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Corporate Presentation December 2024
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Forward-Looking Statements This presentation contains statements about our future expectations, plans and prospects that constitute forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including risks relating to: both our and our collaborators’ ability to successfully research, obtain regulatory approvals for, develop and commercialize products based upon our technologies; our ability to obtain and maintain proprietary protection for our technologies and product candidates; our reliance on third parties to manufacture our preclinical and clinical drug supplies; competitive pressures; our ability to obtain and maintain strategic collaborations; compliance with our in-license agreements; our ability to successfully execute on, and receive favorable results from, our proprietary drug development efforts; market acceptance of our drug candidates; retaining members of our senior management; and our ability to raise additional funds to finance our operations. The forward-looking statements included in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this presentation. For more information regarding risks and uncertainties that could affect the results of our operations or financial condition review our filings with the Securities and Exchange Commission (in particular, our most recent Annual Report on Form 10-K and any subsequently filed Quarterly Reports on Form 10-Q). 2
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Investment Highlights ● Developing novel therapeutics for metabolic and endocrine diseases ဝ Multiple clinical programs demonstrate best-in-class efficacy data ● Metabolic Disease Programs ဝ VK2735: GLP-1/GIP dual agonist for obesity VENTURE Phase 2 obesity study successfully achieved primary, End of Phase 2 mtg planned 4Q24 ဝ VK2735 Oral: GLP-1/GIP dual agonist for obesity Phase 1 study demonstrated positive PoC, reduced in body weight; Phase 2 planned 4Q24 ဝ VK2809: Selective thyroid receptor-β agonist for NASH/MASH VOYAGE Phase 2b trial successfully primary, secondary endpoints, data at AASLD 4Q24 ● Rare Disease Program ဝ VK0214: Selective thyroid receptor-β agonist for X-ALD Phase 1b in patients demonstrated PoC in reducing key biomarkers of disease 3
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Pipeline Overview Near-term events ဝ VK2735 Injectable: End of Phase 2 meeting ဝ VK2735 Oral: Initiation of Phase 2 study 4 Development Programs Indication Stage of Development Status Preclin Phase 1 Phase 2 Phase 3 VK2735 (Dual GLP-1/GIP agonist) Obesity Phase 2 VENTURE study completed; Phase 3 planned VK2735 Oral (Dual GLP-1/GIP agonist) Obesity Phase 1 completed; Phase 2 planned VK2809 (TRβ agonist) NASH Phase 2b VOYAGE trial successfully completed VK0214 (TRβ agonist) X-ALD Phase 1b study demonstrated PoC in X- ALD
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VK2735: Dual GLP-1/GIP Receptor Agonist Metabolic Disorders
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GLP-1/GIP Dual Agonists for Metabolic Disorders 6 GLP-1/GIP Receptor Co-Activation and Downstream Effects ● Peptides secreted by intestines after meals ● Complementary tissue distribution and activities ● Stimulate insulin production, induce satiety ● Therapeutic benefits in obesity, NASH, diabetes Graphics: Trends in Endocrinology and Metabolism 2020, 31(6), 410- 421. Glucagon-Like Peptide 1 Receptor Glucose-Dependent Insulinotropic Polypeptide Receptor GLP-1 Receptor Activity GIP Receptor Activity Indirect Activities
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VK2735 Phase 1 Clinical Study Design 7 ● Randomized, placebo-controlled, stacked SAD/MAD study design ● MAD: Weekly doses for 28 days ● Primary objectives: Safety, tolerability ● Exploratory: Body weight, glucose, liver fat
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VK2735 Phase 1 Study Takeaways 8 ● Encouraging early profile observed in healthy subjects with BMI ≥30 ● Dose-dependent improvement in weight loss of up to 7.8% (6.0% placebo-adjusted) reported after 28 days ● Durable weight loss maintained 21 days after last dose ● Reductions in plasma lipids, liver fat indicate broad metabolic benefits ● PK data suggest excellent exposures from weekly dosing regimen ● Promising safety and tolerability, 98% of AEs mild to moderate
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VK2735 VENTURE Phase 2 Obesity Study Design 9 D1 W4 W19 Randomize Placebo (n=35) Follow-up 2.5 mg VK2735 (n=35) 5.0 mg VK2735 (n=35) 10.0 mg VK2735 (n=35) 15.0 mg VK2735 (n=35) Double-Blind Treatment, 13 Weekly doses 6 Week follow-up Obese subjects, BMI ≥30 or ≥27 with comorbidity Screening, 28 days ● Multicenter, parallel cohort, 13-week trial in obese subjects o 3-week titration blocks applied at doses ≥5 mg ● Primary endpoint: Percent change in body weight at Week 13 vs. placebo W13W7 W10
