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POTENTIAL FUTURE USES FOR RECOMBINANT ADAMTS13

Posted on: March 25, 2022

David L. McGlasson, MS, MLS(ASCP)

Before reading this blog post, I invite the viewer to read the article by Abi Kasberg, PhD posted August 21, 2021 titled Thrombotic Thrombocytopenic Purpura (TTP) Clinical Trials: Targeting the needs left by current treatment options.  It’s a great review of current methods to address ADAMTS13 deficiency and discusses the new component human recombinant ADAMTS13 (rADAMTS-13).

Her opening paragraph is a great description of TTP and the role that ADAMTS13 plays in this inherited or acquired disorder.  I am borrowing it to start this discussion.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy blood disorder that is characterized by the formation of blood clots in small blood vessels, thrombocytopenia, and a lack of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13) activity. The ADAMTS-13 protease is responsible for cleaving von Willebrand Factor (VWF) multimers into smaller fragments in a mechanism that regulates thrombosis. When ADAMTS13 activity is decreased or absent, ultra large VWF multimers (ULVWF) accumulate in the blood which activates platelet adhesion, platelet aggregation, and microvascular thrombosis. Erythrocytes can breakdown during TTP due to the strain of maneuvering around clots, leading to hemolytic anemia. Platelets are consumed by blood clots resulting in limited platelet availability systematically, which can result in bleeding complications. TTP-associated tissue damage can cause multiorgan failure, stroke, and death. TTP carries a high mortality rate of 90% when left untreated.1

Previously the treatment for ADAMTS13 deficiency in a TTP subject was infusion of fresh frozen plasma (FFP) which may include solvent/detergent treated plasma of which the amount is determined by body weight (BW) of the subject. The half-life of infused plasma ADAMTS13 is usually 2-4 days prophylaxis with 10-15 mL plasma/kg body weight (BW) every 2-3 weeks and has been found to be able to control acute events in patients with TTP.2

The plasma perfusion technique is effective.  It does have risks of causing complications such as allergic reactions and anaphylactic episodes and volume overloading with the infused plasma.  Anytime plasma transfusions are used, there come the risks of infection which is very hard to treat in outpatient settings.2

These issues have led to the development of recombinant ADAMTS13 (rADAMTS13) for treatment of TTP and for other issues of hemorrhage; such as acute ischemic stroke (ACI), trauma hemorrhage, and sickle cell disease (SCD).

The first rADAMTS13 to be used in human pharmacokinetics and safety was in congenital thrombotic thrombocytopenic purpura (cTTP). The derivative of rADAMTS13 to be used in this study was BAX930; SHP655. This product was used in subjects that had a diagnosis of cTTP with severe ADAMTS13 deficiency (<6.0%).  This derivative used was tolerated by the subjects without experiencing any adverse occurrences.  No anti-ADAMTS13 antibodies were observed.  Single dosing concentrations of 5, 20, or 40 U/kg BW to adolescents and adults yielded approximate dose effects in relation to maximum plasma concentration and the concentration-time curve.  Dose concentration increases of individual ADAMTS13 antigen and activity were observed and peaked at 1 hour.

Giving escalating BAX930 doses a dose-dependent effect of ADAMTS13 mediated VWF cleavage products and reduced VWF multimeric size were seen. The study by Scully and colleagues showed that pharmacokinetic parameters of BAX930 were equal to those estimated in previous plasma infusion studies and gave evidence of pharmacodynamic activity.  Clinical Trial NCT022160842

