For U.S. Healthcare Professionals Only

ISTH Guidelines recommend CABLIVI* for acute aTTP/iTTP events—initial and relapsing3,6

safety_img_01 study-design

*A conditional recommendation defined as desirable effects of the recommendation probably outweighing the undesirable effects. Assumes timely access to ADAMTS13 testing and clinical diagnosis based on high likelihood of aTTP/iTTP. In de novo patients where no reasonable access to ADAMTS13 activity testing is available, the Guidelines do not recommend CABLIVI; however, treatment of a patient previously diagnosed with aTTP/iTTP could be safely undertaken on clinical grounds without the need for a confirmatory ADAMTS13 test.3

aTTP is also known as iTTP. The terms can be used interchangeably.

ISTH TTP Guidelines are the first evidence-based, international guidelines on the diagnosis, treatment, and management of aTTP/iTTP

Treatment recommendations have
evolved to include PEX, immunosuppressive
therapy, and CABLIVI

Starting CABLIVI early is believed to have the
greatest benefit in the early phase
of acute aTTP/iTTP events (initial or relapsing)

Identifying aTTP/iTTP is crucial for initiation of an appropriate therapeutic strategy

SEE aTTP/iTTP—Diagnosis determined through clinical assessment3

§List includes laboratory tests and results only; exclusive of physical symptoms, such as petechiae.

Hb and hematocrit below reference range, low haptoglobin, elevated LDH, presence of schistocytes in peripheral blood smear.

ISTH did not appraise the evidence of these 2 tools.

START CABLIVI*—Consider early administration of CABLIVI in combination with PEX and immunosuppressive therapy3

Recommended diagnostic and management strategy for initial, acute events with access to
ADAMTS13 results within 7 days

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Who should not start CABLIVI?
  • CABLIVI is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of its excipients
  • Withhold CABLIVI treatment 7 days prior to elective surgery, dental procedures, or other invasive interventions

*A conditional recommendation defined as desirable effects of the recommendation probably outweighing the undesirable effects. Assumes timely access to ADAMTS13 testing and clinical diagnosis based on high likelihood of aTTP/iTTP. In de novo patients where no reasonable access to ADAMTS13 activity testing is available, the Guidelines do not recommend CABLIVI; however, treatment of a patient previously diagnosed with aTTP/iTTP could be safely undertaken on clinical grounds without the need for a confirmatory ADAMTS13 test.3

#List includes laboratory tests and results only; exclusive of physical symptoms, such as petechiae.

**Hb and hematocrit below reference range, low haptoglobin, elevated LDH, presence of schistocytes in peripheral blood smear.

Adapted from ISTH Guidelines for Diagnosis of TTP.

SUPPORT WITH ADAMTS13—ADAMTS13 test results inform treatment decision3


Continue CABLIVI or consider STARTING CABLIVI*


Use clinical judgment to guide treatment and consider other diagnoses


Stop CABLIVI and consider other diagnoses

According to ISTH TTP Guidelines, treatment of relapses for a patient previously diagnosed with aTTP/iTTP could be started safely based on clinical grounds without the need for a confirmatory ADAMTS13 test3

Timely access to ADAMTS13 results is key to providing optimal care
for patients with aTTP/iTTP

Select US labs testing ADAMTS13 activity, inhibitors, and antibodies

These listings do not constitute an endorsement by Sanofi and are not included in the ISTH Guidelines. The above is a selection of national laboratories offering ADAMTS13 tests for activity, inhibitor, and antibody testing. This is not an exhaustive list of labs that offer one or more of these tests or an endorsement of any lab. Other testing options may be available, including at local or regional laboratories. Content is current as of July 2020, and tests may not be available in all states. Please call laboratory to confirm test availability, sample shipping information, and all other logistics.

A Breakthrough in aTTP/iTTP Treatment: Now recommended by the ISTH Guidelines

An aTTP/iTTP expert physician discusses recently published ISTH Guidelines on the diagnosis and treatment of aTTP/iTTP—a rare, life-threatening, autoimmune disease—and the urgency for rapid diagnosis and treatment.

