WEBVTT
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My name is Jane Salmon.
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I'm a rheumatologist and a translational scientist at the Hospital
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for Special Surgery in New York City, and I'm a
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professor of medicine at Weill Cornell Medicine.
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Can you provide an overview of antiphospholipid syndrome and the
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risk of pregnancy complications?
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Antiphospholipid syndrome is relatively rare. There are probably 40 per 100,000
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people who have it. It typically is diagnosed in early years.
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It's kind of unusual to be diagnosed after age 50,
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though it's certainly possible. It's defined by clinical manifestations and
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laboratory tests. And the clinical manifestations are thrombosis in arteries
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or veins and pregnancy complications. The pregnancy complications are placenta-mediated,
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so preeclampsia, placental insufficiency, growth restriction, intrauterine fetal death, and
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also recurrent early miscarriages. The placenta-mediated adverse outcomes are way
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more specific for the syndrome than recurrent miscarriages, which can
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be caused by many things. The laboratory tests are called
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antiphospholipid antibodies. That's why it's antiphospholipid syndrome. And there are
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three laboratory tests. Two of them are autoantibodies that are
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measured typically by an ELISA kind of assay. One is
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called anticardiolipin and one is called anti-beta-2-GP1.
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And the other one, which is the most.
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Specific test and gives you the highest risk for a
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pregnancy complication or thrombosis, is called a lupus anticoagulant.
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It's a functional test. It's not an anticoagulant.
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It's a test in the lab where the serum from
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the patient causes an anticoagulant effect in the test tube,
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but that's because it has an antibody that in the
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body actually triggers clotting. It makes no sense, but it's
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just called an LA test.
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Just forget about the misnomer.
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And another thing that antiphospholipid syndrome is seen in, you know,
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20% of patients with lupus also. APS is an autoimmune
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disease where you have a range of autoantibodies that recognize
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constituents that are expressed quite broadly. So in the pregnancy situation,
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the antibodies clearly target to the developing placenta or the
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trophoblasts just because of some of the surface proteins on
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those cells, on that tissue. So in terms of the
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pregnancy complications, antiphospholipid antibodies are probably one of the highest
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risk factors, most important.
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Causes of these pregnancy complications.
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So certainly if you have 100 people with preeclampsia, most
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of them won't have antiphospholipid syndrome. But if you have many,
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many people with a lupus anticoagulant, they may have preeclampsia
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or placental insufficiency in severe forms.
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It's predominantly females, but not like.
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Lupus, which is 90% females. Men will get it, For example,
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it'll get picked up. We don't know the underlying frequency
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of the antibody presence because we don't check the whole population.
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But in terms of men, if a man has an
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unprovoked pulmonary embolus, it's a very important thing to think
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about as the cause.
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What is the current standard treatment and why is there
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a need for a better option?
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Well, I want to tell you about the conventional treatment.
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I think that's really important.
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So because it was described as a disease of thrombophilia,
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The standard of care treatment, certainly of artery or vein clotting,
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is you heparinize the person.
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And then you convert them to warfarin. The DOACs are
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not effective in this disease.
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And because of the clotting issue, it became dogma that
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the placental manifestations were also because of blood clots. But
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we did studies in animal models that challenge that dogma
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because antibody mediated diseases.
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There are many of them, autoimmune diseases, and they're triggered
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by the disease, the clinical organ damage, the target organ
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destruction is triggered by inflammation.
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Can you provide a history of the research that led
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to this new therapy option?
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So what we discovered was that in mouse models of
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antiphospholipid syndrome, Inflammation occurred at the maternal-fetal interface. And if
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you blocked inflammation, that is you got rid of inflammatory
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cells or you inhibited complement activation or you inhibited TNF,
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blocked TNF, you rescued the mouse models of antiphospholipid-mediated pregnancy complications.
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So that was really the seminal discovery that we made.
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And so then the question was, how can you apply
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this to people? What does this mean?
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You know, we don't want to cure mass pregnancy complications.
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And we also studied another mass model of preeclampsia. There
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was a spontaneous mass model, and we were able to rescue,
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prevent preeclampsia in these mice when they became pregnant. So
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what we had to do was figure out who was
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at the highest risk for pregnancy complications among people with
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antiphospholipid antibodies. And we found that those people with the
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true syndrome, not just the antibodies, either placenta-mediated adverse outcomes
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or previous thromboses, and who had this lupus anticoagulant test,
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those individuals in our prospective observational study, we studied 500
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patients with, without antibodies, with lupus, quite a range.