In other conditions besides TTP, rADAMTS13 has been studied for effectiveness in treating several life-threatening conditions.  In 2014 a study by Vergouwen and colleagues looked at the effect of rADAMTS13 on micro thrombosis and brain injury after experimental subarachnoid hemorrhage (SAH) in mice. After the SAH occurs, frequently there is a delayed cerebral ischemia (DCI) which may display micro-thrombosis and vasospasms.  ADAMTS13 presence prevents thrombus formation in the cerebral microvasculature.  The researchers saw that subjects with DCI have decreased levels of ADAMTS13.  They looked at whether rADAMTS13 reduced cerebral microthrombus formation and brain trauma in an experimental mouse model with a SAH induced condition.  The SAH mice were then induced and treated with rADAMTS13 20 min later and then were terminated after 48 hours. The findings were encouraging in that infusion with rADAMTS13 reduced the extent of micro thrombosis by 50%. 3 Also, the rADAMTS13 decreased brain injury by >60%.  These findings are encouraging for treating other conditions besides TTP.  Clinical studies are now ongoing in this area on other animal models.3

Another study by Witsch (2018) explored the use of rADAMTS13 as a treatment for improving conditions caused by pressure overload injury in mice to improve myocardial issues. They postulated that rADAMTS13 may reduce thrombosis and inflammation in the mouse models of myocardial injury.

They evaluated the effect of rADAMTS13 on cardiac scarring and contractile function under chronic left ventricular pressure overload. The roles of vWF and rADAMTS13 were evaluated.  The issues of ascending aortic constriction may produce a coronary inflammatory response and microvasculature dysfunction causing fibrotic remodeling and cardiac failure in this mouse model. The protocol required the animal model to be treated with rADAMTS13 and evaluated for coronary vascular inflammation, ventricular function, and cardiac fibrosis at different post-op time points ending at 4 weeks.  They found less endothelial-lumen-associated vWF, fewer platelet aggregates, and decreased activated transforming growth factor-β1 levels than in vehicle-treated mice.  Significant preservation of cardiac function and decrease in fibrotic remodeling as a result of rADAMTS13 was evident. They concluded that rADAMTS13 supports the potential of therapeutic use in inflammatory cardiac trauma that may result in fibrosis.4

In 2020, Wirtz examined the use of rADAMTS13 as a therapy to improve shock reversal and coagulation status in a trauma hemorrhage and transfusion rat model.  They observed that in hemorrhagic trauma patient,’’ endothelium is activated which causes excess endothelial synthesis of VWF which could stimulate microthrombi formation.  This can result in blockage of the microcirculation system and endothelial injury. This may aggravate bleeding and cause organ failure.  These traumatic conditions result in ADAMTS13 levels to be severely reduced.  This study examined whether rADAMTs13 would inhibit endothelial injury and organ failure in a rat trauma-transfusion model. Their findings showed that after the use of rADAMTS13 in a rat trauma-transfusion model improves parameters of shock, platelet-driven coagulation, endothelial damage, and organ inflammation.  The importance of ADAMTS13 is shown in this study.  The mediation of the outcome of trauma by ADAMTS13 shows that it can be used as a therapeutic tool to treat hemorrhaging injury animal models.  It still remains to be seen as to its effectiveness in human subjects.5

A study by Rosato (2022) evaluated the absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey.  Decreased levels of ADAMTS 13 contributes to microangiopathy in SCD.  As previously discussed, rADAMTS13 effectively cleaves prothrombotic ultra-large vWF multimers.  We have noted how it could be used in TTP, brain injury, and other trauma.  The next few studies discuss how it is being evaluated in treating SCD.6

A Clinical Trials Study of SHP655 (rADAMTS13) in Sickle Cell Disease (RAISE) is currently ongoing (Clinical Trials) identifier NCT03997760.  SHP655 is a medicine used to treat sickle cell disease.  The main aim of the study is to measure the safety and tolerability of SHP655 in SCD participants. Study participants receive SHP655 or placebo on Day 1. Their SCD was treated according to their doctor’s usual clinical practice.  During the study, participants were asked to follow-up 13 days following SHP655 or placebo administration for safety assessment.  This is a Phase 1 Trial to study SHP655 in SCD at baseline health.  The participants were given baseline infusions at one of 3 dose levels based on BW in a dose escalation for 2 weeks.  This was matched against a placebo group. Numerous time points are being evaluated for a large number of tests relating to the factors affected by SCD and rADAMTS13.  Study was last updated in August 2021 and data is currently being evaluated (as of March 2022).7

Björn Mellgård, MD, PhD, Vice President, Global Program Lead, Rare Genetics and Hematology with Takeda shared insight on 2 studies that Takeda Conducted on TAK-755, a recombinant ADAMTS13 enzyme. Dr. Mellgård Explains What TAK-755 Could Mean for Sickle Cell Treatment.

