Bianchi Giuseppe Professore EmeritoMedicina

Giuseppe Bianchi, MD, Milan University. Training in Pharmacology cardiovascular-renal pathophysiology, biochemistry and clinic in Pharma Companies, Universities of Milan, Parma, Padua, London and Glasgow, PhD in Pharmacology, Specialities in Cardiology and Nephrology. Honorary MD at the Universities of Berlin and Uppsala, awards from British, American, and Italian societies of Hypertension, National Kidney Foundation USA, International Union of Physiological Science USA, Accademia dei Lincei Rome, University of Naples and other scientific organizations.

Former Director of the Division of Nephrology, Dialysis and Hypertension, Chair and School of Nephrology, “Vita Salute” San Raffaele University, Milan University and past Scientific Director of the Prassis Sigma-Tau Cardiovascular Research Institute and of CVie Therapeutic Taiwan and China and past CSO at Windtree Therapeutics USA.

Present: Professor Emeritus at the “Vita Salute” San Raffaele University.

Past and present member of the Editorial Boards of 12 international journals and invited speaker or chairman at more than 600 national and international meetings. He has published more than 300 articles in peer-review journals (including Lancet, J Clin Invest, New Engl J med, PNAS, Science Trans Med etc.)  and more than 200 chapters in books or in meeting proceedings. Over the years, Prof. Bianchi has combined his academic and clinical experience with parallel work in collaboration with pharmaceutical companies (Lepetit S.p.A., Farmitalia Carlo Erba, Prassis Sigma-Tau S.p.A., CVie Therapeutics Taiwan and Windtree Therapeutics USA) in order to develop a targeted therapeutic approach to cardiovascular diseases through laboratory and clinical practice.

Precision Medicine is based on the principle that curative therapy must target the molecular abnormalities involved in the onset and/or maintenance of the disease. These molecular abnormalities may be triggered either by:

1. primary genetic factors, or
2. a variety of genetic, environmental, or biological factors, such as SERCA2a activity deficiency in cardiac failure in both animal models and patients.

The more potent and selective the novel drug is on these molecular targets, the greater the benefit-to-risk therapeutic ratio that may be achieved. The common strategy for both approaches consists of gathering findings from different contexts and then developing scientific hypotheses capable of accommodating them, after properly accounting for their specific context-dependent components.

Prof. Bianchi's clinical and research activities have been focused on the discovery or validation of both types of molecular abnormalities. These studies have addressed:

A) the genetic mechanisms regulating the activity of adducin and the synthesis and metabolism of endogenous ouabain that may affect hypertension with associated cardiac and renal damages.
B) the deficiency of SERCA2 activity in heart failure as the most important cause of cardiomyocyte Ca2+ abnormalities involved in cardiac mechanical abnormalities, arrhythmias, and metabolic dysfunction, including the increase of Reactive Oxygen Species (ROS) due to an increase in mitochondrial Ca2+.

Project A) Initially, this project aimed to find answers to the following questions: Can a "normal" kidney play a primary role in the development of "primary" or "essential" arterial hypertension? And if so, is it possible to develop a "causal" therapy for this form? The pursuit of these answers involved various fields including clinical medicine, pathophysiology, animal modeling, translational medicine, kidney physiology (including micro puncture), cell physiology, molecular biology, genetics, medicinal chemistry, molecular and clinical pharmacology. Naturally, this interdisciplinary approach necessitated collaboration among
experts in different disciplines. Broadly, the strategy can be outlined in seven steps:

1. Defining in an animal model and patients the temporal sequence of pathophysiological changes, along with responses to therapeutic interventions, associated with increased blood pressure following a known type of kidney injury such as renal artery constriction. Insights from these studies informed subsequent steps.
2. Assessing, in appropriate animal model the Milan hypertensive rat (MHS) and in humans, whether a direct intervention like kidney cross-transplantation could influence blood pressure in primary or essential hypertension. These studies revealed that hypertension is influenced by the kidney.
3. Identifying, in the MHS (an animal model sharing similarities with human patients in functional and biochemical abnormalities), the subcellular structures potentially responsible for subtle cellular abnormalities leading to hypertension despite an otherwise "normal" kidney. A membrane cytoskeleton abnormality was discovered, potentially speeding up ion transport across the basolateral membrane of kidney cells, leading to increased tubular Na+ reabsorption (as demonstrated by whole kidney studies in both species) via increased basolateral membrane expression of Na-K pump units.
4. Through various genetic studies, pinpointing the "abnormal" cytoskeleton protein(s) and their association with cellular and whole-body abnormalities leading to hypertension in both animals and humans, along with associated organ damage. Adducin proteins and their gene variants emerged as prime candidates for these effects.
5. Exploring other bodily mechanisms that could modulate the aforementioned constitutive kidney abnormalities. Many hormones play roles in adapting kidney function to bodily needs; endogenous ouabain, targeting the Na-K pump, emerged as a primary candidate for this function.
6. Transitioning from association to validation, a highly selective, potent, and safe chemical compound (Rostafuroxin) was developed for use in animal models and patients. At a concentration of 10-11 M, Rostafuroxin selectively disrupts the binding of mutant adducin or ouabain-activated Na-K pumps to the SH2 domain of cSrc, selectively blocking the effects of mutant adducin and endogenous ouabain on Na-K pumps at both cellular and whole-body levels without affecting their normal functions.
7. Validating the involvement of the two molecular mechanisms (mutant adducin and endogenous ouabain) through two phase II trials in patients. The effect of Rostafuroxin was tested in 518 Caucasians, carriers, and non-carriers of a combination of gene variants (gene profile) known to impact these two molecular mechanisms' effects on cellular and bodily physiopathology. In profile carriers with mild hypertension, Rostafuroxin at a daily oral dose of 0.06 mg resulted in a significant reduction in blood pressure (approximately 23 mmHg), compared to a negligible reduction (about 2 mmHg) observed in non-carriers. Conversely, the response to Losartan and HCTZ in 338 Caucasian patients was unaffected by the profile. Given that the profile is present in about 1/4 of hypertensive patients, these findings could be significant for optimizing blood pressure levels and preventing organ damage in a large number of patients. However, in 172 Chinese patients, the effect of Rostafuroxin was much lower, likely due to faster metabolic degradation in this population.