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And the ones that did worst were had APS and
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a lupus anticoagulant.
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And of those patients, about 40% had an adverse outcome.
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It was a big number, big number.
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So in our study, an adverse outcome was a fetal
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death greater than 12 weeks, preeclampsia or placental insufficiency less
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than 34 weeks, requiring delivery less than 34 weeks, Those
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are the key definitions, one or both of those outcomes.
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So that's a high bar.
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It's not like preeclampsia at 38 weeks where the baby's
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probably going to be okay.
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So it's preeclampsia or placental insufficiency, so.
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Poor growth, poor fetal development, and requiring delivery before 34 weeks.
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So using the target we identified with the mice and
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the risk stratification algorithm, we developed through the observational study,
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we proposed to study TNF blockade in women with antiphospholipid
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syndrome who had a lupus anticoagulant and were on standard
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of care, which is low-dose aspirin and heparin, that's standard
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of care in all these women, and many of them
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had failed standard of care before.
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It was an open-label trial.
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It was not randomized because these women would not consider
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placebo because the vast, 88% of the women we enrolled
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over seven years, 88% of them had had at least
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one pregnancy with the outcome I just described. And only
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37% of those women had a live birth that survived
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hospital discharge. So this was an extremely high risk, highly
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motivated patient population. Over seven years, we enrolled 51 patients.
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Six of them were excluded from the modified intention to
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treat because either they had a pregnancy loss before 10
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weeks or they had a lethal genetic abnormality. So of
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the 45 modified intention to treat patients, Each patient started
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their TNF blocker within eight weeks, six days gestation. So
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many of them were screened before they were pregnant. They
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had had preeclampsia or something like that before, and they
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wanted to know what could be offered to them beyond
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standard of care if they were to embark on another pregnancy.
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We had no dropouts.
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We had very few patients who declined enrollment who would
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have been eligible despite enrolling during COVID.
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This is a group of people who.
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Are desperate and have had life-threatening complications.
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What's the drug? Let me tell you about the drug.
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The drug is called Sertalizumab.
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It's a drug that does not cross the placenta because
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it doesn't have an IgG piece.
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It doesn't bind to FCRN.
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And that's why we selected it. The dose we used
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is the same dose that is approved for rheumatoid arthritis
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and Crohn's disease.
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We didn't dose adjust.
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And patients got drug from week eight till week 28.
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Half-life is 14 days, so generally by the time they delivered,
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there was probably, even if there was a minuscule amount
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that got into the baby, though that's generally unmeasurable, it
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would have been cleared. And the issue about TNF treatment
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during pregnancy, it's not teratogenic, it's not dangerous, but if
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you use a TNF blocker with an FCPs, the vaccine
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schedule in the babies have to be changed because they're
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mildly immunocompromised till they clear all the TNF antibody. So
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the results of the trial are predetermined endpoint was since
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the adverse outcome rate was around 40, it was actually 44%,
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but around 40, our goal.
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Was to get it down to 20.
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Could this intervention result in a 50% improvement in outcome?
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And we needed 45 patients. to prove that we could
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do it. And we got 45 patients. That's when we
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had to stop the study because that was the definition.
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45 valuable patients. And we met our end point. So
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in the modified intention to treat group, it was 20%.
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What 20% adverse outcome, but what is most, to me,
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most interesting is The challenge we've had in defining the
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control group. So we use the historical control group from
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the longitudinal study. That was a 44% adverse echo. We
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then looked at the previous pregnancies of the patients enrolled
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in the IMPACT trial. And there were 135 pregnancies. And
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56 of them were treated with standard of care. because
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the early ones, the diagnosis hadn't been made. They didn't
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know they had antivascular syndrome. And of those standard of
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care treated pregnancies, 70% of them had an adverse outcome.
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So this is the same people who were 20% on
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the treatment. The other important thing is of those 135
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pregnancies that those women had, 37% of them brought home
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a live baby. And in the impact, 95% of the
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babies born, live born, 95% of the patients had live
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born babies. So there were a few that had early
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preeclampsia or intrauterine death. And every live born baby survived
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to hospital discharge. So 95% of the people in the
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trial brought home a healthy child, even if they met
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the outcome. And that's because The previous pregnancies of these women,
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their gestational age at the time they developed preeclampsia was 24, 25,
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26 weeks. And the few who had preeclampsia in the trial,
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it was 30 plus weeks. And at that point, the fetus,
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even if it's growth restricted, is in much better shape.
