HIF-PHs inhibitor for CKD and Renal anemia

1. Hugh Market.

(1) CKD is a major public health problem across the world. India: 145m (17.2%), US: 42m (16.98%), JP: 16m (15.58%) people have CKD.

(2) 90% of EPO, a key factor for erythropoiesis, is made in kidney. Kidney damage leads to EPO deficiency and releases inflammatory factors that inhibit EPO secretion. Inflammation increases hepcidin which inhibits iron absorption and inhibits iron transport to the liver and spleen, leading to reduction of serum iron and finally reduction of HGB. Therefore 60%-80% of CKD patients combine with renal anemia.

2. Unmeet needs with current therapy

(1) rEPO+Chalybeate is current strategy for renal anemia. However, this therapy is mainly used for the treatment of dialysis patients and patients who are about to dialysis (CKD stage 5, taking up only 2.3% of CKD patients), and many non-dialysis patients (CKD stage 3-4, 71.8% of CKD patients) are lack of efficient therapies.

(2) Severe cardiovascular adverse reactions (hypertension, stroke) of rEPO with FDA black boxing warning. Poor response to rEPO therapy for 20% of patients with chronic inflammation.

(3) The expensive price and inconvenient administrate route of biologics.

3. HIF-PHs inhibitor is a potent solution for renal anemia.

(1) The asset prevents HIF-1α degradation from HIF-PH enzymes, simulating the affair in hypoxia, which promotes EPO mRNA transcription and restore EPO secretion.

(2) HIF-PHs inhibition is thought to be a potent solution. Several HIF-PHs inhibitors have been approved in JP, India, AU, and China.

(3) This strategy not only work for renal anemia, but also have a potential to extend chemotherapy anemia and myelodysplastic syndrome (MDS) related anemia indications, which remains a much larger market size.

4. An effective PHD1/2/3 inhibitor.

The asset inhibits PHD1/2/3 activity at nanomolar level, slightly better than competitor FG-4592.

5. Great in vitro activity.

The asset is more effective than FG-4592 on inhibition of EPO secretion by inflammatory factors in Hep3B.

6. Excellent in vivo efficacy.

(1) The asset increased RBC and Hb in a dose-dependent manner in normal cynomolgus monkeys.

(2) The asset can improve the HGB level of model rats in a dose-dependent manner and no drug accumulation was observed after repeated administration.

7. Good safety in phase I trial.

(1) Plasma EPO reached maximum concentration 10-12 hour after dosing. And there was no accumulation of plasma EPO after repeated administration.

(2) After repeated administration of asset (40, 70, 100 mg), the reticulocyte count was significantly increased with the decrement of the hepcidin level, indicating that asset can effectively promote hematopoiesis and regulate iron metabolism.

(3) No severe or serious AEs were observed in this study. The incidence of adverse events was not significantly associated with dose escalation, indicating that asset is safe in healthy subjects.