Rethinking future treatment options for sepsis: from immunosuppressive to immunostimulating drugs
Treatment of sepsis and septic shock has traditionally been limited to infection control and supportive care in the form of fluid therapy and mechanical organ support. Drug discovery efforts have also historically emphasised immunosuppression as important for the future management of these patients. In the face of persistently high mortality rates, however, the biomedical research community is realising the necessity for novel, innovative therapeutic alternatives for sepsis patients.
In one case from January 2017, a woman suffering from a severe episode of fungal sepsis at the Erasme Hospital in Belgium was treated with an unconventional regimen of investigational immune-boosting drugs. This saved her life while simultaneously signalling a turning point in the sepsis and septic shock treatment paradigm. GlobalData believes that this unconventional intervention will save many more lives, as companies such as Bristol-Myers Squibb (BMS) and RevImmune seek to demonstrate its merit in larger randomised clinical trials (RCT).
After the terrorist bombings in Brussels in March 2016, a 30-year old woman sustained extensive fractures, soft-tissue injury, and burns, which led to severe multi drug-resistant bacterial infections and sepsis. After surviving the initial phase of sepsis, a state of hyper-inflammation with a considerably high mortality rate, the woman acquired a severe fungal infection. Secondary infections are frequently seen in patients recovering from the initial onset of sepsis, as they are especially vulnerable to succumbing to opportunistic infections, viral reactivation, and other comorbidities when suffering from an immuno-paralysed state of sepsis.
Immunostimulating drugs BMS’ Opdivo (nivolumab) and Boehringer Ingelheim’s ImmuKine (interferon-gamma) both successfully activated the patient’s immune system, allowing her to survive the invasive fungal infection. Opdivo is currently in Phase I of clinical development in patients with sepsis and septic shock.
Other immunostimulating treatment options, such as BMS’ anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) BMS-936559 and RevImmune’s CYT-107, a recombinant human interleukin-7 cytokine, are in Phase I/IIa and Phase II of clinical development, respectively, for sepsis and septic shock.
While experts are extremely excited about the development of these immuno-stimulating drugs, GlobalData notes that it is essential to identify patients who are likely to respond to this intervention, as it will be unwise to further increase the immune response in patients suffering from a hyper-inflammatory response. In a heterogeneous disease, such as sepsis and septic shock, reliable biomarkers to identify these patients do not exist, urging companies to use a combination of biomarkers, such as low absolute leukocyte count, pro-inflammatory cytokines, anti-inflammatory cytokines, or human leukocyte antigen-D related (HLA-DR) complex, to identify an immuno-paralysed disease state.
More than 100 clinical trials aimed at finding drugs for the hyper-inflammatory response in sepsis and septic shock patients have failed. The hyper-inflammatory course of the disease is thought to be short-lived and responsible for early sepsis mortality, while the immuno-paralysed state is mostly responsible for death during the prolonged onset of the disease. Improved supportive care in terms of early antibiotics and initial fluid resuscitation, as well as the ability to stabilise organ functions within an intensive care unit (ICU) setting, has led to a decreased mortality in the early onset of sepsis.
Positive results from this individual case study highlight the potential benefit of Opdivo and other immuno-stimulating drugs in sepsis and septic shock patients. However, results from large RCTs will eventually be required to fully investigate this promising approach.