company overview...these factors include, but are not limited to, (1) general market, macro-economy,...
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Company Presentation 2020Q2
Hua Medicine华领医药
Disclaimer
This document may contain statements that constitute “forward-looking statements”, including, but not limited to,statements relating to the implementation of strategic initiatives, and other statements relating to our future businessdevelopment and economic performance.
While these forward-looking statements represent our judgments and future expectations concerning the developmentof our business, a number of risks, uncertainties and other statutory requirements may render actual developments andresults to differ materially from our expectations.
These factors include, but are not limited to, (1) general market, macro-economy, governmental and regulatory trends,(2) movements in local and international securities markets, currency exchange rates and interest rates, (3) competitivepressures, (4) technological developments, (5) changes in the financial position or creditworthiness of our customers,obligors and counterparts, and changes in the developments in the markets in which they operate, (6) legislativedevelopments, (7) management changes and changes to our business group structure and (8) other key factors thatmay adversely affect our business and financial model.
We are not under any obligation to (and expressly disclaim any such obligations to) update or alter forward-lookingstatements whether as a result of new information, future events, or otherwise.
This material may not be reproduced, distributed or transmitted to any other person or incorporated in any way intoanother document or other material without the prior written consent of us.
This document is not:
(a) an offer of securities for sale in Hong Kong or elsewhere; or
(b) an invitation to enter into an agreement to acquire, dispose of, subscribe for or underwrite securities; or related tothe issue of any securities.
This document (and the information contained herein) is not for publication or distribution to any person(s) except aswritten permitted by us.
Company Overview
Mission, Vision and Strategy
4Copyright © Hua Medicine 2020
Become a global diabetes care company• By launching dorzagliatin commercially, first in China and then globally• Either as monotherapy or in combination with approved anti-diabetes drugs• Employing AI to develop personalized treatment for the entire heterogenic
universe of Type 2 diabetes patients worldwide
A leading, clinical-stage innovative drug development company in China focused on developing novel therapies for the treatment of diabetes
Mission
Objectives
Strategy
Establish dorzagliatin as the cornerstone therapy for the treatment of diabetes by restoring glucose homeostasis in Type 2 diabetes patients
Leverage Hua’s internal team and strong partnership network to continue advancing our current pipeline Partner with either China-based or international pharmaceutical companies
to make dorzagliatin available to patients, in both China and regions outside of China
SAIL Ge Li J Baldwin
Founding Investors
Hua Medicine – A Global First-in-Class Biotech
5Copyright © Hua Medicine 2020
Hua Medicine
Global rights to dorzagliatin composition of matter, chemical process, formulation and multiple products in FDC with OADs
Met Primary Endpoint in pivotal Phase III monotherapy trial, for China regulatory approval purposes
First-in-Class (GKA) drug to significantly and sustainably reduce HbA1c safely
First Novel Concept addressing impaired glucose homeostasis - the underlying cause of T2D
Demonstrated viability in combination with DPP-4 inhibitors
Suitable for T2D patients with kidney disease
Combination trials with metformin and SGLT2 are on going at various stages
Massive market opportunity – global T2D population is 453 mm (120 mm in China alone)
RMB 1.1bn cash as of December 31, 2019
China-Based First-In-Class
Li ChenCEO & CSO
Bob NelsenChairman
Arch Ventures
2019 Highlights
6Copyright © Hua Medicine 2020
Clinical trials: Achieved primary efficacy endpoint in a 24-week double blinded placebo controlled Phase III trial in drug
naïve T2D patients in China, with very low hypoglycemia incidents and good safety profile Completed enrollment in a metformin add on Phase III registration trial Completed HMM0110, which demonstrated desirable pharmacokinetics profile in patients with end stage chronic
kidney disease, indicating the potential use of dorzagliatin among T2D patients with moderate, severe and end stage chronic kidney disease (i.e. stages 3-5 of CKD) Completed HMM0111, investigating the PK and PD parameters of dorzagliatin either alone or in combination with
sitagliptin in T2D patients in the United States, with positive results
Other: Granted a formulation patent for dorzagliatin in China Filed six patent applications covering the IPR of fixed dose combination of dorzagliatin with six classes of oral-
antidiabetic drugs Initiated a formal collaboration with Dr. Franz Matschinsky, recipient of 2020 Rolf Luft Award Presented AI based machine learning results at the American Diabetes Association’s 79th Scientific Sessions,
providing a non-biased methodology to sub-classify T2D patients Announced that global operation headquarters and R&D center will be established in Shanghai’s ZhangJiang
Science City Fully validated cGMP commercial manufacturing processes for API and drug product to support the China launch
of dorzagliatin Former U.S. FDA Officer Dr. Fuxing Tang joined Hua Medicine as Chief Technology Officer, VP of Formulation
R&D and Product Development Cash position as of December 31, 2019: RMB 1.1bn
Phase III Topline Results were Presented in the Keynote Lectures of 2019 CDS Plenary Session
7
NH N
N
N
NN
Copyright © Hua Medicine 2020
Professor Zhu Dalong, Chairman of CDS, hosting 2019 CDS plenary session
Professor Zhu Dalong, presenting dorzagliatin Phase III topline data at the 2019 CDS plenary session
Dr. Yang Wenying, ex-Chairwoman of CDS, attending the 2019 CDS plenary session
2019 CDS Plenary Session audience members
Ongoing Phase III Trials: HMM0301 / HMM0302 Study Design
8
Study Design for: HMM0301: 52-week completed March 2, 2020
Dorzagliatin Mono-therapy Trial for Drug Naïve T2D Patients (463 Patients) HMM0302: 24-week completed February 16, 2020
Dorzagliatin Metformin Add-on Therapy Trial for Metformin Users (766 Patients)
Screening Placebo Run-in 24 Weeks Double-blind 28 Weeks Open-label Follow-up
~2 Weeks 4 Weeks Treatment Period Treatment Period 1 Week
V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16
-4W -1W 0W 4W 8W 12W 16W 20W 24W 28W 34W 40W 46W 52W
HbA1c, FPG
2h-PPG
Safety
Screening Placebo Run-in0301: HMS5552 75mg BID
0302: HMS5552 75mg BID + metformin0301: placebo BID
0302: placebo BID + metformin
0301: HMS5552 75mg BID0302: HMS5552 75mg BID +
metforminFollow-up
RandomizationMonotherapy – (2:1)
Metformin Add-on – (1:1)Primary Efficacy Endpoint For
NMPA SubmissionLong-term Safety
Endpoints
Primary endpoint of HbA1c reduction of 0.4% over placebo, p-value < 0.05
Copyright © Hua Medicine 2020
湖北
广东
Update from COVID-19
9Copyright © Hua Medicine 2020
Clinical Achievements
February 16, 2020: Completed last patient out, 24-week patient visit for HMM0302
March 2, 2020: Completed last patient out, 52-week (plus one week follow-up)
patient visit for HMM0301
Continued strict adherence to national guidelines, and enforced additional
pharmacovigilance and quality control
Other
February 3, 2020: Hua employees returned to work
remotely
March 2, 2020: Hua employees began returning to
offices in China
Things to note
Potential delays in release of top-line results and NDA-
enabling work
2020 Outlook
10Copyright © Hua Medicine 2020
Clinical trial readout:
HMM0301 monotherapy Phase III trial 52-week results
HMM0302 combination with metformin Phase III trial 24-week,
52-week results
HMM0112 combination with empagliflozin Phase I trial results
Other:
Initiate studies of dorzagliatin for other potential indications
Prepare and finalize NDA submission in China
Expand and prepare commercialization, sales and marketing
team for planned 2021 product launch in China
Engage international and China-based pharmaceutical
companies in discussions regarding partnership for China and
ex-China territory
Dorzagliatin
A First-in-Class Anti-Diabetic Therapy Focused on Treating the Underlying Cause of Type 2 Diabetes
Most large multinational pharmaceutical companies with a metabolic disease franchise have tried to create a viable and safe glucokinase activator (GKA) to treat type 2 diabetes, none have entered phase III
Dorzagliatin is the first GKA to achieve the primary efficacy endpoint with desirable safety profile at 24-weeks in a Phase III trial
Targeting the glucose sensor role of GK, dorzagliatin is conceptually differentiated from previous GKA which worked on lowering the blood glucose and treated GK as a glucose processor only
Current State of the Type 2 Diabetes Landscape
12Copyright © Hua Medicine 2020
Large market
What is the unmet need?
Why hasn’t anyone else developed a
GK?
Over 450 million people with type 2 diabetes, globally; 120 million+ in China alone
Over US$80 billion plus of pharmaceutical sales globally every year
Not one approved drug currently treats the underlying cause of type 2 diabetes – loss of glucose sensitivity and impairment of glucose homeostasis
Restoring the function of impaired glucokinase is the only scientifically validated means to restore glucose sensitivity in homeostasis
How Do We Stop Type 2 Diabetes?