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So we.
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didn't eliminate the adverse outcomes, but they were much less
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severe and were challenged because it's not a randomized placebo-controlled trial.
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The patients, some of them said to us when we
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screened them, if you can't offer me something beyond standard
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of care, I'm not gonna embark upon another pregnancy. The
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other supportive piece of information is that 10 of the
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patients from IMPACT, including one who had an adverse outcome
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and didn't bring home a live baby, 10 more patients
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had subsequent pregnancies.
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And all of them were successful with no outcome.
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But, you know, they were in the trial already, so
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they can't count, but they're, I think, meaningful data.
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What does the breakthrough therapy designation mean for moving forward
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with clinical trial designs?
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It means that the FDA recognizes this is an important
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unmet need. It means they think that our study has potential.
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And it means that they may accelerate the review. But
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there's no other study ongoing. Either our data will make
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the bar or they won't. So they're going to look
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at our data and all the different versions we conceived
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of as background control.
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Is there anything you would like to add about the
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patient population?
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We learned a great deal from this partnership we had
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with the patients who wanted to be in research. who
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wanted to look for options for themselves and others. And
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we were fortunate that the regulators and the ethics committees
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and all of that were compelled by the preliminary data,
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the safety of the drug, because there's a lot of
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experience with Sertalizumab in pregnancy, in patients with rheumatoid arthritis
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and inflammatory bowel disease, but also the mouse studies were
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pretty compelling mechanistically. By being brave enough, these women, to
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be in this study, I think we learned a lot.
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And I think they were grateful for the opportunity. So
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my pitch is we have to do research. We have
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to help the lives and the health of pregnant women
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and protect them. by doing research and not excluding them
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or protecting them from research. I think it's a radical
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idea that you're going to give a biologic to a
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pregnant person to help her and not say she's excluded
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from a trial because she's a pregnant person.
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My name is Jane Salmon.
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I'm a rheumatologist and a translational scientist at the Hospital
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for Special Surgery in New York City, and I'm a
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professor of medicine at Weill Cornell Medicine.
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Can you provide an overview of antiphospholipid syndrome and the
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risk of pregnancy complications?
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Antiphospholipid syndrome is relatively rare. There are probably 40 per 100,000
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people who have it. It typically is diagnosed in early years.
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It's kind of unusual to be diagnosed after age 50,
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though it's certainly possible. It's defined by clinical manifestations and
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laboratory tests. And the clinical manifestations are thrombosis in arteries
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or veins and pregnancy complications. The pregnancy complications are placenta-mediated,
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so preeclampsia, placental insufficiency, growth restriction, intrauterine fetal death, and
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also recurrent early miscarriages. The placenta-mediated adverse outcomes are way
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more specific for the syndrome than recurrent miscarriages, which can
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be caused by many things. The laboratory tests are called
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antiphospholipid antibodies. That's why it's antiphospholipid syndrome. And there are
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three laboratory tests. Two of them are autoantibodies that are
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measured typically by an ELISA kind of assay. One is
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called anticardiolipin and one is called anti-beta-2-GP1.
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And the other one, which is the most.
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Specific test and gives you the highest risk for a
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pregnancy complication or thrombosis, is called a lupus anticoagulant.
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It's a functional test. It's not an anticoagulant.
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It's a test in the lab where the serum from
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the patient causes an anticoagulant effect in the test tube,
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but that's because it has an antibody that in the
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body actually triggers clotting. It makes no sense, but it's
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just called an LA test.
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Just forget about the misnomer.
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And another thing that antiphospholipid syndrome is seen in, you know,
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20% of patients with lupus also. APS is an autoimmune
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disease where you have a range of autoantibodies that recognize
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constituents that are expressed quite broadly. So in the pregnancy situation,
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the antibodies clearly target to the developing placenta or the
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trophoblasts just because of some of the surface proteins on
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those cells, on that tissue. So in terms of the
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pregnancy complications, antiphospholipid antibodies are probably one of the highest
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risk factors, most important.
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Causes of these pregnancy complications.
