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Listen to audio from accredited CME activities from Paradigm Medical Communications, featuring expert faculty discussions and the latest clinical insights. Visit the link in each episode description to access the full activity and claim CME credit.
Maria Dall’Era: Hello, everybody. Thank you very much for joining us for this
exciting podcast today. My name is Maria Dall’Era, and I’m the Chief of
Rheumatology at the University of California, San Francisco. My emphasis is on
studying various mechanisms of lupus, the treatment of lupus, outcomes in lupus,
and I care for many patients with lupus. I am grateful and honored to be joined today
by my wonderful colleague and friend, Dr Askanase, and I’ll let her introduce herself.
Anca Askanase: Hi. Such a pleasure to be joining Maria today for this podcast
where we will share with you some thoughts about new and emerging mechanisms
in the treatment of systemic lupus. I’m Anca Askanase. I’m the Chair of the
Department of Medicine and the Cadwell Professor of Medicine, Chief of
Rheumatology at Hospital for Special Surgery in New York City.
Maria: Great. Thank you so much, Anca. We’re going to focus this podcast today on
how we can impact on the B-cell compartment in lupus to try to improve outcomes in
our patients living with lupus and lupus nephritis. We’re living in a very exciting time
in lupus. I think you would agree, Anca, that we have this pipeline of new and
emerging therapies for the treatment of lupus and lupus nephritis like we’ve never
seen in the past.
One of the large classes of medications that we are seeing are those medications
that specifically target B cells, but in different ways. It’s very exciting. What we’d like
to do today is go through some of those therapies, but link those therapies to the
pathogenesis. How do these therapies actually impact the B-cell compartment?
Because there are different ways that we can target B cells in lupus.
Anca: I agree, Maria. This is a really exciting time for us as lupus investigators, for
patients living with lupus, for the world of scientific discovery. We have been very
fortunate to have new therapeutic options and to start being able to think about
remission, and actually considering remission as the target in lupus, but also starting
to think about the possibility of cures, which is unprecedented. I recall the days when
as good as it gets was our outcome measure, so I think that we’ve made enormous
progress.
This progress has been made possible by the new treatments. Some are FDA
approved, some in development, but truly a really major shift in the way we think
about lupus, and in the way we’re able to treat lupus, and in the outcomes, and in
making sure that people with lupus get back to their lives. I’m truly very excited about
this.
I agree that part of the major discoveries in lupus therapeutics have been in the B
cell compartment, and better understanding how to modulate and deplete some of
those cells. We have made so much progress since the early days of trying the first
anti-CD20 therapy in systemic lupus, and we all have been disappointed, but also
did not give up on CD20.
[We’ve been] disappointed because those initial clinical trials for rituximab in
systemic lupus and lupus nephritis did not achieve the primary endpoint, so that was
disappointing to us. I recall a publication that was called Rituxan: Wanted Dead or
Alive from the early days. When it became clear that while the trials were not
positive, we as lupus physicians really believed that targeting the B cell and this
particular medication was effective in treating lupus. A lot of observational studies,
and a lot of epidemiological work, suggested that we were correct. That targeting
CD20 with rituximab was actually providing good treatment benefits.
Since then we have been very fortunate that belimumab came around and taught us
about how to block BAFF, B-cell–activating factor, or BLyS, B-lymphocyte stimulator,
and how that impacted the world of lupus. Belimumab was the first treatment fully
approved by the FDA for the treatment of systemic lupus, in 2011. Fifteen years
later, we’re able to have a lot more treatment possibilities for people with lupus, both
in targeting B cells, but also in other therapeutic targets.
B Cell Targets in Lupus
Maria: I agree completely. And when we think about targeting B cells, I always like to
remember that B cells mediate disease via a variety of mechanisms. We often think
about the lineage cells as being the producers of autoantibodies. We know that
antinuclear antibodies are the sine qua non of lupus. And we know that, for example,
anti-double-stranded DNA antibodies, as well as other antibodies, are important in
mediating various mechanisms of the disease, including specifically lupus nephritis.
