Italo Linfante
Following the recent publication in Stroke: Vascular and Interventional Neurology of results from HEMERA-1, a prospective, multicentre trial evaluating the safety of novel neuroprotective agent PP-007 (Prolong Pharmaceuticals) alongside mechanical thrombectomy in acute stroke patients, lead investigator Italo Linfante (Miami Neuroscience Institute, Miami, USA) delves deeper into the data and discusses some of the studys wider implications with NeuroNews.
What is the background to this study, and why did you and your co-investigators initiate it?
Several randomised clinical trials have shown overwhelming superiority of mechanical thrombectomy over medical management for patients with acute stroke secondary to large vessel occlusion (LVO). In these trials and in large-volume case series post trials, despite high rates of complete recanalisation of the occluded vessel, functional independence at 90 days ranges approximately between 4171% of patients.13
In experimental ischaemia models, middle cerebral artery occlusion (MCAO) induces redistribution of cerebral blood flow (CBF), and activation and engagement of leptomeningeal anastomoses (LMA). The amount of redistribution and increase of CBF in LMA can significantly influence final infarct volume.68 In fact, in experimental ischaemia models and in patients with acute stroke secondary to LVO, increased CBF in LMA reduces the activation of several neurotoxic molecules in penumbral tissue, slows core expansion, and ultimately induces protection from neuronal ischaemic injury. Conversely, poor blood flow in LMA is associated with a faster growth of the ischaemic core.6
PEGylated bovine carboxyhaemoglobin, or PP-007, is a carbon monoxide (CO)-releasing and oxygen-transfer molecule with pleotropic neuroprotective effects. As demonstrated in several experimental ischaemia models, such as temporary rats MCAOs, the neuroprotection induced by PP-007 is due to a combination of: increased blood flow in pial collaterals; optimisation of oxygen transport in ischaemic tissue; and plasma expansion effect secondary to the pegylated nature of the compound.1216 Furthermore, since PP-007 also acts as a CO donor and small amounts of CO were found to have anti-inflammatory properties, PP-007 was observed to reduce proinflammatory cytokines.8,13 Dose escalation studies were performed in normal volunteers, patients with sickle cell anaemia and patients with subarachnoid haemorrhage too.
Could you very briefly describe the design and methodology of the study?
We aimed to evaluate the safety and feasibility of PP-007 in acute stroke patients undergoing mechanical thrombectomy. HEMERA-1 was a Phase 1, multicentre, prospective randomised controlled clinical trial. Anterior-circulation LVO patients were assigned in a 3:1 ratio to receive either PP-007 (320mg/kg; 30-minute bolus followed by two-hour infusion) plus mechanical thrombectomy or mechanical thrombectomy alone within 24 hours after symptom onset. Comprehensive safety evaluation was performed by an independent data safety monitoring board (DSMB) and an independent imaging core lab.
Could you briefly summarise the key findings of HEMERA-1, now published in Stroke: Vascular and Interventional Neurology?
From 10 January 2021 to 30 June 2022, a total of 17 patients were recruited. Age, baseline National Institutes of Health stroke scale (NIHSS) and Alberta stroke programme early computed tomography score (ASPECTS) were 74.812.7 years, 17.34.2, and 7.91.8, respectively. Twelve patients were randomised PP-007 plus mechanical thrombectomyone was randomised but not treatedand four patients were randomised to mechanical thrombectomy alone. Recanalisation of the occluded vessel was achieved in all patients.
Was there anything in these results, positive or negative, that surprised you?
No significant safety concerns were identified for the adjunctive use of PP-007 in patients undergoing mechanical thrombectomy after the DSMB reviewed all patients data in detail for every organ system, independently from the investigators. A transient systolic blood pressure increase (2040mmHg) during the bolus was observed in all PP-007 patients without any clinical consequences.
Do you have any concerns at all regarding the transient increase in systolic blood pressure seen in patients treated with PP-007 in the trial?
No, because the increase in blood pressure is consistent with the plasma-expander properties of PP-007. This temporary increase in blood pressure had no safety concerns, as adjudicated by the DSMB and the imaging core lab.
It is noted in the paper that patients treated with intravenous thrombolysis were not eligible for HEMERA-1do you think it is inherently likely that subsequent studies can produce even more positive outcomes, given the known benefits of thrombolytics may be compounded by the neuroprotective effects of PP-007?
As per US Food and Drug Administration (FDA) request, to avoid drug-drug interaction, we did not enrol patients who received alteplase (tPA) or tenecteplase (TNK) in HEMERA-1. Once the data were analysed and adjudicated to be safe, we then enrolled an additional 14 patients to evaluate safety of the combination of tPA or TNK, and PP-007. The data were reviewed by two additional DSMB meetings and a core imaging lab independent from the investigators. No safety concerns were found, with the data set to be submitted for publication.
With this study having been successful, can you shed any light on the randomised controlled trial that will now follow to assess PP-007s efficacy?
We are currently planning a multicentre, Phase 2b/3 randomised clinical trial for efficacy. Patients with acute stroke secondary to LVO undergoing mechanical thrombectomy will be randomly assigned to receive PP-007 or placebo. The trial will have an adaptive design and a shift analysis of the modified Rankin scale (mRS) at 90 days as its primary endpoint. Secondary endpoints will include NIHSS changes, infarct growth on follow-up imaging etc. We hope to submit the randomised trial design to the US FDA by the end of the year.
How many stroke patients could be positively impacted by this neuroprotective drug if it does continue to progress through trials and into clinical practiceand how much of a difference could it make for them?
Data from the American Heart Association (AHA) report that, every year, more than 750,000 people in the USA have a stroke, and 87% of them are ischaemic.15 In my humble opinion, if the trial will show efficacy, all ischaemic stroke patients can be potentially treated with PP-007. In addition, if PP-007 is beneficial for ischaemic stroke patients, perhaps this advanced molecule could be used in other organs affected by ischaemic conditions.
There have been some fairly mixed data and findings on neuroprotection over the past few yearswhat do you think the overall landscape looks like for neuroprotection, and are we getting closer to elucidating its potential role in acute stroke care?
Many promising therapeutic agents for neuroprotection have been identified to target the complex pathophysiological events occurring at the level of the neurovascular unit during ischaemia.45 However, none of these agents have proven to be beneficial in clinical studies to date. It must be considered that most of these studies predated the mechanical thrombectomy era and, most likely, neuroprotection may not be evident without effective recanalisation of the occluded artery. In my opinionnow that we are in the mechanical thrombectomy era, with high recanalisation ratesthere will be a tremendous effort to develop pharmacological agents that are able to slow down core expansion and preserve the ischaemic penumbra to improve outcomes in patients with acute stroke secondary to large-artery occlusions.
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Original post:
Positive HEMERA-1 data pave the way for further neuroprotection trials during 'thrombectomy era' - NeuroNews International