Project B) SERCA2a activation
Among a series of compounds synthetized to optimize their interaction with the Na-K pump, one molecule, subsequently named Istaroxime, has been characterized because its cardiac inotropic activity was associated to none or mild pro-arrhythmic activity, much lower than that of the known Na-K pump inhibitors. A series of appropriate studies in different contexts have demonstrated that Istaroxime, beside its Na-K pump inhibition sustaining its inotropic action, also displays a SERCA2a stimulatory activity that may mitigate the arrhythmias and favor diastolic relaxation with the associate improving of thee heart pumping capacity. Moreover, during Istaroxime infusion there is the formation of a main and long-lasting metabolite, PST3093, endowed with the sole SERCA2a activity at plasma concentrations well above the ones stimulating SERCA2a in vitro.

Istaroxime has been investigated in vivo in animal models of HF, displaying safety and efficacy in improving the cardiac indexes of both systolic and diastolic function. It was then developed for the in-hospital intravenous treatment of Acute Heart Failure patients. The results of the Phase I and II clinical trials, involving 350 patients, indicated that Istaroxime is a safe and effective luso-inotropic agent able to improve Pulmonary Capillary Wedge Pressure (PCWP), Cardiac Index (CI) (especially in patients with basal CI < 2.5 L/min/m2), without reducing, but even slightly enhancing SBP, and mildly reducing heart rate when intravenously infused for 6 hours. A Phase IIb clinical trial in patients with acute heart failure investigated the safety and efficacy of Istaroxime over a 24 hour at the intravenous infusion of 0.5 and 1 g/kg/min. It was shown that Istaroxime increased stroke volume index (SVI) and decreased the indexes of venous congestions, such as left atrium area (LAA) and inferior vena cava diameter (IVCD) after 24 hours infusion at the low dose of 0.5 g/kg/min, that persisted up to 48 hours from Istaroxime infusion start, when the parent compound is no more present in plasma, while the Istaroxime long-lasting metabolite PST3093 plasma concentrations are high enough to stimulate SERCA2a. As at 72 hours from the infusion start, the plasma concentration of the metabolite PST3093 is still in the concentration range able to stimulate SERCA2a, it is likely that an infusion of 24 hours may produce beneficial cardiac effect for 72 hours. Compared to the placebo treated patients, these beneficial effects occur without affecting plasma Hs-TnT and a decrease by 57% of the cardiovascular adverse events. These long term Istaroxime beneficial effects are very likely supported by the metabolic ones produced by the PST3093 SERCA2a activation mentioned above.

With a medicinal chemistry program, a pure and very selective SERCA2a activator has been developed that, after intravenous or oral administration in an animal model of heart failure, demonstrated a pharmacological profile similar to that of PST3093.

Conclusions

Rostafuroxin and Istaroxime, along with its metabolites, are first-in-class drugs targeting specific molecular mechanisms underlying clinical symptoms. The available experimental and clinical data support the notion that they may be 'causal' drugs with an unprecedentedly high level of benefit-to-risk ratio, compared to that of the same class available drugs. This is because the available drugs target normal physiological mechanisms, aiming to mitigate the
clinical symptoms caused by the pathological ones.

Update

The results with the corresponding conclusions described above were already available on December 2018, when these projects were transferred to Windtree Therapeutic (USA). Unfortunately, as of today (March 2024), the management of this company has not yielded significant results regarding the progression towards the use of these compounds in the clinical practice. This failure is mainly due to the choice of a business driven developmental strategy disregarding the previous scientific knowledge and skill needed to assess the causal mechanisms of clinical symptoms and how to correct them with a “causal” drug. The
choice of the vasoconstrictor effect of the higher doses of istaroxime for the cardiogenic shoch therapy is an example of this Windtree’ strategy. This strategy ignores that, compared to the lower doses, the previous data showed a clear reduction of the patients’ benefits/risk ratio at the higher doses. After countless unsuccessful attempts to correct this wrong strategy, in April 2022 prof Bianchi rejected the Windtree ‘proposal to continue the collaboration with Windtree.