Thanks for joining me today. I'm Dr. Jay Raval. I'm an Associate Professor and Senior Director of Transfusion Medicine and Therapeutic Pathology at the University of New Mexico in Albuquerque.

Thanks for attending today's talk and I am pleased to be able to give today's presentation entitled “A breakthrough in aTTP treatment. Cablivi, now recommended by the ISTH guidelines.”

This presentation is sponsored by Sanofi. I, the speaker, am presenting on behalf of Sanofi and am receiving compensation from the company for this presentation. Of note, this presentation is not eligible for CME credit.

Today's objectives are four-fold. The first is going to be providing an overview of acquired thrombotic thrombocytopenic purpura or aTTP and the urgency for rapid diagnosis of this condition. Number two, review pivotal trial data for Cablivi. Three, review the ISTH guidelines of the diagnosis and treatment approaches for TTP. Four, apply learnings to a patient case study that we'll go over.

Let's quickly overview aTTP. ADAMTS13 enzyme plays a really important role in normal primary haemostasis and the blood clotting process. As you can see here in these diagrams, starting from the left and moving to your right, the normal blood clotting process begins when the endothelium releases ultra-large Von Willebrand factor or ultra-large vWF. That is noted by the long purple chains here. Normally, these exist in the bloodstream only for a short amount of time because ADAMTS13 is a special enzyme that comes along and cleaves these ultra-large vWF strands into smaller more physiologic bits, which then can interact normally with platelets and collagen in order to provide the platelet plug. This is primary haemostasis. These cleaved strands circulate and, of course, are ready to respond whenever there is injury at the level of the vascular endothelium.

However, in aTTP there is an ADAMTS13 deficiency that results and this causes a few problems. First of all, these ultra-large vWF strands are no longer cleaved but left large and intact. These are giant molecules and unfortunately, they are also very pathologic. These ultra-large vWF molecules accumulate and they hyperactively interact with platelets to form microthrombi that obstruct the flow of blood. As you can see in these diagrams, on the left you have the uncleaved vWF strands. They are left in their very large forms, and on the right you can see how they are hyperactively interacting with platelets to form these microthrombi that, of course, obstruct the flow of blood and these poor red cells are trying to sneak through and are injured in the process producing the characteristic schistocytes that you can see right there.

This is a problem because it is a consumptive thrombocytopenia and so, the patient, as a result, has a low platelet count. That intravascular haemolysis that is occurring results in what is called a microangiopathic haemolytic anaemia. The presence of schistocytes on the peripheral blood film support this. Because the patient is anaemic there is also going to be organ ischaemia and this is a systemic condition. It effects almost all organ beds and impacts the entire body. Of course, the deleterious complications that can result from this include stroke, MI, early death, and of course a variety of neurologic complications.

aTTP is a rare, rapidly progressing, relapsing autoimmune disease. Not only is it uncommon, but the risk of missing the disease is potentially fatal. The incidence is about 2 to 5 cases per million per year here in the United States. The average age of your patient with TTP is anywhere from 30 to 50 years old. Importantly, TTP can either be inherited or acquired, but almost 95% or more of the TTP cases are going to be acquired and that's the type of TTP we are discussing here today.

As I mentioned, this is a potentially fatal illness and so rapid diagnosis as well as prompt treatment is essential for treating this condition. You can see on the left, mortality rates remain very high in this condition with untreated disease. Up to 90% or more of patients will succumb to their disease when their TTP is left untreated. Even if prompt therapy is initiated with plasma-exchange and immunosuppression, there is still a mortality rate in the acute setting of 8% to 20%, which means that even when you use the traditional gold standard of PEX plus immunosuppression, these folks are not necessarily going to survive. That is a really important point to remember.

