Hengrui is seeking IND approval for HRS9531, an orally administered GLP-1/GIP dual receptor agonist, in China. The subcutaneous formulation is being evaluated in phase 2 trials for patients with type 2 diabetes and for patients who are overweight.
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| Metabolic actions of GLP-1 and GIP on key target tissues. |
In 2021, Hengrui filed a patent (WO/2023/098777) for the subcutaneous injection and oral tablet of GLP-1/GIP dual receptor agonist. The oral version contains 2.5-30 mg API of 18#.
| 18# in the patent |
Results of clinical study of subcutaneous HRS9531
In June 2023, Hengrui reported the PK and PD results of the phase 1 study of subcutaneous HRS9531:
Sixty and 30 subjects were recruited into SAD and MAD respectively. The most common adverse events were abdominal distension and nausea in SAD, and urine ketone body present and nausea in MAD.
Drug exposure were proportional to dose from 0.9-8.1 mg. The median Tmax and mean t1/2 were 48-72 h and 156-182 h in SAD, and 48-72 h and 169-192 h after the fourth dosing in MAD, respectively.
In December 2023, Hengrui announced the findings of the phase 1b trial for HRS9531:
The proportions of patients achieving FPG target (<7 mmol/L) and 2-hour postprandial plasma glucose (2h-PPG) target (<10 mmol/L) on Day 29 in the HRS9531 1.5 mg and 4.5 mg groups were higher than those in the dulaglutide group and placebo group.
GLP-1s in Hengrui
Hengrui has an extensive pipeline targeting GLP-1 with several products in the phase 2 stage. The following table provides details of Hengrui's GLP-1 products:
|
Product |
MoA |
Admin |
Stage |
Indication |
Initiation |
|
HR17031 |
Insulin/GLP1 |
SC, QD |
Phase 2 |
Diabetes |
2022.04 |
|
HRS-7535 |
GLP-1 |
Oral, QD |
Phase 2 |
Diabetes |
2023.02 |
|
Overweight |
2024.02 |
||||
|
HRS9531 |
GLP-1/GIP |
SC, QW |
Phase 2 |
Diabetes |
2023.08 |
|
Overweight |
2023.09 |
||||
|
Overweight without diabetes |
2023.05 |
||||
|
HRS9531 |
GLP-1/GIP |
Oral |
IND |
- |
2024.03 |
|
SHR-1816 |
GLP-1/GCGR |
SC, QW |
Phase 1 |
Healthy |
2022.04 |
|
Noiiglutide |
GLP-1 |
SC, QD |
Phase 2 |
Diabetes |
2019.02 |
|
Overweight |
2021.03 |
Noiiglutide is a once-daily GLP-1 analogue modified from liraglutide, discovered by Hengrui and Hansoh. Currently, Hengrui's pipeline no longer includes the once-daily product. A recent report has shown the effectiveness of Noiiglutide in treating patients with obesity:
Across all noiiglutide dosage levels, least squares mean reductions in body weight from baseline to week 24 ranged from 8.03 to 8.50 kg, compared with 3.65 kg in the placebo group (all p-values <.0001). In the noiiglutide groups (0.12, 0.24, 0.36 mg/day), a significantly higher proportion of participants achieved a weight loss ≥5% (68.8%, 60.0%, 73.0%) and ≥10% (37.5%, 36.9%, 39.7%), compared with the pooled placebo group (≥5%: 29.0%; ≥10%: 8.1%).
It was noticed that SHR-1816 had been removed from the pipeline without any prior reports.
In 2024, Hengrui reported the results of a phase 1 study of HRS-7535, an oral GLP-1 receptor agonist, in healthy participants:
In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo.
GLP-1s in spousal company
It is common knowledge that Sun Piaoyang manages Hengrui, and his wife's company, Hansoh, is also researching similar products, including the co-developed noiiglutide.
PEG-Loxenatide is a GLP-1 receptor agonist approved to be administered weekly and used for treating patients with diabetes. This medication was approved in 2019 in China. The table below displays the effectiveness of the treatment on HBA1C and body weight change as per the meta-analysis.
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| Lague of inclined interventions in evaluating change of HBA1C (A) and weight (B) |
Then, Hansoh brings another GLP-1/GIP dual agonist HS-20094 to the phase 2 clinical stage for patients with diabetes (2024.02) and those who are overweight (2023.10). In December 2023, Hansoh released the initial data of the phase 1 study:
Following a single dose of HS-20094, the median Tmax ranged from 8 to 48h. The mean t1/2 was estimated to be approximately 6-7days (160-166h), thus supporting a once-weekly dosing regimen. After 4 weeks of doses or dose-titrations（up to 15mg）, the median Tmax was 12-24h. The geometric mean of T1/2 was estimated to be 155.8-169.9 h. The total exposure of HS-20094 increased in an approximately dose-proportional manner.
HS-20094 demonstrated a decreasing trend in glucose AUC. A dose-dependent weight loss was observed in the MAD part. The mean (SD) reduction of body weight from baseline was 4.74 (1.687)kg on day 29 in 15mg dose cohort compared to 0.45 (1.460)kg in the placebo cohort.
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