization provides financial assistance and educational resources including a podcast to patients that helps them better understand ongoing research in the field as well as the importance of clinical trials.
They also help eligible patients find and sign up for ongoing clinical trials. In line with those efforts, ACIS is developing a patient registry that will better connect drug developers to patients that can benefit from their treatments. In addition to general demographic information, the registry captures information such as the ocular cancer type, what mutations the patients have, and any treatments they have received. The registry currently has information from about 1,000 patients and the organization hopes to add more patients in the coming months.
“The community needed an advocacy organization,” Burchett told GEN. There were other research organizations, but there really wasn’t anybody doing a lot of work in the advocacy area. And I thought that was a huge injustice to the community. So we got to work.”
Importantly, ACIS offers hope to patients through community, education, and resource sharing. Ocular melanomas are rare and though the field has made progress, scientists still have much to learn about these tumors. The tumors affect people of different ages including children, teenagers, and young adults.
Existing research has confirmed some genetic risk factors for ocular melanomas including mutations in genes like BAP1. They also mostly affect people of northern European descent with blue eyes. Some evidence suggests that greater exposure to ultraviolet rays may also drive tumor development. Comprehensive eye exams are important for early detection and treatment to have a chance at preserving vision in the affected eye.
When Burchett was diagnosed, she, like many other patients at the time, were given a grim prognosis as the cancer is life-threatening without treatment. Receiving a cancer diagnosis is emotionally devastating which is why patient communities like ACIS are so critical, Burchett said.
In addition to the physical toll that radiation takes on the body, what’s less obvious are the significant physical and emotional challenges associated with losing an eye. This includes problems with depth perception and vision issues in the unaffected eye, as well as mental strain as the brain tries to compensate for the lost vision. “It’s a huge diagnosis to deal with because it’s lifelong. I watched these patients just struggle and I thought, there’s gotta be a better way,” she said.
Its ability to treat the tumor without destroying patients’ vision is one of the reasons that Burchett is excited about the potential of Aura’s treatment. Especially because it works without requiring radiation. “If we could get a vision-sparing treatment especially for small tumors [that] can spare as much of their vision as possible, it’s best for the patient. They’ll still be able to function like they used to,” she said. “The data from Phase II is phenomenal. If we can get these approved, it’s a game changer.”
Planning for Phase III
Aura has begun enrolling participants in its Phase III trial from around the world. They hope to enroll about 100 patients. Since it seems the most efficacious dosing, participants will receive three cycles of the therapy for their regimen. Aura is also using the same inclusion criteria to select participants as it did in Phase II. That means patients in early stages of disease with small tumors who are also at low risk for metastatic disease. If Phase III goes well, the next step for Aura will be filing for a biologics license application. Phase III should wrap up in 2026.
For their part, Burchett and her team at ACIS are continuing to educate patients about the importance of participating in clinical trials. Not knowing that trials exist for their condition is one reason why patients don’t enroll even if they fit the inclusion criteria. In some cases, treating physicians may talk them out of signing up for trials.
Furthermore, some patients might also be concerned about being placed in the placebo group for fear that their tumor will get bigger or metastasize during the trial phase. Documenting tumor growth with comprehensive eye exams and pictures is helpful here, Burchett said. This way patients have a clearer picture of how fast their tumor is progressing. And that could provide the assurance they need to move forward with a trial even if they are part of the placebo group.
“I had a medium-sized tumor and I waited four months to have it treated,” Burchett said. “When I finally had it done, my tumor was the exact same size [as] when they first diagnosed me. I’m here almost 14 years later and I don’t have any metastasis. So waiting four months did not harm me at all.”