And even when patients do have a treatment response and remission based on PEX and immunosuppression therapy, a high recurrence is still a big risk for these folks. According to 1 retrospective review, approximately 50% of patients experienced a recurrence within 30 days of stopping their plasma-exchange. In another study, 90% of patients over their lifetime, who had TTP, had at least one additional episode. Patients, actually, often refer to themselves as ticking timebombs because they know that this is something that can occur and recur, and they wake up every morning making sure and worried that: has it recurred? Do I need to look for signs of recurrence? It is something that is on the minds of certainly the clinicians but the patients as well.

What are the diagnoses and treatments for aTTP? As I mentioned this is a systemic condition. You can see here in this diagram all sorts of organ systems may be involved. Certainly, the skin and that is where you see the petechial rash as well as other findings. Look at these major organs here that are potentially affected. The brain may be affected because of the microangiopathic haemolytic anaemia as well as the ischaemia that occurs because of these thrombotic lesions that are prohibiting blood flow from flowing normally. All sorts of neurologic finds can occur here as well. In approximately 25% of patients the heart is involved. We do not always think about the heart as an organ impacted by aTTP, but in fact, in about a quarter of patients there is cardiac involvement. This can be characterised by something like EKG-abnormalities or frank myocardial infarction. All these organ systems can take a hit. If you have got someone who is thrombocytopenic and has microangiopathic haemolytic anaemia, you have got to consider the diagnosis of aTTP. Folks have platelet counts of under 30,000 per microliter, typically, along with those characteristic findings of low platelet counts. If you have got that in conjunction with a peripheral blood film that indicates schistocytosis in an anaemic patient, aTTP should be suspected. Importantly, ADAMTS13 activity testing has really come a long way in terms of being available to patients that might have aTTP. Being able to assess the patient using the ADAMTS13 activity test is essential to supporting the diagnosis of aTTP.

Treatment options in aTTP have evolved recently where plasma exchange and immunosuppression have historically been the standard of care. These standards of care include daily plasma exchange in anyone who is at high risk of having TTP, or even any risk, particularly if there is no identifiable cause to explain the findings otherwise. This would continue until the platelet count is normalised.

Plasma exchange is great for TTP for a couple of reasons. One, it removes these ultra-large vWF multimers that are in circulation, as well as the auto-antibodies that are the immune source of this condition. It also replenishes the ADAMTS13 enzyme when you use plasma as the replacement fluid during this procedure.

The other facet of treating this illness is going to involve immunosuppressive therapy. This is where drugs are used to inhibit the underlying immune mechanism that is fuelling the disease. This is the auto-antibody formation that directs antibodies against ADAMTS13 that cause aTTP, and this is what we're going to be targeting with immunosuppressive therapy.

Even though these two modes of treating TTP have been around for a while, it is important to recognise that they are not designed to target the actual pathologic lesion here. That is the binding of the platelets to the ultra-large vWF multimers, and ultimately, what is obstructing blood flow in the microvasculature.

This is where Cablivi (caplacizumab-yhdp) comes in. Caplacizumab-yhdp is an agent that specifically inhibits the interaction between Von Willebrand factor and platelets. Its mechanism of action is designed as such where it interferes with that platelet vWF binding to break down as well as prevent formation of these pathologic microthrombi.

Let us talk a little bit more about Cablivi. Importantly, Cablivi is indicated for the treatment of adult patients with acquired TTP, used in combination with the standard of care treatments of plasma exchange and immunosuppressive therapy. It was approved for this use by the FDA in 2019 and, as we will get to later, the ISTH guidelines that recently came out recommend Cablivi in certain situations. We are going to talk about that.

Cablivi is the first and only therapy, as I mentioned, that specifically targets these pathologic microthrombi in adults that have aTTP. You can see right here in the diagrams, if you are looking at blood flow going from the left to the right, in these patients with aTTP these pathologic microthrombi are present and blood flow is impaired, partly due to physical obstruction, and partly due to red cell shearing and the inability to transport oxygen to the organ beds. In patients that have Cablivi, this vWF-directed antibody binds the A1 domain of Von Willebrand factor and inhibits the interaction between vWF and platelets. You can see right here, with this particular pharmaceutical agent on board, these pathologic lesions more or less are broken up and obstruction of blood flow is reduced.

