In a head-to-head diet-induced obese (DIO) mouse study,ASC47 low dose combination 1 (ASC47,3 mg/kg,subcutaneous (SQ),once every four weeks plus semaglutide,30 nmol/kg,SQ,once daily),demonstrated superior weight loss compared to semaglutide monotherapy (30 nmol/kg,showing an average total body weight reduction of 36.2% compared to 23.1%,a 56.7% greater reduction in body weight compared to semaglutide monotherapy.

Human equivalent dose of ASC47 low dose 1 (3 mg/kg,once every four weeks) in mice is estimated to be approximately 20 mg based on the body surface area conversion. Interim data from a Phase I single ascending dose (SAD) study in Australia in subjects with elevated low-density lipoprotein cholesterol (LDL-C) showed that ASC47,via SQ injection,demonstrated a good tolerability profile up to 90 mg. The Australian SAD study is still ongoing with higher doses of ASC47.

ASC47 low dose combinations with semaglutide restored the body composition of obese mice to the level of healthy non-obese mice. At the end of treatment,the percentage of total muscle mass over the total body weight of obese mice treated with ASC47 low dose combination treatments (68.8%) was similar to healthy non-obese mice (66.0%),indicating healthy weight loss. Semaglutide monotherapy was unable to restore body composition to healthy levels.

ASC47 low dose combination treatments were well tolerated in obese mice and exhibited a statistically significant reduction in levels of liver enzymes such as alanine aminotransferase (ALT) compared to vehicle treatment in obese mice.

HONG KONG,Dec. 18,2024 -- Ascletis Pharma Inc. (HKEX:1672,"Ascletis") announces encouraging efficacy results from its study in diet-induced obese (DIO) mice combining ASC47,a first-in-class muscle-preserving weight loss drug candidate for the treatment of obesity,with semaglutide.

ASC47 is an adipose-targeted,once-monthly subcutaneously (SQ) injected thyroid hormone receptor beta (THRβ) selective small molecule agonist,discovered and developed in-house at Ascletis. ASC47 possesses unique and differentiated properties to enable adipose targeting,resulting in dose-dependent high drug concentrations in the adipose tissue.

Interim data from a Phase I single ascending dose (SAD) study in Australia in subjects with elevated low-density lipoprotein cholesterol (LDL-C) (NCT06427590) showed that ASC47,demonstrated a half-life of 21 days. Further,ASC47 demonstrated a good tolerability profile up to 90 mg with no serious adverse events (SAEs) and no discontinuations due to adverse events (AEs). The majority of AEs were mild (grade 1). There were no gastrointestinal or cardiac AEs reported,as well as no abnormal liver enzymes reported (Link). The Australian SAD study is still ongoing with higher doses of ASC47.

In previous preclinicalstudies,ASC47 regular dose (45 mg/kg,once every two weeks) monotherapy demonstrated total body weight reduction of 24.6%,similar to semaglutide monotherapy (23.1%,once daily). ASC47 regular dose increased total muscle mass by 5.8%,compared to a decline in total muscle mass of 9.3 % for semaglutide (Link).

Detailed Preclinical Data of ASC47 Low Dose Combinations

The objective of the head-to-head ASC47 low dose combination DIO mouse study was to compare ASC47 low doses (3 mg/kg or 9 mg/kg) and low frequency (SQ,once every four weeks) combined with semaglutide (30 nmol/kg,once daily) against semaglutide monotherapy (30 nmol/kg,once daily). ASC47 low dose combination 1 (ASC47,once daily)treatment was superior to semaglutide monotherapy (30 nmol/kg,achieving 56.7% more relative weight loss compared to semaglutide monotherapy (Table 1).

Table 1. ASC47 low dose combination treatments demonstrated superior weight loss to semaglutide monotherapy

Group

Dosing

Total body

weight change

from baseline

Total muscle

mass/total body

weight

Cumulative

caloric intake

(kCal)

Healthy non-obese

mice

Vehicle

+8.53%

66.0%

308

Obese mice

Vehicle

+8.53%

46.6%

378

Obese mice treated

with ASC47 low

dose 1

ASC47,

3 mg/kg,

SQ,Q4W

+5.54%

48.6%

388

Obese mice treated

with ASC47 low

dose 2

ASC47,

9 mg/kg,Q4W

-1.55%

52.1%

348

Obese mice treated

with semaglutide

Semaglutide,

30 nmol/kg,QD

-23.1%

57.2%

211

Obese mice treated

with ASC47 low

dose combination 1

ASC47,

3 mg/kg

SQ,Q4W

+

semaglutide,QD

-36.2%

(p<0.0001 vs

semaglutide

monotherapy)

