Dr. Marjan Minou, Dr. Navideh Fahim, and Dr. Syeda Taufeeq Fatima - Research Supervisor: Professor Peivand Pirouzi

1. RESEARCH STUDY PRESENTATION OF
AC-201 IN PATIENTS WITH TYPE
2 DIABETES MELLITUS
Dr. Marjan Minou, Dr. Navideh Fahim and Dr. Syeda
Taufeeq Fatima
2014
Research Project Supervisor: Pr. Peivand Pirouzi

2. OUR TODAY AGENDA
• Sponsor of this study
• Mechanism of action for AC-201
• Study design
• Inclusion criteria
• Exclusion criteria
• Results
• References

3. TWI BIOTECHNOLOGY
• TWi Biotechnology's product pipeline consists of 3 drug candidates which are
either immune modulator or play key role in immune modulation. These 3
drug candidates each present a new therapeutic mechanism for its
intended indications. The new drugs current in development are as follow：
• AC-201
• AC-301
• AC-701

5. AC-201
• AC-201 is an IL-1β modulator small molecule drug with an active ingredient
• AC-201 is an oral active IL-1β modulator
• AC-201 modulates the intracellular synthesis of the cytokine IL-1Beta.
Inhibition of IL-1Beta signalling
• down-regulate IL-1 receptors
• treat patients with inflammatory diseases:
• arthritis,
• diabetic nephropathy (DN)
• diabetic mellitus (DM)

7. NEUROPATHY
Neuroinflammation is characterized by
glial activation and elevation in local
pro-inflammatory cytokine production

8. AC-201 MECHANISM
OF ACTION FOR
TYPE 2 DIABETES

9. AC-201 MECHANISM
OF ACTION FOR
GOUT FLARE
PROPHYLAXIS

10. CYTOKINES IL-1
• Promoted acute inflammatory response
• Stimulates liver to produce acute phase reactions (i.e; CRP)
• Stimulates coagulation pathway
• Promotes synthesis of collagen
• Increase adhesion factor to endothelial cells to enable migration of WBCs
• Stimulates increase tissue temperature to help fight infection

11. AC-201 STUDY
• AC-201 has been studied less than 300 patients
under US FDA IND regulation.
• These studies have shown AC-201 to be well-
tolerated.
• the worldwide for metabolic indications, including
• type 2 diabetes
• gout flares.

12. STUDY DESIGN

13. STUDY DESIGN
• Phase 2 study
• 21 sites in the US (N=150) and Taiwan (N=109)
• 24-week
• 259 patients
• Randomized1:1:1:1
• Double-blind, placebo-controlled,
• Dose-ranging,
• Twice daily (BID) 25 mg, 50 mg, or 75 mg AC-201, or
placebo

14. INCLUSION CRITERIA:
• .Understand research
• .Sign ICF
• .Both sexes
• .20-75 y.o.

15. INCLUSION CRITERIA:
• 5.10%≥HbA1c ≥7.5%
• The A1C test result reflects your average blood sugar level for the past two to
three months. Specifically, the A1C test measures what percentage of your
hemoglobin — a protein in red blood cells that carries oxygen — is coated
with sugar (glycated). The higher your A1C level, the poorer your blood
sugar control and the higher your risk of diabetes complications)
•
• Normal Value: HgA1c test is between 4% and 5.6%.
• Pre- diabetes: HgA1c levels between 5.7% and6.4%
• Diabetes: HgA1c levels of 6.5% or higher

16. INCLUSION CRITERIA:
.BMI ≤45 kg/m2
• (BMI is used to broadly define different weight groups in adults 20 years old
or older. The same groups apply to both men and women.
• Underweight: BMI is less than 18.5
• Normal weight: BMI is 18.5 to 24.9
• Overweight: BMI is 25 to 29.9
• Obese: BMI is 30 or more

17. INCLUSION CRITERIA:
• FPG ≤270 mg/dL (Fasting Plasma Glucose)
• Normal Value: 4 to 5.5 mmol/l (70 to 99 mg/dl)
• Pre- diabetes 5.5 to 7 mmol/l (101–125 mg/dl)
• Diabetes: 7 mmol/l (126 mg/dl) and above means a risk
of diabetes

18. INCLUSION CRITERIA:
• Diagnosis of type 2 diabetes mellitus for ≥6 months
• Stable regimen of oral anti-diabetic medications for ≥3 months
• Willingness to maintain stable diet and exercise throughout the study
• Willingness to maintain current doses/regimens of vitamins and dietary
supplements throughout the study
• Female patients of childbearing potential and female partners of male
patients must be willing to use adequate contraception during the study. All
females of childbearing potential must have a negative urine pregnancy
test at screening

19. EXCLUSION CRITERIA

20. CONCOMITANT MEDICATION
• Current treatment with any of the following medications within 2
months of screening
• Anti inflammatory drugs, including chronic daily use of
• systemic corticosteroids (aspirin ≤325 mg per day is allowed)
• IL-1 modulators: anakinra and rilonacept
• Immunosuppressive drugs: TNF inhibitors
• IL-6 monoclonal antibody