13Copyright © Hua Medicine 2020
To maintain blood glucose levels within a healthy range, achieving glucose homeostasis
Goal in treating diabetes:
Lowering blood glucose levels alone will not stop the progressive degenerative nature of diabetes, leading to complications
T2D is a Progressive Disease with Degenerationof β Cell Function and Increasing Insulin Resistance
14
Source: Vivian Fonseca, Diabetes Care, 2009, Vol 32, S2; Source: J Merier, R Bonadonna Diabetes Care (2013) 36, S1131 Retrospective survey.
Type 2 diabetes is a progressive disease with deterioration of β cells function Loss of glucose sensitivity in Type 2 diabetes patients is the first step in the progressive destruction of β cells Impaired β cells function results in hyperglycemia stress which causes progressive damage of β cells Deterioration of the 1st phase insulin secretion is the leading cause of impaired glucose homeostasis
Patients with Monotherapy: HbA1c Increased by 1%Every 2 Years, β-Cell Function Decreased Accordingly1
Impaired β-Cell Function Results in HyperglycemiaStress which Causes Progressive Damage of β Cells
Hyperglycemia High FFA
Levels
Increased Secretory Demand
per β-Cell
Oxidative Stress ER Stress
0
2
4
6
8
10
12
14
0 1 2 3 4 5 6 7 8 9 10 11
A1C
(%)
Time (Years)
Coefficient of Failure = 0.47 A1c %/yearr2=0.95
Copyright © Hua Medicine 2020
• Deficiency in the ability of glucose to trigger insulin release • Cells have lost glucose sensitivity and early phase insulin
release is reduced• Reduction in glucose sensitivity is the key culprit behind Type
2 Diabetes
Current Diabetes Medicine Can Not Restore β-cell Function
15
Restoration of glucose sensor function required
Copyright © Hua Medicine 2020
Recent research indicates that we have not solved the fundamental cause of diabetes
TreatmentGroup
• Impaired glucose tolerance (IGT)• Treatment-naïve type 2 diabetes (<12
months)
Treatment length
• 12-month treatment• Stop medication for 3 months• Measure β-cell function at 15 months
Treatment arms
• Metformin alone (12m)• Liraglutide (GLP-1) + metformin • Glargine (3m) + metformin (9m)• Placebo
Conclusion • Interventions that improved β-cell function during active treatment failed to produce persistent benefits after withdrawal
• Suggests continued intervention may be required to alter the progressive β-cell dysfunction
Organs in which GK occurs
Brain Muscles Fat
~5mM <4mM >10mM
GLP-1
Glucose
Insulin
α cells
βcells
LiverIntestines
>5.5mM
Glucose Controls Whole Body Glucose Homeostasis
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Glucose is a hormoneGlucokinase is a sensorGlucose Homeostasis is Controlled by Glucose via Glucose Sensor GK
Source: 陈力,2016 《药物进展》
GK Sensor Role Glucose Storage and Production
Glucagon+
++
+
+ +
+
-
-
Glucose Homeostasis
Glucose is controlled within a
very narrow range:
4- 6.5mM
Set point:5mM
Copyright © Hua Medicine 2020
Threshold controlled glucose homeostasis
Fix the Sensor, Control Diabetes
17Copyright © Hua Medicine 2020
Hyper
Hypo
Hyper
Hypo
Glucagon
GLP-1
Acarbose
PPAR
SGLT2
Metformin
Insulin
DorzagliatinCornerstone Control of Glucose Homeostasis
SUDPPIV
Messenger: glucose level
Set Point: 5 mmol/liter1
Threshold: 4-6 mmol/liter1
Controller: Glucokinase in the pancreas and small intestine-Glucose Sensor
Effector: insulin, glucagon, GLP-1 (glucagon-like peptide 1)
Operator: hexokinase 1-32, SGLT-2, GKL (Liver GK)
Glucokinase is a Glucose Sensor in Glucose Homeostasis
18
Source: Franz Matschinsky, Mol. and Cell Biology of Type 2 Diabetes and Its Complications, 1998, vol 4, pp 14-291 A common measure of blood glucose levels is hemoglobin A1c, or HbA1c, which measures average glycated blood glucose levels for the 3 months prior to testing. HbA1c levels for people without diabetes is between 4% and 5.6% (equivalent to 4-5.6 mmol/liter), for people with impaired glucose tolerance (IGT), or pre-diabetics, is between 5.74% and 6.4% (equivalent to 5.74 -6.4 mmol/liter) and for people with diabetes is 6.5% or higher (equivalent to 6.5 mmol/liter or higher).
2 In addition to GK (also referred to as hexokinase type 4), Hexokinase types 1-3 play a role in the glucose homeostasis process. Unlike a properly functioning GK, which is only active at blood glucose levels over 5.5 mmol/liter, hexokinase types 1-3 are active in the presence of even small amounts of glucose in the bloodstream – providing as a bodily survival mechanism needed energy to the brain, muscles and other core bodily functions.
When the sensor malfunctions or is impaired, automatic control is lost
Messenger: air temperature
Set Point: 22o Celsius
Threshold: 21-23o Celsius
Controller: Thermo Sensor (thermostat)
Effector: Electronic signal
Operator: Heater, Cooler, Ventilator
Operation
Cooler
Heater
Ventilator
Operation
Insulin / GLP-1
Glucagon
Liver GK
Glucose Homeostasis in Human Body Thermostat in a Building
Copyright © Hua Medicine 2020
Key Recognitions of Glucokinase
19
Discovered in the 1960s Published in Science Magazine in 2003 by Dr. Franz Matschinsky, “Godfather of
Glucokinase”, in collaboration with Roche Partner with Hua Medicine in advancing GKA Winner of Rolf Luft Award 2020
Science 2003:
Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy“In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels,
improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These
findings may lead to the development of new drug therapies for diabetes.”
Copyright © Hua Medicine 2020
Source: Franz Machinsky et al . Science: Vol 301, Issue 5631, 18 July 2003
Rolf Luft Award 2020 awarded to Dr. Franz Matschinsky by Karolinska
InstitutetFor the discovery that glucokinase (GK) is the sensor controlling glucose-stimulated
insulin secretion in the pancreatic β-cell and initiating GKA discovery
Dorzagliatin Has the Potential to Repair the Glucokinase Glucose Sensor
20
T2D Patients Disposition Index
(0.1)
0.0
0.1
0.2
0.3
0.4
12 Week 13 Week
Med
ian
Cha
nge
from
Bas
elin
e of
DI
Placebo 75mgBID
P=0.0461
P=0.0387
Phase II
02468
0 1 2 3 4100mg_Day -1100mg_Day 7
02468
0 1 2 3 450mg_Day -150mg_Day 7
Hours
C-P
eptid
e Le
vel (
ug/L
)
0
2
4
6
8
0 1 2 3 4Placebo_Day -1Placebo_Day 7
0
2
4
6
8
0 1 2 3 425mg_Day -125mg_Day 7
Meal
T2D Patient Early-stage insulin release Phase Ib
T2D Patient Early Insulinogenic index
0.05 0.050.06
0.10
0
0.05
0.1
0.15
75mg BID 75mg QD
ΔC30
/ΔG
30
Baseline Day 32
24.66%
167.67%*
Phase Ic
Type 2 Diabetes Rat Pancreas
0153045607590
Control Diabetic HMS-L HMS-H
Num
ber o
f In
sulin
-Im
mun
opos
itiv
e C
ells
(b)
Control
HMS-L HMS-H
Diabetic
Pre-clinical
Copyright © Hua Medicine 2020
November 2019: HMM0301 Phase 3 Topline Results
21Copyright © Hua Medicine 2020
First drug candidate focused on the underlying cause of type 2 diabetes, glucose sensing,
to meet its primary efficacy endpoint over 24 week Phase III trial
1.07% HbA1c reduction from baseline of 8.35% in dorzagliatin treated group compared to 0.5%
HbA1c reduction from baseline of 8.37% in placebo group (p-value < 0.0001)
45.4% of patients treated with dorzagliatin achieved target HbA1c level of 7.0% or less at 24-
weeks compared to 21.5% of patients treated with placebo (p-value < 0.0001)
Patients treated with dorzagliatin achieved homeostasis control rate of 45.0% compared with
21.5% in placebo group (p-value < 0.0001)
Dorzagliatin was well tolerated and had a good safety profile
No death, no drug-related serious adverse event over 24 week
Less than 1% incidence of hypoglycemia over 24 week and no severe hypoglycemia
The 28 week open label safety outcome trial of HMM0301 is complete — Last patient out
was March 2, 2020
HMM0301 Phase III 24-week topline results in Chinese drug-naïve patients with Type 2 Diabetes
(10.3%)(10.3%)
(33.1%)(33.1%)
January 2020: Positive Results of HMM0111 Validates the Synergy of DPP-4 and GKA
22
Post Prandial Glucose Level
Note: AUEC represents area under the effect curve
AUEC (0-4hr) Co-administration orally of dorzagliatin and
sitagliptin at steady state demonstrated no impact on their PK properties
OGTT showed synergy in glucose lowering effect over both monotherapies
It has also demonstrated that dorzagliatin add-on to sitagliptin increases C-peptide secretion over dorzagliatin and sitagliptin alone, suggesting a synergistic effect of improved β-cell function.