However, we also know that B cells have other roles, in terms of producing
inflammatory cytokines, costimulating T cells, and antigen presentation.
So by blocking the B-cell compartment, we actually can effect many changes that
can improve disease activity and reduce inflammation. I like to think about B-cell
maturation and differentiation as occurring in distinct stages. At each stage, whether
it’s pro-B, pre-B, naïve, plasma blast, plasma cell, memory cell, different antigens are
expressed on the surface. Examples would be CD19 at some of the earliest stages,
and CD20. The BAFF receptor, which is a key receptor for the molecule that you
mentioned, belimumab, which of course binds to BAFF receptor. It’s important to
think about which B lineage cells are expressing which of these antigens when we
think about which therapy we want to use to treat our patients. I always like to link
the therapies to the pathogenic pathways because it helps me understand how I’m
going to use these particular therapies. This is very helpful when we think about the
therapies.
Targeting BAFF
You already brought up a molecule that targets BAFF, which is a very important
cytokine in the TNF superfamily, and is very important in supporting B-cell
maturation and differentiation and survival at that transitional B cell stage.
It’s critical in that stage. Anca, you talked about the molecule belimumab and the fact
that it transformed the treatment of lupus over time. Maybe you could quickly go over
the high-level results from the key phase 3 trials, BLISS-52 and BLISS-76.
Anca: Both of those trials were run in parallel. The results from the BLISS-52 were
slightly more positive than the ones from BLISS-72. It was by the involvement of the
community of investigators and patients with lupus that this molecule was approved
for the treatment of lupus, and the first drug to be approved for lupus was a big deal.
Failure to do so would have resulted in a lot of delay in what we’ve seen to be almost
an explosion of new therapeutic drug development in the years that followed. So the
data in the beginning seemed like it was not as positive as we would have liked it to
be, and part of that is that this was the first large registrational trial. We were not
quite sure what to do with steroids, we were not quite sure what to do with the
background medications. We were not insisting on steroid taper throughout the
duration of the study. All of those things resulted in a lower delta between treatment
and placebo. It was about 9% for the BLISS-76 study. At the time the rheumatology
community felt a little disappointed, because we all had hoped for a much larger
difference between treatment and placebo, but throughout subsequent studies of the
subcutaneous formulation, the lupus nephritis, of belimumab trials, the confidence in
the efficacy of belimumab in lupus and lupus nephritis increased.
I think it’s very clear now that belimumab is a very effective drug for the treatment of
lupus with good efficacy in the musculoskeletal, mucocutaneous, and immunologic
domains. It also has shown a decrease in the risk of flares. All of these data suggest
good efficacy of belimumab. And it is the first one that has actually allowed us to
consider the possibility of disease modification in lupus. The other thing that also has
become apparent over the last 15 years of studying belimumab is that this is a very
safe drug. It turns out that the side effects between the treatment and the placebo
arms are very similar. So I think that both our confidence in the efficacy, but also the
safety of belimumab, has increased over time.
Maria: Agree. And now, of course, we also have the approval in lupus nephritis, as a
component of triple therapy. You and I had the pleasure of working on those
guidelines for the American College of Rheumatology. Also, belimumab as part of
triple therapy is also endorsed by the EULAR recommendations, which were recently
published as well.