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10 ● Well-balanced demographics among cohorts ● Gender breakout generally 2:1 to 3:1 women to men ● BMI, weight consistent across Tx arms Mean Baseline Characteristics Placebo (n=34) 2.5 mg (n=35) 5.0 mg (n=35) 10.0 mg (n=35) 15.0 mg (n=35) Age 48 50 52 47 51 Sex, M:F (%) 18:82 23:77 34:66 34:66 23:77 White (%) 77 80 89 74 80 Weight (kg) 105 103 98 103 101 BMI (kg/m2) 39 38 36 37 37 VK2735 VENTURE Study Demographics
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-15 -12 -9 -6 -3 0 Placebo (n=34) VK2735 2.5 mg (n=35) VK2735 5.0 mg (n=35) VK2735 10.0 mg (n=35) VK2735 15.0 mg (n=35) Change from baseline (%) 11 Mean % Change in Body Weight After13 Weeks *** *** ● Significant reduction in body weight observed after 13 weeks ● Up to approximately 15% reduction from baseline ● Dose dependent effect observed across cohorts Percent change -1.7% -9.1% -10.9% -12.9% -14.7% Placebo-adjusted - -7.4% -9.2% -11.3% -13.1% p-value vs. placebo - <0.0001 <0.0001 <0.0001 <0.0001 ***p<0.0001 *** VENTURE Study Achieves Primary Endpoint Baseline weight (kg) 105 kg 103 kg 98 kg 103 kg 101 kg ***
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VENTURE Phase 2 Results: Rapid, Progressive Weight Loss Observed Change From Baseline Body Weight Over 13 Weeks ● Progressive weight loss observed in all VK2735 dosing cohorts ● All doses statistically significant vs. placebo starting in Week 1 and maintained through Week 13 ● Dose dependent effects observed ● No evidence of plateau suggests further body weight reduction possible with continued dosing 12 Notes: ***p<0.0001. Patients were required to have baseline BMI ≥30 kg/m2 or BMI≥27 kg/m2 with at least one weight-related comorbid condition. Patients treated with VK2735 were titrated to final doses as indicated: 2.5 mg cohort = 2.5 x 13 weeks 5 mg cohort = 2.5 mg x 3 wks, 5 mg x 10 wks 10 mg cohort = 2.5 mg x 3 wks, 5 mg x 3 wks, 7.5 mg x 3 wks, 10 mg x 4 wks 15 mg cohort = 5 mg x 3 wks, 7.5 mg x 3 wks, 10 mg x 3 wks, 15 mg x 4 wks 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Week -16 -14 -12 -10 -8 -6 -4 -2 0 (LSM±SE) Body Weight Percent Change from BaselineVK2735 5/7.5/10/15 mg VK2735 2.5/5/7.5/10 mg VK2735 2.5/5 mg VK2735 2.5 mg Placebo -1.7 % -9.1 %*** -10.9 %*** -12.9 %*** -14.7 %***
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0 15 30 45 60 75 90 Placebo (n=34) VK2735 2.5 mg (n=35) VK2735 5.0 mg (n=35) VK2735 10.0 mg (n=35) VK2735 15.0 mg (n=35) Change from baseline (%) 13 Patients Reporting ≥10% Weight Loss at 13 Weeks *** *** ● Up to 88% of patients experienced ≥10% weight loss ● Majority of patients receiving ≥5 mg demonstrated ≥10% weight loss ● Lowest 2.5 mg dosing cohort showed 10x placebo rate Percent of patients 3.7% 39.3% 62.1% 70.4% 88.0% p-value vs. placebo - 0.0036 0.0002 <0.0001 <0.0001 **p<0.01, ***p<0.001 *** VENTURE Study Achieves Key Secondary Endpoint Baseline weight (kg) 105 kg 103 kg 98 kg 103 kg 101 kg **
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-1.2 -8.5 -9.4 -11.8 -12.9 -0.9 -8.3 -8.7 -10.9 -12.6 -15 -12 -9 -6 -3 0 Placebo (n=12) 2.5 mg (n=17) 5 mg (n=17) 10 mg (n=18) 15 mg (N=11) % Change From Baseline Week 12 Week 16 *** *** *** *** *** *** *** VENTURE Phase 2 Study: Maintenance Following Last Dose Mean % Change in Body Weight After 12 and 16 Weeks● Subset of patients who participated in PK assessment ● Week 16 represents 4 weeks from last dose ● Across combined cohorts, 94% of weight loss maintained at Week 16; 83% at week 19 ● Suggests monthly dosing regimen may be feasible 14 *** ***p<0.001
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15 ● Majority of weight loss maintained at 4-week and 7-week follow-up visits ● Suggests monthly maintenance dosing may be feasible Study week Weeks after last dose 2.5 mg (n=17) 5.0 mg (n=17) 10.0 mg (n=18) 15.0 mg (n=11) Combined VK2735 arms 16 weeks 4 98% 92% 92% 96% 94% 19 weeks 7 91% 82% 75% 87% 83% VK2735 VENTURE: Maintenance of Weight Loss to Week 19 Proportion of Weight Loss Maintained Following Last Dose, PK subset
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16 ● Rapid shift from pre-diabetic to normoglycemia over 13 weeks ● Shifts suggest reduced risk of diabetes among patients receiving VK2735 Parameter1 Placebo 2.5 mg 5.0 mg 10.0 mg 15.0 mg Combined VK2735 arms Pre-diabetic at baseline2 14 21 21 16 16 75 Number shifting to normoglycemic at Week 13 (%)3 4 (29%) 17 (81%) 16 (76%) 10 (63%) 15 (94%) 58 (78%) p-value vs. placebo4 - 0.0041 0.0132 0.0813 0.0004 0.0005 VK2735 VENTURE: Shift in Diabetes Status at Week 13 Shift in Diabetes Status From Baseline to Week 13 Notes: 1) Observed values, no imputation for missing data. 2) Defined as patients with fasting plasma glucose 100 mg/dL to 125 mg/dL or HbA1c 5.7% to 6.4%. 3) Defined as fasting plasma glucose <100 mg/dL or HbA1c <5.7%. 4) Fisher’s exact test.