Compared to sitagliptin, Dorzagliatin showed clear advantage on post-prandial glucose level (PPG) control in 0-4 hr in the Oral Glucose Tolerance Test (OGTT) study
Dorzagliatin + sitagliptin gives the best effect on overall PPG reduction 15 patients were included in the trial.
378339
253
0
100
200
300
400
500
600
AUEC
0-4h
(hr*
mg/
dL)
Sitagliptin(100mg QD)
Dorzagliatin (75mg BID)
Sitagliptin (100mg QD)+
Dorzagliatin (75mg BID)
Phase I U.S. Drug-drug Interaction Trials
Copyright © Hua Medicine 2020
-33% (p<0.01)
-10% (p<0.01)
Jan 2020: Positive Results of HMM0110
23
Study:
HMM0110 was conducted in China to evaluate whether dorzagliatin can be readily used in Type 2diabetes (T2D) patients with impaired renal function.
Conclusion:
In subjects with end stage renal disease and are not on dialysis, the study indicated nosignificant impact on PK properties subjects exposed to dorzagliatin.
This result supports dorzagliatin as a promising solution and potential supplementaryoption for T2D patients with moderate, severe and end stage chronic kidney disease (i.e.,stages 3-5 of CKD) which can provide satisfactory blood glucose control safely and withoutdose adjustment.
Most of current oral antidiabetic drugs are not readily suitable for patients with renal impairment,especially at moderate, severe and end stages, as current oral treatments either require doseadjustment (e.g., metformin and the top-selling DPP-4 inhibitors) or are contraindicated (e.g.,SGLT-2 inhibitors).
Stage 3-5 CKD patients of T2D patients in China is about 21.9%
Copyright © Hua Medicine 2020
Jan 2020: Positive Results of HMM0110 Supports the Potential of Dorzagliatin in T2D Patients with Moderate, Severe and End Stage Chronic Kidney Disease (i.e. stages 3-5 of CKD)
A proprietary algorithm is developed at Hua Medicine based on clinically validated biomarkers
Potential as Cornerstone Therapy for Personalized Diabetes Care
24
1 The Type 2 diabetes (T2D) patients are classified into 6 different subtypes: low insulin resistance (LIR), severe insulin resistance (SIR), SIR with diminished β-cell function (SIR_ β∆), severe impaired glucose intolerance (SIGT), SIGT with diminished β -cell function (SIGT_ β∆), and IR with severely diminished β -cell function (SIR_Sβ∆)
Source: Poster 2019 ADA Scientific Sessions
Dorzagliatin has the potential to serve as the next generation cornerstone treatment of T2D– Personalized diabetes care in progress with novel algorithm development
Personalized Type 2 Diabetes Medicine: A Comprehensive Solution for Diabetes Patients
T2D_A LIR
T2D_B SIR
T2D_CSIR_β∆
T2D_DSIGT
T2D_ESIGT_β∆
T2D_FSIR_Sβ∆
Personalized Type 2
Diabetes Care
SolutionHua Algorithm
Type 2 diabetes (T2D) Patients1
Drug naive OAD combo Injectable
Dorzagliatin Mono Dorzagliatin + Metformin
Dorzagliatin + SGLT-2 or
DPP-4
Dorzagliatin + GLP-1 or
insulin
IGTGCK
Impaired
Pre-diabetic
Dorzagliatin
Copyright © Hua Medicine 2020
AI based machine learning results: providing a non-biased methodology to sub-classify T2D patients
SGLT-2
Metformin
PPAR
DPP-4
GLP-1
AGI
Insulin
Dorza+
Metformin tolerated
T2D_CV
T2D_ND
T2D Obesity
AGI tolerated
T1D SevereT2D Severe
T2D NASH
Extended
Injectable
Activates
25
Repair Sensor, Adopt Combo Therapy & Rebuild Homeostasis
Copyright © Hua Medicine 2020
First-line in China for IGT driven T2D patients Combination therapy: FDC with 6 classes OAD covers major T2D patients Endogenous GLP-1 combo with DPP-4 inhibitors: additional indication in ND Combo with SGLT-2: T2D with metabolic syndrome Insulin sparing when add-on to late stage diabetes
Dorzagliatin profile
26Copyright © Hua Medicine 2020
Priority attributes
Secondary attributes
Key opportunity
Restore glucose homeostasis——optimize time-in-range Protect β-cells and β-cell function HbA1c reduction with advanced glycemic control No/Limited hypoglycemia No GI side effect
T2D with diabetic kidney disease Sustained efficacy Limited side effects/no major adverse effects Neurodegeneration disease benefits
27Copyright © Hua Medicine 2020
Hua Medicine R&D Pipeline
Trial # Drugs Disease indication Study type Pre-clinical Phase I Phase II Phase III NDAHMM0301 Dorzagliatin Drug naïve T2D Registration trial
HMM0302 Dorzagliatin & metformin Metformin tolerated T2D Registration trial
HMM0311 Dorzagliatin +/vs OAD To be determined Label expansion
HMM0312 Dorzagliatin +/vs OAD To be determined Label expansion
HMM0109 Dorzagliatin Hepatic impaired T2D Label expansion
HMM0110 Dorzagliatin Renal impaired T2D Label expansion
HMM0111 Dorzagliatin + DPP-4 Obese T2D PK/PD & DDI
HMM0112 Dorzagliatin + SGLT-2 Metabolic syndrome PK/PD & DDI
HMM0113 Dorzagliatin + atorvastatin Label expansion PK/PD & DDI
HMM0114 Dorzagliatin + valsartan Label expansion PK/PD & DDI
HMM0115 Dorzagliatin + sulfonylurea SU-tolerated T2D PK/PD & DDI
HMM0116 Dorzagliatin + acarbose Acarbose tolerated T2D PK/PD & DDI
HMM0117 Dorzagliatin + liraglutide GLP-1 tolerated T2D PK/PD & DDI
HMM0119 Dorzagliatin + pioglitazone NASH T2D PK/PD & DDI
HMM1201 Dorzagliatin + insulin Basal insulin tolerated T2D Insulin sparing
HMM1202 Dorzagliatin + insulin Drug naïve severe T2D Pre-clinical
mGLUR5 PD-LID Pre-clinical
Currently Ongoing Planned
Study Results Coming in the Next 12 Months
28Copyright © Hua Medicine 2020
4
1
2
3
5
Hua & Partners
Highly Experienced R&D Team with Extensive Chinaand Global Pharmaceutical Experience
Founder & CEO
Li Chen, Ph.D., Founder & Board Director CSO and Founding Director of Roche R&D Center (China), responsible for development of
China’s drug discovery strategy, creation of discovery portfolio and management of operations Former head of HTC technology atRoche Adjunct professor at Tongji University, Ph D advisor Over 90 publications and patents in basic research and medical sciences
30Copyright © Hua Medicine 2020
Yilei Fu, BS, MBAVP, Quality Assurance
Daniel Du, Ph.D., MDSVP, RCM
Jin She,Ph.D.VP, Chemistry CMC
GeorgeLinEVP, CFO Yi Zhang, Ph.D.,MD
SVP, ClinicalR&D
Wenjie Xu, BS, MBA VP, Commercial
Strategy and Marketing
Haoliang Song, PhDSr Director
Non-ClinicalSafety
Shuang Ren, Ph DSr Director
Clinical Pharmacology
FuxingTang, Ph.D. VP, CTO, Chemistry CMC
World-renowned Advisors and Influential Key Opinion Leaders
31
Chinese KOLsAdvisors
Franz Matschinsky, M.D. Professor of biochemistry and biophysics at the University
of Pennsylvania, Perelman School of Medicine Founded Penn Diabetes Research Center of the
University of Pennsylvania Founder of the Islet Cell Biology Core in the University of
Pennsylvania Received Banting Award (1995), Rolf Luft Award (2020) Formulated the glucokinase glucose sensor concept “Glucokinase is a glucose sensor, diabetes gene and
drug target”
Xiaoying Li, MD, Ph.D. Director of Endocrinology, Zhongshan Hospital Vice President, Chinese Diabetes Society Published articles in numerous prestigious journals
such as the Lancet Diabetes and Endocrinology,Cell Metabolism
Dalong Zhu, M.D. Director of Endocrinology, Nanjing Drum Tower
Hospital Current President, Chinese Diabetes Society Published articles in numerous prestigious journals
such as the Lancet Diabetes and Endocrinology,Diabetes
Wenying Yang, M.D. Director of Endocrinology, Director of Department of
Internal Medicine, Vice Chairman of Ethics Committee at China-Japan Friendship Hospital
Ex President, Chinese Diabetes Society Published articles in numerous prestigious journals
such as New England Journal of Medicine, Lancet Diabetes and Endocrinology
Ralph A. DeFronzo, M.D. Professor and Division Chief of Diabetes Division at the
University of Texas Health Science Center Deputy Director of Texas Diabetes Institute Led the U.S. development of metformin, and FDA
approval in 1995 Discovered a new approach to diabetes treatment that
targets glucose reabsorption in the kidneys, which led to the development and approval of SGLT-2
Received several prestigious awards, including the Lilly Award (1987) by the American Diabetes Association, Banting Lectureship Award (1988) by the Canadian Diabetes Association, Novartis Award (2003), ADA’s Albert Renold Award (2002), the ADA’s Banting Award (2008), and the Harold Hamm International Prize (2018)
Published over 800 articles in peer-reviewed medical journals
Copyright © Hua Medicine 2020
A Blue Chip Board
Li Chen George LinChairman
Robert Nelsen Lian Yong Chen
William Keller Alec TsuiWalter Kwauk Junling Liu
32
FIL Capital Management (Hong Kong)