Dual Targeting APRIL and BAFF
Now, when we think about the mechanism of action of belimumab in targeting BAFF,
which, again, is that key cytokine for B-cell survival and differentiation at that
transitional cell stage, this brings to mind another cytokine, which I think of as kind of
a homologous cytokine to BAFF, which is APRIL. We know that APRIL is very
important in plasma cell survival. Specifically, through its interaction with a cell
surface receptor called BCMA. There is a molecule that has been studied called
telitacicept, which is a dual BAFF/APRIL inhibitor. The question in the community
was, are we going to see better efficacy if we block both of those cytokines? And the
second question is, is there going to be a problem with safety if we block both of
those cytokines? Because, as you said, belimumab has been shown to be an
extraordinarily safe medication for our patients with lupus, and we have over a
decade of experience now using it. If we also block the plasma cell compartment
with an APRIL inhibitor, are we going to see problems in terms of changes in our
protective antibody status and things like that? So we do have this molecule,
telitacicept. Many of our listeners might have seen the New England Journal
publication last year, which was the phase 3 trial of this molecule, all done in China,
with the primary endpoint at week 52 of the SRI-4, the same endpoint that was used
in the belimumab trials. This trial in China showed extraordinary efficacy. In fact, the
rates of SRI-4 were higher than we’ve ever seen before, which was very interesting.
They also showed glucocorticoid sparing. However, there were some signals of
adverse events that were not seen in the pure belimumab trials. Again, this is not
surprising, based upon the mechanism of action of this drug, but there were more
patients who experienced declines, for example, in serum IgG, IgM, some infectious
adverse events. Interestingly, this molecule, to the best of my knowledge, is not
moving forward right now in the United States. Is that your impression as well?
Anca: That is correct. There’s a lot of interest in new drug development in lupus, and
I think that this was not a decision based on concerns about the drug or its safety.
This was a decision based on, will this drug be able to find its place amongst so
many other therapeutic options?
Maria: I agree, and I think it’s going to be interesting, because it is a very interesting
mechanism. Targeting both of these cytokines and what are we going to see in terms
of differences in organ system manifestation responses, in biomarker responses. I
think that we’re going to learn from the experience of our Chinese colleagues.
B-cell Depletion Via the BAFF Receptor
Another molecule that I find very exciting, and that has completed phase 2, is a
molecule called ianalumab. This is a very interesting one, isn’t it, Anca? Why don’t
you describe how it acts first.
Anca: It has a dual mechanism. It acts through both BAFF blockade but also
producing some ADCC through afucosylation of the Fc receptor. It does some B-cell
depletion, but also BAFF blockade. In the early days of using B-cell depletion, there
was the concern that as B cells are depleted, there may be a surge of BAFF that
could be responsible for some immediate worsening of some of the skin or arthritis
manifestations in patients where depletion has occurred. This is intriguing as a
possibility of getting around some of those concerns and some of those quick after
rituximab or obinutuzumab flares. I think that these early data are very exciting. The
fact that the study was able to have an incredibly low placebo response is
unprecedented. The SRI-4 response for the placebo arm of that study was 9%.
Normally it is somewhere in the 30% to 40% range.
The study was designed with much more stringent inclusion-exclusion criteria and
adjudication of outcomes. This is probably responsible for this much lower placebo
response for the treatment arm. The response rate was 44%. The absolute
difference is over 30%. This was a really a well thought through and very well
executed trial. Now we’re waiting to hear about their phase 3 data and how that’s
going to stand up to these really intriguing response rates from the phase 2.
The study also reported normalization of complement, decreases in autoantibodies,
CD19, B-cell depletion, and also surprisingly fewer adverse events in the treatment
arm versus placebo. All in all, a really robust phase 2 response. Hopefully we will
understand a little better all of these in their phase 3.
Type II Anti-CD20
Maria: Excellent. This brings us to our next molecule. We’re talking now about B-cell
depletion. We’ve moved from impacting B-cell survival with belimumab, and also
similarly with telitacicept, to ianalumab, which is a B-cell depletion agent, and now
we’re going to talk about another B-cell depleter, which is obinutuzumab, which has
garnered a tremendous amount of excitement. As our listeners know, we have
positive phase 3 trials, both in lupus nephritis and in extrarenal lupus. And we have
the FDA approval in 2025 for lupus nephritis, and we’re awaiting approval for
extrarenal lupus. Anca, you mentioned this at the very beginning of this podcast, that
in the early 2000s, there was a lot of excitement about rituximab, which I think of as
the prototypic first-generation anti-CD20. A chimeric molecule, it had its limitations,
as you mentioned. It’s an imperfect B-cell depleter, both in the peripheral blood and
in the tissues. Now we have this next-generation molecule, obinutuzumab, which
targets the same cell surface molecule, CD20, but it targets it in a different way.