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% Change in BW: -14.7% -17.1% -8.0% -18.9% -10.8% -15.6% -26.5% -20.0% -22.5% Duration in Weeks 13 16 20 24 26 48 48 52 72 Comparison With Published Data for Other Weight Loss Agents 17 -30 -25 -20 -15 -10 -5 0 VK2735 (15 mg) CagriSema (4.5+2.4mg) Semaglutide (2.4 mg) CT-388 (22 mg) Cagrilintide (4.5 mg) Pemvidutide (2.4 mg) Triple-G (12 mg) MariTide (280 mg) Tirzepatide (15 mg) % Change From Baseline Change in Body Weight Across Competitive Landscape ● VK2735 weight loss appears competitive with other agents despite shorter trial duration ● Longer-term data will be key for determining maximal efficacy Notes: Data represent change from baseline. Indicates approximate tirzepatide 12-week weight loss in Phase 3 Surmount 1 study (~8%). 1: Approximate value as reported by company 1
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Number of patients reporting (%) Placebo (n=35) VK2735 2.5 mg (n=35) VK2735 5 mg (n=35) VK2735 10 mg (n=35) VK2735 15 mg (n=35) VK2735 Combined (n=140) Discontinued treatment early 5 (14%) 2 (6%) 4 (11%) 5 (14%) 7 (20%) 18 (13%) Discontinued study early 2 (6%) 1 (3%) 1 (3%) 2 (6%) 2 (6%) 6 (4%) Overall TEAEs 24 (69%) 25 (71%) 31 (89%) 30 (86%) 32 (91%) 118 (84%) Drug related TEAEs 16 (46%) 21 (60%) 27 (77%) 26 (74%) 30 (86%) 104 (74%) Drug related TEAEs leading to study discontinuation 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (3%) 1 (1%) VENTURE Study Discontinuation Rates Well-Balanced 18 ● Discontinuations well balanced between placebo, VK2735 treatment groups ● Majority (92%) of drug related TEAEs among VK2735 patients mild or moderate ● One VK2735 treated patient experienced SAE of dehydration, probably drug related Notes: Study safety population, defined as all patients who were randomized and received at least one dose of study drug or p lacebo.
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VENTURE Phase 2 Study: GI Tolerability Summary 19 ● Majority (95%) GI specific TEAEs among VK2735 patients mild or moderate Common GI related TEAEs Number of patients reporting (%) Placebo (n=35) VK2735 2.5 mg (n=35) VK2735 5 mg (n=35) VK2735 10 mg (n=35) VK2735 15 mg (n=35) VK2735 Combined (n=140) GERD 1 (3%) 2 (6%) 5 (14%) 4 (11%) 6 (17%) 17 (12%) Nausea Mild 7 (20%) 6 (17%) 11 (31%) 9 (26%) 15 (43%) 41 (29%) Moderate 0 (0%) 3 (9%) 5 (14%) 4 (11%) 7 (20%) 19 (14%) Severe 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Vomiting 0 (0%) 3 (9%) 6 (17%) 6 (17%) 10 (29%) 25 (18%) Abdominal pain 1 (3%) 1 (3%) 2 (6%) 1 (3%) 2 (6%) 6 (4%) Diarrhea 3 (9%) 11 (31%) 6 (17%) 7 (20%) 4 (11%) 28 (20%) Constipation 4 (11%) 7 (20%) 10 (29%) 9 (26%) 10 (29%) 36 (26%) Decreased appetite 0 (0%) 2 (6%) 5 (14%) 9 (26%) 6 (17%) 22 (16%) GERD: Gastroesophageal reflux disease.
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Rate of Reported GI AEs Over Time - 2.5 mg Vomiting Nausea Diarrhoea Constipation 0 4 8 12 16 20 24 28 32 36 40 44 48 % of Subjects in Each Week W13W12W11W10W9W8W7W6W5W4W3W2W1 Rate of Reported GI AEs Over Time - 5.0 mg Vomiting Nausea Diarrhoea Constipation 0 4 8 12 16 20 24 28 32 36 40 44 48 % of Subjects in Each Week W13W12W11W10W9W8W7W6W5W4W3W2W1 Time Course of GI AEs Through 13 Weeks; 2.5 mg and 5 mg Cohorts 20 ● GI AEs most common, expected per GLP-1 mechanism: nausea, vomiting, diarrhea, constipation ● Generally observed early, subside over time * * *2.5 mg cohort received fixed 2.5 mg doses for 13 weeks, no titration. * Denotes up-titration per schedule: 2.5 mg x 3 wks, 5 mg x 10 wks.
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Time Course of GI AEs Through 13 Weeks; 10 mg and 15 mg Cohorts 21 ● GI AEs most common, expected per GLP-1 mechanism: nausea, vomiting, diarrhea, constipation ● Generally observed early, subside over time Rate of Reported GI AEs Over Time - 10.0 mg Vomiting Nausea Diarrhoea Constipation 0 4 8 12 16 20 24 28 32 36 40 44 48 % of Subjects in Each Week W13W12W11W10W9W8W7W6W5W4W3W2W1 Rate of Reported GI AEs Over Time - 15.0 mg Vomiting Nausea Diarrhoea Constipation 0 4 8 12 16 20 24 28 32 36 40 44 48 % of Subjects in Each Week W13W12W11W10W9W8W7W6W5W4W3W2W1 * * * * ** *Denotes up-titration per schedule: 2.5 mg x 3 wks, 5 mg x 3 wks, 7.5 mg x 3 wks, 10 mg x 4 wks. *Titration: 5 mg x 3 wks, 7.5 mg x 3 wks, 10 mg x 3 wks, 15 mg x 4 wks.