Copyright © Hua Medicine 2020
Hua Suppliers & Partners
33
Copyright © Hua Medicine 2019
High quality drug development partners
WuXi AppTec Discovery NCD Clinical CMC
TigerMed Regulatory Clinical
dMed Data Mgmt PV
Covance
Desano Discovery CMC
Frontage Clinical
Jiuzhou CMC
Envigo NCD
Regulatory Clinical
Industry-wide Recognition
34Copyright © Hua Medicine 2020
In 2016, Hua obtained the Annual R&D Achievement Award of the 7thBayHelix Association Chinese Medicine Award
In 2017, Hua was awarded the first China (Shanghai) Free Trade Zone System Pilot Program Innovation Representative Enterprise
In 2018, Hua Medicine was awarded the 2017 Innovation and Entrepreneurship Award by the Pudong New Area People’s Government
In 2018, Dr. Li Chen was selected as one of the 40 Most Influential People in the Pharmaceutical Industry, in celebration of the 40th Anniversary of Economic Reform and Opening Up
In 2018, dorzagliatin's Phase II results were published in The Lancet Diabetesand Endocrinology, Dr. Dalong Zhu and Dr. Li Chen, etc., and were awarded the"Most Influential Research Awards" in the Chinese Diabetes Society’s 2018China Top 10 Diabetes Research
In 2019, Dr. Li Chen was appointed as part-time researcher in the new drugindustry of Shanghai Institute of Materia Medica, Chinese Academy of Sciences
In 2019, Dr. Li Chen was appointed as a Director of the Biomedical Commissionin the Shanghai Economic and Information Bureau of the 2nd Shanghai Youth andIntellectuals Association
Financial Review
Financial Summary
36Copyright © Hua Medicine 2020
Cash Balance: RMB1,105.6 million of cash at 12/31/2019 vs. 1,443.3 million at 12/31/2018. Total cash decrease of RMB337.7million, consisted of • Net cash used in operating activities was RMB342.1 million• Net cash used in investing activities was RMB9.5 million• Net cash used in financing activities was RMB1.2 million.• Net effect of exchange rate changes was RMB15.1 million
1,443.31,105.6
2018 2019
(RMB’ million)
Net cash used in operation activities of RMB342.1 million mainly includes cash payment of RMB 238.3 million for the research and development activities and of RMB46.3 million for the administrative workforce employment.
Financial Summary- continued
37Copyright © Hua Medicine 2020
Research and development expenses ofRMB321.9 million in 2019 vs. RMB269.1 million in 2018• an increase of RMB25.3 million related to the
progress of our Phase III clinical trials and additional Phase I clinical trials conducted in 2019
• an increase of RMB32.6 million associated with headcount increase and milestone bonus payments and share-based payments
Administrative expenses of RMB146.6 million in 2019 vs. RMB100.4 million in 2018• increase related to the establishment of our
finance and corporate development team and commercial strategy and marketing team,
• Increase in activities associated with market research and ongoing public listing costs in 2019
Financial Summary- continued
38Copyright © Hua Medicine 2020
Other income of RMB29.6 million in 2019 vs. RMB10.4 million in 2018• an increase of RMB13.1 million in government grants• an increase of RMB6.1 million in bank interest income from short-term time deposits.
Other gains of RMB16.3 million in 2019 vs.RMB63.8 million in 2018• Smaller appreciation of the U.S. dollar against the RMB in 2019
Loss before tax of RMB425.3 million in 2019, compared to RMB3,604.0million in 2018• 2018 included RMB3,266 million of loss in fair value of convertible redeemable preferred shares
before the listing date in 2018.
Adjusted net loss* of RMB350.9 million in 2019, compared to RMB279.3 million in 2018.
* Adjusted net loss was calculated by taking loss before tax for the year and adding back (a) share-based payments; and (b) loss on changes in fair value of financial liabilities at FVTPL.
Appendix
Study Phase Objectives CountryNumber of Subjects Completion Date
HMM0101 Phase Ia Single dose study in healthy subjects to evaluate safety, and PK/PD China 60 January 2014
HMM0102 Phase Ib 5.5 day multiple-dose study in Type 2 diabetes subjects to evaluate safety, and PK/PD China 53 October 2014
HMM0103 Phase IcFour-week multiple-dose study (75 QD and 75 BID) in Type 2 diabetes subjects to evaluate safety, efficacy, and PK/PD
China 24 February 2015
HMM0104 Phase I A drug-drug interaction with metformin in Type 2 diabetes subjects to evaluate DDI, and PK/PD United States 15 November 2015
HMM0105 Phase I A mass balance study in healthy subjects United States NA April 2017
HMM0107 Phase I A drug-drug interaction with CYP3A inhibitor itraconazole in healthy subjects China NA December 2017
HMM0108 Phase I A drug-drug interaction with CYP3A inducer rifampin in healthy subjects China NA April 2018
HMM0110 Phase I Phase I study to evaluate impact of renal impairment on Dorzagliatin PK China 16 December 2019
HMM0111 Phase I A drug-drug interaction with sitagliptin in Type 2 diabetes subjects to evaluate DDI, and PK/PD United States 15 December 2019
HMM0201 Phase II 12-week multiple-dose study in Type 2 diabetes subjects to evaluate safety, efficacy, and PK/PD China 258 August 2016
Total 10 trials 449 Patients
Hua Has Conducted Comprehensive Clinical Trials
40Copyright © Hua Medicine 2020
Dorzagliatin Demonstrated Excellent Human PK Properties and Targeted Organ Distribution
41
Ph 1a & 1b Combined, 5mg – 200mg
Source: Li Chen, Y Zhang et al ADA 75th Scientific Session, June 5-9, 2015, BostonNote: AUCinf represents area under a plasma concentration-time curve from the time of administration to infinity, while Cmax represents maximum concentration
Phase Ia and Ib
Dorzagliatin showed very well-behaved and predictable PK profile, linear correlation of dose vs exposure Dorzagliatin augments glucose sensor functions in pancreas α, β cells and intestine L cell Dorzagliatin also exhibited a half-life of eight to ten hours, supporting a twice daily regimen Phase Ib included 53 Type 2 diabetes patients with 10 randomized on placebo
0
5,000
10,000
15,000
20,000
0 25 50 75 100 125 150 175 200
Expo
sure
Dose (mg)
Cmax (ng/mL) AUCinf (h*ng/mL)
Copyright © Hua Medicine 2020
Dorzagliatin Modulates GK Function as Glucose Sensor
42
Phase Ia trial targeted healthy adults in China with a single ascending dose (SAD)
Patients were fasted over night and having HMS5552 next morning at time hr 0, continued fasting till hr 4 when meal is given
Dose dependent reductions in glucose and increases in insulin secretion when fasting plasma glucose levels and post-prandial plasma glucose levels were measured during the four hours prior to a meal, and in the two hours after
Phase Ia included 60 healthy volunteers in six treatment groups with different dosages
3.00
4.00
5.00
6.00
7.00
8.00
9.00
(0.5
)
(0.2
5) 0
0.25 0.
5 1 2 3 4
4.25 4.
5 5 6
Glu
cose
Lev
el (m
mol
/L)
Time (hour)
Placebo 5mg 10mg 15mg
25mg 35mg 50mg
Fasting (0~4hr)Meal (at 4hr)
0
20
40
60
80
100
120
140
(0.5
)
(0.2
5) 0
0.25 0.
5 1 2 3 4
4.25 4.
5 5 6
Insu
lin L
evel
(uU
/mL)
Time (hour)
Placebo Low Dose (5mg~15mg)High Dose (25mg~50mg)
Fasting (0~4hr)Meal (at 4hr)
Phase Ia
Copyright © Hua Medicine 2020
0%
10%
20%
30%
40%
50%
60%
Peak
C-p
eptid
e R
espo
nse
(%)
Time Post Oral Glucose Load (min)
NGT IGT T2D
Dorzagliatin Resets the Thresholds in T2D Patients with Improved Glucose SensitivityProof of Mechanism of Action in Phase I Study
43
Source: R.W.Bergstrom J. Clin. Endocrinol. Metab. (1990), 71(6):1447-53 Source: DL Zhu, Y. Zhang, L Chen et al ADA 75th Scientific Session, June 5-9, 2015, Boston
Impaired threshold of GSIR in IGT and T2D patients Dorzagliatin resets the threshold of GSIR in T2D patients
012345678
0 1 2 3 4Placebo_Day -1Placebo_Day 7
012345678
0 1 2 3 425mg_Day -125mg_Day 7
012345678
0 1 2 3 4100mg_Day -1100mg_Day 7
012345678
0 1 2 3 450mg_Day -150mg_Day 7
Hours Hours
C-P
eptid
e Le
vel
(ug/
L)C
-Pep
tide
Leve
l (ug
/L)
Meal
Phase Ib
30 18060 90 120
Copyright © Hua Medicine 2020
Dorzagliatin Reduces Hypoglycemia Risk by improving α-cell Sensitivity
44
Source: DL Zhu, Li Chen et al ADA 75th Scientific Session, June 5-9, 2015, BostonNote: Each dose group had 10 patients, with 2 placebo and 8 treatment patients in each. According to the American Diabetes Association, A1c below 3.9 mmol/liter means “hypoglycemia alert value.” This is distinct from “clinically significant hypoglycemia,” which is A1c below 3 mmol/literNote: Dosages were administered on day 1, and days 3-8.
