BrainWaves #115 Novel immunotherapies in demyelinating disease

Transcript

Hey podcast listeners, Jim Sigler here for Brainwaves.

The last year has witnessed a breakthrough in disease modifying therapies for multiple sclerosis.

As I'm sure you're aware, we have witnessed the first FDA approval for the treatment of primary progressive MS, a monoclonal antibody infusion called Ocrelizumab.

And as we discussed back in January, there are new diagnostic criteria for MS that encourage earlier and more aggressive treatment.

By combining these two things, newer treatments and evolving diagnostic criteria for MS, along with other advances in health care and technology, we're more prepared now than ever before to manage patients with this chronic and frequently disabling disease.

And hopefully our patients will all be the better for it.

In this week's episode of the Brainwaves podcast, we'll talk about what led to this revolutionary therapy, Ocrelizumab, and how or why it may or may not be so different from the drugs that came before it.

Don't go anywhere.

Here with me in Studio 3 in Philadelphia for this week's program is Dr.

Christopher Perrone.

My name is Chris Perrone.

I'm the Neuroimmunology Fellow at University of Pennsylvania.

Hey Chris, thanks for being here today.

Thanks for having me.

So the purpose of today's show is to describe the advent of B cell modulating therapies in multiple sclerosis and the approval of a new MS therapy, Ocrelizumab.

To start, I think it'd be helpful to know what a B cell is.

So what are B cells and how are they thought to play a role in multiple sclerosis?

Sure, Jim.

We used to think of MS primarily as a T cell mediated disease.

Both T and B cells are lymphocytes, or immune cells, which are derived from the bone marrow.

B cells, which migrate to the thymus to mature, are classically involved in what we know as cell mediated immunity.

B cells migrate to secondary lymphoid organs, such as the spleen and lymph nodes to mature, and are classically thought of as driving humoral or antibody mediated immunity.

As no antibodies have been found to cause MS, B cells initially seem to be less likely a target for therapy.

However, over the last 20 years, our understanding of B cell biology and its role in autoimmune disease has expanded by leaps and bounds.

Historically, as Dr. Perrone's getting at, the brain was thought to be immunoprivileged.

No white blood cells allowed.

Damage to the central nervous system tissue would lead to activation and clean-up by cells that already existed there, meaning microglia and dendritic cells.

But years of research have disproven this oversimplified defense network.

With injury due to infection or inflammation, microglia release cytokines and chemokines, which attract peripheral blood mononuclear cells like lymphocytes and monocytes, and the dendritic cells present antigenic targets to T cells, which have now entered the nervous system to help clean up the mess.

In the peripheral blood, these cells can present foreign or self-antigens to T cells, triggering their activation and migration into the central nervous system.

Also in the periphery, B cells can release a number of pro-inflammatory cytokines, such as interleukin-6, tumor necrosis factor, and granulocyte macrophage/colonial stimulating factor.

Further, B cells have also been found to migrate into the central nervous system, establishing meningeal follicles, whereby they may perpetuate the immune response described previously, which is why we see oligoclonal bands in the CSF of almost 90% of patients with relapsing remitting MS.

It is by these mechanisms that B cells are now understood to play an important role in MS.

So basically, B cells' misinterpret nervous system tissue as pathologic tissue.

Yes.

It makes sense that if abnormal B cell activity is contributing to MS, then selectively suppressing or destroying these cells can control someone's symptoms.

So, maybe we could move on to how B cell modulating therapies evolved.

Yeah, so when developing a B cell therapy, it's important to be selective, as you wouldn't want a therapy that would completely wipe out stem cells that produce other immune cells.

Similarly, you would not want to destroy plasma cells, which are a terminal B cell that produces antibodies, as this would make it difficult to mount an immune response to pathogens one had already been exposed to.

A self-surface marker on B cells, known as CD20, is found on pre-B cells, naive B cells, and memory B cells, but actually not on stem cells or differentiated plasma cells.

The development of a chimeric, or a mouse-human antibody, against CD20 (this would be Rituximab) paved the way for a selective depletion of B cells, implicated in autoimmune pathologies such as a mass, without sacrificing stem cells or prior antibody-mediated immunity.

Add-on trials and the Hermes trial showed reduced clinical and radiographic relapses in relapsing remitting patients on Rituximab.

To cut in again here, when I think of Hermes, I jumped to the stroke collaborators who demonstrated the overwhelming efficacy of thrombectomy within six hours.