The efficacy and safety of Cablivi were established in a pivotal clinical study and this was the HERCULES study. This was a phase III double-blind randomised control trial of 145 adult patients that had acquired TTP. All of these patients received standard of care plasma exchange plus immunosuppression of some type. You can see here on the right, corticosteroids were given in 96% and 97% of patients in either arm, 39% and 48% of patients received Rituximab and 16% and 3% received others. Clearly well-matched in terms of the type of immunosuppression they received in this study. I am going to take a moment to quickly describe the protocol here, because it is important that everyone understands exactly how this trial was conducted. As I mentioned, it was a double-blind randomised control study and at the first plasma exchange folks were randomised in a 1:1 fashion to one of two different arms.

Again, everyone received plasma exchange and immunosuppressive therapy, the standard of care, but half of the individuals received caplacizumab (or Cablivi) at an 11 mg dose in addition to that. The other group received placebo. Ultimately 72 patients were enrolled in the Cablivi arm versus 73 patients in the control arm. Cablivi was given every day. We will talk more in a moment about the dose. It was given every day while plasma exchange was occurring and then it was also given 30 days after plasma exchange was stopped, so an additional month of Cablivi after treatment response had been achieved and plasma exchange was halted. After that, there were up to 28 days of additional treatment that could occur if underlying disease activity was found to be persistent or present by clinician assessment. Lastly, there was a 28-day treatment-free follow-up period. The folks in the placebo arm got the exact same sort of treatment except they were given placebo throughout the trial. Again, the option of having a treatment extension with placebo being given was offered, and then a 28-day treatment-free follow-up period as well.

The primary efficacy endpoint in the study was time to normalisation of platelet count. That is something that anyone that treats aTTP is always watching: how are the platelet counts doing and how quickly are they coming up? It was a reasonable primary efficacy endpoint to choose. You can see right here that folks that received Cablivi along with plasma exchange and immunosuppressive therapy achieved a normal platelet count significantly faster than those that received standard of care therapies plus placebo.

A second endpoint that was chosen for this study was the total composite outcome of aTTP related events during the study drug period. These events included aTTPrelated death, aTTP-related recurrence during treatment, or at least one major thromboembolic event. If you look at the composite endpoint in which if a patient got any one of those then they met the composite endpoint, you can see right here significantly fewer aTTP-related events were found in the Cablivi arm compared to those that were observed in the placebo treated arm. This was in fact a 74% reduction, 9 versus 36 events, and was found to be statistically significant.

In combination with plasma exchange and immunosuppressive therapy, Cablivi was also found to impact another secondary endpoint. This was the overall number of recurrences during treatment and throughout the 28-day follow-up treatment period. You can see right here, if you look at the number of folks that needed to have reinitiation of plasma exchange, for those in the placebo arm, 28 individuals needed to have plasma exchange reinitiated because they had disease recurrence. That's compared to only 9 in the Cablivi arm. That was a 67% recurrence reduction that was found to be significantly different. Let's take a deeper look at the 9 patients in the Cablivi arm that had a recurrence. In 6 of the 9 patients that required reinitiation of PEX after treatment with Cablivi was stopped, all 6 patients had ADAMTS13 activity levels <10%, indicating the underlying disease was still active. Based on the pathophysiology of this disease, suppressed ADAMTS13 activity may signify the need for extended treatment with Cablivi up to 28 days beyond the initial 30 days post-PEX period.

One way to monitor these patients is ADAMTS13 activity levels to make sure they are still not severely deficient before considering stopping Cablivi.

Looking at some healthcare resource utilisation data, because of course these patients are in the hospital for quite some time and receive intensive therapies with plasma exchange and immunosuppression. You can see right here, folks that received Cablivi along with standard of care therapies had fewer days in ICU, fewer days in hospital, and fewer days of plasma exchange. These data were collected prospectively and descriptive statistics were run but these were not tested for significance, and the clinical significance of these data is unknown.