Phase Ib
Patients showed significant reduction in FPG, with no severe hypoglycemia
0
2
4
6
8
10
12
0 1 2 3 4
FPG Glucose Level in Different Dosages150mg 200mg
0
2
4
6
8
10
12
0 1 2 3 4
Hour Hour
FPG > 3.9mM/L FPG > 3.9mM/L
Day -2 Day 3 Day 8
FPG
Lev
el (m
mol
/L)
Copyright © Hua Medicine 2020
•Oral doses were given to patties fasted overnight over 10 hours•Measures FPG level for additional 4 hour post dose•No server hypoglycemia at 200 mg BID, but significant reduction of FPG
Proof of Concept Personalized Type 2 Diabetes Medicine
45
Proof of Concept — Personalized Type 2 Diabetes Medicine
1 Oral Glucose Tolerance Test
24
20
200
28 day treatment75 mg QD75 mg BID
Chinese T2D PatientsNaive or OAD treated
D HbA1c > 0.6%* Improve β cell function Well tolerated Response rate: > 80%
OGTT1
*HbA1c treatment standard by ADA
Step By
Step
HbA1c: 7 – 11% FPG: 7.0 – 16 mM TG < 8.0 & BMI < 35
HbA1c FPG TG & BMI
HOMA-b HOMA-IR DI30/G30
Copyright © Hua Medicine 2020
Phase Ic
Dorzagliatin Showed Best Effect Combining with Metformin
46
Post Prandial Glucose Level
Note: AUC represents area under the curve, while AUEC represents area under the effect curve; SD represents mean standard deviation
Glucose AUC (0-4hr) Demonstrated no drug- drug interaction between Dorzagliatin and metformin
Demonstrated synergies in the glucose lowering potential of the combination of Dorzagliatin plus metformin as compared to either metformin or Dorzagliatin as a monotherapy
Compared to metformin, Dorzagliatin showed clear advantage on post-prandial glucose level (PPG) control in 0-4 hr in the Oral Glucose Tolerance Test (OGTT) study
Dorzagliatin + Metformin gives the best effect on overall PPG reduction No hypoglycemia adverse effects in the study 15 patients were included in the trial for treatment of 13 days
110.2
73.0
46.7
0
20
40
60
80
100
120
AUEC
0-4h
(hr*
mg/
dL)
Metformin (500mg)
Dorzagliatin (50mg)
Metformin (500mg)+
Dorzagliatin (50mg)
Phase I U.S. Drug-drug Interaction Trials
Copyright © Hua Medicine 2020
(0.31)
(0.47)
(0.69)¹(0.79)²
(1.12)³(1.6)
(1.4)
(1.2)
(1.0)
(0.8)
(0.6)
(0.4)
(0.2)
0.0
Placebo 75mgQD 100mgQD 50mgBID 75mgBID
Sustained Efficacy in HbA1c ReductionProof of Concept in Phase II Study
47
1 P<0.05 compared to placebo group. 2 P<0.01 compared to placebo group. 3 P<0.001 compared to placebo group. 4 LOCF represents for “last observation carried forward”. 5 The averages calculated applied least-square mean averages. 6 The averages calculated applied mean square averages.
(1.50)
(1.25)
(1.00)
(0.75)
(0.50)
(0.25)
0.00
0 2 4 6 8 10 12
Placebo 75mgQD 100mgQD50mgBID 75mgBID
Double blinded, placebo controlled and randomized Phase II trial with 258 patients in China over 22 clinical centers Published in Lancet in May 2018
...with the 75 mg BID group showing HbA1c reduction effect starting from week fourDorzagliatin reduced HbA1c levels dose dependently...
HbA
1c C
hang
e fr
om B
asel
ine
(%)
HbA
1c C
hang
e fr
om B
asel
ine
(%)
Dorzagliatin: Proof-of-Concept (POC) Achieved with Sustained Efficacy
The chart above showcases HbA1c change from baseline after the 12-week treatment period (PPS, LOCF4)5, with the results showing that Dorzagliatin reduced HbA1c levels dose dependently with 75 mg QD, 100 mg QD, 50 mg BID and 75 mg BID, after the treatment period
In the 75mg BID group, both fasting plasma glucose level (FPG) and post-prandial glucose level (PPG) were well controlled without increasing hypoglycemia or dyslipidemia risk
The chart above showcases HbA1c change from baseline over time (PPS)6
Results showed that HbA1c reduction was significant starting from week four, and continued in weeks eight and 12
Phase II
Copyright © Hua Medicine 2020
Drug Naive Patients Achieved Better HbA1c Reduction in Phase II Trial
48
HbA1c Reduction in OAD Patients HbA1c Reduction in Drug Naive Patients
Notes: P<0.05 compared to Placebo group
OAD or Naive / NumberHbA1c Reduction from Baseline (%)
Placebo 75 mg QD 100 mg QD 50 mg BID 75 mg BID
OAD 34/31/28/32/27 (0.41) (0.15) (0.42) (0.70) (0.97)*
Drug Naive 19/22/22/18/22 (0.17) (0.85)* (0.95)* (1.04)* (1.21)*
Type 2 diabetes drug naive patients achieved better HbA1c reduction in all active groups 75mg BID works well in both drug naive and OAD patients
(1.50)
(1.25)
(1.00)
(0.75)
(0.50)
(0.25)
0.00
0 2 4 6 8 10 12
HbA
1c C
hang
es fr
om B
asel
ine
(%)
weekPlacebo 75mgQD 100mgQD 50mgBID 75mgBID
(1.50)
(1.25)
(1.00)
(0.75)
(0.50)
(0.25)
0.00
0 2 4 6 8 10 12
HbA
1c C
hang
es fr
om B
asel
ine
(%)
weekPlacebo 75mgQD 100mgQD 50mgBID 75mgBID
Phase II
Copyright © Hua Medicine 2020
49
Note: Data are n(%). AE=adverse event. SAE=serious adverse event. WBC=white blood cells. HDL = High-density Lipo protein1 Drug-related AE: means AE that the investigator judged as Probably Related or Possible Related to the investigational drug; One patient was counted at most once per category; One patient may be counted in multiple categories
Dorzagliatin is well tolerated with low hypoglycemia incidence and low drug-related adverse events
The incidence of adverse events (AE) reported in all 5 treatment groups was similar
No drug-related serious AE (SAE) or severe hypoglycemia
No identified causal relationship between groups and AE incidence; no confirmed HMS5552 dose-related AEs
No clinically significant laboratory, vital sign, physical examination or electrocardiograms (ECG) abnormalities
Dorzagliatin shows lipid and body weight neutral profile
No occurrence of drug-related SAEs or severe hypoglycemia as demonstrated by the Treatment-Emergent Adverse Event (TEAE) Overview belowDorzagliatin is Safe and Well Tolerated
Phase II
Satisfactory Safety Data Observed and EvidencedProof of Concept in Phase II Study
Placebo(n=53)
75 mg Oncedaily (n=53)
100 mg Once
Daily (n=50)50 mg TwiceDaily (n=51)
75 mg TwiceDaily (n=51)
Active Total (n=205)
Any AE 27 (51%) 30 (57%) 31 (62%) 24 (47%) 27 (53%) 112 (55%)Mild AE 27 (51%) 27 (51%) 31 (62%) 22 (43%) 25 (49%) 105 (51%)Moderate AE 2 (4%) 3 (6%) 2 (4%) 3 (6%) 3 (6%) 11 (5%)Severe AE 0 1 (2%) 0 1 (2%) 0 2 (1%)Any SAE 0 1 (2%) 1 (2%) 1 (2%) 0 3 (2%)Drug-related1 AE 1 (2%) 5 (9%) 6 (12%) 6 (12%) 3 (6%) 20 (10%)AE Leading to Drug Discontinuation 0 1 (2%) 0 2 (4%) 0 3 (2%)
Drug Related1 0 0 0 1 (2%) 0 1 (1%)Not Drug Related 0 1 (2%) 0 1 (2%) 0 2 (2%)
AE Occurring in ≥5% of Patients in Any GroupUpper Respiratory Tract Infection
3 (6%) 6 (11%) 6 (12%) 1 (2%) 4 (8%) 17 (8%)
Hyperuricaemia 2 (4%) 3 (6%) 6 (12%) 3 (6%) 4 (8%) 16 (8%)Dizziness 0 2 (4%) 4 (8%) 4 (8%) 0 10 (5%)Protein Present in Urine 1 (2%) 3 (6%) 2 (4%) 0 2 (4%) 7 (3%)Urinary Tract Infection 3 (6%) 1 (2%) 3 (6%) 0 1 (2%) 5 (2%)Blood Creatine Phosphokinase Increased 5 (9%) 0 1 (2%) 1 (2%) 1 (2%) 3 (1%)
WBC Urine Positive 1 (2%) 1 (2%) 0 2 (4%) 3 (6%) 6 (3%)Hepatic function Abnormal 1 (2%) 2 (4%) 1 (2%) 3 (6%) 0 6 (3%)HDL Decreased 1 (2%) 1 (2%) 0 1 (2%) 4 (8%) 6 (3%)Ventricular Extrasystole 0 0 1 (2%) 0 3 (6%) 4 (2%)Nasopharyngitis 0 0 1 (2%) 3 (6%) 0 4 (2%)Hypoglycaemia (≤3.9 mmol/L) 0 3 (6%) 2 (4%) 3 (6%) 3 (6%) 11 (5%)Hypoglycaemia (≤3.0 mmol/L) 0 1 (2%) 0 0 1 (2%) 2 (1%)
Copyright © Hua Medicine 2020
High HbA1c Control Rate and Response Rate AchievedProof of Concept in Phase II Study
50
All Dorzagliatin treatment groups achieved significant HbA1c response compared with placebo, with 44.9% achieving reduction of HbA1C to <7% and 75.0% achieving 10% and above reduction. The results have been published on Lancet
50 mg BID1 and 75 mg BID1 showed excellent HbA1c response rates and target rates
13.2%
30.2%
32.0%
44.0%
44.9%
0% 10% 20% 30% 40% 50% 60%
Placebo
75mgQD
100mgQD
50mgBID
75mgBID
Rates of Achieving Glycemic Control and Treatment Response as Measured by HbA1c Changes
Both 50 mg BID and 75 mg BID groups showedexcellent HbA1c control rate (HbA1c < 7.0%) 2
The same two treatment groups also showed excellent HbA1c response rate (HbA1c change > 10% reduction from baseline)2
1
1
1
1
The chart above showcases HbA1c response rate at week 12 (FAS), with the criteria being achieving HbA1c reduction of >10% at week 12
75.0% of the 75 mg BID group patients were able to reduce their HbA1c baseline levels by greater than 10% by week 12