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So certainly if you have 100 people with preeclampsia, most
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of them won't have antiphospholipid syndrome. But if you have many,
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many people with a lupus anticoagulant, they may have preeclampsia
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or placental insufficiency in severe forms.
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It's predominantly females, but not like.
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Lupus, which is 90% females. Men will get it, For example,
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it'll get picked up. We don't know the underlying frequency
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of the antibody presence because we don't check the whole population.
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But in terms of men, if a man has an
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unprovoked pulmonary embolus, it's a very important thing to think
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about as the cause.
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What is the current standard treatment and why is there
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a need for a better option?
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Well, I want to tell you about the conventional treatment.
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I think that's really important.
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So because it was described as a disease of thrombophilia,
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The standard of care treatment, certainly of artery or vein clotting,
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is you heparinize the person.
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And then you convert them to warfarin. The DOACs are
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not effective in this disease.
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And because of the clotting issue, it became dogma that
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the placental manifestations were also because of blood clots. But
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we did studies in animal models that challenge that dogma
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because antibody mediated diseases.
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There are many of them, autoimmune diseases, and they're triggered
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by the disease, the clinical organ damage, the target organ
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destruction is triggered by inflammation.
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Can you provide a history of the research that led
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to this new therapy option?
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So what we discovered was that in mouse models of
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antiphospholipid syndrome, Inflammation occurred at the maternal-fetal interface. And if
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you blocked inflammation, that is you got rid of inflammatory
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cells or you inhibited complement activation or you inhibited TNF,
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blocked TNF, you rescued the mouse models of antiphospholipid-mediated pregnancy complications.
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So that was really the seminal discovery that we made.
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And so then the question was, how can you apply
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this to people? What does this mean?
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You know, we don't want to cure mass pregnancy complications.
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And we also studied another mass model of preeclampsia. There
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was a spontaneous mass model, and we were able to rescue,
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prevent preeclampsia in these mice when they became pregnant. So
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what we had to do was figure out who was
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at the highest risk for pregnancy complications among people with
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antiphospholipid antibodies. And we found that those people with the
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true syndrome, not just the antibodies, either placenta-mediated adverse outcomes
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or previous thromboses, and who had this lupus anticoagulant test,
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those individuals in our prospective observational study, we studied 500
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patients with, without antibodies, with lupus, quite a range.
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And the ones that did worst were had APS and
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a lupus anticoagulant.
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And of those patients, about 40% had an adverse outcome.
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It was a big number, big number.
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So in our study, an adverse outcome was a fetal
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death greater than 12 weeks, preeclampsia or placental insufficiency less
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than 34 weeks, requiring delivery less than 34 weeks, Those
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are the key definitions, one or both of those outcomes.
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So that's a high bar.
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It's not like preeclampsia at 38 weeks where the baby's
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probably going to be okay.
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So it's preeclampsia or placental insufficiency, so.
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Poor growth, poor fetal development, and requiring delivery before 34 weeks.
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So using the target we identified with the mice and
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the risk stratification algorithm, we developed through the observational study,
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we proposed to study TNF blockade in women with antiphospholipid
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syndrome who had a lupus anticoagulant and were on standard
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of care, which is low-dose aspirin and heparin, that's standard
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of care in all these women, and many of them
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had failed standard of care before.
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It was an open-label trial.
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It was not randomized because these women would not consider
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placebo because the vast, 88% of the women we enrolled
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over seven years, 88% of them had had at least
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one pregnancy with the outcome I just described. And only
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37% of those women had a live birth that survived
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hospital discharge. So this was an extremely high risk, highly
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motivated patient population. Over seven years, we enrolled 51 patients.
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Six of them were excluded from the modified intention to
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treat because either they had a pregnancy loss before 10
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weeks or they had a lethal genetic abnormality. So of
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the 45 modified intention to treat patients, Each patient started
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their TNF blocker within eight weeks, six days gestation. So
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many of them were screened before they were pregnant. They
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had had preeclampsia or something like that before, and they
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wanted to know what could be offered to them beyond
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standard of care if they were to embark on another pregnancy.
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We had no dropouts.
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We had very few patients who declined enrollment who would
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have been eligible despite enrolling during COVID.
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This is a group of people who.
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Are desperate and have had life-threatening complications.
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What's the drug? Let me tell you about the drug.
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The drug is called Sertalizumab.