When you think about rituximab and obinutuzumab, we think about these categories
of anti-CD20s. Rituximab is an example of a type 1 anti-CD20, and obinutuzumab is
an example of a type 2. Type 1 and type 2 differ based upon their biochemical and
structural properties. Obinutuzumab, as you mentioned early on, is a
glycoengineered molecule with afucosylation of its Fc region, which enables better
binding to Fc gamma receptor 3A, which then enables better antibody-dependent
cellular cytotoxicity. Also with this molecule, there’s less internalization of CD20.
We see a lot of internalization of CD20 with rituximab, which we think impacts its
efficacy. And importantly, with obinutuzumab, one of the reasons why we think that
there’s such better not only peripheral B-cell depletion, but importantly, tissue B-cell
depletion, we think the reason for that is direct kind of apoptotic cell death induced
by this molecule in the tissues. It’s very exciting what we’ve seen, and that leads me
to talking about the phase 3 extrarenal trial, which was ALLEGORY. Anca, do you
want to talk a little bit about this trial?
Anca: Another really exciting study where some of the rules of how phase 3 clinical
trials work were a little broken. We were concerned that if placebo response rates go
past 40%, the trial is very unlikely to prove efficacy. And yet, there it is. This is the
trial where the placebo response was 53.5%, but the treatment arm ended up being
76.7%. This level of efficacy, almost 77% of the patients had an SRI-4 response—it’s
unprecedented. We are entering a time of better understanding of how to design
clinical trials so that we can ensure that effective drugs show efficacy. Part of this
comes down to the inclusion criteria. The study required patients to not only be
autoantibody positive, but also to have low complement. Probably that is the reason
both for the high placebo response, and also for the large treatment effect. So this
treatment difference is 24%. That is quite a large difference. So both a large
treatment difference and percentage of responders. So this drug is an effective drug.
We know this. We have been accustomed to using anti-CD20 therapy, and now we
have efficacy data that is paralleling our clinical impressions that B-cell depletion is
highly effective in the treatment of patients with systemic lupus. Now, as expected,
the adverse events were slightly higher in the treatment arm compared with placebo.
There were some infectious complications, infusion reactions, but none that have
created major concerns for investigators, patients, or clinicians taking care of people
with lupus. All in all, we’re all eagerly awaiting the FDA approval for obinutuzumab
for nonrenal lupus while we’re all starting to use more obinutuzumab for the
treatment of lupus nephritis.
Now Maria, you already mentioned that we have been thinking about triple therapy,
and we have been using triple therapy for lupus nephritis. You and I have thought
about this when we were putting together the American College of Rheumatology
guidelines for the treatment of lupus nephritis, but obinutuzumab was not available at
the time. So the guidelines will probably need to be updated to include the option of
obinutuzumab. Triple therapy for lupus nephritis includes steroids, a mycophenolic
acid analog, and an advanced therapy, be it with belimumab, voclosporin, and we
submit to you now that obinutuzumab should also be an option for triple therapy for
lupus nephritis.
Maria: I fully agree. The evidence that underlies exactly what Anca just stated is the
REGENCY phase 3 trial, which demonstrated efficacy of obinutuzumab versus
placebo in combination with background mycophenolate. We have the evidence that
obinutuzumab should be included as an option for triple therapy. In fact, the EULAR
recommendations, which came out after the ACR, have endorsed obinutuzumab as
another potential option for triple therapy.