The safety of Cablivi was also established in over 100 patients across two studies. These were the phase II TITAN trial as well as the phase III HERCULES trial that we have talked about. If you look at this big list of different organ systems and the adverse events that occurred, you can see that there is a variety of events that happened, but the most common adverse events actually were related to severe bleeding. That is not too surprising again because if you think about it, Cablivi interferes with the binding of platelets to vWF and, in essence, that is Von Willebrand disease. It is not too surprising to see that a bleeding event is a potential adverse event that can occur. You can see right here, in the right-hand side of this diagram and table, severe bleedings are reported in 1% of patients for each of the following events; that include epistaxis, gingival bleeding, upper-GI haemorrhage and metrorrhagia. Overall bleeding events were also slightly higher in the Cablivi group at 58% versus 43% in the placebo group.

A lot of words on this slide, but it is important to take it all in, make sure we break it down and understand what is here. Regarding the safety information, the main contraindication and the sole absolute contraindication is a previous severe hypersensitivity reaction to caplacizumab-yhdp or any of its excipients. Things like urticarial rash or more severe hypersensitivity reactions would indicate such a reaction to Cablivi and these folks should not receive it.

Beyond that, however, there are some other factors and patient conditions that we will discuss. If you look at the bleeding risk that is involved when patients receive Cablivi, bleeding can occur. If you have a patient that is going to be at increased risk of bleeding, that needs to be taken into consideration. If clinically significant bleeding does start to occur in someone on Cablivi, stop Cablivi. If you need to, Von Willebrand factor concentrates can be administered to correct the haemostatic profile of the patient. Then the decision of whether or not to restart Cablivi needs to be made. If Cablivi is ultimately restarted, then you should closely monitor that patient for any findings of bleeding. If you have the luxury of time and you know a patient is going to be having an elective surgery, a dental procedure, or any other type of intervention in which bleeding could occur, it is best to withhold Cablivi for seven days prior to that procedure. Then, of course, if emergency surgery is needed, then the use of vWF concentrate may be considered to rapidly correct haemostasis because, again, you do not have that luxury of time leading up to the procedure. Regardless of whether it is a planned or emergent intervention, after the risk of surgical bleeding has passed and the decision to resume Cablivi is made, you want to make sure that you monitor your patients closely for signs of bleeding that might occur.

We talked about the bleeding symptoms and signs that can occur in terms of serious adverse reactions. The most common things that were found were events such as epistaxis, headache, and gingival bleeding, which were found to occur in over 15% of patients that did receive Cablivi. That is an additional point to remember.

Of course, any time you are giving multiple drugs that can interfere with either primary or secondary haemostasis, the risk of bleeding increases. In patients that are on anticoagulants, you want to be careful when administering Cablivi because, of course, those two agents together can potentially increase the risk of bleeding even more. Close assessment and monitoring is going to be required in these individuals.

Lastly, there is no available data on Cablivi for the use in pregnant women and so, with regard to the pregnant female or the fetus, no data is available.

Now let us talk quickly about the Cablivi dosing and administration. As mentioned earlier, Cablivi treatment begins in the early stages of aTTP diagnosis and continues for at least 30 days post-PEX. I'd like to walk through the 3 phases of dosing that your patients will experience and some of the considerations along the way.

Phase 1 is Day 1 initiation of Cablivi, beginning with an 11-mg bolus IV injection at least 15 minutes prior to PEX treatment, followed by a second dose, 11-mg SC injection, after the PEX treatment is completed. This Day 1 dosing follows the HERCULES trial design and provides the appropriate therapeutic dose of Cablivi for your aTTP patients.

Phase 2 is the daily administration of Cablivi, 11-mg SC injection, after completing each daily PEX treatment. This will continue throughout the PEX treatment period. Of note, if a dose is missed during this phase, Cablivi should be given as soon as possible.

Phase 3 is the daily administration of Cablivi, 11-mg SC injection, for 30 days after cessation of daily PEX treatment. This phase also includes the option for treatment extension up to an additional 28 days if signs of underlying disease persist, such as suppressed ADAMTS13 activity. Of note, if a dose is missed during this phase, Cablivi can be administered within 12 hours of normal time of administration. But beyond that 12 hour time frame, the missed dose should be skipped and the next daily dose of Cablivi administered following the usual dosing schedule.