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VENTURE Phase 2 Study Takeaways 22 ● Up to 14.7% mean weight loss observed after 13 weeks of VK2735 treatment ● Promising tolerability, 92% of all drug related TEAEs mild to moderate ● Durable weight loss observed, >90% of efficacy retained 4 weeks after last dose ● PK suggestive of potential monthly regimen ● Majority of GI-related AEs occur early in treatment, resolve ● Phase 3 trials planned
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VK2735: Oral Formulation Metabolic Disorders
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Oral Formulation Overview 24 ● Exploratory work pursued to develop oral formulation of VK2735 ● Multiple variations evaluated in multiple species ● Highly iterative process ● Resulted in oral tablet with reproducible exposures ● Tablet formulation progressed into Phase 1 clinical trial ● Ongoing efforts to understand breadth, applicability of oral formulation
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VK2735-101 Oral Study 25 ● Phase 1 MAD study design ● Placebo-controlled extension of ongoing trial ● Primary objectives: Safety, tolerability ● Exploratory assessments: Body weight, glucose, lipids after 28 days First in human study design - N=8-10 per cohort (~4:1 active:placebo) - Titration utilized for doses >2.5 mg Multiple dose cohort 1 2.5 mg x 4 weeks Treatment 28 days Multiple dose cohort 2 2.5, 5.0, 5.0, 5.0 mg DLRT Multiple dose cohort 3 5, 10, 10, 10 mg DLRT DLRT Multiple dose cohort 4 15, 20, 20, 20 mg DLRT DLRT = Dose Level Review Team Multiple dose cohort 5 20, 40, 40, 40 mg DLRT Multiple dose cohort 6 40, 60, 60, 60 mg DLRT Multiple dose cohort 7 60, 80, 80, 80 mg DLRT Multiple dose cohort 9 60 QD, 80 QD 80 QOD, 80 QOD mg DLRTMultiple dose cohort 8 80, 100, 100, 100 mg > > DLRT
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26 ● Generally balanced demographics among cohorts ● BMI, weight consistent across Tx arms Mean Baseline Characteristics Placebo (n=19) 2.5 mg (n=8) 5 mg (n=7) 10 mg (n=6) 20 mg (n=8) 40 mg (n=8) 60 mg (n=9) 80 mg (n=9) 100 mg (n=9) Age 38 34 29 35 35 33 44 44 44 Sex, M:F (%) 47:53 63:37 43:57 17:83 63:37 25:75 33:67 56:44 44:56 White (%) 68 75 71 100 88 63 89 100 67 Weight (kg) 99 102 97 97 111 89 108 102 103 BMI (kg/m2) 36 36 34 36 36 33 37 35 35 VK2735 Oral Study Demographics Notes: Safety population, includes all randomized subjects who received at least one dose of study drug or placebo.
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Oral VK2735 Phase 1 Results: Weight Change After 28 Days 27 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 Placebo (n=18) 2.5 mg (n=8) 5 mg (n=6) 10 mg (n=6) 20 mg (n=8) 40 mg (n=7) 60 mg (n=9) 80 mg (n=9) 100 mg (n=9) % Change From Baseline Baseline BW (kg) 98.3 102.3 95.3 97.1 111.3 90.0 107.7 102.0 102.7 Mean % Change in Body Weight at Day 28 ● Dose dependent reduction in body weight observed across VK2735 dosing cohorts ● Up to approximately 7% placebo- adjusted weight loss at 100 mg *** Notes: Baseline BMI ≥30 in all subjects.*p<0.05, **p<0.01, ***p<0.001. % Change in BW: -1.4% -0.3% -0.8% -1.1% -3.5% -5.1% -4.1% -5.2% -8.2% Placebo-adjusted: - 1.0% 0.6% 0.3% -2.2% -3.7% -2.7% -3.9% -6.8% p-value vs placebo: - - - - 0.017 0.0001 0.0026 <0.0001 <0.0001 * *** *** **
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VK2735 Oral Phase 1 Results: Progressive Weight Loss Observed Change From Baseline Body Weight Over 28 Days ● Overall dose dependent effects among VK2735 cohorts ● Progressive weight loss observed at doses ≥20 mg; no plateau at D28 ● Trends suggests further weight reduction possible with longer dosing period 28 x *p<0.05; **p<0.01; ***p<0.001. p-value for comparison of LS mean difference from baseline between treatment and placebo, adjusted for baseline body weight. 0 8 15 22 28 Study Day -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 from Baseline (%, LSM ± SE) Body Weight Percent Change VK2735 80/100/100/100 mg VK2735 60/80/80/80 mg VK2735 40/60/60/60 mg VK2735 20/40/40/40 mg VK2735 15/20/20/20 mg VK2735 5/10/10/10 mg VK2735 2.5/5/5/5 mg VK2735 2.5 mg Placebo -1.4 % -0.3 % -0.8 %-1.1 % -3.5 %* -5.1 %*** -4.1 %** -5.2 %*** -8.2 %***
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0 8 15 22 28 34 43 49 57 Study Day -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 from Baseline (%, LSM ± SE) Body Weight Percent Change VK2735 80/100/100/100 mg VK2735 60/80/80/80 mg VK2735 40/60/60/60 mg VK2735 20/40/40/40 mg VK2735 15/20/20/20 mg VK2735 5/10/10/10 mg VK2735 2.5/5/5/5 mg VK2735 2.5 mg Placebo -0.9 % 0.8 % 0.0 % -1.5 % -3.1 % -4.5 %** -2.6 % -4.0 %* -8.3 %*** VK2735 Oral Phase 1 Results: Weight Loss Through Day 57 Change From Baseline Body Weight Over 57 Days ● Weight loss effects largely maintained through Day 57 ● 4 Weeks from last study dose ● Suggests maintenance may be feasible at lower doses vs. induction 29 Notes: Baseline BMI ≥30 in all subjects. *p-value < 0.05, **p-value < 0.01, ***p-value < 0.001. p-value for the comparison of the LS Mean Difference from baseline between treatment and placebo. x Last dose