1 BID denotes “bis in die” (twice a day), while QD denotes “quaque die“ (once a day). 2 Full analysis set (FAS) data.
The chart above showcases HbA1c control rate at week 12 (FAS), with the criteria being achieving glycemic control as measured by HbA1c < 7.0% at week 12
44.9% of the 75 mg BID group patients achieved target clinical response
28.0%
48.8%
55.6%
67.4%
75.0%
0% 20% 40% 60% 80%
Placebo
75mg QD¹
100mg QD¹
50mg BID¹
75mg BID¹
Phase II
Copyright © Hua Medicine 2020
Compelling Sets of Composite Endpoint Observed
51
Source: “Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycemia in Type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme” by B. Zinman et al Diabetes, Obesity and Metabolism 14:77-82, 2012Note: Dorzagliatin data was from Phase II trial conducted over 12 weeks, while the study comparison was conducted on 26 week clinical trials.
35%
26%22%
15%
9%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
75m
g BI
D
50m
g BI
D
100m
g Q
D
75m
g Q
D
Plac
ebo
40%
32%
25%
15%11%
8% 8%6%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Lira
1.8
mg
(GLP
-1)
Lira
1.2
mg
(GLP
-1)
Exen
atid
e(G
LP-1
)
Gla
rgin
e
Sita
glip
tin(D
PP-4
)
Sulp
hony
lure
a
Plac
ebo
Thia
zolid
ined
ione
Patie
nts
Rea
chin
g C
ompo
site
Out
com
e fo
r HbA
1c
<7.0
%, n
o H
ypog
lyce
mia
and
no
Wei
ght G
ain
(%)
Injections PlaceboOral
...compared with other Type 2 diabetes treatment composite endpoints over 26-week treatment periods
Favorable composite response rate of Dorzagliatinin a 12-week treatment period...
The composite response rate of Dorzagliatin in a 12-week treatment reached 35.4% in the 75 mg twice daily group and demonstrated its favorable profile in glucose reduction, as well as low risk of hypoglycemia and weight gain
The clinical trial results have been published on Lancet
In the trial, the 75 mg BID group reached a composite response rate of 35.4% over a 12-week treatment period, which compares favorably with other treatment methods tested over a 26-week period
Phase II
Copyright © Hua Medicine 2020
Dorzagliatin Improved β-cell function and Reduced Insulin Resistance
52
Reduced Insulin Resistance Improved β-cell Function
Note: HOMA-IR represents homeostatic model assessment – insulin resistance, while DI measures β-cell function
One week after the conclusion of the trial, patients continue to see sustained effect in the HOMA-IR and Disposition Index
Improves pancreatic β-cell functionReduces insulin resistance
Chinese drug naive Type 2 diabetes patients 3 month treatment
(2.0)
(1.5)
(1.0)
(0.5)
0.0
12 Week 13 Week
Med
ian
Cha
nge
from
Bas
elin
e of
HO
MA-
IR
Placebo 75mgBID
P=0.0307 P=0.0240
(0.1)
0.0
0.1
0.2
0.3
0.4
12 Week 13 Week
Med
ian
Cha
nge
from
Bas
elin
e of
DI
Placebo 75mgBID
P=0.0461
P=0.0387
Phase II
Copyright © Hua Medicine 2020
Dorzagliatin Improved β-cell Function and Decreased Insulin Resistance
53Source: R Wang, H Liu, L Chen, Y Duan, Q Chen, S Xi J. Diabetes Res 2017
Type 2 Diabetes Rat Pancreas Type 2 Diabetes Rat Liver
Hua conducted several non-clinical studies in rats, mice and dogs. It showed that Dorzagliatin rescued glucose sensor function in pancreas and liver, and it improved glucose and insulin sensitivity
Study results showed that number of insulin-immunopositive cells in pancreas and GK-immunopositive cells in liver increased significantly after the administration of low-dose and high-dose Dorzagliatin
0153045607590
Control Diabetic HMS-L HMS-H
Num
ber o
f Ins
ulin
-Im
mun
opos
itive
C
ells
(b)
0
20
40
60
80
100
Control Diabetic HMS-L HMS-H
Num
ber o
f GK
-Im
mun
opos
itive
C
ells
(%)
(b)
Control
HMS-L HMS-H
Diabetic Control
HMS-L HMS-H
Diabetic
Copyright © Hua Medicine 2020
Profile Compound Developer Clinical Stage CommentaryChemical Structure
Full GKA (β > 1)
Dorzagliatin Phase III Only GKA to have advanced to Phase III
RO4389620 Generated large amounts of unexpected human metabolites
AMG 151 / ARRY-403
High incidences of hypoglycemia and elevated serum triglycerides
MK-0941Lack of sustained glycemic efficacy, increased incidence of hypoglycemia and elevations in triglycerides and blood pressure
Partial GKA(β < 1)
AZD-1656Reduced Vmax of GK and demonstrated limited efficacies in Type 2 diabetics
PF-04937319Phase II completed in US / IND approved in
China
Liver Selective GKA
TTP399Sustained efficacy and safety through 24 week; less efficacious than sitagliptin
PF-04991532Reduced Vmax of GK and demonstrated limited efficacies in Type 2 diabetics
Only Hua has advanced GKA to Phase III clinical trials
Dorzagliatin is Designed to Overcome the Flaws Witnessed in the Past GKA Candidates
54
Dorzagliatin targets GK both in pancreas and liver Dual acting with full activation properties fit the profiles of a therapeutic agent to modulate glucose homeostasis in Type 2
diabetes patients
Selective Acting
on GK in Liver
Glucokinase Activator
Dual Acting on GK in
Pancreas and Liver
NH N
N
N
NN
Copyright © Hua Medicine 2020
Dorzagliatin Chemical Structure is Unique
55
Hua Dorzagliatin Roche RO4389620
Merck MK-0941 AstraZeneca AZD-1656
NH N
N
N
NN
Copyright © Hua Medicine 2020
Hypoglycemia can be Prevented by Maintaining nH Close to Native Form of GK Enzyme
56
GK
A EC
50(u
M)
Glucose (mM)
0 1 10 100
8
7
6
5
4
3
1
0
2
nH=1.5
nH=1.0
Vmax, S0.5 and nH
GKA: “A” can change the Vmax and S0.5 of GK α measures the change of affinity to glucose by GKA β measures the change of catalytic efficiency by GKA n is Hill coefficient (nH)
GK
Act
ivity
(uM
/min
)
Glucose (mM)
16141210
86
20
4
18202224
0 5 10 15 20 25 30
00.1 uM0.3 uM1 uM
3 uM10 uM30 uMDecreasing α
Increasing β
[S]0.5Vmax
Dorzagliatin Does Not Modulate nH of GK to UnityEnzyme Activity Predictive Model
GKA Alters GK Enzyme Kinetic Properties
Wild type GK has an nH of 1.7 Dorzagliatin at 10 uM maintains GK nH of 1.5 GKA change nH toward unity (nH = 1.0) will disrupt GK glucose
sensing function and cause hypoglycemia
Copyright © Hua Medicine 2020
Dorzagliatin has Desirable Enzyme Kinetics Profile
Source: Li Chen, American Diabetes Association (ADA) 79th Scientific Sessions, 7-11 June, 2019, San Francisco, USA
Conclusion
The increase of GK Vmax with a GKA is desirable for developing a therapeutic agent for the treatment of patients with type 2 diabetes who suffered from a down regulation of GK expression.
