The first patient has been enrolled in a randomized, controlled, investigator-initiated clinical trial in up to 150 patients for the treatment with Ruconest (recombinant human C1 inhibitor) of patients with confirmed COVID-19 (SARS-CoV-2) infections hospitalised with related severe pneumonia at the University Hospital Basel in Basel, Switzerland.
In April 2020, Pharming Group N.V. reported encouraging results from a compassionate use programme at the University Hospital Basel, in which four male patients and one female patient (between 53-82 years of age) with COVID-19, suffering from related severe pneumonia, who did not improve despite standard treatment, including hydroxychloroquine and lopinavir/ritonavir, had been administered Ruconest. Following treatment, fever resolved in four of the five patients within 48 hours, and laboratory markers of inflammation decreased significantly (CRP, IL-6). Soon thereafter, four of the five patients were discharged from the hospital as fully recovered. One patient had increased oxygen requirement and was eventually transferred to the ICU for intubation but has also since made a full recovery.
Following these encouraging results, the Company, in partnership with treating physician Dr Michael Osthoff from the University Hospital of Basel, saw potential for a larger investigator- initiated, multinational, multicentre study to investigate the full extent of the role of Ruconest in the treatment of severe pneumonia related to a COVID-19 infection. If successful, the clinical trial could also lead to additional studies in patients suffering from other diseases with severe respiratory or other organ failure complications driven by activation of the complement system as part of a systemic hyperinflammatory syndrome, also known as a ‘cytokine storm’.
Ruconest is a recombinant C1 esterase inhibitor (C1INH) approved for the treatment of HAE in the EU and US. C1INH is a protein that naturally occurs in the human body. It regulates several inflammatory pathways in the body by inhibiting certain proteins that are part of the
human immune system. Systemic hyperinflammation is a hallmark of more severe stages of COVID-19 leading to acute respiratory distress syndrome, mechanical ventilation and ultimately death. Treatment with Ruconest may; 1) dampen uncontrolled complement activation and collateral lung damage and 2) reduce capillary leakage and subsequent pulmonary edema by direct inhibition of the kallikrein-kinin system and 3) reduce the generation of microthrombi by inhibiting MASP-1 induced clot formation and factor XII amplified thrombo-inflammation.
C1 inhibitor is an acute phase reactant, meaning that the body naturally increases production during inflammatory conditions, such as infections. Despite this, a relative deficiency may occur and complement activation continues unchecked, often leading to a cytokine storm, a dangerous biochemical process that worsens the complications of COVID-19 infection, such as organ failure and death.
This clinical study in hospitalised patients with COVID-19 seeks to identify if the administration of additional C1 INH can control or stop the systemic hyperinflammation syndrome or cytokine storm. Once results from either an interim analysis or after all patients have been treated, headline data will be made publicly available.
Prof. Bruno Giannetti, Pharming’s Chief Medical Officer comments:
“COVID-19 has proven that there is a significant need for better understanding of how the immune system fights infections. We have learned that cytokine storms caused by complement system activation cannot be controlled by targeted anti-inflammatory therapies. Instead, broad anti-inflammatory agents are required to stop the activation of multiple inflammation pathways. Ruconest’s multiple interactions with key inflammation pathways therefore make it a promising candidate to prevent the severe complications observed in COVID-19 patients. This investigator-initiated clinical trial in partnership with Dr Michael Osthoff, will be important not only for the treatment of pneumonia as a result of COVID-19 infection, but will also provide key insight into the future treatment of complement system influenced diseases.”
Dr Michael Osthoff, University Hospital Basel and the treating physician, says:
“After the encouraging results observed in five patients treated with Ruconest in our clinic, it is justified to investigate this drug and its unique mode of action of targeting several inflammatory cascades in a clinical trial with a large number of patients. We will gather precious information about efficacy, safety and appropriate dosing of the drug in the treatment and prevention of the severe complications of COVID-19. After a short period of remission, we observe a worrisome increase of new COVID-19 cases in Europe, whilst in a number of other countries the disease still spreads almost uninhibited. The need for a treatment of COVID-19 associated complications is more urgent than ever.”