68.8%

(p=0.0001 vs

semaglutide

monotherapy)

251

(p=0.0385 vs

semaglutide

monotherapy)

Obese mice treated

with ASC47 low

dose combination 2

ASC47,

30 nmol/kg

SQ,QD

-35.9%

(p<0.0001 vs

semaglutide

monotherapy)

68.8%

(p=0.0001 vs

semaglutide

monotherapy)

267

(p=0.001 vs

semaglutide

monotherapy)

Note: Treatment duration: 28 days; Obese mice: diet-induced obese mice; SQ: subcutaneous; QD: once daily; Q4W: once every four weeks

Human equivalent dose of ASC47 low dose 1 (3 mg/kg,once every four weeks) in mice is estimated to be approximately 20 mg based on the body surface area conversion. Interim data from a Phase I single ascending dose (SAD) study in Australia in subjects with elevatedLDL-Cshowed that ASC47,indicating healthy weight loss. Semaglutide monotherapy was unable to restore body composition to healthy levels (Table 1).

Cumulative caloric intake of obese mice with ASC47 low dose combination treatments at the end of treatmentwas statistically higher than that of obesemice with semaglutide monotherapy treatment (Table 1),suggesting that ASC47 has different mechanisms of action from incretin-based drugs.

ASC47 low dose combination treatments were well tolerated in obese mice and exhibited a statistically significant reduction in levels of liver enzymes such as alanine aminotransferase (ALT) compared to vehicle treatment in obese mice (Table 2).

Table 2. ASC47 low dose combination treatments demonstrated statistically significant ALT reduction compared to vehicle treatment in obese mice

Group

Dosing

ALT(U/L)

Healthy non-obese

mice

Vehicle

31.5

Obese mice

Vehicle

234

Obese mice treated

with ASC47 low

dose 1

ASC47,Q4W

182

Obese mice treated

with ASC47 low

dose 2

ASC47,Q4W

159

Obese mice treated

with semaglutide

semaglutide,

30 nmol/kg,QD

32.9

(p<0.0001 vs vehicle treated obese mice;

no significant changes vs healthy non-obese mice)

Obese mice treated

with ASC47 low

dose combination 1

ASC47,QD

54.1

(p<0.0001 vs vehicle treated obese mice;

no significant changes vs healthy non-obese mice and

semaglutide monotherapy treated obese mice)

Obese mice treated

with ASC47 low

dose combination 2

ASC47,

30 nmol/kg

SQ,QD

70.0

(p<0.0001 vs vehicle treated obese mice;

no significant changes vs healthy non-obese mice and

semaglutide monotherapy treated obese mice)

Note: Treatment duration: 28 days; Obese mice: diet-induced obese mice; SQ: subcutaneous; QD: once daily; Q4W: once every four weeks

Both ASC47 low doses statistically and significantly reduced fasting blood glucose,cholesterol and LDL-C compared to vehicle treated obese mice (Table 3).

Table 3. ASC47 low dose treatments demonstrated statistically significant decreases in fasting blood glucose,cholesterol and LDL-C compared to vehicle treated obese mice

Group

Dosing

Fasting blood glucose

(mmoL/L)

Cholesterol

(mmoL/L)

LDL-C

(mmoL/L)

Healthy non-obese

mice

Vehicle

7.5

3.53

0.50

Obese mice

Vehicle

9.2

6.98

1.41

Obese mice treated

with ASC47 low

dose 1

ASC47,Q4W

6.9

(p=0.0017 vs vehicle

treated obese mice;

no significant changes

vs semaglutide

monotherapy treated

obese mice)

4.08

(p<0.0001 vs vehicle

treated obese mice;

no significant changes

vs semaglutide

monotherapy treated

obese mice)

0.58

(p<0.0001 vs vehicle

treated obese mice;

no significant changes

vs semaglutide

monotherapy treated

obese mice)

Obese mice treated

with ASC47 low

dose 2

ASC47,Q4W

5.7

(p<0.0001 vs vehicle

treated obese mice;

no significant changes

vs semaglutide

monotherapy treated

obese mice)

3.32

(p<0.0001 vs vehicle

treated obese mice;

no significant changes

vs semaglutide

monotherapy treated

obese mice)

