By Grant Zeng, CFA
Earlier today (March 13, 2017), DiaMedica (TSX:DMA.V) reported positive results from its Phase Ib bridging trial. The study was designed to compare the profile of DM199 to the approved urinary KLK1 product (trade name Kailikang®) on the market in Asia for acute ischemic stroke (AIS). The reference drug (Kailikang) is administered intravenously and has a very short half-life.
Background of the Phase Ib Trial
The goal of the Phase Ibridge clinical study of DM199 is to determine the safety, optimal dose & delivery.
The Phase I controlled trial was an open-label single ascending study, where healthy volunteers received one of four single doses of DM199 (n=36), administered as a 30-minute intravenous (IV) or a single subcutaneous (SQ) infusion. Plasma DM199 concentration, biomarker concentrations, and other safety and pharmacokinetic parameters were measured in the trial.
In December 2016, the company reported positive results from intravenous (IV) part of the clinical trial. The study results demonstrated the dose dependent levels of DM199 and identified a dose of DM199 via intravenous (IV) administration that produced pharmacokinetic and pharmacodynamic activity that were comparable to those produced by the reference drug, human urinary KLK1 (trade name Kailikang®) approved in Asia.
This clinical study also provided clinically relevant safety data via intravenous delivery of DM199 for the first time at dose levels comparable to the currently approved human urinary KLK1 product.
No treatment limiting adverse events were reported in any dose group. A few patients experienced mild orthostatic hypotension which is consistent with the mechanism of action and demonstrated drug activity. The Company plans to publish the full results of the study in a peer reviewed journal.
The Updated Result from the SC Part of the Phase Ib Trial
Today the Company is reporting an improved subcutaneous (SC) dose of DM199 producing sustained plasma levels superior to the reference drug.
The DM199 SC delivery provides sustained levels of the KLK1 protein, offering a potentially superior profile to the reference drug, which has a very short exposure window. The dosing of DM199 will be significantly more convenient and potentially provide improved efficacy to the short half-life of the reference drug. DM199 has the same amino acid sequence as the reference drug, identical biochemical activity, and demonstrated similar physiological effects.
No treatment-limiting adverse events were reported in any dose group. The Company plans to publish the full results of the study in a peer reviewed journal.
More frequent delivery could improve efficacy:
- Kailikang® has very short half-life potentially limiting efficacy;
- Administered 1 times/day 50-minute slow infusion;
- KLK1 levels decline quickly after infusion;
- 1 times/day IV dosing may not be enough KLK1 in system for optimal efficacy;
- 1 vs. 3 times/day dosing IV urinary KLK1 clinical trial study recently initiated;
- IV DM199 delivery
- DM199’s very low manufacturing cost will support economics of increased dosing frequency
- SQ DM199 delivery
- Significantly longer half-life vs. IV Kailikang®
- Promote elevated KLK1 levels throughout the day, not just after infusion
- Support full 21-day treatment regimen at home – delivery every 1 to 3 days
- Today, many patients in China do not come back to hospital for daily 50-minute slow infusion affecting efficacy and sales.
The Phase Ib trial has now identified the optimal dosing of DM199, both IV and SQ compared to the Kailikang (urinary KLK1). Kailikang is administered via IV for 50 minutes daily for 21 days. The challenge is that within minutes of stopping the slow infusion, KLK1 drops right off. A single SQ dose of DM199 maintains KLK1 levels for 3 days thus supporting less frequent dosing and more importantly anticipated increased efficacy by having KLK1 levels elevated for the full day instead of just during the infusion period and minutes after stopping the infusion with Kailikang.
The company is also leveraging the existing efficacy and understanding of Kailikang by over 300,000 patients who have received treatment to date. Thus, efficacy can be improved by using the company’s long acting SQ delivery, targeting patients with greatest likelihood to respond, targeting patients with lower KLK1 levels and shortening the treatment window from the 48 hours approved by Kailikang while still capturing more stroke patients.
DiaMedica intends to seek worldwide approval for DM199 as a novel therapy for acute ischemic stroke (AIS). The company will also position DM199 in China as an improved product over the urine-sourced KLK1 protein currently used there. With the potential that effective treatment can be initiated up to 48 hours after the first sign of symptoms, DM199 may fill a large unmet need for stroke patients who cannot receive tPA, benefiting millions of people around the world who currently have limited treatment options.
DiaMedica intends to initiate a Phase II study of DM199 for AIS in 2017. The Phase II trial will enroll approximately 100 AIS patients and start treatment within 24 hours of stroke over 21 days. The primary end points include:
- Safety and tolerability
- Biomarkers - blood flow and inflammation
- Modified Rankin Scale (mRS)
- National Institute of Health Stroke Scale (NIHSS)
- Activities of Daily Living on Barthel Index (BI)
The Company plans to use the results of this Phase Ib study to guide Phase II dosing in upcoming clinical trials.
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