Subiyi, a new diabetic foot drug, publishes important results in authoritative journals

Taiwan Hesheng Technology's blockbuster new drug "Subiyi" (R&D code: ON101) Phase III trial data and drug action mechanism were published on September 3 in the internationally renowned SCI medical journal JAMA Network Open

"Subiyi" is the world's first drug to treat diabetic foot wounds and ulcers by regulating the mechanism of macrophages, and successfully achieves the international multi-center phase III clinical goal, fully demonstrating clinically significant efficacy and drug safety.

"Regulating the efficacy of innovative macrophage drugs in the treatment of wounds in patients with diabetic foot ulcers: a phase three international multi-center randomized clinical trial" main content of the paper:

Approximately 80% of lower limb amputations are caused by chronic diabetic foot ulcers (DFU), causing a heavy burden on medical care and medical expenses

Hyperglycemia will increase the ratio of pro-inflammatory M1 and pro-regenerative M2 macrophages, making it difficult for wounds to heal.

ON101 is composed of two raw materials: PA-F4 to Handxiang extract and S1 Centella asiatica extract.

The clinical pharmacokinetic study was conducted on 12 patients with DFU in single and repeated doses, applying ON101 twice a day.

The previous data fully supports the safety of ON101 and clearly shows its therapeutic potential to promote wound healing

This trial followed the "fully and well-controlled study" of the US Food and Drug Administration, and designed a randomized, controlled, and evaluator-blinded three-phase study.

According to the (CONSORT) unified standard reporting guidelines, this trial was enrolled between November 23, 2012 and May 11, 2020.

After the end of the screening period (up to 7 days), patients who are judged as qualified by the trial plan host will be randomly enrolled in a 1:1 ratio through a computer-generated block and receive up to 16 weeks of ON101 or hydrophilic fiber dressing treatment

The end-of-treatment visit (visit 10, V10) is the visit at the 16th week after randomization or the visit to prove complete wound healing (whichever occurs first)

In terms of interventions, demographic data, medical history, disease status, radiological examinations, and eligibility are evaluated during the screening period (before randomization)

ON101 is produced in accordance with the International Pharmaceutical Auditing Cooperation (PIC/s) Pharmaceutical Production Quality Management Regulations, and is a topical cream

If the target ulcer worsens (defined as Wagner level 3), the host can decide whether to terminate the patient's treatment

In terms of data collection and outcome measures, the primary efficacy endpoint compared the two groups' wound healing rates at the end of the 16-week treatment period

In the safety endpoint, adverse events, clinical laboratory values, and statistical analysis of vital signs are evaluated.

For the primary efficacy endpoint, chi-square test and logistic regression model were used for analysis, with intervention as a fixed factor, and baseline ulcer size and adjusted Wagner grade as covariates
.
The results of the logistic regression model are expressed using odds ratio (OR), P value and related 95% confidence interval (CI)
.
Part of the endpoint is expressed in hazard ratio (HR)
.
At the same time, an exploratory factorial analysis of related variables, such as ulcer duration, ulcer size, and patient's HbA1c is carried out
.
The Kaplan-Meier method and log-rank test were used to calculate the time to complete healing of the ulcer
.
HR and 95% CI were estimated using the Cox proportional hazards model
.
Regression analysis was performed on the ratio of ulcer surface area change and the ratio of ulcer surface area change from baseline after correction based on the baseline ulcer area and Wagner classification
.
Fisher's exact test was used to evaluate the incidence of target ulcer infection and recurrence
.

If an adverse event (AE) occurs after the intervention begins, it is considered an adverse event (TEAE) during treatment
.
Summarize the frequency and proportion of AE, TEAE and serious TEAE in total patients according to system organ classification and preferred terms
.
Fisher's exact test was used to compare the two groups for all adverse events during treatment
.
Use clinical laboratory test data to tabulate the changes from baseline, and use analysis of covariance to compare between groups
.
All tests are two-sided tests.
If the P value<.
05, it is significant, and the data are expressed as the mean ± standard deviation (SD)
.

