Diabetic macular edema (DME) is a leading cause of vision loss related to diabetes. As of 2012, an estimated 9.6 million people in the United States alone had diabetic eye disease (diabetic retinopathy), with DME occurring in about 10% of patients.
Increased blood sugar levels (hyperglycemia) caused by diabetes can damage the cells in the retina. Over time, this damage can cause the small blood vessels to become leaky and allow fluid and proteins from the blood to enter the retina. DME is characterized by an accumulation of fluid in the macula of the retina. Its hallmark feature is a retinal thickening.
Management of DME
Current DME treatments include VEGF inhibitors, corticosteroids and laser therapy. VEGF inhibitors block the actions of vascular endothelial growth factor (VEGF); a signaling protein that causes the retinal vessels to become leaky. VEGF inhibitors are injected into the eye, typically on monthly intervals, and can provide significant vision improvements - but not all DME patients respond adequately to these treatments. Clinical studies have shown that up to 40% of patients failed to experience an adequate response to VEGF inhibition. However, due to a lack of alternatives, many of these patients continue to receive anti-VEGF treatments to prevent their vision from worsening further.
Steroids improve vision to a lesser degree than anti-VEGF and also increase the risk of cataracts and glaucoma. Laser therapy was the previous standard of care for DME and is now used as needed in conjunction with other treatments.
KalVista and its founding scientists from the Joslin Diabetes Center associated with Harvard Medical School were pioneers in the discovery of a new mechanism potentially contributing to the development of DME. Plasma kallikrein - an enzyme - was found to be excessively activated in patients with DME. Our most advanced compound, an intravitreally administered plasma kallikrein inhibitor known as KVD001, has completed Phase 2 clinical trial in patients with DME.
The Phase 2 trial consisted of 129 patients who had previously been treated with anti-VEGF therapy, and still had significant edema and reduced visual acuity. The sham-controlled, double-masked clinical trial evaluated two dose levels of KVD001, 3µg and 6µg. Four intravitreal injections or sham were administered over three months with a three month follow up period. The study was conducted at 38 sites in the United States.
The KVD001 Phase 2 clinical trial study was designed to evaluate patients who were poor responders to previous treatment with anti-VEGF therapy. The primary efficacy endpoint in the trial was change in best corrected visual acuity (BCVA) at 16 weeks compared to sham. The 6µg dose showed a difference of +2.6 letters versus sham, which was not statistically significant (p=0.223), and the 3µg dose showed a difference of +1.5 letters (p=0.465). No significant differences were observed in the secondary endpoints of central subfield thickness (CST) or the diabetic retinopathy severity scale (DRSS). KVD001 was generally safe and well tolerated with no drug-related serious adverse events.
In the overall study population, KVD001 demonstrated a protection against vision loss. In the sham treated group 54.5% of patients experienced a reduction in vision compared to 32.5% in the 6µg dose (p=0.042). The study also included a pre-specified subgroup analysis investigating the impact of baseline visual acuity on response. After excluding those patients with the most severe vision loss (visual acuity of <55 letters at baseline), the remaining 70% of the total patient population showed a difference in BCVA compared to sham of 4.9 letters (p=0.056) at the 6µg dose.
We also believe an orally delivered therapeutic could provide significant clinical benefit to DME patients compared to the current DME drugs delivered via injection. We're excited by the possibility of developing an oral option for DME patients and look forward to your interest as our research continues.