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VK2735 Oral Phase 1 Results: Exploratory Maintenance Cohort Change From Baseline Body Weight Over 28 Days ● Exploratory cohort to evaluate higher-lower exposure regimen ● Progressive weight loss maintained despite 50% dose reduction over final 2 weeks ● Suggests low maintenance dose may retain/extend body weight reduction 30 x 0 8 15 22 28 Study Day -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 from Baseline (%, LSM ± SE) Body Weight Percent Change VK2735 60/80/80*/80* mg VK2735 60/80/80/80 mg Placebo *: p-value < 0.05, **: p-value < 0.01, ***: p-value < 0.001. Cohort 9: Day 1-14 QD, Day 15-28 QOD p-value for the comparison of the LS Mean Difference from baseline between treatment and placebo, adjusted for the baseline weight. LS Means and p-values are from a MMRM model using all available data (up to Day 57). -1.4 % -5.2 %*** -4.0 %** Comparison between high, low exposure 80 mg regimens; 80 mg QD (red) and 80 mg QoD (green, denoted 80* mg). 80 mg QD (red): 60 mg daily x 1 wk, 80 mg daily x 3 wks. 80 mg QoD (green): 60 mg daily x 1 wk, 80 mg daily x 1 wk, 80 mg QoD x 2 wks. **p<0.01, ***p<0.001. Transition to 80 mg QoD for D15-D28 (Green line only) -1.4% -4.0%** -5.2%***
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18 0 0 33 63 86 75 88 100 0 0 0 0 25 57 38 63 100 0 20 40 60 80 100 Placebo (n=17) 2.5 mg (n=8) 5 mg (n=6) 10 mg (n=6) 20 mg (n=8) 40 mg (n=7) 60 mg (n=9) 80 mg (n=9) 100 mg (n=9) % of Subjects ≥3% Weight Loss ≥5% Weight Loss Oral VK2735 Phase 1 Results: Subjects with ≥3% and ≥5% Weight Loss Proportion of Subjects With ≥3% and ≥5% Weight Loss From Baseline at Day 28● Dose response shows increased proportion of subjects with 3% and 5% weight loss at higher doses with increasing VK2735 dose ● Potential to improve with higher dose and/or longer dosing period 31 Notes: Baseline BMI ≥30 in all subjects. *p<0.05 vs. placebo, **p<0.01, ***p<0.001. Observed values, subjects with baseline and Day 28 body weight assessments.. ** ** ** *** *** ** * **
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% Subjects: 26% 25% 14% 33% 38% 63% 22% 89% 100% % Change in BW: -1.4% -0.3% -0.8% -1.1% -3.5% -5.1% -4.1% -5.2% -8.2% VK2735 Results: Weight Change vs. Early Satiety or Decreased Appetite 32 -10 -8 -6 -4 -2 0 2 4 6 8 10 Placebo (n=18) 2.5 mg (n=8) 5 mg (n=6) 10 mg (n=6) 20 mg (n=8) 40 mg (n=7) 60 mg (n=9) 80 mg (n=9) 100 mg (n=9) % Change From Baseline % Subjects BW % change Baseline BW (kg) 98.3 102.3 95.3 97.1 111.3 90.0 107.7 102.0 102.7 Notes: Baseline BMI ≥30 in all subjects. ● Majority of subjects dosed ≥40 mg reported reduced appetite/increased satiety at Day 28, including all subjects in 100 mg cohort ● Satiety/appetite an established clinical result following GLP-1/GIP activation ● Longer term dosing may demonstrate further reduction in body weight Subjects reporting early satiety or decreased appetite (%) 20 40 80 60 Change From Baseline Body Weight vs. Satiety 100
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VK2735 Oral Phase 1 Study: Adverse Events and Discontinuations 33 ● Discontinuation rates low, balanced across treatment and placebo cohorts ● Majority of observed TEAEs (99%) were reported as mild to moderate Number of subjects Placebo (n=19) VK2735 2.5 mg (n=8) VK2735 5 mg (n=7) VK2735 10 mg (n=6) VK2735 20 mg (n=8) VK2735 40 mg (n=8) VK2735 60 mg (n=9) VK2735 80 mg A (n=9) VK2735 80 mg B (n=9) VK2735 100 mg (n=9) Discontinued study early 2 (11%) 0 (0%) 1 (14%) 0 (0%) 0 (0%) 1 (13%) 1 (11%) 1 (11%) 0 (0%) 0 (0%) Treatment emergent adverse events, TEAEs 16 (84%) 6 (75%) 6 (86%) 4 (67%) 6 (75%) 7 (88%) 9 (100%) 9 (100%) 8 (89%) 9 (100%) Drug related TEAEs 11 (58%) 4 (50%) 4 (57%) 3 (50%) 4 (50%) 7 (88%) 6 (67%) 9 (100%) 7 (78%) 9 (100%) Serious adverse events 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (11%) 0 (0%) 0 (0%) 0 (0%) Notes: Study safety population, defined as all patients who were randomized and received at least one dose of study drug. Dat a as of March 18, 2024. Patients treated with VK2735 were titrated to final doses as indicated: 2.5 mg cohort = 2.5 daily x 4 weeks; 5 mg cohort = 2.5 mg daily x 1 wk, 5 mg daily x 3 wks; 10 mg cohort = 5 mg daily x 1 wk, 10 mg daily x 3 wks; 20 mg cohort = 15 mg daily x 1 wk, 20 mg daily x 3 wks; 40 mg cohort = 20 mg daily x 1 wk, 40 mg daily x 3 wks; 40 mg cohort = 60 mg daily x 3 wks; 80 mg A = 60 mg daily x 1 wk, 80 mg daily x 3 wks; 80 mg B = 60 mg daily x 1 wk, 80 mg daily x 1 wk, 80 mg QoD x 2 wks; 100 mg cohort= 80 mg daily x 1 wk, 100 mg daily x 3 wks.
