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Subject Interpretation of ACC.14 Abstract
Writer ViroMed
Date 2014/04/08

Abstract
A Phase 2, Double-blind, Randomized, Placebo-controlled, Multicenter Trial of the Safety and Efficacy of Plasmid DNA Expressing 2 Isoforms of Hepatocyte Growth Factor in Patients with Critical Limb Ischemia 

Background: Hepatocyte growth factor (HGF) has shown promise in treating patients with critical limb ischemia (CLI). We performed this phase II study to assess the safety and efficacy of the intramuscular (IM) injection of VM202, plasmid DNA expressing 2 isoforms of HGF, in CLI patients.

Methods: We enrolled 52 patients in Rutherford class 4-5. Patients were randomly assigned in a 2:2:1 fashion to low-dose VM202 (8 mg; n=21), high-dose VM202 (16 mg; n=20) or placebo (saline; n=11). IM injections were given in the affected index calf on days 0, 14, 28 and 42. Safety and efficacy of VM202 were evaluated over 12 months. Safety endpoints included monitoring adverse events (AE) according to severity and relationship to the study drug. Efficacy endpoints included a change in visual analog scale for pain, ulcer healing, ankle brachial index (ABI) and transcutaneous oxygen pressure (TcPO2).

Results: A total of 438 AEs were reported in 49 of the 52 patients; all AEs were considered to be unrelated to the study treatment. Serious AEs were reported by 6 (54.5%), 9 (42.9%) and 11 (55%) placebo, low-dose and high-dose patients; the number of reported SAEs was 7, 26 and 19, respectively. One SAE (peroneal deep vein thrombosis) wasprobably related to the study drug. No malignancies or proliferative retinopathies were seen. One placebo and 1 low-dose patient died, but the deaths were deemed unrelated to the treatment. The high-dose group showed the most improvement in major efficacy parameters. TcPO2 significantly increased at 12 months in high-dose patients compared with low-dose and placebo groups (p<0.05). Ischemic ulcer area was reduced >50% 12 months after treatment in 88% (7/8) of high-dose and 77% (10/13) of low-dose patients compared with 20% (1/5) in the placebo group (p<0.05, placebo vs high or low-dose). Rest pain was reduced 9 months post-injection in 70% (14/20) of high-dose, 52% (11/21) of low-dose and 36% (4/11) of placebo patients (p=NS). The mean change in ABI from baseline to 9 months was higher in the high-dose (0.095) than in the low-dose (0.052) or placebo (0.004) groups (p=NS).

Conclusions: These results suggest that VM202 injections are safe and may result in improvements in efficacy variables in CLI patients.

 

* Red parts are those missing or marked incorrectly when posted on ACC website. We have asked the ACC Abstract webpage administrator to correct the mistakes.

 

Interpretation of the Results

1. Interpretation of Efficacy Results

(1) Observed meaningful improvements in all efficacy parameters (ulcer healing, TcPO2 level, ABI, VAS) through intramuscular injection of VM202.

(2) Observed clear and consistent improvement in all parameters in high dose group (VM202 - 16 mg).  

 

Placebo

Low Dose

High Dose

Statistical Results

TcPO2 Level

Observed meaningful increase in high dose group

p<0.05, placebo vs low dose vs high dose1)

Number of Patients with Improved VAS (%)

4/11

(36%)

11/21

(52%)

14/20

(70%)

p=NS2)

Change in Ankle Brachial Index (ABI)

0.0004

0.052

0.095

p=NS2)

Number of Patients with Ulcer Healing (%)

(50% or more reduction)

1/5

(20%)

10/13

(77%)

7/8

(88%)

p<0.05, placebo vs

high dose or low dose3)

1) p<0.05, placebo vs low dose vs high dose: statistically meaningful (p<0.05) results when comparing each group.

2) p=NS(Not significant) – When compared there were so significance among the groups.
(1) In case of VAS, when compared to baseline, the high dose group showed statistically meaningful (p<0.05 ) results 1, 2, 3, 6, 9, 12 months after injection.

(2) In case of ABI, when compared to baseline, the high dose group showed statistically meaningful (p<0.05 ) results 6 and 9 months after injection.

3) p<0.05, placebo vs high dose or low dose: when compared to placebo group, high dose and low dose group results showed statistically meaningful (p<0.05) results.

 

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The clinical results presented during ACC.14 were data submitted to the ACC on November, 2013 for review. To meet ACC’s regulation on data submission we had to limit the level of data released during the presentation and prepare our material accordingly. To summarize the results, we have observed the safety as well as clinically and statistically meaningful therapeutic effects in various efficacy parameters through the clinical study of VM202.