Importantly, you want to discontinue Cablivi in your patient if more than two recurrences occur while on Cablivi. It is three strikes and you are out rule. If a patient is getting Cablivi and they have three or more recurrences, clearly something is different about this patient than your average aTTP patient. They might have an underlying infection. There may be issues with how the drug is being administered if they are self-administering it at home. All of these things need to be investigated.

Now let us talk about the ISTH guidelines on the diagnosis and treatment approaches for TTP. Why were these guidelines even created in the first place? It turns out the ISTH make guidelines for many conditions, but with regard to TTP, they recognise that TTP is a rare, life-threatening blood disorder. Even when appropriate care and therapies are given promptly, there is still considerable mortality and morbidity in the acute phase of the treatment with regard to TTP. Unfortunately, most healthcare providers have very limited experiences with managing TTP. Making a document that would provide guidance to these providers was thought to be extremely important. These guidelines are the first evidence-based international guidelines on the diagnosis and treatment of aTTP.

The diagnosis can be, of course, as we talked about earlier determined through clinical assessment and the ISTH guidelines certainly support that. When a patient is assessed, the pre-test probability of that patient having aTTP is determined. There are a variety of ways to do this. If it is ultimately found that the aTTP is diagnosed or at least there is a high clinical suspicion of it, that is going to be one branch of the diagram you see here on the left. In contrast, if the patient has a low or intermediate clinical suspicion of aTTP, that'll take them down an alternate path. The things that you want to look for on clinical assessment are listed right here. We have talked about them previously.

In these folks that have a high clinical suspicion of having aTTP, plasma exchange and immunosuppressive therapy are going to be initiated immediately. At that point, assuming timely access to ADAMTS13 testing is available, the recommendation is to also consider starting Cablivi prior to receiving ADAMTS13 activity test results. You want to also make sure that ADAMTS13 testing is ordered promptly as well. Certainly, before that first plasma exchange procedure is performed. That is going to help guide what you do going forward. If it turns out that in this high clinical suspicion patient with findings highly characteristic of aTTP, if there are positive ADAMTS13 results, in other words, if it is severely deficient, less than 10% activity levels, ISTH guidelines have stated Cablivi should be continued. If there are borderline ADAMTS13 results identified, somewhere in this grey zone of 10%-20% activity levels, the guidelines indicate that clinical judgement should be used to guide further treatment. Of course, other diagnoses should still be considered in the differential. On the very right you can see that if the ADAMTS13 testing results are negative for aTTP, in other words if the activity level is over 20%, Cablivi should be stopped, because at this point, even if the clinical suspicion was high, the ADAMTS13 testing does not appear to support it and so, the ISTH recommends ceasing Cablivi administration. Importantly, if ADAMTS13 testing is not available, the ISTH guidelines indicate that Cablivi should not be added.

If you have a patient, however, upfront, who has a low or intermediate clinical suspicion of aTTP, again, in the absence of another diagnosis that warrants a different type of therapy, consideration of initiating plasma exchange and immunosuppressive therapy should occur. Again, ADAMTS13 activity testing should accompany this. Whether or not plasma exchange or immunosuppressive therapy is started, when these results for ADAMTS13 activity testing come back, the same three options are seen here. If the results are positive in terms of aTTP disease, in other words, an undetectable or severely deficient ADAMTS13 activity, if you have not already started plasma exchange and immunosuppressive therapy, then that should be promptly initiated. In addition, Cablivi should also be considered as well, because again, even though the clinical suspicion was originally low to intermediate, now, with ADAMTS13 testing to more strongly support the diagnosis, plasma exchange, immunosuppression, and Cablivi can all be considered according to the ISTH guidelines. If the results are borderline ADAMTS13 activity testing results, so in that 10%-20% range, clinical judgement should be used to guide treatment.

