Ash 2017 – Herculean effort scores Ablynx a late-breaker
Every year the organisers of Ash select six especially deserving trials for presentation at a late-breaking session on the conference’s last day. Among those honoured this year was the pivotal Hercules study of Ablynx’s lead project, caplacizumab.
This might strike some as surprising: Hercules met its primary endpoint of time to platelet count response but looking at the median time to response suggests a much smaller benefit. And Ablynx admitted that on enrolment it was not even sure whether subjects had had the blood clotting disorder that caplacizumab seeks to treat – inclusion criteria stated only that a clinical diagnosis was required, ahead of confirmatory diagnostic tests. Nevertheless, Ash defended its process of selecting late-breakers, explaining papers can be selected for their wider clinical relevance.
Moderating the Ash late-breaker press conference, Dr Robert Brodsky of Johns Hopkins School of Medicine, said Ablynx’s Hercules study was chosen from 75 papers submitted as late-breakers. As for the median benefit, he conceded that there were “other factors that are going to need to be considered” when evaluating the clinical relevance. Ultimately, “getting these patients out of the hospital is very important”, he stated.
Statistically the Hercules trial met its scientific goal, increasing the likelihood of subjects with acquired thrombocytopenic purpura (TTP) to achieve stable platelet counts by 55% at any point in the analysis (p<0.01).
TTP is a rare condition where a subject presents at a hospital with thrombotic microangiopathy resulting in thrombosis in capillaries and arterioles. Standard treatment is plasma exchange (PE), whereby patients’ plasma is replaced with fresh frozen plasma from donors; in Hercules caplacizumab was given after a single standard PE and on top of any future PEs, and compared versus PEs alone.
But one issue is the median time to platelet stabilisation, which reading off the Hercules response curves totals barely a few hours. Medians are typically used in statistical analyses of survival or response curves, supported by hazard ratios, though in Hercules Ablynx has not commented about median improvement.
Presenting the Hercules data to an Ash press conference, Ablynx’s chief medical officer, Robert Zerlin, argued that the “totality of the curve” was key, as were secondary measures like recurrence and subsequent use of PE. In caplacizumab’s phase II study, Titan, Ablynx did stress median benefit in platelet stabilisation as primary endpoint, and said this came out at 1.92 days.
Alongside the primary endpoint the presentation also provided additional data on secondary endpoints on healthcare utilisation, including a 38% reduction in plasma exchange, and a 65% drop in the amount of time spent in hospital for patients admitted into the ICU. Overall hospital days were also reduced by 31%.
Is it TTP?
However, there is also the separate question of whether patients recruited into Hercules actually had TTP, which could have a significant impact on caplacizumab’s target market.
TTP results from autoimmune inhibition of the enzyme Adamts13, preventing this from cleaving von Willebrand factor, which in its multimeric form causes platelets to string together and aggregate. A patient presenting with thrombotic microangiopathy would typically be given a PE, before having their Adamts13 levels tested.
If their Adamts13 levels are above 10% this would imply a more common root cause – haemolytic uraemic syndrome – for which standard treatment is Alexion’s Soliris. Only if Adamts13 levels remain suppressed would a diagnosis of TTP be made.
In Hercules, however, Adamts13 levels were not tested before caplacizumab was given, meaning that there was no certainty that enrolled subjects had TTP. Asked about this, Mr Zeldin said: “The turnaround time for Adamts13 can vary out to a number of days, and it was important to get these patients treated with caplacizumab as quickly as possible.”
“As it turns out, in fact, the clinical diagnosis of TTP was spot on for the overwhelming majority of the 145 patients randomised,” he added. A source told EP Vantage that Adamts13 can typically be assessed within a day; Ablynx has separately argued that some centres do not test for Adamts13.
This is important. The market for caplacizumab is smaller with the drug used only after Adamts13-based diagnosis of TTP, versus a scenario where mere clinical manifestation of thrombotic microangiopathy suffices.
Ablynx believes that there will be no requirement to perform the Adamts13 test before initiating treatment with caplacizumab, though ultimately any decisions on labelling and reimbursement will be up to regulators and payers.
The chances of Ablynx capturing a significant population of patients who are not in fact Adamts13 deficient therefore need to be considered.
This is an updated version of an earlier story