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VK2735 Oral Phase 1 Study: GI Tolerability Summary 34 ● Tolerability continues to be promising; nausea increasing (mild) at higher doses Common GI related TEAEs Number of subjects reporting (%) Placebo (n=19) VK2735 2.5 mg (n=8) VK2735 5 mg (n=7) VK2735 10 mg (n=6) VK2735 20 mg (n=8) VK2735 40 mg (n=8) VK2735 60 mg (n=9) VK2735 80 mg A (n=9) VK2735 80 mg B (n=9) VK2735 100 mg (n=9) GERD 1 (5%) 0 (0%) 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (11%) 2 (22%) 0 (0%) 0 (0%) Nausea Mild 2 (11%) 0 (0%) 1 (14%) 0 (0%) 2 (25%) 2 (25%) 2 (22%) 6 (67%) 4 (44%) 6 (67%) Moderate 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Severe 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Vomiting 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (11%) 1 (11%) 1 (11%) Abdominal pain 2 (11%) 0 (0%) 1 (14%) 1 (17%) 0 (0%) 0 (0%) 1 (11%) 0 (0%) 0 (0%) 0 (0%) Diarrhea 4 (21%) 0 (0%) 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (11%) 1 (11%) 1 (11%) 1 (11%) Constipation 3 (16%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (33%) 2 (22%) 1 (11%) 4 (44%) Notes: Safety population, includes all randomized subjects who received at least one dose of study drug or placebo. 80 mg Cohort A = 60 mg x 1 wk, 80 mg x 3 wks; 80 mg Cohort B = 60 mg x 1 wk, 80 mg x 1 wk, 80 mg QoD x 2 wks; GERD: gastroesophageal reflux disease.
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VK2735 Oral Phase 1 Study Takeaways, Next Steps 35 ● Up to 8.2% reduction in body weight observed after 28 days of oral dosing ● Progressive effect suggests further weight loss possible with longer treatment ● Majority of weight loss maintained 4-weeks following final dose ● Dose-dependent exposures with daily dosing; accumulation likely ongoing at D28 ● Excellent tolerability profile through 100 mg dose level; 99% of AEs mild to moderate ● Mild nausea reported at higher doses, likely addressable with slower titration ● Minimal GI AEs; low rates of vomiting, diarrhea, constipation in higher dose cohorts ● Exploratory transition from 80 mg QD to 80 mg QoD suggests feasibility of lower dose maintenance regimens ● Phase 2 study planned for 4Q24
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VK2809: Selective Thyroid Receptor-β Agonist NASH/MASH
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Thyroid Hormone Receptor Overview 37 Nuclear hormone receptors: 2 main types Positive effects ● Regulates lipid metabolism ● Reduces LDL-C, triglycerides, atherogenic proteins ● Improves metabolic control Therapeutic goal, lipid setting: Beta receptor selectivity, minimize alpha effects Thyroid hormone receptor beta (TRβ) Liver Negative effects ● Proarrhythmic potential ● Elevates heart rate ● Bone/cartilage effects Thyroid hormone receptor alpha (TRα) Heart, skeletal muscle
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VK2809: Unique Liver-Targeted Characteristics VK2809, Novel Prodrug VK2809A, Potent TRβ Agonist, 2.2 nM Ki 38 Selective activation, differentiated chemistry lends VK2809 liver selectivity; potentially minimizes risk of systemic effects ● Cyp3A4-mediated cleavage of prodrug ● 3A4 is primarily expressed in liver ● Results in targeted delivery of drug to liver Following oral dosing: P O O Cl O HO O HO O P O O -O - 14C QWBA (4 h) Heart Liver Large Intestinal Contents Brain Kidney Small Intestinal Contents High Low Heart Liver Large Intestinal Contents Brain Kidney Small Intestinal Contents High Low
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VOYAGE Study: 12-Month Phase 2b Study of VK2809 39 D1 M3 MRI-PDFF M13 Safety Randomize Placebo Follow-up 1.0 mg VK2809 QD 2.5 mg VK2809 QD 5 mg VK2809 QOD 10 mg VK2809 QOD Double-Blind Treatment, 12 months 4 Weeks Biopsy-confirmed NASH/MASH Screening, Biopsy MRI-PDFF ● Multi-arm, dose-ranging, 12-month Phase 2 trial o Primary endpoint: Change in MRI-PDFF vs. placebo at 3 months o Secondary endpoint: Change in histology at 12 months (NAS, fibrosis markers, etc.) M12 Biopsy, MRI-PDFF