But here, Dr. Perrone's referring to Hermes as the phase 2 clinical trial of 104 patients who received either Rituximab or placebo.

What the Hermes trial did was they randomized patients to two infusions of either Rituximab or placebo, with the primary outcome being the development of new gadolinium-enhancing lesions in the next 24 weeks.

The results were impressive.

Over this period, half of patients who received placebo had some new lesions on their follow-up scans.

Whereas in the Rituximab arm, 20% of these patients had new lesions.

Relapse rates were also significantly fewer in number for the Rituximab arm.

And over the course of the next year, half as many Rituximab-treated patients had relapses compared to the placebo group.

So I mean, the idea was that they had found certain B-cell mediated mechanisms in the central nervous system, like the establishment of meningiopholicals, which were sort of B-cell rich, which then put forth the idea that using a B-cell therapy might be beneficial.

And the interaction between B-cells and T-cells in the periphery, we know that T-cells don't always trigger just by themselves.

They have to be triggered by B-cells presenting antigens to them via antigen presenting cells.

And so it was more trying a different angle at the biology of MS, you know, finding a different drug target.

And the first experiment with it was with Rituximab.

Okay.

And Rituximab was well tolerated in those original studies?

Yeah.

It was really well tolerated.

The only adverse effects were really just infusion reactions like flushing and flu-like symptoms, and those would abate with repeat doses.

Furthermore, the therapy only had to be administered once every six months compared to other MS medications that are dosed much more frequently, such as every other day injections.

So these characteristics actually fueled the development of more anti-CD20 therapies, most notably, Ocrelizumab, which is really what we're going to talk about today.

And it seems that Rituximab was actually quite effective for relapsing remitting MS, but the medicine didn't actually receive a primary indication or an FDA approval for the treatment of MS.

Can you talk about as to why this is?

There are actually a number of reasons cited for why Rituximab didn't receive a primary indication for the treatment of MS.

As a disease modifying therapy in MS currently has to be designed as a chronic therapy, there was a concern about acquired resistance.

Many Rituximab antibodies have been found, and resistance can actually be seen in as many as half of treated lymphoma patients, which is one of the other approved indications for Rituximab.

Rituximab is also a chimeric antibody, meaning that it has domains that are derived from mice and others derived from human sources.

While Rituximab is generally well tolerated, human anti-chimeric antibodies, haka's, have been found.

And while they are not believed to contribute necessarily to resistance, they may contribute to adverse reactions.

I'll jump in and say here that with Rituximab, which again is part mouse, part human, it's mostly limited by the infusion reaction, which is common.

You're putting mouse antigens into your bloodstream, so it makes all too much sense that your body's going to react to it.

Fevers, chills, headache, puritis, and so on.

But it's manageable.

There was an interest in developing a fully humanized antibody, which ultimately became Ocrelizumab. 95% of all adverse reactions are mild or moderate, and they resolve with temporary interruption or discontinuation of the infusion.

In the remaining 5% of patients who react, more severe angioedema or anaphylaxis could occur.

And these risks attenuate with subsequent infusions.

The human anti-chimeric antibodies, or HACAs as Dr. Perrone mentioned, are not that uncommon.

Maybe a third of patients can get them.

And whether they form because of ineffective B-cell depletion, because B-cells are still around to mount an antibody response, or whether they inhibit the effect of Rituximab, it's not perfectly clear.

Either way, we needed a more effective, consistent immunotherapy.

But we're getting ahead of ourselves here.

There's a little more to be said about Rituximab.

Like do we know if it's effective in primary progressive MS, or just a relapsing remitting variant?

So while the Olympus trial was a test of using Rituximab in primary progressive patients, it was formally a negative study.

Though it is interesting that you bring that up because...

It was negative because the primary endpoint of clinical disease progression, or sustained worsening in disability, was no different in those who received Rituximab versus those who received placebo.

Yeah, because a subset of younger patients, and those who are noted to have enhancing lesions, were actually shown to have a slow disease progression.

It was thought that actually a therapy with maybe fewer potential sources of resistance may result in a greater effect for primary progressive patients.

Is it that the Rituximab seemed to be less effective with time, or it was just a more severe disease to begin with?

So it seems that Rituximab, in terms of treatment of primary progressive patients, was effective in patients who were younger, earlier on in the disease, likely having a more inflammatory component as suggested by the enhancing lesions.