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It's a drug that does not cross the placenta because
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it doesn't have an IgG piece.
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It doesn't bind to FCRN.
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And that's why we selected it. The dose we used
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is the same dose that is approved for rheumatoid arthritis
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and Crohn's disease.
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We didn't dose adjust.
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And patients got drug from week eight till week 28.
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Half-life is 14 days, so generally by the time they delivered,
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there was probably, even if there was a minuscule amount
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that got into the baby, though that's generally unmeasurable, it
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would have been cleared. And the issue about TNF treatment
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during pregnancy, it's not teratogenic, it's not dangerous, but if
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you use a TNF blocker with an FCPs, the vaccine
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schedule in the babies have to be changed because they're
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mildly immunocompromised till they clear all the TNF antibody. So
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the results of the trial are predetermined endpoint was since
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the adverse outcome rate was around 40, it was actually 44%,
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but around 40, our goal.
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Was to get it down to 20.
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Could this intervention result in a 50% improvement in outcome?
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And we needed 45 patients. to prove that we could
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do it. And we got 45 patients. That's when we
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had to stop the study because that was the definition.
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45 valuable patients. And we met our end point. So
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in the modified intention to treat group, it was 20%.
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What 20% adverse outcome, but what is most, to me,
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most interesting is The challenge we've had in defining the
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control group. So we use the historical control group from
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the longitudinal study. That was a 44% adverse echo. We
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then looked at the previous pregnancies of the patients enrolled
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in the IMPACT trial. And there were 135 pregnancies. And
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56 of them were treated with standard of care. because
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the early ones, the diagnosis hadn't been made. They didn't
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know they had antivascular syndrome. And of those standard of
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care treated pregnancies, 70% of them had an adverse outcome.
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So this is the same people who were 20% on
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the treatment. The other important thing is of those 135
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pregnancies that those women had, 37% of them brought home
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a live baby. And in the impact, 95% of the
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babies born, live born, 95% of the patients had live
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born babies. So there were a few that had early
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preeclampsia or intrauterine death. And every live born baby survived
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to hospital discharge. So 95% of the people in the
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trial brought home a healthy child, even if they met
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the outcome. And that's because The previous pregnancies of these women,
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their gestational age at the time they developed preeclampsia was 24, 25,
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26 weeks. And the few who had preeclampsia in the trial,
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it was 30 plus weeks. And at that point, the fetus,
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even if it's growth restricted, is in much better shape.
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So we.
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didn't eliminate the adverse outcomes, but they were much less
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severe and were challenged because it's not a randomized placebo-controlled trial.
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The patients, some of them said to us when we
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screened them, if you can't offer me something beyond standard
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of care, I'm not gonna embark upon another pregnancy. The
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other supportive piece of information is that 10 of the
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patients from IMPACT, including one who had an adverse outcome
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and didn't bring home a live baby, 10 more patients
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had subsequent pregnancies.
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And all of them were successful with no outcome.
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But, you know, they were in the trial already, so
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they can't count, but they're, I think, meaningful data.
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What does the breakthrough therapy designation mean for moving forward
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with clinical trial designs?
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It means that the FDA recognizes this is an important
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unmet need. It means they think that our study has potential.
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And it means that they may accelerate the review. But
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there's no other study ongoing. Either our data will make
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the bar or they won't. So they're going to look
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at our data and all the different versions we conceived
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of as background control.
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Is there anything you would like to add about the
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patient population?
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We learned a great deal from this partnership we had
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with the patients who wanted to be in research. who
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wanted to look for options for themselves and others. And
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we were fortunate that the regulators and the ethics committees
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and all of that were compelled by the preliminary data,
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the safety of the drug, because there's a lot of
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experience with Sertalizumab in pregnancy, in patients with rheumatoid arthritis
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and inflammatory bowel disease, but also the mouse studies were
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00:16:01.289 --> 00:16:07.889
pretty compelling mechanistically. By being brave enough, these women, to
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00:16:07.950 --> 00:16:10.559
be in this study, I think we learned a lot.
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And I think they were grateful for the opportunity. So
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my pitch is we have to do research. We have
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to help the lives and the health of pregnant women
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and protect them. by doing research and not excluding them
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or protecting them from research. I think it's a radical
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idea that you're going to give a biologic to a
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pregnant person to help her and not say she's excluded
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from a trial because she's a pregnant person.
