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Neurological conditions like Multiple Sclerosis (MS) are an incredibly important area of research when it comes to drug discovery, but under that (sometimes mistaken) umbrella diagnosis occur other, rarer diseases, such as Neuromyelitis Optica Spectrum Disorder (NMOSD).

Until recently, NMOSD was regarded as an optic-spinal form of MS. Although the clinical manifestation of NMOSD may resemble MS, the NMOSD-specific serum autoantibody (AQP4-IgG) can be detected in up to 80% of patients, confirming it as a distinct clinical entity to MS. Despite this, 41% of NMOSD patients have reported an initial misdiagnosis of MS, according to Horizon Therapeutics.

NMOSD is a rare and debilitating autoimmune disease driven by severe, recurrent central nervous system (CNS) attacks which can result in blindness, paralysis, and death. Depending on a patient’s underlying genetic makeup, it can affect anywhere between 0.4 to two or three people out of 100,000. Women are nine times more likely to be affected, and the median age of disease onset is 40 years old.

Affecting the optic nerves and spinal cord, NMOSD (also referred to as NMO) can lead to problems like optic neuritis and transverse myelitis, which some patients will only have, and 41% of patients may become legally blind in one eye at around five years after disease onset.

Yet, according to NMO UK, others might also have antibodies recognised as being associated with this disorder, such as Aquaporin 4 (AQP4) and Myelin Oligodendrocyte Glycoprotein (MOG). However, each person with NMOSD will experience different symptoms, and each will require individually tailored care and support.

Changing the game with evidence and efficacy

Speaking with Kristina Patterson of Horizon Therapeutics, pharmaphorum discussed the recent data presented on UPLIZNA as a treatment for NMOSD at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) late last year, firstly enquiring after the reception of the latest findings.

“NMOSD, is a rare and very devastating disease. It is a disease that can take away a person’s sight, a person’s mobility, a person’s ability to really just live their life,” Patterson explained. “We’re very excited, and we found that others were very excited as well when we presented data at ECTRIMS, demonstrating the unique mechanistic profile of UPLIZNA.”

“In fact,” she continued, “one provider, one physician, that I spoke with actually called it a game changer for therapeutics in NMO.”

An enthusiastic response, indeed, given one of the big hurdles is getting physicians to sign onto a drug. Yet, the data that Horizon presented demonstrated consistent efficacy in NMOSD patients treated with UPLIZNA, regardless of a particular genetic polymorphism or genetic variability that can diminish responses to other monoclonal antibody therapies. Furthermore, until only a few years ago, there were no approved therapies for NMOSD, with no evidence-based medicine either.

In the trial, the primary endpoint was achieved, with 89% of patients in the AQP4-IgG+ group remaining relapse-free during the six-month period post-treatment versus 58% of placebo patients.

“Now,” Patterson said, “we have evidence-based medicine, and we have approved drugs, and now it’s really about figuring out the right drug for the right patient. That’s really the next step in NMO. What we did is, from the very beginning when UPLIZNA was designed, [we] said let’s think about how a person’s underlying genetic makeup can impact their treatment outcomes and try to, basically, be able to treat as many patients as possible. That thinking started at the very beginning with the design of the drug.”

The integral role of B-cell biology

The new data that Horizon presented was from two analyses of the phase 3 pivotal trial of UPLIZNA that aimed to clarify the relationship between peripheral B-cell subsets in the blood, AQP4IG levels, and disease attacks.

In NMOSD, damage is caused when CD19-positive expressing B-cell lymphocytes (plasmablasts and plasma cells) produce AQP4-IgG, triggering an escalating autoimmune reaction. Depletion of CD19 positive B-cells is thought to remove important contributors to autoimmune reactions, including inflammation, lesion formation or astrocyte damage.

UPLIZNA is a targeted CD19 B-cell depleter developed specifically to induce broad, deep, and durable B-cell depletion. It is a monoclonal antibody that specifically binds to CD19-positive, surface antigens present on pre-B and mature B-cell lymphocytes, including plasmablasts and some plasma cells. Following cell surface binding to B lymphocytes, UPLIZNA supports antibody-dependent cellular cytolysis (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

“Horizon has a great interest in studying the integral role of B-cell biology and NMOSD. .” Patterson explained. ”Specifically, what we’re showing here is that antibody secreting CD19 positive B-cells correlate with disease activity in NMO, and that UPLIZNA not only depletes or gets rid of these antibody secreting B-cells but also diminishes the levels of these disease-causing autoantibodies that target Aquaporin-4.”

