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Critical Biologics Corporation(CBC), based in Cambridge, MA, is a development stage biotechnology company committed to making innovative products available to address significant unmet medical needs. We believe that the traditional commercial approach of targeting a single facet of a therapy- drug, device, diagnostic, or monitor- ignores the fact that often these modalities are employed in combination by physicians to treat the increasingly complex diseases of their patients.
The initial therapy licensed by CBC provides a breakthrough biotechnology approach that harnesses the body’s innate mechanism for localizing inflammation to the site of injury and preventing inappropriate systemic inflammation from occurring. This innate mechanism is managed through a vital protective protein called plasma gelsolin (“pGSN”) that is normally circulating at high concentrations in the blood of healthy people. Multiple studies in both animals and patients have shown that depletion of this highly conserved, naturally occurring protein is associated with poor outcomes including death that results from inappropriate systemic inflammation. Identification of critical pGSN depletion is accomplished by measuring a patient’s circulating pGSN level by means of the company’s proprietary assay (“SolinDx™”). Patients with critically low pGSN levels are at very high risk of severe complications including death. Once a dangerously low pGSN state is identified, repletion of the natural circulating reserves of pGSN can now be accomplished by administration of the company’s human recombinant form of pGSN (rhu-pGSN, “Solinex™”).
If successful, this therapy will prevent the development of inappropriate systemic inflammation which, in turn. will prevent a variety of severe clinical complications including death. The first clinical indications for this "theranostic" approach (that includes both the diagnostic test and the drug) to detect and treat documented cases of critical depletion of their natural pGSN, "hypogelsolinemia", are critically ill patients at high risk of severe complications of their disease and patients with end-stage renal disease (“ESRD”) on hemodialysis.
The role of pGSN in the localization of inflammation is so important that evolution has conserved this protein’s molecular structure across a broad spectrum of animal species. CBC has been developing recombinant human pGSN (“rhu-pGSN”) as a protein replacement therapy (“Solinex™”). This non-glycosylated protein is produced in E. coli and natural folding of this protein is assured during the purification process. CBC, working through its contract manufacturing partner, has achieved commercially viable yields of purified rhu-pGSN from the fermentation process to allow this drug candidate to be developed with the expectation that it will positively impact patient outcomes and produce substantial cost savings in the targeted indications.
CBC has demonstrated that Solinex™ is safe in rats and monkeys, the latter having been given up to ten times the normal blood levels for 28 days without any clinical or histological abnormalities seen. CBC has also demonstrated that Solinex™ is effective at alleviating life-threatening complications in a variety of relevant animal models of critical illness, including the prevention of death in two otherwise fatal mouse models of massive inflammation. CBC is currently completing a phase 2a, randomized, placebo-controlled trial of Solinex™ in critically ill patients at high risk of death with hypogelsolinemia documented by use of SolinDx™, the company’s proprietary pGSN diagnostic assay.
Using a diagnostic like SolinDx™ to target a therapeutic like Solinex™ to patients most likely to respond is referred to as a “theranostic” strategy. The FDA is currently encouraging biopharmaceutical companies to use theranostic strategies to develop their drugs more safely, effectively and efficiently. Genentech’s Herceptin®, developed in conjunction with a diagnostic test for an abnormal breast cancer protein, is a good example of a successful theranostic approach. With this approach, Genentech demonstrated increased survival for patients on Herceptin® through a clinical trial program that was much more efficient than would otherwise have been required. Since SolinDx™ can diagnostically identify hypogelsolinemic patients with a very high risk of complications and death, CBC anticipates being able to show statistically significant Solinex™ efficacy from a trial of only 320 patients (as compared to 1,700 patients in the absence of SolinDx™ targeting). Furthermore, the benefit of using SolinDx™ for theranostic targeting is not limited to just the clinical evaluation of CBC’s product candidate, Solinex™. For any product candidates, the use of SolinDx™ in a critical care or hemodialysis therapeutic development program to identify high-event rate patient populations is likely to allow differences between the treatment and placebo to reach statistical significance by enrolling dramatically smaller number of patients thereby resulting in substantial clinical trial cost savings and more rapid regulatory approvals.
Harvard nephrologists recently demonstrated in a 200 subject study, that end stage renal disease (ESRD) patients dying within their first year of dialysis had severe hypogelsolinemia, whereas survivors did not. In fact, this study showed that patients with severe hypogelsolinemia have a statistically significant and markedly elevated (9-fold increased) risk of death from either cardiovascular events or infection. This risk of death increased to a remarkable 27-fold for hypogelsolinemic patients using a catheter for vascular access in hemodialysis as opposed to a surgically constructed vascular access (fistula or shunt). These findings are especially compelling since the study results are already adjusted for all of the usually prognostic patient characteristics. These findings suggest CBC’s proprietary diagnostic screening for hypogelsolinemia is the most powerful known predictor of death for ESRD patients within their first year of hemodialysis.
CBC has additionally compiled a comprehensive database that demonstrates a strong correlation between hypogelsolinemia and increased complications and death in a variety of conditions including physical trauma, major surgery, bone marrow transplantation, burns, pneumonia, and end-stage renal failure. In these patients, the lower the pGSN levels the higher the risk of developing fatal complications from their underlying disease. In animal models with similar degrees of pGSN depletion as those seen in patients, restoration of pGSN levels using rhu-pGSN ameliorates the progressive systemic tissue injury and reduces mortality. In CBC’s current pharmacokinetic phase 2a study, the preliminary results from the low dose group in the study of Solinex™ given as a one hour IV infusion to critically ill patients with documented hypogelsolinemia, suggest that the drug is well tolerated and able to restore the pGSN level to a concentration above the critical threshold for these patients, usually for 24 hours.