21. EXCLUSION CRITERIA:
• Hx severe hypoglycemic episodes within 6 months of screening
• Poor mental function or patient difficulty in complying
• 8. Hypersensitivity to AC-201 or anthraquinone derivatives
• 9. Surgery within 30 days prior to screening

22. EXCLUSION CRITERIA:
• Hx type 1 diabetes and/or ketoacidosis
• Hx diabetic neuropathy :
Requiring active medical /surgical management:
chronic pain syndromes
gastroparesis
skin ulceration
amputation
• Hx long-term therapy with insulin (>30 days)
within 1 year of screening
• Pregnancy or lactation

23. EXCLUSION CRITERIA:
RENAL RELATED
• Hx:
• Serum creatinine >1.5 mg/dL for males
• >1.4 mg/dL for females
• Bilateral renal artery stenosis
• Solitary kidney
• Post renal transplant

24. EXCLUSION CRITERIA:
CARDIOVASCULAR RELATED
• Hx
• Unstable Angina,
• MI,
• Uncontrolled Arrhythmias,
• CVA
• TIA
• Revascularization, including PTCApercutaneous transluminal coronary
angioplasty, within 6 months of screening
• Uncontrolled hypertension: systolic BP>160 mmHg
• diastolic BP>100 mmHg on ≥3 at screening)
• Heart failure: Class III or IV (Hospitalization)

25. EXCLUSION CRITERIA:
SKIN RELATED
• Presence of cancer or history of cancer within the past 5 years
• Excluded: BCC & SCC (basal or squamous cell carcinoma)
• Carcinoma in situ of the cervix

26. EXCLUSION CRITERIA:
INFECTION RELATED
• Hx:
• HIV +ve/ AIDS
• TB, active TB (pulmonary, extra-pulmonary, or military),
BCG +ve confirmed by CXR within 6 months prior to screening
• Epstein-Barr Virus (EBV),
• cytomegalovirus (CMV), or
• hepatitis C virus (HCV) within 4 weeks prior to screening
• chronic active (not latent) hepatitis B virus, HCV, or CMV

27. EXCLUSION CRITERIA:
LIVER RELATED
• Hx:
• Drug or Alcohol abuse
• AST: Aspartate aminotransferase >3 ULN
• ALT : Alanine aminotransferase >3 × ULN
• Total bilirubin >1.5 × ULN at screening
• Triglycerides >500 mg/dL at screening

28. EXCLUSION CRITERIA:
ENDOCRINAL RELATED
• Acute infections that may affect blood glucose control within 4 weeks prior
to screening
• Hx autoimmune disease or collagen vascular disease
• Hx hyperthyroidism or hypocorticism
• Participation in any AC-201 studies within 1 year prior to screening
• Participation in an investigational drug study within 30 days prior to screening
• Any other serious diseases which, in the opinion of the investigator, might
pose a risk to the patient or make participation not in the patient's best
interest.

29. RESULTS

30. RESULTS
In the Full Analysis after 24 weeks of treatment
A1C reductions
• placebo-corrected 20 %,( least A1C reductions )
• 25 mg AC-201 60 %,
• 50 mg AC-201 75 %* (*p<0.05)
• 75 mg AC-201 93 %

31. ADVERSE EFFECT
• The most frequent adverse event with AC-201 was
• Diarrhea
• placebo, 25 mg, 50 mg, 75 mg
• 9%, 19%, 16%, 32%
• Mild and Transient.

32. SERIOUS ADVERSE EVENTS
25 mg 50 mg 75 mg placebo
AF 1
CAD 1
GI Bleeding 1
Hepatitis 1
Lumbar
Radiculopathy
1
Renal Mass 1
Stress
incontinence
1
Breast cancer 1
Pneumonia 2
%4.6 %3.1 %3 %1.5

33. ADVERSE DRUG REACTION
• Nausea
• Diarrhea
• Muscle spasm
• Headache
• Back pain
• Chromatouria
• Upper respiratory tract infection

34. CONCLUSION
• AC-201 showed:
• Good dose response
• Well tolerated up to 75 mg BID,
• Potential as a treatment for T2DM
• A unique mode of action targeting the inflammation pathway
associated with both impaired : Beta-cell function
Insulin resistance.
•

35. REFRENCES
• http://www.rndsystems.com/cb_detail_objectname_cb08i2_IL1betaNeuroinf
lammation.aspx
• http://www.prnewswire.com/news-releases/twi-pharmaceuticals-
announces-positive-phase-iib-clinical-trial-results-of-ac-201-in-patients-with-
type-2-diabetes-165107926.html
• http://clinicaltrials.gov/ct2/show/results/NCT01276106?term=biotechnology&
rank=115&sect=X437106#limit
• http://www.twipharma.com/rAndD/3/6/2