Keynote presentation at Evolution Asia Summit 2019 Dr Ye Hua, Founder & CEO, BioNova Pharmaceuticals

1. Partner of Choice for Drug Development in China
Discovering Key Regulatory Reforms to Enable
Accelerated Drug Development and Approval in
CHINA
Ye Hua, MD, MPH
Chairman & CEO
BioNova Pharmaceuticals Ltd.

2. • Regulatory reform continues1
• Priority review2
• Breakthrough & conditional approval3
• A case study of savolitinib4
Agenda

3. NMPA reform deepens

4. 《国务院关于改革药品医疗器械审评
审批制度的意见》44号文（2015）
• Clear IND/NDA backlog
• Encourage innovation for medicinal
products
• Transparent review and approval
process and status
Key policies
《关于深化审评审批制度改革鼓励
药品医疗器械创新的意见》厅字42
号（2017）
• Policy, communications/dialog,
review and approval
• For patients, based on clinical
needs, priority review at discretion
• Products that fill the gap of unmet
medical needs get conditional
approval on accelerated regulatory
pathway

5. • IRB review and approval prior to IND
– Leading PI site IRB review and approval
– Central IRB
• IND application 60 days
– Pre-IND meeting
– Complete IND dossier
– Inspection for cause
• CDE process
– Project PM
– Online status
• Global NDA submission
– NMPA joins ICH as a Regulatory Member in June 2017
– Sino-US NDA dual submission to FDA and NMPA （中美双报）
A few highlights

6. NMPA 60-Day Review
IND Submission
Format Review
Acceptable
Yes or No
Notification of
IND Received
Application
Payment
Review
Conclusion
60 WD/
90 CDs
5 Days
60 Days
• Interactions with CDE
– No direct communications to
CDE reviewers
– Communications must go via
regulatory PM

7. • CDE new drug review/approval reform made “dual submission”
possible
• CDE encourages industry to submit NDA as global first or co-first
– The regulatory review comments will probably come from US FDA first
– Approval is likely US prior to China
• Key technical requirements
– Similar registration trials, if not the same, to be used for “dual submission”
– Global multicenter trials enrolled with acceptable number of Chinese patients
– Drug DMPK fully addressed albeit racial differences
FDA/NMPA NDA dual submission

8. • Regulatory reform continues1
• Priority review2
• Breakthrough & conditional approval3
• A case study of savolitinib4
Agenda

9. 1 To be discussed at the pre-NDA meeting
2 RPM to setup review team and manage the progress
3 Secure reviewer resources for priority review
4 Prioritize clinical center and CMC site inspections
5 Review period 6 months
CDE priority review

10. • Clinical value hierarchy
CDE criteria for priority review
No standard of care, of highest value
Better treatment option, good clinical value
Additional Rx choice, minimum requirement
for NDA approval
Unmet need
Better Rx
“me too”

11. • Department of science and technology - key innovative scientific 5-
year project
– Scientific novelty: new target, NME, etc. (pre-clinical stage)
– Technology advances: new formulation, etc. (pre-clinical stage)
– Application / usage advances: better efficacy, better safety, etc. (clinical stage)
• Certificate to CDE for priority review
• CDE notifies inspection center to prioritize inspection processes
Other qualifications and processes

12. Disease Area Amount
Oncology 71
GI Tract Disorders 63
ID 53
Circulatory System 34
Psychiatry 30
Hematology 28
Endocrine 24
Respiratory and
Allergy
22
Dermatology and
ENT
22
Analgesic 21
Neurological
Disorders
17
Autoimmune 12
Distribution of priority review (small molecule)
Data from CDE 2018

13. • Regulatory reform continues1
• Priority review2
• Breakthrough & conditional approval3
• A case study of savolitinib4
Agenda

14. • Data driven - how good is good enough?
– Change treatment paradigm
– Fill the gap of unmet medical need
– Purpose: to accelerate new drug approval for life-threatening diseases
• FDA BTD
– Most data are from early phase development (i.e., Phase 1 / 2 trials)
– Most data are from a single clinical trial (i.e., 67% from 1 trial)
– Limited number of patients and mostly seen in oncology
– Often single-arm, open-label trial using surrogate endpoint (e.g., ORR)
• Typically > 50% ORR
– Often need a RCT to confirm efficacy and safety for full approval
Breakthrough therapy