In conjunction with the study, the program sponsor of SHP655 Takeda shared insight on the TAK-755 product at the American Society of Hematology (ASH) 2021 meeting. The Phase 1, randomized, double-blind, placebo-controlled, multicenter ascending single dose study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of rADAMTS13 in patients with SCD.  After reviewing the safety data by the dose escalation committee investigators found no reports of drug-related serious adverse events, and no binding or inhibitory antibodies to ADAMTS13 were seen. “There is published data in the literature indicating an in the body between ADAMTS13, so slightly lower levels”, Mellgård said,” but also an increase of the substrate for this enzyme ADAMTS13, and the substrate is a protein called vWF.” Patients have shown higher levels of vWF and lower levels of ADAMTS13 activity during venous occlusive disease (VOC).  There may be a therapeutic benefit to increasing the plasma concentration of ADAMTS13 using a rADAMTS13 that would enhance cleavage of ultra-large vWF multimers.

“This imbalance may then create a tendency for clotting in SCD patients, and we are exploring that,” Mellgård said. “It would be fantastic to be able to contribute with treatment for SCD patients but it’s still very early days.”8

To date there are no cleared human rADAMTS13 products available for human use.  However, there is great potential in the future for these products as another tool in the arsenal for controlling bleeding and thrombosis in a variety of conditions that can be mobile in treatment plans not just limited to treatment of TTP.

 

BIBLIOGRAPHY

  1. Kasberg, A. Thrombotic thrombocytopenic purpura (TTP) Clinical Trials: Targeting the needs by current treatment options. CLOT CLUB. https://diapharma.com/news-and-events/thrombotic-thrombocytopenic-purpura-ttp-clinical-trials-targeting-the-needs-left-by-current-treatment-options/. August 2021.
  2. Scully M, Knobi P, Kentouche K, et al: recombinant ADAMTS13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpure. Blood;130(19):2055-2063. 2017.
  3. Vergouwen MD, Knaup L, Rollogs TH et al: Effect of recombinant ADAMTS13 on micro-thrombosis and brain injury after experimental subarachnoid hemorrhage. J of Thromb and Hemost. 12:943-947. 2014
  4. Witsch T, Martinod K, Serville N et al: Recombinant Human ADAMTS13 Treatment Improves Myocardial Remodeling and Functionality AFTEr Pressure overload Injury in Mice. J Am Heart Assoc 2018;7:e007004. DOI: 10.1161/JAHA.117. pg. 1-13,
  5. Wirtz MR, Daan P, van den Brink, Joris JTH et al: Therapeutic application of recombinant human ADAMTS13 improves shock reversal and coagulation status in a trauma hemorrhage and transfusion rat model. Intensive Care Medicine Experimental 2020 8(Suppl1):42. 2020.
  6. Rossato P, Glantschrig H, Leidenmuhler P, Kopic A et al: Absence of exaggerated Pharmacology by recombinant ADAMTS13 in the rat and monkey. Blood Coagul Fibrinolysis. 2022;33(1):56-60.
  7. A Study of SHP655 (rADAMTS13) in Sickle Cell Disease (RAISE) gov Identifier: NCT03997760
  8. Melllgard B Explains What TAK-755 Could Mean for Sickle Cell Treatment. https://www.hcplive.com/view/bjorn-mellgard-tak-755-sickle-cell-treatment. 2021.

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