The results suggest that large changes of nH over 20% at 10 uM GKA concentration compared with drug free state may lead to clinical hypoglycemia as an indicator for setting the GSIR threshold below 4 mM glucose.
DorzagliatinInfluence of GKAs on key parameters of GK enzymatic
kinetics.
Piragliatin PF-04937319
MK-0941 AZD1656
Copyright © Hua Medicine 2020 58
IGT
T2D_4T2D_1
Pre-Diabetes Early Stage Diabetes Late Stage Diabetes
T2D_5
ObesityT2D_6T2D_2 T2D_3
Subtype Predominate InfluentialFactor
T2D_1 Severe Impaired Glucose Tolerance
T2D_2 Impaired β-cellFunction
T2D_3
T2D_4
T2D_5
T2D_6
Severe Impaired β-cell Function
Impaired Glucose Tolerance with aging
Severe Insulin Resistance withobesity
Impaired β-cell Function and Severe insulinresistance
Type 2 Diabetes Patients Subtype Analysis: Unbiased Machine Learning for Future Personalized T2D Care
This study demonstrated a viability of subclassifications type 2 diabetes patients through hyperdimensional machine learning framework
Although the study is conducted in a limited T2D patient population compared with the clustering analysis reported previously, our results were based on a much higher dimension of variables from our high quality clinical trial data.
Different subtypes have responded differently to dorzagliatin in HbA1c reduction, but all of them showed improved HOMA2-β and reduced HOMA2-IR, which supports dorzagliatin in combination with other T2D medicines in a personalized T2D care
Our results also suggests that each T2D subtypes may represent a unique state in the disease progression
Source: Lingge Feng, American Diabetes Association (ADA) 79th Scientific Sessions, 7-11 June, 2019, San Francisco, USA
Copyright © Hua Medicine 2020 59
Combination Therapy Options:Fix Sensor, Remodel Homeostasis, Control Diabetes
SGLT-2
Metformin
PPAR
DPP-4
GLP-1
AGI
Insulin
Dorza+
DorzaMet
T2D_CV
Endo-GLP-1
T2D Obesity
Prevention
T1D Severe
T2D NASH
Extended
Injectable
Prevention
Copyright © Hua Medicine 202060
Massive China Diabetes Market with Drug Naïve Patients
60
China has the largest diabetes population globally, with half undiagnosed
China Has the Largest Diabetes Population with c.125 million T2D …with Diagnosis Rate Lower than Global Average
Number of Type 2 Diabetes Patients and Diagnosis Rate, Expected to Grow Significantly
Million
106 109 113 117 120 126 127 131 135 138 142 146 149 153 157 160 43.9% 44.7% 45.3% 46.1% 47.7% 50.4% 53.4% 56.6% 60.1% 63.9% 67.9% 71.3% 74.3% 77.1% 79.7% 82.2%
2013 2014 2015 2016 2017 2018 2019E 2020E 2021E 2022E 2023E 2024E 2025E 2026E 2027E 2028E
Number of T2D Patients in China Diagnosis Rate
50.4%
77.6%
54.2%
China US Global
Geographic Distribution of Global T2D Patients, 2018
125.7 , 27.0%
31.4 , 6.8%
307.6 , 66.2%
ChinaUSRoW
China Diabetics:
Increase in aging population
Unhealthy diet Lack of physical
activity
With improvements in social healthcare insurance system, increased healthcare expenditures and healthcare awareness, and rising penetration of medical examination, diagnosis rate in China is expected to rise from 50.4% in 2018 to 82.2% in 2028
Source: Frost & Sullivan
Diagnosis Rate , 2017
Copyright © Hua Medicine 2020
1
Note: 1 the data refers to the actual diagnosis rate in China in 2018
Strong Demand for Next Generation OAD from Physicians and Patients
61
US Anti-diabetics Drug Market Breakdown By Drug Categories
Source: Frost & Sullivan
Global anti-diabetics drug market reached US$68.9 bn in 2017, and is expected to reach US$137.7 bn by 2028
New drug class with novel mechanism of action has been very well accepted by physicians and patientsDorzagliatin is a new generation of novel drug with breakthrough potential
1995 2005 2017
Market Size: US$3.2 bn Market Size: US$16.1 bn Market Size: US$34.6 bn
Insulin68%
Biguanides7%α-glucosidase
inhibitors7%
Sulfonylureas18%
Insulin48%
Biguanides4%
α-glucosidase inhibitors
6%
Sulfonylureas + Glinides
13%
Thiazolidinediones(TZD)29%
Insulin54%
GLP-114%
Biguanides1%
Sulfonylureas + Glinides
2%SGLT-25%
DPP-424%
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33.0 38.1 42.5 47.0 51.2 57.3 65.9 76.5 90.3 103.8 118.4 123.2 135.6 149.1 161.0 173.9
2013 2014 2015 2016 2017 2018 2019E 2020E 2021E 2022E 2023E 2024E 2025E 2026E 2027E 2028EChina Anti-diabetics Market Size
China Anti-Diabetes Market Has Significant Headroom for Growth
62
Innovative drug categories will be a key growth driver for China anti-diabetics market
Breakdown of China Anti-diabetics Market, 2018
China Anti-diabetics Market
Billion RMB with wholesale price level
Driven by rising income, improving affordability and emerging innovative anti-diabetes drugs, China anti-diabetics market is expected to grow at 11.7% CAGR from 2018 to 2028
Billion RMB, with wholesale price level
+11.7%
Anti-diabetics in the China market are dominated by traditional drugs. Sales revenue from newer emerging drug categories like DPP-4, GLP-1 and SGLT-2 inhibitors are still relatively small
With rising income, expansion of national medical insurance system and growth of innovative anti-diabetes drugs, the China anti-diabetes market is projected to grow significantly from RMB57.3 billion in 2018 to RMB135.6 billion in 2025, and RMB173.9 billion in 2028
RMB57.3 billionMarket
Source: Frost & Sullivan
Insulin46.0%
Biguanides9.5%
DPP-43.0%
GLP-11.2% Others
8.8%
α-glucosidase Inhibitor17.2%
Sulfonylureas7.8%
Glinides4.3%
Glitazones2.2%
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Top 15 Anti-Diabetic Global Sales —1H2019
63
1,908 1,732 1,702 1,654 1,408 1,3721,111 1,063
737 726 720 690 620 557 542
0
500
1,000
1,500
2,000
2,500
Trul
icity
®
Janu
via®
*
Lant
us®
*
Vict
oza®
*
Hum
alog
®
Nov
oRap
id®
*
Jard
ianc
e®*
Janu
met
®*
Leve
mir®
*
Farx
iga®
*
Nov
oMix
®*
Tres
iba®
*
Hum
ulin
®*
Oze
mpi
c®
Basa
glar
®
Top 15 Anti-Diabetic Global Sales – By Sales Value (in USD mn)
Top 15 Anti-Diabetic Global Sales – By Sales Growth (Y-o-Y comparison against 1H2018)
1300%
129%
85%
47% 47% 46% 46%31% 27% 25% 14% 7% 3% 3% 2%
0%
50%
100%
150%
200%
250%
Oze
mpi
c®
Fias
p®
Soliq
ua®
Basa
glar
®
Ryz
odeg
®
Jard
ianc
e®*
Xulto
phy®
Trul
icity
®
Glu
coph
age®
*
Tres
iba®
*
Farx
iga®
*
Glu
coba
y®*
Nov
o O
ther
Invo
kam
et®
Touj
eo®
Oral Non-Insulin Injectables InsulinNote: * denote drugs sold in China.
557 75 56 542 70 1111 156 1908 464 690 726 380 325 92 479 1H Sales(in USD mn)
+31% +46% +14% +25% +1300% +47%Sales Growth
#2—#6 Drugs all declining #8—#9 declining
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Top 15 Declining Anti-Diabetic Global Sales —1H2019
64
Top 15 Declining Anti-Diabetics Sales (Ranked by total sales) (in USD mn)
Top 15 Declining Anti-Diabetes Sales (Ranked by sales decline)(Y-o-Y comparison against 1H2018)
-23%
-17%-14%
-10% -8% -8% -6% -6% -5% -5% -5% -4% -3% -1% 0%
-40%
-30%
-20%
-10%
0%
Invo
kana
®*
Lant
us®
*
Leve
mir®
*
Hum
alog
®
Hum
ulin
®*
Byet
ta®
*
Insu
man
®
Janu
met
®*
Janu
via®
*
Vict
oza®
*
Apid
ra®
Bydu
reon
®*
Nov
oRap
id®
*
Nov
oMix
®*
Amar
yl®
*
Oral Non-Insulin Injectables Insulin
1,732 1,702 1,6541,408 1,372
1,063737 720 620
286 283 190 192 55 480
500
1,000
1,500
2,000
2,500
Janu
via®
*
Lant
us®
*
Vict
oza®
*
Hum
alog
®
Nov
oRap
id®
*
Janu
met
®*
Leve
mir®
*
Nov
oMix
®*
Hum
ulin
®*
Invo
kana
®*
Bydu
reon
®*
Amar
yl®
*
Apid
ra®
Byet
ta®
*
Insu
man
®
Note: Soliqua is Non-Insulin Injectables.