Lastly, if in these low to intermediate clinical suspicion patients for having aTTP, if they are negative ADAMTS13 activity testing results, in other words if the activity is over 20%, do not add Cablivi and certainly consider other diagnoses.

Now let's apply everything we've learned to a patient case. Let's meet Sandy. She requires urgent medical attention. She is a 40-year-old female who is African American and she has been complaining of frequent pain and soreness in her abdomen, a recent new onset lack of energy so, new fatigue, and a headache without resolution as well as forgetfulness. This is all unusual for her. She reports having a fever of 102 degrees Fahrenheit three weeks earlier and she has seen visible bruising and blotching on her skin within the past 10 days. There is no mention of any recent irritants, stressors, or travel. She says: “I know I was sick a few weeks ago from a bug that was going around the office. I did not think it would last this long. These headaches are making it hard to focus. I just feel tired all the time.” She reports the possibility of a cold that she had, an upper respiratory infection, lasting several weeks without improvement and now she is getting worse. In her past medical history, nothing really significant is seen here, as you can see, no family or social history are available.

On physical exam, when looking at her vital signs, she is slightly febrile at 100.4 degrees Fahrenheit, her blood pressure, heart rate, respiratory rate are all stable and she is saturating well on room air. On physical exam she is noted to be normocephalic, atraumatic, her ENT exam is normal, she has mild tenderness on abdominal exam and bruising and purpura are noted on the extremities.

A laboratory assessment is performed. You can see right here that there is a normal white count but low haemoglobin, and so the patient is slightly anaemic as you can see here. Platelets are very low, 15,000 per microliter, haptoglobin is low. She has reticula cytosis at 3% and her LDH is elevated along with her total bilirubin also being elevated. Importantly, her serum creatinine appears to be normal at this time. All of these findings are characteristic of a thrombocytopenia accompanied by a microangiopathic haemolytic anaemia. This is supported when the findings from the peripheral blood film come back and a schistocytosis is identified.

You can see right here, because Sandy's physician diagnoses her with aTTP based on a high clinical suspicion, she immediately falls into this pathway of the ISTH guidelines for how to treat aTTP. Of course, plasma exchange and immunosuppressive therapy are immediately initiated and caplacizumab is considered. In this specific case, Sandys' physician decides to start her on caplacizumab because of her high probability.

When those ADAMTS13 testing results come back, that is ultimately going to determine what is done with Cablivi, as well as potentially alter plasma exchange and immunosuppressive therapy.

If you look at Sandy, plasma exchange is performed for five days. Cablivi was given in the way we described, so daily, and corticosteroids were also administered. Now, we are just waiting for the ADAMTS13 activity results to guide next steps. Sandy is responding nicely and her platelets are slowly starting to increase. What do we find? ADAMTS13 activity results are positive for aTTP. In other words, less than 10% ADAMTS13 activity and the anti-ADAMTS13 auto-antibody tests were positive as well. Sandy now has further evidence to strengthen the case for having aTTP.

It supports the high suspicion seen with the initial clinical assessment and laboratory assessment and Sandy's doctor decides that caplacizumab is going to continue, and that's exactly what happens.

Per the ISTH guidelines Cablivi would be continued to be administered as part of her therapy in addition to standard of care. After five days of plasma exchange, Cablivi, and corticosteroids on board, she does respond. Cablivi is continued for another 30 days after daily plasma exchange is stopped, and corticosteroids are stopped after about two weeks. You can see right here in the documentation on the left-hand side, Cablivi was stopped at that thirty-day post plasma exchange time point. Because even though Sandy was looking great, feeling great, and doing well, her clinician said: “I am going to use the ADAMTS13 activity assay to assess whether there is any persistence of disease activity.” And when that repeat ADAMTS13 activity test came back at day 35, you can see right here, it was greater than 20% and so, the clinician felt confident that the underlying immune process that drives aTTP had been quenched and Cablivi was stopped.