Statistical analysis showed that there were 236 patients in FAS (males accounted for 74.
1%; females accounted for 25.
9%; average age was 57 ± 10.
9 years)
.
The average HbA1c at baseline was 8.
1% (SD 1.
63), and there was no significant change at the end of treatment (the average HbA1c in the ON101 group was 8%, and the control group was 7.
9%), and the time to diagnose diabetes in 144 patients (61%) was> 10 years
.
The FAS patients were randomly assigned: 114 cases (48.
3%) in the hydrophilic fiber dressing group and 122 cases (51.
7%) in the ON101 group
.
16 patients (13.
1%) in the ON101 group and 21 patients (18.
40%) in the hydrophilic fiber dressing group terminated the study early (37 cases in total)
.
Some of the patients recommended by the host to use decompression devices did not follow the recommendations due to the humid climate in Taiwan
.
Among the 236 patients, 184 (78%) had Wagner grade 2 ulcers, 117 (49.
6%) had plantar ulcers, and 64 (27.
1%) had baseline HbA1c ≥ 9%
.
The average ulcer size was 4.
8 cm2 (SD 4.
41), and the average duration of the target ulcer before enrollment was 7.
15 months
.

The main efficacy results showed that 74 patients (60.
7%) in the ON101 group and 40 patients (35.
1%) in the hydrophilic fiber dressing group achieved wound closure within 16 weeks (OR: 2.
84; 95% CI: 1.
66–4.
84; P =.
0001)
.
Similar results were observed in mITT.
61.
9% (73/118) of the ON101 group and 33.
9% (38/112) of the control group had closed ulcers (OR: 3.
15; 95% CI: 1.
82–5.
43; P <.
0001)
.
The degree of wound closure was evaluated by an independent evaluator
.

The duration of the ulcer, the size of the ulcer, and the patient's HbA1c level are related to the poor prognosis of DFU
.
Therefore, the baseline ulcer duration (6 months as the cut-off point), baseline ulcer area (5 cm2 as the cut-off point), and baseline HbA1c level (9% as the cut-off point) were subgroup analyzed
.
The analysis showed that compared with the control group, the ON101 group had a significant OR advantage (P = .
035 when HbA1c> 9%; P = .
027 when ulcer duration> 6 months; ulcer size> 5 cm2 P =.
009)
.

Secondary efficacy results showed that in FAS (HR: 1.
80; 95% CI: 1.
23–2.
65, P = .
002,) and mITT population (HR: 1.
91; 95% CI: 1.
29–2.
83; P = .
001;) , Patients in the ON101 group had better wound healing rates than those in the hydrophilic fiber dressing group
.
The cumulative incidence of complete healing per week also reflects the continuous increase in the possibility of complete wound healing in the ON101 group starting from the 4th week
.
The time required for the ON101 group to reach the median population healing was 98 days, while the hydrophilic fiber dressing group could not, because only 35.
1% of the patients in this group healed their wounds during the treatment period
.
The average reduction of ulcer surface area between the two groups (last treatment visit compared with baseline) was 78% (P = .
87).
There was no significant difference in the incidence of 50% reduction in ulcer surface area between the two groups
.
During the treatment period, only a small amount of target ulcer infection occurred in the two groups (7 cases of ON101 compared with the group; P =.
78;)
.
For the recurrence rate of completely healed wounds during the follow-up period, the ON101 group was 20.
3%, and the hydrophilic fiber dressing group was 17.
5%, which was not statistically significant (P = .
8;)
.

In terms of safety, there were no statistical changes or differences between the two groups
.
76 patients reported adverse events during treatment, of which 7 cases (5.
7%) in the ON101 group and 5 cases (4.
4%) in the control group considered treatment-related
.
No serious AE is related to ON101 treatment
.
One case of osteomyelitis was related to the control group, and one patient (0.
8%) assigned to the ON101 group died of septic shock, acute kidney injury, and acute respiratory failure, and it was judged not to be related to treatment or ulcer progression
.

This trial is the world's first international multi-center phase III randomized controlled trial to explore the regulation of M1/M2 macrophage test drugs for the treatment of DFU
.
ON101 has an excellent effect of promoting the complete healing of DFU
.
Hyperglycemia is the source of chronic DFU, which delays the transformation of M1-M2 macrophages and prolongs the inflammation period
.
ON101 can restore the balance of M1/M2 macrophages caused by hyperglycemia, promote M1-M2 transformation, and accelerate the healing of ulcer wounds.
It can not only treat new ulcers, but also treat high-risk ulcers, including ulcers lasting more than 6 Months, ulcer size> 5 cm2 and HbA1c> 9% showed the robust efficacy of ON101
.

This test is designed according to the US FDA guidelines
.
During the 16-week treatment period, the complete wound healing rate (35.
1%) of the hydrophilic fiber dressing in the control group was consistent with the trend of a 12-week intention-to-treat analysis by Jeffcoate et al
.
(28.
2%) in the previous trial .
This means that the design and execution of this trial are consistent with other randomized controlled trials
.
ON101 can be used after debridement, self-administered at home, and its convenience is the same as the hydrophilic fiber dressing reference
.

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