-5.3% -16.7% -5% -10% -3% -5.8% -14% -1% -8% -23% -4% 0% -4.9% -8% -6% Sales Decline
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# of innovative drugs approved1
Local MNC
Source: CDE; EvaluatePharma; GBI; McKinsey analysisNote: 1. Including both innovative chemical drugs and biologics.2. As of October 25, 2019.
Innovations led by China NMPA accelerate the speed of new drug launches and narrow the gap between China and global market
65
4
4045
28
3
9
6
2016
1
54
2018 2019YTD2
34
2017
7
41
Selected brands approved in 2019
必特
Launch lag between China and global first launch 2016 2019
Launch lagYears
Brand(4)
Launch lagYears
Brand(28)
3.9 0.6
14.0 2.2
…
Average 8.4 Average 4.6
Average launch lag in 2019 still skewed by “legacy” delays from prior years
… 8.8
6.9
8.8
1.6
1.8
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Source: Company reports; EvaluatePharma; Fuji Keizai; Industry association; Prospectus; Testa Marketing; WHO (2014); McKinsey analysisNote: 1. Newly launched drugs (since 2015) with largest sales and at least three years of sales numbers.
Launch performance of selected drugs1 acrossmarkets
1,600
Y4Y2Y1Y0 Y3 Y3Y5 Y0 Y4Y1 Y2 Y5 Y0 Y3Y1 Y4Y2 Y5
XX Relative average sales
1x ~2x ~5x
Selected Examples
Recent launch performance in China has improved compared to historical launches
Recent
Japan ~2x of China
United States ~5xof China
Historical
Japan ~6x of China
United States ~30xof China
The launch performance of new drug launches in China is improving, although there is still a large gap compared to markets such as the United States and Japan
Improved launch performance in China
66Copyright © Hua Medicine 2020
New oral anti-diabetic drugs, especially DPP-4 and GLP-1 which entered the national medical insurance in 2017, are quickly growing market share.
67
Market Share of Oral Anti-diabetic Drugs
Source: Dorzagliatin Hospital Potential and SF Planning • March. 28, 2019 • © IQVIA 2019
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China non-insulin anti-diabetes (NIAD) market sales value by class
68Source: IQVIA analysis data on hospital market in China Note: MAT 201909: 2018.10-2010.09
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(mln RMB)
China NIAD value share by class (%)
69Source: IQVIA analysis data on hospital market in China Note: MAT 201909: 2018.10-2010.09
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Comparison of Treatment Analysis of Type 2 Diabetes in China and the United States
70Source: Frost & Sullivan
Almost all T2D patients will need insulin as they gradually lose most of the β-cells Medications comparison of type 2 diabetes in China and US are illustrated below. One major difference is that alpha-glucosidase inhibitors are still
used as first line drugs if metformin is not tolerated in China, whereas in US, alpha-glucosidase inhibitors are less popular.
In US, for most patients who need the greater efficacy of an injectable medication, a GLP-1 receptor agonist should be the first choice, ahead of insulin. However, GLP-1 is not recommended in combination injectable therapy in China.
Monotherapy
Insulin secretagogues
α-glucosidase inhibitors
DPP-4 inhibitor TZDSGLT2
inhibitorGLP-1
receptor agonist
Basal insulinOR OR OR OR OR OR
ADD
Basal insulinGLP-1
receptor agonist
Rapid-acting Insulin
Premixed InsulinOROR AND/OR
Metformin +
Metformin is the first-line therapy in both China and US, while insulin secretagogues and alpha-glucosidase inhibitors may also used as first-line drug in China if metformin is not tolerated.
MetforminInsulin secretagogues/
α-glucosidase inhibitors
OR
Dual and Triple Therapy Several options are available as second line treatment combined with metformin. SGLT-2 inhibitor, GLP-1 receptor agonist, basal insulin, insulin secretagogues, DPP-4 inhibitor and TZD
are recommended in both China the U.S. In China, insulin secretagogues including sulfonylureas and meglitinides are recommended while in the U.S, only sulfonylureas are recommended.
Combination Injectable Therapy
Recommended only in US Recommended both in US and China Recommended only in China
GLP-1 receptor agonist is prior to insulin in US while in China, it is not recommended in combination injectable therapy.
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Primary Anti-diabetics in China and United States
71Source: Currency exchange rate of USD1: RMB7.1815, USD1:DKK6.7529. Annual cost calculation assumes patients are on drug 360 days a year.https://www.yaozh.com , https://www.drugs.com.Note: 1,2,3 Price of health insurance negotiation
Prices and Average Daily Cost of Top Anti-diabetics in China
Brand Name Generic Name Category Standard Dosage
Drug Sales in 2018
(RMB bn)
Daily Cost(RMB)
Estimated Annual Cost
(RMB)
Glucobay® Acarbose α-glucosidaseInhibitors 3x0.1g/day 5.3 1.1 396
Lantus® Insulin Glargine Insulin 200U/week 4.5 17.7 6,372Novomix® 30 Insulin Aspart 30 Insulin 200U/week 4.5 7.1 2,556Ka Bo Ping® Acarbose α-glucosidase
Inhibitors 3x0.1g/day 3.1 8.2 2,952
Chang Xiu Lin® Recombinant Insulin Glargine Insulin 200U/week 2.7 14.0 5,040
Glucophage® Metformin Biguanides 2x0.5g/day 2.5 2.8 1,008
Novolin® 30R Isophane Protamine Biosynthetic Human Insulin Insulin 200U/week 2.4 5.4 1,944
Novorapid® Insulin Aspart 30 Insulin 200U/week 1.9 7.2 2,592Novonorm® Repaglinide Glinides 2x1mg/day 1.7 6.2 2,232
Amaryl® Glimepiride Sulfonylureas 2mg/day 1.4 4.6 1,656
Victoza® Liraglutide GLP-1 agonist 1.2mg/day1.8mg/day
27.341.0
9,82814,760
Byetta® Exenatide GLP-1 agonist 10μg/day20μg/day
43.353.3
15,58819,188
Januvia® Sitagliptin DPP-4 inhibitor 100mg/day 7.7 2,772Invokana® Canagliflozin SGLT-2 100mg/day 4.1 1,476Forxiga® Dapagliflozin SGLT-2 10mg/day 4.2 1,512
Insulin+
New Drug with
Novel MOA
Insulin+
Older General
OAD+
Branded Generic
New Injectable Anti-diabetic
Reimbursable Drugs in China
New Drug with Novel MOA
Prices and Average Daily Cost of Top Anti-diabetics in US
Brand Name Generic Name Category Standard Dosage Drug Sales in 2018(USD bn)
Daily Cost (USD)
Daily Cost (RMB)
Estimated Annual Cost
(RMB)
Victoza® Liraglutide GLP-1 agonist 1.2mg/day1.8mg/day 2.6 21.7
32.6155.8234.1
56,10284,153
Januvia® Sitagliptin DPP-4 inhibitor 100mg/day 2.0 15.3 109.9 39,478Trulicity® Dulaglutide GLP-1 agonist 1.5mg/week 2.5 28.6 205.4 73,941Lantus® Insulin Glargine Insulin 200U/week 1.8 8.7 62.5 22,492
Humalog® Recombinant Insulin Lispro Insulin 200U/week 1.8 9.09 65.3 23,508
Novorapid® Insulin Aspart Insulin 200U/week 1.4 10.5 75.4 27,146Levemir® Insulin Detemir Injection Insulin 200U/week 1.0 9.5 68.2 24,552
Jardiance® Empagliflozin SGLT-2 10mg/day 1.0 17.5 125.7 45,243Janumet® Sitagliptin DPP-4 inhibitor 2*(50mg:1000mg)/day 0.8 16.0 114.9 41,364Invokana® Canagliflozin SGLT-2 100mg/day 0.7 17.5 125.7 45,243Farxiga® Dapagliflozin SGLT-2 10mg/day 0.6 17.5 125.3 45,114
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Dorzagliatin Existing Patent Portfolio
Apr. 6, 2009
Dec. 20, 2013
Apr. 6, 2029
Dec. 20, 2033
Dec. 14, 2017May 28 , 2019
Dec. 14, 2037
May 28, 2039
PCT/CN 2019/088861 other five applications FDC
PCT/CN 2017/116209 Family (ZL 201711342429.9 and twodivs) Formulation
PCT/EP 2013/077563Family Process
PCT/EP 2009/054067Family Compound
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