Neuro-ophthalmology enters new era of treatment
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Neuro-ophthalmologists have a lighthearted attitude about the perception of their specialty because, for many years, neuro-ophthalmology was strictly a diagnosing specialty.
“The joke was that we were ‘diagnose and adios,’” Healio | OSN Neurosciences Section Editor Andrew G. Lee, MD, said. “We were very good at being detectives for disorders that didn’t have good treatments.”
Lee said neurologic disorders such as ischemic events, stroke or optic atrophy cause nerve damage that is not reversible, so neuro-ophthalmologists could help patients by identifying the condition but not much more.
“Once the brain or any brain tissue, including the optic nerve, has damage, it really can’t regenerate,” he said.
Lee was not the only neuro-ophthalmic expert to recall one of the inside jokes of the specialty’s past. Y. Joyce Liao, MD, PhD, had a similar anecdote.
“There’s an old joke that neuro-ophthalmologists admire diseases,” she said. “We are the kind of people who are fascinated by unexplained vision loss and smart enough to figure it out. But now, we’re really at the forefront of trying to generate new, effective therapy, and this is only possible through clinical trials and translational research.”
Over the course of the last few years, the addition of new therapies has caused a shift. Neuro-ophthalmologists are no longer just admirers of disease. Now when they identify conditions, they can help patients find the right therapies.
“Just in optic nerve diseases, there are novel therapeutic approaches like gene therapy, neuroprotection and cell-based therapy,” Liao said. “This can potentially be administered through an ocular formulation, which may be associated with lower side effects than a systemic formulation like a pill or an intravenous infusion.”
There are also some nonpharmacologic interventions, Liao said. One of the areas she is most excited about is visual stimulation.
“This could be visual stimulation in the normal sense, meaning that you are basically using your eyes to look at something to stimulate the visual part of the brain to perhaps enhance another drug’s efficacy,” she said. “Neurons fired together survive together.”
Another possible approach is to stimulate the brain directly. Doing that helps enhance neurons and connection of networks.
“These are some of the key things that are being explored in a really explosive way in neuro-ophthalmology,” Liao said.
Lee said the paradigm began to shift with a few key innovations, particularly in stroke care.
“We have ‘clot busters’ now,” he said. “So, earlier diagnosis and recognition of strokes have moved to a new era where stroke intervention and comprehensive stroke centers are routine now for the care of patients who have transient vision loss or have had an ischemic event related to a stroke and present to the neuro-ophthalmologist.
“The changing paradigm in stroke has made us into diagnosing and treating doctors, especially if we are in the window of opportunity.”
Immunology
Treatment of transient vision loss due to ischemic events is not the only area undergoing rapid innovation in neuro-ophthalmology. Lee said a new specialty, neuroimmunology, is emerging to treat chronic disorders that are often autoimmune or inflammatory.
“There are new treatments that are both disease-modifying therapies and, in some cases, lifesaving or vision-saving,” he said. “These monoclonal antibodies have made the treatment of a lot of our previously untreatable or poorly treated disorders reversible.”
Lee said conditions such as neuromyelitis optica (NMO) and other blinding and paralyzing disorders required regular treatment with conventional immunosuppressants or steroids, often with harsh side effects for patients. Now, FDA-approved monoclonal antibodies have made some previously blinding diseases into manageable disorders.
“That’s what we mean when we say we’re moving towards being treatment doctors,” Lee said.
Prem Subramanian, MD, PhD, added that innovative therapies for patients with diplopia and ptosis caused by myasthenia gravis also have advanced the field.
“Before, we had to treat these patients with steroids or possibly have them do eyelid crunches to help with ptosis,” he said. “But these treatments had lots of side effects, and they weren’t very specific. Now, our therapies are aimed more specifically at treating the underlying disease and putting it into remission with fewer side effects.”
Since 2019, three drugs have obtained FDA approval for NMO: Soliris (eculizumab, Alexion) in 2019, followed by Uplizna (inebilizumab-cdon, Horizon Therapeutics) and Enspryng (satralizumab-mwge, Genentech) in 2020.
According to a release from the FDA, a study showed that eculizumab helped reduce relapses of neuromyelitis optica spectrum disorder by 95% over 48 weeks. Patients also experienced fewer hospitalizations and had less need for treatment with corticosteroids and plasma exchange for acute attacks.
In a clinical trial comprising 230 patients, Uplizna demonstrated a 77% reduced risk for relapse. A recent study that used MRI data showed that it helped reduce formation of asymptomatic optic nerve lesions in patients with neuromyelitis optica spectrum disorder.
In a post hoc analysis of the SAKURA phase 3 studies, researchers found that patients treated with Enspryng had a 79% reduction in risk for severe relapse compared with placebo. In a double-masked period and open-label extension, the drug also reduced relapse risk by 51% compared with patients originally in the placebo group.
