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A small molecule AMP activated protein kinase (AMPK) activator, denoted O304, as a novelinnovative drug for the treatment of type 2 diabetes

Periodic Reporting for period 2 - AMPK-DIAB (A small molecule AMP activated protein kinase (AMPK) activator, denoted O304, as a novelinnovative drug for the treatment of type 2 diabetes)

Reporting period: 2017-09-01 to 2018-06-30

The objective of the project was to perform a proof-of-concept phase IIa trial in type 2 diabetic (T2D) patients and monitor metabolic and cardiovascular effects to reach the stage where interest and investment from third parties in the continued clinical development of the drug is possible. O304 is currently the only direct AMPK activator in clinical development. The project has been delivered according to plan and the clinical study has yielded highly positive results. The Phase IIa clinical trial has been successfully completed with 59 of the planned 60 T2D patients completing the study, and 58 patients endured all the MRI examinations before and after treatment. Five patients did not compete the study for mainly personal reasons not related to the treatment.
"In the second reporting period, the project has achieved its key objectives:
No serious adverse events have been reported. The study report has been provided as deliverable. O304 reduced fasting plasma glucose levels and insulin resistance, lowered systemic blood pressure, and increased microvascular perfusion, all beneficial effects in T2D patients. These results have been published ""PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients"" View the article here: https://insight.jci.org/articles/view/99114.
In addition, the results provide evidence that O304 may be beneficial in diabetic kidney disease (DKD). Globally, approximately 40% of Type 2 diabetes (T2D) patients develop DKD, and diabetes is the leading cause of kidney failure, requiring dialysis or a kidney transplant. The increasing prevalence of DKD parallels the dramatic worldwide rise in prevalence of diabetes caused by the global pandemic of obesity.
Unfortunately, however, the current standard of care with anti-hypertensive ACEi/ARB drugs which reduce glomerular hypertension shows very limited efficacy, and despite decades of research on the various mechanisms such as fibrosis and inflammation, no new drugs have been approved in the last 15 years for the treatment of DKD or chronic kidney disease (CKD). Thus, there is a great need for novel, more efficient drugs to prevent and treat DKD and CKD.

Glomerular filtration is an essential process whereby fluid in the blood is filtered by the kidneys. Glomerular ‘hyperfiltration’ mediated by intraglomerular hypertension is common in the early stages of T2D and believed to provoke a later decline in globular filtration rate (GFR), ultimately potentially leading to kidney failure. The balance shifts to glomerular hyperfiltration as a result of high intraglomerular pressure caused by increased blood flow into and decreased blood flow out from the glomerulus.

SGLT2 inhibitors are recently introduced anti-hyperglycaemic agents that show improved renal outcome in T2D patients with established cardiovascular disease by reducing estimated globular filtration/hyperfiltration (eGFR) via activation of tubuloglomerular feedback that reduces blood flow into the glomerulus. However, SGLT2 inhibitors are contra-indicated in T2D patients with impaired renal function due to lack of anti-glycaemic effect in this group of patients."
AMPK is a major regulator of glucose and lipid metabolism and of tubular transport of water and ions in the kidney. Multiple interventional studies in animal models have suggested potentially beneficial effects of AMPK activation in DKD– effects that might translate into cardiorenal protection. In T2D patients, O304 both lowered systemic blood pressure and increased microvascular perfusion. Moreover, post hoc analyses of phase I and IIa clinical trials of O304 show that O304 potently reduced eGFR by a rapid, stable and reversible haemodynamic effect both in T2D patients on metformin and in obese non-diabetic subjects.

O304 also reduced eGFR both in T2D patients with no anti-hypertensive treatment or on top of ACEi/ARB drug treatment (standard of care for DKD), indicating that O304 either reduces eGFR by the same mechanism but more efficiently or by a different mechanism than ACEi/ARB drugs. Thus, O304 reduces blood glucose and insulin resistance, lowers blood pressure, increases microvascular perfusion, and reduces renal filtration/hyperfiltration in T2D patients – beneficial metabolic and haemodynamic effects that are likely to translate into long-term protection of kidney function and thus reduced incidence of diabetic kidney disease. These results are published Health Europa Quarterly Issue 6, https://www.healtheuropa.eu/ampk-o304-diabetic-kidney-disease/86703/.

The results of the phase IIa trial have enabled Betagenon to become involved in active discussion/meetings with multiple Big pharma. Betagenon has engaged an expert MD in internal and renal medicine with Big pharma experience to aid in the discussions with Big pharma. Betagenon has alsop engaged a Licensing Strategist, Denise Goode, who has extensive experience with out-licensing negotiations with Big pharma, to head these activities. No major issues have emerged from deep due diligence by Big pharma, and Betagenon is aiming to sign a licensing agreement with a global Big pharma.