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-60 -50 -40 -30 -20 -10 0 Placebo (n=62) VK2809 1 mg QD (n=17) VK2809 2.5 mg QD (n=59) VK2809 5 mg QOD (n=36) VK2809 10 mg QOD (n=57) Change from baseline (%) 40 Median Relative % Change in Liver Fat at 12 Weeks *** *** ● Significant liver fat reduction observed at 12 weeks ● Up to 57% median reduction ● Overall liver fat effect similar to prior 12-week NAFLD study ● Liver fat reductions were sustained or improved through Week 52 Percent change -5.4% -37.5% -49.5% -42.5% -56.7% p-value vs. placebo - 0.075 <0.0001 <0.0001 <0.0001 ***p<0.001 *** VOYAGE Study Achieves Primary Endpoint Baseline liver fat 20.4% 21.7% 20.3% 18.4% 21.5%
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0 15 30 45 60 75 Placebo (n=41) VK2809 1 mg QD (n=14) VK2809 2.5 mg QD (n=52) VK2809 5 mg QOD (n=27) VK2809 10 mg QOD (n=44) Proportion of Patients (%) 41 Patients Demonstrating Resolution of NASH With no Worsening of Fibrosis *** ** ● NASH resolution without worsening of fibrosis1 ● Key regulatory endpoint Proportion of patients 29.3% 71.4% 65.4% 63.0% 75.0% p-value vs. placebo - 0.0215 0.0023 0.0091 0.0001 ** VK2809 NASH Resolution Observed in up to 75% of Patients *p<0.05; **p<0.01; ***p<0.001 1) Resolution of NASH defined as NAS inflammation score of 0-1, ballooning score of 0. * Notes: Includes all patients with baseline and post -baseline MRI, and week 52 biopsy.
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0 15 30 45 60 Placebo (n=41) VK2809 1 mg QD (n=14) VK2809 2.5 mg QD (n=52) VK2809 5 mg QOD (n=27) VK2809 10 mg QOD (n=44) Proportion of Patients (%) 42 Patients Demonstrating ≥1-Stage Fibrosis Improvement, With no Worsening of NASH * ● Patients with ≥1-stage improvement in fibrosis, without worsening of NASH1 ● Key regulatory endpoint Proportion of patients 34.1% 57.1% 44.2% 51.9% 56.8% p-value vs. placebo - 0.1543 0.4414 0.0304 0.0497 * VK2809 Treatment Improves Fibrosis Stage *p<0.05; **p<0.01; ***p<0.001 1) No worsening of NASH defined as no increase from baseline in ballooning, inflammation, or steatosis. Notes: Includes all patients with baseline and post -baseline MRI, and week 52 biopsy.
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0 10 20 30 40 50 Placebo (n=41) VK2809 1 mg QD (n=14) VK2809 2.5 mg QD (n=52) VK2809 5 mg QOD (n=27) VK2809 10 mg QOD (n=44) Proportion of Patients (%) 43 Patients Demonstrating ≥1-Stage Fibrosis Improvement and Resolution of NASH * ● Patients with ≥1-stage improvement in fibrosis AND resolution of NASH1 Proportion of patients 19.5% 50.0% 40.4% 40.7% 47.7% p-value vs. placebo - 0.0856 0.0508 0.0206 0.0115 * VOYAGE Demonstrates Fibrosis Improvement and NASH Resolution *p<0.05; **p<0.01; ***p<0.001 1) Resolution of NASH defined as NAS inflammation score of 0-1, ballooning score of 0. Notes: Includes all patients with baseline and post -baseline MRI, and week 52 biopsy.
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VK2809 Demonstrates Consistent Safety, Tolerability Profile 44 ● Majority of TEAEs (97%) mild or moderate ● Discontinuations due to AEs well balanced between placebo, treatment groups ● GI-related AEs similar to placebo Most common AEs to date Number of subjects reporting (%) Placebo (n=65) VK2809 1 mg QD (n=17) VK2809 2.5 mg QD (n=66) VK2809 5.0 mg QOD (n=37) VK2809 10.0 mg QOD (n=61) VK2809 Combined (n=181) Treatment emergent adverse events, TEAEs 51 (78.5%) 14 (82.4%) 55 (83.3%) 29 (78.4%) 58 (95.1%) 156 (86.2%) Drug-related TEAEs1 22 (33.8%) 7 (41.2%) 13 (19.7%) 9 (24.3%) 24 (39.3%) 53 (29.3%) TEAEs leading to discontinuation 6 (9.2%) 2 (11.8%) 1 (1.5%) 2 (5.4%) 6 (9.8%) 11 (6.1%) Drug-related GI adverse events 12 (18.5%) 4 (23.5%) 3 (4.5%) 1 (2.7%) 7 (11.5%) 15 (8.3%) Nausea 5 (7.7%) 2 (11.8%) 2 (3.0%) 1 (2.7%) 3 (4.9%) 8 (4.4%) Diarrhea 2 (3.1%) 3 (17.6%) 2 (3.0%) 1 (2.7%) 3 (4.9%) 9 (5.0%) Notes: Study safety population, defined as all patients who were randomized and received at least one dose of study drug. 1 ) Deemed by investigator as possibly, probably, or definitely related to study drug.