Anca: Isn’t this extraordinary? We have 3 approved treatments for lupus nephritis,
just allowing for more nuanced treatment for people with lupus, and also allowing for
the possibility of thinking of combination therapies, just because our efficacy
outcomes, while they are a lot better than they have been in the past, the response
rates, the complete renal response is still a little shy of 50%. Thinking about how to
improve those response rates with either more effective treatment, but also thinking
about combination regimens is quite timely. I think that what we also learned is that
the anti-CD20 treatments are not all quite the same. It seems that tissue depletion
with rituximab, with a first-generation type 1 anti-CD20 therapy, is not as robust as it
is with obinutuzumab, both in the periphery and in the tissue. Some data from the
REGENCY lupus nephritis trial suggest that obinutuzumab allows for a much deeper
B-cell depletion in tissues, and that is probably responsible for the improved efficacy.
Maria: I agree. And I think it’s very exciting. In the REGENCY trial, we have that
subset of participants who had repeat biopsies at week 76, which was the time of the
primary endpoint. As you said, Anca, we saw very nice depletion of both B lineage
cells in general, and also in plasma lineage cells, in the tissue in the obinutuzumab
patients versus the placebo patients. It’s really nice to have that tissue-level data
supporting this mechanism of action. We have not had that before. I completely
agree with what you said in terms of thinking about in the future where this field is
going, is how to combine these targeted therapies. That’s why it’s so important. To
understand, what is the mechanism of these agents? What cells are we actually
targeting? And in what way, so we can think logically and rationally about how to
perhaps combine them in the future as we move forward.
This brings us to the next large group of therapies, which you mentioned at the very
top of the podcast, Anca, which are the cell therapies. Again, we’ve come from B-cell
modulation with survival factors, to B-cell depletion therapies.
Bispecific T-Cell Engagers
Now we’re going to talk about the excitement about another class of therapies, the
cell therapies that also lead to B-cell depletion, but by different mechanisms than
what we’ve already spoken about. We’re going to start this off by talking about the
class of molecules called bispecific T-cell engagers. I find these to be exciting
molecules, and I like to think in broad strokes about bispecific T-cell engagers, that
there are 2 major categories. The first are the very small, short half-life molecules
that often require continuous infusions, and these are called the BiTEs. The other
large category is more of a formal IgG construct. That has a larger molecule, longer
half-life. The other thing that we have to think about, besides the structure that I’ve
just mentioned, is what are the targets? We talked in the very beginning of the
podcast about different antigens expressed on various B cells at different stages of
development.
We have CD19 that’s expressed early, and all the way through to some plasma
blasts that also express CD19. But CD19 is extinguished when a B cell gets to a
long-lived plasma cell stage. That’s one of the limitations. CD20 appears later in the
pre-B, but CD20 is not on the plasma blast. Then we have BCMA, which is highly
expressed on the long-lived plasma cell. We can think about these different antigens,
where they’re expressed and as we think about how we use these bispecific T-cell
engagers, and how we use more of the traditional cell therapies.
Anca: BCMA is a very interesting target. I think that we have started to use that
target in some of the T-cell engagers. One that comes to mind is teclistamab, which
has already shown some early efficacy data in people with systemic lupus and other
autoimmune diseases. You were also mentioning the CD19 blinatumomab, which
also has shown efficacy in phase 2 trials. Data is accumulating very quickly about
the use of T-cell engagers. T-cell engagers are in use and have been approved for
the treatment of hematologic malignancies, so there is a little bit of a body of data in
terms of safety and mechanisms of action. They are obviously new to the
autoimmune space, and there’s a lot more learning that we all have embarked on
and better understanding of how these new molecules work, and where they might fit
in the treatment algorithm.
But there’s another molecule that I think needs to be included here. That is the T-cell
engager that engages the CD20 on the B cells and the CD3 on the T cell to create
that synapse between the T and the B cells that ultimately results in killing of what
we hope are the pathogenic B cells. Data from this particular mechanism with a drug
called mosunetuzumab has already been published and it showed great promise in
15 patients with systemic lupus. So early data, small numbers, but interesting
mechanism of action.