While that was a subset that was identified in the Olympus trial, there was definitely an interest in trying to make a more targeted therapy with fewer adverse effects that could potentially lead to an even more significant finding.

And that's when we have Ocrelizumab join the show.

So why are we switching gears and now treating patients with okra?

So Ocrelizumab is a fully humanized monoclonal anti-CD20 antibody that binds to a different but overlapping epitope of CD20.

So fully human, no mouse parts this time.

Ideally putting patients at less of a risk for developing infusion reactions and antibodies targeted against that medication.

And clinicians tested this drug in a pair of clinical trials, opera 1 and 2.

Which are actually identical phase 3 randomized controlled trials with a primary endpoint of annualized relapse rate compared between relapsing remitting patients on Ocrelizumab and relapsing remitting patients on interferon beta, Rebif.

Ocrelizumab showed a 64% reduction in annualized relapse rate, 94% fewer enhancing lesions, and 95% fewer T2 lesions.

This data was certainly impressive.

Just to clarify here, this trial used an active comparator, which means they compared the treatment of Ocrelizumab to an active treatment that was known to reduce relapses and new lesions.

They also tested Ocrelizumab in primary progressive patients in what is called the oratorio trial, which was a phase 3 randomized controlled trial comparing primary progressive patients receiving Ocrelizumab compared to placebo.

And that showed a significant reduction in disability progression measured by time 25 foot walk, as well as lesion and brain volume on MRI.

I really want to emphasize this part.

You'll recall that before oratorio, there was not a single drug that had been shown to prevent disease progression in patients with primary progressive MS.

Nothing.

Ocrelizumab, on the other hand, reduced the 12-week progression of a patient's disability by 24% compared to placebo.

The follow-up 25 foot walk test was also better than expected in those who received Ocrelizumab.

Patients on Okra had half as many newer areas of brain injury on follow-up MRI.

And finally, when it came to volume loss of the brain over time, both patients on Okra and placebo had smaller total brain volumes over 2.5 years of treatment.

However, patients who received Okra had 20% less of that loss.

So it wasn't just one positive outcome metric.

Everything was better if you received Okra.

There hasn't been a head-to-head trial with regard to Rituximab and Ocrelizumab.

So in terms of efficacy, it's going to be hard to address that.

But in terms of adverse effect profiles, while we haven't compared them directly because they were in different trials, it seems that adverse effects like infusion reactions would be lower in the population getting Ocrelizumab.

What about the other side effects to Okra?

So there were a few patients, less than 1%, actually, that developed anti-Ocrelizumab antibodies.

And so there was less of a provoked immune response to the drug compared to what we see with Rituximab.

So that is perhaps why the adverse event profile might indicate better tolerance of Ocrelizumab.

The only other adverse effects besides the infusion reactions were respiratory and skin infections, as well as higher rates of malignancy, including breast cancer.

But with this safety profile and its observed effect in MS patients in both the opera 1 and 2 trials, as well as the oratorio trial, it was approved in March of 2017 for use in relapsing remining MS, as well as the first drug approved for primary progressive MS.

Well, I can certainly say that that sounds incredibly encouraging, especially for our patients with primary progressive MS where there wasn't really even a treatment.

But I don't know if everyone's necessarily going to qualify for this therapy.

And like you said, and like with all other drugs, it's a medication that's not without risk.

If I were to start a patient on Okra, what kind of pre-testing do I need to do for my patients?

And is there a typical protocol for administration?

Yeah, so prior to initiating Ocrelizumab, Hepatitis B virus screening should be performed as the medications actually contraindicated in patients with active Hepatitis B.

Also if any vaccinations need to be given, they should be administered at least six weeks prior to the initiation of Ocrelizumab.

A patient should also be up to date according to cancer screening guidelines.

Other tests that may be performed are a baseline CVC, complete metabolic panel, VZV Titer, Quantifier on Gold, HIV, and baseline CD19.

And when you give it, is there a standard dose and what's the kind of protocol?

The recommended dose of Ocrelizumab is 600 milligrams.

And all infusions are preceded by 100 milligrams of methylprednisolone or equivalent steroid, diphenhydramine, and acetaminophen.

The first infusion is split into two doses of 300 milligrams each and administered 14 days apart.

All subsequent infusions, which occur at intervals of six months, are single 600 milligram infusions.