 

In general, during phase II, the safety of increased dosage of the drug is investigated more thoroughly compared to phase I and the efficacy parameter to determine the drug’s effect during phase III is decided. The patient inclusion/exclusion criteria are also established during phase II. In other words, the goal of phase II is to find clinically meaningful efficacy parameter and to establish optimal conditions to increase success rate of phase III clinical study.

 

In this phase II study, efficacy parameters that produced statistically meaningful results when comparing VM202 group and placebo group were ulcer healing and TcPO2 level. For ulcer healing, the data was analyzed only for the number of ulcers that were healed by clinically meaningful standard of 50% or more reduction in ulcer area or completely healed. Through this analysis we were able to observe clinically meaningful level of clear ulcer healing effect in VM202 group compared to placebo group. We were also able to observe clinically meaningful level of increase in TcPO2 level in VM202 group compared to placebo group. These results of consistent improvement in two different parameters can be considered to have significant clinical meaning.

 

For ABI and VAS, we observed in high dose VM202 group a continuous statistically meaningful level of improvement during the 12 months after treatment compared to before treatment (baseline), even though the results did not show statistically meaningful difference when compared to placebo group. In the high dose group the average change in ABI compared to baseline was an increase of 0.095 (bypass surgery is considered successful when there is an increase of 0.1). The high dose group also had the statistically meaningful result (p<0.05) compared to placebo group in the number of patients with 25% improvement (over 0.1), a clinically meaningful improvement. In VAS (pain reduction) the high dose group also had clinically meaningful level of pain reduction 12 months after treatment compared to baseline and twice the number of patients with pain reduction (70%, 14/20) compared to placebo group (36.4%, 4/11).

 

Above results fit the treatment mechanism of the drug and show consistent improvement in all efficacy parameters, indicating a very successful phase II clinical study. The reasoning behind our interpretation becomes clearer if you compare it to results from other similar clinical studies.

 

Based on these successful clinical results, the main evaluation parameter (primary efficacy endpoint) for phase III can be determined after the “End of Phase II” meeting with the US FDA. We believe the consistency of VM202’s therapeutic effects observed in our clinical study will be a great help during phase III planning consultation with the US FDA.

 

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2. Interpretation of Safety Results

(1) The adverse effects (AE) recording requirement during safety monitoring required recording of even the most trivial symptom, sickness, and condition occurred after the administration of the drug. This does not mean that the drug is the cause of these AEs. The AEs recorded in this clinical study were all determined to have no correlation with the drug.

(2) Serious adverse effects (SAE) are classified as AEs that require hospitalization or extension of hospitalization, cause continuous degradation or meaningful disability, cause death or is life threatening, or have other medically important effect. The one SAE reported during this clinical study (peroneal deep vein thrombosis) was unable to be proven to have no relation to VM202 and as such have been categorized into possibly related level of SAE. If this SAE could have been connected to VM202 as a meaningful SAE, it would have been handled with more importance during last November’s PI meeting and during the ACC presentation. Because of the nature of the disease, however, it was the PIs opinions that there are no scientific causal relationship between the SAE and VM202. Also, this SAE was determined by Data Safety Monitoring Board (a committee of experts for safety assessment related to clinical studies) to have no significance and the US FDA did not mention about this SAE either. Therefore this is not a critical SAE.

à Peroneal deep vein thrombosis is a rare disease caused by thrombosis formed in the veins of lower limbs, which occurs in 1 out of 1,000 per year. It is known to occur in those who are bedridden, suffer external injury, post surgery, pregnant, have history of thrombosis, or genetically predisposed.

à When looking at the time point the disease developed (211 days after injection) and VM202’s treatment mechanism, it was initially considered the disease had no relation to the drug. But because no relation between the drug and the disease could be clearly proven, it was categorized as ‘Possibly related’ in the AE Causality categories (Not relatedPossibly relatedProbably relatedDefinitely related). (The English abstract had the wrong category)

à This disease was completely treated with the use of thrombolytic agents like Enoxaparin and warfarin.

(3) Because VM202-PAD clinical study was conducted using severe patients, there are always possibilities for death and amputations among the patients. These are also evaluated for connection to the test drug and are used as an efficacy parameter to see how much reduction is observed in mortality rate and amputation rate after administration of the drug. In this clinical study there was one death in placebo group and one death in low dose group, both of which were determined to have no correlation to the test drug. Mortality rate and amputation rate are not part of the efficacy parameters used for evaluation during phase II, but there is a possibility to evaluate its use during phase III.