The reason why there’s more excitement about T-cell engagers in systemic lupus is
the fact that they don’t require preconditioning. They can be off the shelf, so
available for immediate use. The safety may be slightly better than what is seen with
cell therapy. There’s a lot more to come about T-cell engagers.
CAR-T Cells in SLE
Anca: I think that we’d like to spend a few minutes talking about cell therapy,
because the early publication from the Erlangen group in September 2023 truly
galvanized investigators, patients, and therapeutic drug developers into embarking
on this new way of thinking about therapy as opposed to creating a monoclonal
antibody. We’re now thinking about living drugs, taking the patient’s own cells,
engineering them, and putting them back into the patient, or engineering healthy
donor T cells and using those to target pathogenic B cells. So the cells are made
from the patient’s own T cells. Those are the autologous CAR Ts. Those that are
made from healthy donors, they’re allogeneic CAR Ts. A lot of data has
accumulated. Published reports include somewhere over 200 patients already have
been treated with these therapies. The world is moving very quickly to better
understand the role of these living drugs in the treatment of lupus. I think that we’re
also struggling with whether we should be targeting against CD19, BCMA, or can we
possibly target both? I think that this is a truly revolutionary time to think about the
possibilities of these very powerful modalities of treatment. The data from the initial 5
patients and the 8 patients reported suggested cures, suggested the possibility of
immune reset—so remission off medication. Truly, we never dared to think about this
until now.
Maria: I agree. I think that’s really what has set apart this class of agents. As you
said, we like to think of them as living drugs, because these T cells that are reinfused
back into our patients are actively proliferating, secreting cytokines, which also leads
to some of the potential toxicities that we are learning how to deal with. Things like
cytokine release syndrome and another one called ICANS, which is a neurologic
toxicity, which we’re learning how to treat and to prophylax against. But it’s truly
revolutionary. As you said, the background therapies have been removed. You
know, we think about all the trials that we have mentioned in this podcast thus far, up
until now, all of the new agents were added to background therapies. Whereas in the
cell therapy trials, the background agents are taken off. So that is unique. As you
said, this notion of "resetting the immune system." We’re trying to define what that
means, aren’t we?
Anca: Yes.
Maria: As a community. But nevertheless, it’s exciting and interesting. The other
thing I think, when I think in broad strokes about the CAR T cells, of course there are
also other CARs. There’s CAR-NK for example. You think about the CAR T cells,
and we think about the T-cell engagers. What sets these apart from the other
molecules that we talked about is that the T-cell engagers and the CAR Ts don’t
need any other effector cells to lead to the B-cell depletion, the B cell killing, They
don’t need any other cells. They are the cells. The T cells are the cells that are
mediating the B-cell killing. Whereas with all the other therapies that we talked about
that are B-cell depletion agents, we talked about rituximab, we talked about
obinutuzumab, and we talked about ianalumab. Those monoclonal antibodies
depend on other effector cells to mediate the killing, whether they’re monocyte and
macrophages or they are NK cells. That’s also a distinguishing feature with the CAR
Ts and the T-cell engagers.
I think as we move forward, as you said, Anca, this is an exciting time now that we
have all of these therapies that we’re going to have to choose from, and we’re going
to have to decide, and we’re going to have to learn and do studies to understand
which of our patients would benefit from which therapy at which time, then think
about combinations as we move forward. So, it’s truly a hopeful time for our patients
living with lupus, with all of these options. And I believe the outcomes for our patients
are so much better than they were even 5 years ago.
Anca: Absolutely. I could not agree more. I think that the future looks brighter than
we ever hoped for. I think that this is what truly makes this time as lupus
investigators unique and very, very special. We’re very grateful to you for having
joined us for this podcast. Thank you for listening, and we hope to hear from you,
and we hope to talk to you very soon.
Maria: Yes. Thank you so much for joining us, and we do hope to be able to see you
at upcoming meetings and on upcoming podcasts. Thank you so much.