Some key takeaways about aTTP. It is a rare, rapidly progressing disorder. It is autoimmune in nature and is a medical emergency. All of these things make aTTP very dangerous. Even the people that routinely see aTTP can be fooled by its clinical presentation. Unfortunately, this is a condition where missing the diagnosis can be potentially fatal or can leave the patient with more morbidity than they would have if plasma exchange and immunosuppressive therapies had been initiated earlier. It is a tricky disease.

The ISTH TTP guidelines recommend Cablivi in combination with those two standard of care treatments, plasma exchange and immunosuppressive therapy, in adults with acute aTTP. This can be used for either a de novo aTTP episode, the first episode that a patient has, or it can be for any relapses. These ISTH TTP guidelines help to guide the use of Cablivi in this rare condition. You can see right here, if you see aTTP, if you diagnose it with your clinical and initial laboratory assessments, you want to start standard of care therapies with plasma exchange and immunosuppressive therapy, and then consider the early administration of Cablivi, if there is a high clinical suspicion and if you have timely access to ADAMTS13 testing. You want to use ADAMTS13 activity testing to support your treatment decisions from that initial point onwards. Those three things are pivotal.

Cablivi is, of course, the first and only FDA approved guideline recommended therapy for the treatment of adults with aTTP in combination with plasma exchange and immunosuppressive therapy. It is important to remember that Cablivi prevents the pathophysiologic formation of microthrombi in aTTP.

Cablivi's use in conjunction with standard of care therapies results in a significantly faster time to platelet normalisation, as well as a significant reduction in the composite endpoint of aTTP-related death, recurrence, or at least one major thromboembolic event during the treatment period.

Additionally, there were also significantly fewer recurrences in those patients that received Cablivi plus standard of care versus those that just received standard of care plus placebo during the treatment period and for the 28 days after.

Thank you again for your attention, I hope you found the content of this presentation informative and helpful. If you have more questions about Cablivi, please visit the website shown here or contact your local Sanofi representative.

© 2022 Genzyme Corporation. All rights reserved.

CABLIVI and Sanofi are registered trademarks of Sanofi or an affiliate.


ISTH Guidelines Overview

ISTH Guidelines Pocket Guide




CABLIVI is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of its excipients. Hypersensitivity reactions have





CABLIVI is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of its excipients. Hypersensitivity reactions have included urticaria.


  • CABLIVI increases the risk of bleeding. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of subjects. Overall, bleeding events occurred in approximately 58% of patients on CABLIVI versus 43% of patients on placebo.
  • In the postmarketing setting cases of life-threatening and fatal bleeding were reported in patients receiving CABLIVI.
  • The risk of bleeding is increased in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies). It is also increased with concomitant use of CABLIVI with drugs affecting hemostasis and coagulation.
  • Avoid concomitant use of CABLIVI with antiplatelet agents or anticoagulants. If clinically significant bleeding occurs, interrupt use of CABLIVI. Von Willebrand factor concentrate may be administered to rapidly correct hemostasis. If CABLIVI is restarted, monitor closely for signs of bleeding.
  • Withhold CABLIVI for 7 days prior to elective surgery, dental procedures or other invasive interventions. If emergency surgery is needed, the use of von Willebrand factor concentrate may be considered to correct hemostasis. After the risk of surgical bleeding has resolved, and CABLIVI is resumed, monitor closely for signs of bleeding.


The most common adverse reactions (>15% of patients) were epistaxis (29%), headache (21%) and gingival bleeding (16%).


Concomitant use of CABLIVI with any anticoagulant or antiplatelet agent may increase the risk of bleeding. Avoid concomitant use when possible. Assess and monitor closely for bleeding with concomitant use.


There are no available data on CABLIVI use in pregnant women to inform a drug associated risk of major birth defects and miscarriage.

  • Fetal/neonatal adverse reactions: CABLIVI may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
  • Maternal adverse reactions: All patients receiving CABLIVI, including pregnant women, are at risk for bleeding. Pregnant women receiving CABLIVI should be carefully monitored for evidence of excessive bleeding.


CABLIVI (caplacizumab-yhdp) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.

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Instructions for Use

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