“That’s a lot of progress that has been made in the spectrum of treatments that we can offer,” Subramanian said. “Each one of these three FDA-approved therapies for NMO is very specifically targeted to something in the disease process. It’s been shown to be much more effective in reducing the likelihood that the patient might have a relapse and have a blinding event.”
Advances in NMO therapy have been among the biggest and most impressive innovations in neuro-ophthalmology, Subramanian said.
“You had a disease that was blinding, crippling and often fatal,” he said. “When these patients presented to the neuro-ophthalmologist, you were kind of telling them, ‘Get a cane, and get a good life insurance policy.’ Now, we can tell them we have medicines that will let them live a pretty normal life and not have the same horrible risk of going blind, being paralyzed or having a fatal outcome.”
Another area for targeted therapy is thyroid eye disease (TED), with several pipeline drugs looking to join Tepezza (teprotumumab-trbw, Horizon Therapeutics) on the list of FDA-approved treatments. Kimberly P. Cockerham, MD, Healio | OSN Neurosciences Board Member, said having a pharmacologic therapy for TED has been a game changer.
“More has happened in the last decade in terms of changing the way I care for complex neuro and orbit patients than the preceding 50 years,” she said. “Teprotumumab makes the extraocular muscles and intraconal fat behind the globe shrink back to a more normal volume in a way that nothing else does. My surgeries certainly don’t, but neither does IV steroids or other therapeutics.”
Cockerham said she first started prescribing teprotumumab during the COVID-19 pandemic when many primary care and endocrinology offices were closed and surgical interventions were curtailed.
“It came along at just the perfect time,” she said. “I definitely had to take on a larger role in the management of the patients and be the primary prescriber but also the primary monitor.”
The shift to having a TED treatment available, with even more candidates in the pipeline, has been radical, Cockerham said.
“I believe there are approximately nine products in the pipeline, which is unheard of in orbital therapeutics,” she said. “There had been no development whatsoever in thyroid eye disease and orbital disease in general. When teprotumumab was first in development, I remember it had a really hard time getting the initial funding because there was this impression that there weren’t enough patients that had the disease. It’s still relatively rare, but the fact that we have therapeutics for a rare disease like thyroid eye disease is very exciting.”
Cockerham is an investigator on clinical trials of VRDN-001 (Viridian Therapeutics), a monoclonal antibody that inhibits the activity of insulin-like growth factor-1 receptor. In a phase 2 proof-of-concept study, researchers randomly assigned 27 patients with active TED to one of four treatment groups: two infusions of either 3 mg/kg of VRDN-001, 10 mg/kg of VRDN-001, 20 mg/kg of VRDN-001 or placebo.
At 6 weeks, 67% of patients in the three VRDN-001 groups had at least 2 mm in reduction of proptosis and at least a two-point reduction in clinical activity score. In the 10 mg/kg group, 83% of patients met the overall response rate.
Additionally, mean proptosis reduction and reduction in clinical activity score remained consistent at 12 weeks. Based on these results, VRDN-001 will continue on to phase 3 assessment in both active and chronic TED, Cockerham said.
“The drug is working in two infusions with efficacy that’s more dramatic than teprotumumab,” she said. “The durability is yet to be seen in terms of a longer follow-up, but the safety appears to be superior.”
Monoclonal antibodies have spurred massive changes in neuro-ophthalmology, but Lee said there might be even more opportunities to use these newer therapies. He said he expects that physicians will start moving to monoclonal therapy earlier in the disease process.
“We already have some experience with TED and teprotumumab and giant cell arteritis and tocilizumab,” he said. “It will just continue to evolve toward the earlier use of monoclonal antibodies to modify diseases at their core rather than treating them after they already have significant, irreversible vision loss by using maintenance therapy to avoid relapses. In addition to being treatment doctors, we’re going to be prevention doctors.”
Gene therapy
Another area of innovation in neuro-ophthalmology is gene therapy and stem cell transplant. Lee said these pathways open up even more opportunities to treat previously untreatable diseases.
“We really don’t have anything to reverse optic neuropathy,” he said. “However, the development of gene therapy, like CRISPR-Cas9, has the potential to reverse previously irreversible genetic conditions that affect the optic nerve, the mitochondria or other genes.”
Lee said CRISPR acts as a sort of GPS to help RNA find specific bits of DNA, while Cas9 is like a genetic molecular scissor.
“Once we locate where the gene needs to be cut, the genetic scissor can cut it, and we can give the new gene or the new gene product using a viral vector to carry the new gene into the cell.”
Liao said gene therapy is not a new concept in ophthalmology.