“That’s really getting at the pathophysiology of the disease,” she continued. “Once again, this started at the very beginning with the design of UPLIZNA. Not only was it designed to be able to be effective in people regardless of this underlying genetic polymorphism, but it was designed to target the right B-cells, those CD19 positive B-cells that actually make the pathogenic antibodies that cause disease.”

Clearly thorough, precise, and intensive research and development, yet surely time onerous?

“Well, science is something that takes time,” Patterson reasoned. “And, like I said, this was thought about at the very beginning. This really went into this thought process, went into the design of the drug, and we have been studying B-cell biology ever since […] Here, we really take a deeper dive into that and look at the different types of B-cells, and how they may impact disease activity.”

A physician’s first-hand knowledge

That is perhaps why UPLIZNA is the first and only targeted B-cell depleting monotherapy approved by the EMA and the FDA for this disease in adults who have NMOSD and who have the autoantibodies to Aquaporin-4. A crucial treatment to be developed, given the symptoms of sufferers’ terrible attacks – the specifics of which Patterson is well-versed in, a neurologist with subspecialty training in neuro-immunology.

“Before I came to industry, I guess it was a year and a half ago now, I was actually treating patients with NMO,” Patterson explained. “I had several dozen patients […] in my clinic. I can tell you first-hand how devastating these attacks are. Just one attack can completely, irreversibly change a patient’s life. As I said, patients can go blind, they can be in a wheelchair, and there are all sorts of symptoms in between that affect mobility, and sight, among other symptoms.”

And that is why UPLIZNA, what it can offer in terms of treatment, was received so well at ECTRIMS.

“It’s really been it’s been remarkable to actually have something to offer these patients, to have evidence-based medicine, a proven effective therapy like UPLIZNA, with a demonstrated safety profile and every six months dosing,” Patterson said. “It’s really quite remarkable to be able to offer patients that and to be able to offer patients hope that there is a therapy: a therapy in a therapy that targets the pathophysiology, the underlying cause of the disease to prevent attacks and prevent that disability.”

“UPLIZNA is dosed every six months,” she explained. “[The drug] provides six months of protection against disease activity, and then, after the first two loading doses, it’s actually one infusion, one 90-minute infusion every six months to receive six months of protection against these devastating attacks.”

Future Horizon focus

Given the highly positive reception of the UPLIZNA data at ECTRIMS, pharmaphorum could only ask: what next?

“We have a lot of exciting new data in the works,” Patterson shared. “It’s going to cover B-cell biology, really all patient-centric research as well. We really look forward to sharing this with you at future congresses, but we’ll have to wait and see exactly what the results show.”

Nonetheless, Patterson was keen to share what Horizon had taken away from ECTRIMS itself.

“I would say that the overall message or the overall impression that Horizon had from this Congress was just that the medical and scientific knowledge around NMO is rapidly growing. This is a field that, even though it’s a rare disease, there’s been so much progress made in such a short period of time. Even at a congress that’s focused more on multiple sclerosis, there was so much research about NMOSD there.”

About the interviewee

Dr Kristina Patterson joined Horizon Therapeutics in July 2021 as a medical director in neuroimmunology. Prior to that, she was a practicing neurologist and NIH funded investigator at the University of Pennsylvania with expertise in Neuromyelitis Optica Spectrum Disorder (NMOSD), Multiple Sclerosis, Autoimmune Encephalitis, and IgG4-mediated neurological diseases. Throughout her career, she has been passionate about optimising therapeutic interventions for rare autoimmune disorders. Dr Patterson is a graduate of Northwestern University Feinberg School of Medicine in Chicago, where she received her medical degree and earned a doctorate in Neuroscience. She completed residency in Neurology and a fellowship in Neuroimmunology at the University of Pennsylvania in Philadelphia. She resides in Philadelphia with her husband and son.

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