15. • Communication and prior agreement with
CDE with regard to clinical trial protocol
for conditional approval
‒ Surrogate endpoint that supports clinical benefit
‒ Based on early phase / interim data to support
conditional approval, and requirements on post-
approval confirmatory trial
‒ Orphan drug that has been approved overseas
• Meeting with CDE to discuss whether
early data are sufficient to submit NDA for
conditional approval
• If confirmatory trial is positive, conditional
approval will be changed to full approval;
or approval will be revoked
NMPA conditional approval

16. • Unmet medical need
– No treatment
– Available Rx were approved by single-arm trials
– Proof of clinical meaningful ORR and DOR
• Efficacy
– Outstanding response rate (e.g., ibrutinib in MCL)
– Durable response (e.g., pembrolizumab in HNSCC)
• Target population
– Biomarker driven (e.g., ALK, T790M+)
Some considerations for single-arm trial BTD

17. • Surrogate endpoint for regulatory approval
– High correlation between surrogate endpoint and clinical benefit (e.g., PFS vs OS)
– The weaker the correlation between surrogate endpoint and clinical benefit, the
more supportive data needed
– The more efficacy variation of surrogate, the more supportive data needed
• Intermediate clinical assessment
– Laboratory or image evaluations
• NAS score, fibrosis score
• Image evaluation (e.g., RECIST)
• Biomarkers
– Tumor burden (e.g., Bcr-Abl Philadelphia chromosome)
– Testosterone
Some considerations for surrogate endpoint

18. • Regulatory reform continues1
• Priority review2
• Breakthrough & conditional approval3
• A case study of savolitinib4
Agenda

19. • HGF/MET dysregulation is seen in
many solid tumors
– NSCLC, GC, RCC, HCVC, CRC, etc.
• c-MET dysregulation presents
with 4 alterations
– MET gene amplification
– MET protein over-expression
– exon 14 skipping
– HGF/MET autocrine/paracrine loop
signaling pathway
• One of the drug resistant
mechanism for EGFR/T790M+
HGF/MET pathway

20. Exon 14 skipping and savolitinib
Savolitinib’s activity is more
than 10-fold than crizotinib
TCGA, Nature. 2014 Jul 31; 511(7511): 543-50
Paik PK, et al. Cancer Discov. 2015 Aug; 5(8): 842-9

21. • MET exon14 skipping tumors are known to be associated with faster
disease progression and poor prognosis
• 2017 ASCO reports exon 14 skipping NSCLC not responsive to chemo or
I/O
Exon 14 skipping tumor presents unmet medical need

22. • MET exon 14 skipping virtually
exclusive with other driver gene
(e.g. EGFR, ALK, ROS1, HER2，K-
Ras, B-Raf, etc.)
• Low incidence overall (e.g., similar
to ROS1)
• MET exon 14 occurs more
frequently in pulmonary
sarcomatoid carcinoma (PSC)
which is approximately 3-4%
NSCLC
• Commonly seen in women,
smokers, elderly (>65 YO)
Clinical enrichment and target population

23. Breakthrough single-arm, open-label phase 2 trial
Prescreening /
Screening
(MET mutation)
PD, death or
unacceptable
toxicity
Histologically
confirmed
locally
advanced or
metastatic
PSC (Cohort
A) / other
NSCLC
(Cohort B)
• 600mg, QD, after meal
• Every 21 days/cycle
• Tumor evaluation every 2 cycles in the first
year, then every 4 cycles thereafter
Overall
survival
f/u every 3
months
• Central pathology confirmation (PSC only)
• c-Met sanger sequencing by central lab

24. • Simon two-stage design
– Null hypothesis: ORR≤30%, alternative hypothesis: ORR ≥50%
– Significance level of 0.05 for a two-sided test, with a power of 80%
– Stage one: 15 patients for each cohort, PR patients≤5, reject alternative
hypothesis
– Stage two: 35 patients, all together 50 evaluable exon 14+ patients
• Efficacy endpoints
– Primary: ORR (≥ 50%)
– Secondary: PFS (6 mo or longer)
• Safety
– Global safety data to support NDA (single agent vs. combination Rx)
Discussions and agreements with CDE

25. • Regulatory reform continuous and NMPA has been
increasingly accommodating for innovative Rx
• Accelerated approval is more and more commonly used
for new drugs with high unmet medical needs, especially
in oncology
• 60-day IND process is working but Sino-US dual NDA
submission needs to be demonstrated
Conclusions

26. Just do it!

27. Thank you！
yehua@hotmail.com