“Gene therapy as treatment for any kind of disease was first approved by the FDA for vision,” she said. “As these therapies progress, I think they will first take root in the eye because it’s such an accessible organ.”
Liao is a lead investigator in clinical research in gene therapy for Leber hereditary optic neuropathy (LHON), the most common maternally inherited optic nerve disease. It is common in boys in their teenage years or younger, and Liao said they usually present with rapidly progressing bilateral blindness.
“They have severe central vision loss and better peripheral vision, and that is because enough bad copies of the mitochondria accumulate, and it has a cliff effect,” she said. “In a way, it’s like age-related macular degeneration where it hits the central vision. However, the difference is it’s severe and very rapid.”
While AMD might progress over the course of years, LHON can cause blindness in both eyes in as little as 1 month, Liao said. In a previous trial, Liao worked with a 20-year-old patient who had been experiencing a void in his central vision. Within a month of initiating therapy on the study drug, Raxone (idebenone, Santhera Pharmaceuticals), he was already beginning to see improvement.
“He actually went all the way back to 20/20 vision, which is amazing,” she said. “He was able to go on to his promising job and future career.”
Liao is also an investigator in trials for drugs that target other genetic disorders, including autosomal dominant optic atrophy (ADOA).
“The newest waves of treatment are specifically targeting genetic disorders, which are the most devastating, especially to a family,” she said. “ADOA is the most common hereditary optic neuropathy, so I’m really glad that we’re able to offer something, and I think the future is bright.”
As more therapies enter the tool kit of neuro-ophthalmologists, Lee said their role will continue to change. Long gone are the days of “diagnose and adios.”
“We’re moving away from our old paradigm, which was ‘diagnose and goodbye,’” he said. “It will be ‘prevent, diagnose, treat and rehab.’”
New roles could end up leading to a different culture within the specialty. Lee said expanding parameters and responsibilities will ultimately have a positive impact on neuro-ophthalmology through the new people recruited.
“I think it’s an exciting time for us in the future because it will bring in more people to our specialty who in the past may have been less inclined to join a specialty where you weren’t actually treating people. Adding this treatment and prevention arm to our armamentarium of neuro-ophthalmology probably will increase interest in the field,” he said.
Lee said that all of these changes might be a lot for some neuro-ophthalmic veterans, and they will have to adapt to the changing world.
“If they’re not ready to enter into the modern era of monoclonal antibodies and gene therapy, they’ll probably have to partner with someone, maybe even a junior doctor, who is willing to do these things,” he said. “For the young people, it will just be normal, and that’s a good thing. We want people to enter into our field knowing they can diagnose and treat.”
Even will all the advances in the field, Subramanian said neuro-ophthalmology remains highly diagnostic. He said neuro-ophthalmologists will need to continue to work collaboratively with colleagues to find the right treatments for their patients.
“We need to help them say when the right time is to prescribe a therapy for a patient but also to know when the patient’s therapy isn’t working,” he said. “We’re the ones who evaluate the patient and say, ‘It looks like you are having further field loss. We need to do something differently in order to treat your disease properly.’”
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- References:
- FDA approves Genentech’s Enspryng for neuromyelitis optica spectrum disorder. https://www.gene.com/media/press-releases/14873/2020-08-14/fda-approves-genentechs-enspryng-for-neu. Published Aug. 14, 2020. Accessed June 16, 2023.
- FDA approves new therapy for rare disease affecting optic nerve, spinal cord. https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-rare-disease-affecting-optic-nerve-spinal-cord. Published June 11, 2020. Accessed June 16, 2023.
- New data show Genentech’s Enspryng significantly reduces severity and risk of relapse in neuromyelitis optica spectrum disorder. https://www.gene.com/media/press-releases/14879/2020-09-09/new-data-show-genentechs-enspryng-signif. Published Sept. 9, 2020. Accessed June 16, 2023.
- New analysis of MRI findings show Uplizna (inebilizumab-cdon) reduced the formation of asymptomatic optic nerve lesions in people with neuromyelitis optica spectrum disorder (NMOSD). https://ir.horizontherapeutics.com/news-releases/news-release-details/new-analysis-mri-findings-show-upliznar-inebilizumab-cdon. Published March 14, 2023. Accessed June 16, 2023.
- For more information:
- Kimberly P. Cockerham, MD, can be reached at cockerhammd@gmail.com.
- Andrew G. Lee, MD, of Houston Methodist Hospital, can be reached at aglee@houstonmethodist.org.
- Y. Joyce Liao, MD, PhD, of Stanford University School of Medicine, can be reached at yjliao@stanford.edu.
- Prem Subramanian, MD, PhD, of University of Colorado Health, can be reached at prem.subramanian@cuanschutz.edu.
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