And this is the same whether you have primary progressive MS or relapsing remitting disease?

Correct.

Certainly less frequent than the every other day injections of interference.

Most definitely.

For giving the drug, guidelines recommend assessing CD19 counts and a CVC every three to six months.

Now, why a CD19 level, you ask?

It's because CD19 and CD20 co-localize on B cells.

But when you give a patient an anti-CD20 monoclonal antibody, sometimes that CD20 antigen can be pulled off or it can be internalized in a cell as a reaction to the drug binding.

So finding that there's a low CD20 level in the blood might not actually tell you the status of your B cell population, but a low CD19 level will.

Global leukemia.

Ideally you would want the CD19 count to be zero to show that you have had an effective response to the therapy.

And furthermore, as you get closer to the six month interval when they need to be redosed, you might also catch that their B cells are beginning to repopulate before the six month period and that may dictate changes in interval dosing going forward.

So with Ocrelizumab now being effective, at least for both primary progressive MS and for relapsing remitting MS, and we know that Rituximab is definitely effective for relapsing remitting disease, but we don't know how well they would compare head to head.

Is there any evidence that one or the other will be compared to each other in the future?

Yeah, that's actually a good question.

There is actually a trial being conducted at the University of Colorado designed to explore switching patients from Rituximab to Ocrelizumab and then comparing the two therapies in terms of their safety and tolerability.

So hopefully I'll have the answer to that one soon.

Okay, yeah.

Next I'd like to segue into other B cell mediated neurologic diseases because MS is not the only one.

You'd imagine that if Rituximab and Ocrelizumab were effective in MS, then they should both be effective for conditions like NMO and sometimes we use Rituximab in severe cases of NMO.

Is that what we're seeing in clinical trials that maybe Ocrelizumab could be effective in these other B cell diseases?

Yeah, you certainly bring up another good point.

Unlike in MS, NMO is a disease entity that is driven by a pathogenic antibody to the Aquaporn IV channel.

As B cells are critical to antibody production, depletion of these cells are an ideal, more targeted therapy for NMO.

And that proof of concept has been shown by a number of studies examining the use of Rituximab in NMO patients.

It would stand to reason that Ocrelizumab would also work in NMO, though I don't know of any clinical trials at this point in time they're being conducted to look at the efficacy of Ocrelizumab in NMO.

So if rotuximab is good for MS and Ocrelizumab is as good, maybe even better, is there something else that's even more superior to Ocrelizumab that we're studying or that we can look forward to in the future?

While they're working on it, more targeted B cell therapies are being developed.

A new fully human monoclonal antibody, ofatumumab, actually binds to a distinct epitope on CV20 and dissociates more slowly, suggesting that it may have greater efficacy.

A recent Phase II randomized controlled trial in relapsing remitting patients showed new brain MRI lesion activity was suppressed by over 99% in the first 24 weeks.

This evidence has given the go ahead to a Phase III randomized controlled trial with an active comparator of terephthalenamide.

As more is being learned about the immunologic underpinnings of multiple sclerosis and related disorders, it's certainly an exciting time to be in this field.

I think that was an excellent review of the newer therapies in MS, specifically the latest drug Ocrelizumab, which again was just approved by the FDA for the primary progressive and relapsing remitting MS just in March of last year.

I'm sure they like the dosing schedule.

That's true.

Once every six months is a good schedule for patients in terms of...

Compliance.

Yeah, compliance.

Yeah, it's definitely helpful in that regard.

And we look forward to the future B cell, the pleating therapies and other therapies for MS.

Thanks for joining me in the show, Chris.

Thanks for having me, Jim.

Dr. Christopher Perrone.

He currently serves as the Neuroimmunology Fellow at the Hospital of the University of Pennsylvania.

That's all for our show this week.

Thank you all so much for listening.

And if you like what you heard, but you haven't told us that you like the show, then tell us by reading the show on iTunes or Google Play or wherever you get your podcasts.

You can also follow us on Twitter at Brainwaves Audio or Facebook at facebook.com/brainwavespodcast.

The Brainwaves Podcast is produced out of Philadelphia, Pennsylvania, Jim Siegler, senior producer.

Incredible thanks to Dr. Christopher Perrone for joining on today's show and sharing his expertise on the topic.

The music for our program was courtesy of Steve Combs, Packey Derm, and Lee Rosefear.

I'm Jim Siegler and I'll talk to you again soon.

Bye.

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