0.44

(p<0.0001 vs vehicle

treated obese mice;

no significant changes

vs semaglutide

monotherapy treated

obese mice)

Obese mice treated

with semaglutide

Semaglutide,QD

6.4

(p=0.0001 vs vehicle

treated obese mice)

3.90

(p<0.0001 vs vehicle

treated obese mice)

0.61

(p<0.0001 vs vehicle

treated obese mice)

Note: Treatment duration: 28 days; Obese mice: diet-induced obese mice; SQ: subcutaneous; QD: once daily; Q4W: once every four weeks

In obese mice,ASC47 low dose combination treatments reduced statistically and significantly more fasting blood glucose,cholesterol and LDL-C than semaglutide monotherapy treated obese mice (Table 4).

Table 4. ASC47 low dose combination treatments demonstrated superior fasting blood glucose,cholesterol and LDL-C reductions compared to semaglutide monotherapy

Group

Dosing

Fasting blood

glucose

(mmoL/L)

Cholesterol

(mmoL/L)

LDL-C

(mmoL/L)

Obese mice treated

with ASC47 low

dose combination 1

ASC47,QD

5.3

(p=0.0024 vs

semaglutide

monotherapy)

2.65

(p=0.0003 vs

semaglutide

monotherapy)

0.35

(p=0.0045 vs

semaglutide

monotherapy)

Obese mice treated

with ASC47 low

dose combination 2

ASC47,QD

4.7

(p<0.0001 vs

semaglutide

monotherapy)

2.57

(p=0.0002 vs

semaglutide

monotherapy)

0.36

(p=0.0055 vs

semaglutide

monotherapy)

Obese mice treated

with semaglutide

Semaglutide,QD

6.4

3.90

0.61

Note: Treatment duration: 28 days; Obese mice: diet-induced obese mice; SQ: subcutaneous; QD: once daily; Q4W: once every four weeks

"We are excited by these data showing that adipose-targeted ASC47 low dose combination treatments achieved 56.7% more relative weight loss compared tosemaglutide monotherapy. Importantly,in the preclinical study,adipose-targeted ASC47 low dose combination treatments produced healthy weight loss,increasing our confidence that ASC47-based combination therapies may clinically improve weight loss and muscle preservation compared to incretin-based drugs alone," said Jinzi Jason Wu,Ph.D.,Founder,Chairman and CEO of Ascletis," Unlike liver enzyme elevations observed with an apelin receptor (APJ) agonist,low doses of ASC47 in combination with an incretin-based drug showed statistically significant reductions in liver enzymes. We are advancing development of ASC47 as both a monotherapy at regular doses and a combination therapy at low doses for the treatment of obesity and other metabolic diseases."

Ascletis Obesity Portfolio

ASC47 is an adipose-targeted,once-monthly subcutaneously injected THRβ selective small molecule agonist. Interim data from a Phase I single ascending dose (SAD) study in Australia in subjects with elevated low-density lipoprotein cholesterol (LDL-C) (NCT06427590) have been released. ASC47 is currently in the clinical trials of patients with obesity in Australia,with topline data of Phase IIa study expected in the second quarter of 2025. In addition to ASC47,Ascletis is also developing ASC30,a GLP-1 receptor (GLP-1R) biased small molecule that can be dosed once daily orally or once monthly subcutaneously. Both ASC30 once-daily oral tablet (NCT06680440) and ASC30 once-monthly SQ injection (NCT06679959) are currently in Phase Ib clinical trials in the U.S. for the treatment of obesity,with topline data expected in the first quarter of 2025.

About Ascletis Pharma Inc.

Ascletis is an innovative R&D driven biotech listed on the Hong Kong Stock Exchange (1672.HK),covering the entire value chain from discovery and development to GMP manufacturing. Led by a management team with deep expertise and a proven track record,Ascletis has rapidly advanced its pipeline,focusing on two therapeutic areas with unmet medical needs from a global perspective: metabolic diseases and viral diseases. Ascletis has multiple clinical stage drug candidates in its R&D pipeline.

For more information,please visit www.ascletis.com.

Contact:

Peter Vozzo

ICR Healthcare

443-231-0505 (U.S.)

Peter.vozzo@icrhealthcare.com

Ascletis Pharma Inc. PR and IR teams

+86-181-0650-9129 (China)

pr@ascletis.com

ir@ascletis.com