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VK2809 VOYAGE Takeaways 45 ● Achieves primary endpoint demonstrating robust reduction in liver fat at 12 weeks ● Histologic endpoints demonstrate NASH resolution, improvement in fibrosis, and combination of both at 52 weeks ● Significant reductions in plasma lipids LDL-C, triglycerides, Lp(a), ApoB, ApoC-III ● Excellent tolerability, rate of GI-related side effects similar to placebo ● Promising safety, 94% of AEs mild to moderate
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VK2809 Competitive Advantages ● Currently >40 NASH programs in Phase 2 or Phase 3 development ● What differentiates VK2809 from the crowd? 46 o Orally available o Liver-targeted o Reduces liver fat, resolves NASH, improves fibrosis o Well tolerated Preferred route of administration for chronic therapy o Reduces systemic lipids, may improve overall metabolic profile Bodes well for potential long-term CV benefit No elevations in other lipids that may require polypharmacy Potential to be best-in-class, small molecule TRβ therapeutic for NASH/MASH No GI impact, no pruritis or other tolerability issues to date Reduces risk of undesired effects in other tissues
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X-Linked Adrenoleukodystrophy VK0214: Selective Thyroid Receptor-β Agonist
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% Difference: -42.0% -79.7% -76.6% -54.3% p-value: <0.0001 <0.0001 <0.0001 <0.0001 VK0214: Summary Profile ● Potent small molecule thyroid receptor agonist ● 8 nM Ki at TRβ receptor ● >20:1 selective for β:α ● Oral formulation, once-daily dosing ● Robust lipid lowering effects in multiple models VK0214 48 Demonstrates in vitro and vivo efficacy comparable to VK2809 -80 -60 -40 -20 0 Plasma Triglycerides Plasma Cholesterol Liver Triglycericdes Liver Cholesterol % Reduction VK0214 treated vs. vehicle Change in Lipids Following 12 Weeks of Dosing With VK0214; Rodent NASH model
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TRβ and X-Linked Adrenoleukodystrophy Caused by mutation in gene for the ATP-Binding Cassette transporter D1 (ABCD1) ● Peroxisomal transporter of very long chain fatty acids (VLCFA) Graphic adapted from http://www.x-ald.nl/origin-and-metabolism-of-vlcfa/. ABCD1: Normal function to transport VLCFA into peroxisome for degradation X-ALD: Defective ABCD1 leads to accumulation of VLCFA in tissues High VLCFA levels disrupt cell membranes; inflammatory demyelination in brain tissue; motor neuron deterioration TRβ Agonists: Stimulate expression of compensatory transporters ABCD2, 3; may mitigate VLCFA elevation 49
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VK0214 Phase 1b Study in Adrenomyeloneuropathy 50 Screening 21 days D1 D14 D21 D28D7 D35 Randomize Placebo (up to n=12) Follow-up 20 mg VK0214 (up to n=9) 40 mg VK0214 (up to n=9) Higher doses pending low/mid data Double-Blind Treatment, Days 1 - 28 7-day follow-up Adult males with adrenomyeloneuropathy ● Multicenter, parallel cohort, 28-day Phase 1b trial in adrenomyeloneuropathy o Higher doses may be explored pending review of initial cohorts ● Safety, tolerability, change in VLCFAs in male patients with AMN
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4.0 -16.6 -19.5 5.2 -12.8 -18.0 20.8 -17.4 -17.6 23.1 -8.4 -14.8 -25 -20 -15 -10 -5 0 5 10 15 20 25 Placebo (n=6) 20 mg QD (n=8) 40 mg QD (n=9) % Change From Baseline C22:0 C24:0 C26:0 C26:0-LPC VK0214 Phase 1b Results: Significant Reductions of Plasma VLCFAs Mean Change in VLCFAs After 28 Days1,2,3 ● Significant reductions in mean VLCFA levels compared to placebo ● Reductions in mean plasma levels of 26 carbon lysophosphatidyl choline (C26:0-LPC) derivative, a key diagnostic marker 51 p-values vs. placebo *p<0.05; **p<0.01; ***p<0.001 * *** ** * * * 1) Least squares mean change from baseline to Day 28. 2) P-value vs. placebo: Two-sided t-test using mixed model for repeated measures. 3) C26:0-LPC data for 20 mg, 40 mg cohorts include results from n=7, n=8 subjects, respectively. **
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4.7 -19.4 -20.2 8.6 -16.3 -22.0 17.5 -22.1 -26.8-30 -25 -20 -15 -10 -5 0 5 10 15 20 Placebo (n=6) 20 mg QD (n=9) 40 mg QD (n=9) % Change From BaselineLDL-C ApoB Lp(a) VK0214 Phase 1b Results: Significant Reductions of Lipid Markers Mean Change in Lipid Markers After 28 Days1,2 ● Statistically significant reductions vs. placebo for both doses of VK0214 ● Important implications for long- term cardiometabolic benefits 52 p-values vs. placebo *p<0.05; **p<0.01; ***p<0.001 * * *** *** *** 1) Least squares mean change from baseline to Day 28. 2) P-value vs. placebo: Two-sided t-test using mixed model for repeated measures. ***
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Number of subjects reporting (%) Placebo (n=6) VK0214 20 mg (n=9) VK0214 40 mg (n=9) VK0214 Combined (n=18) Discontinued treatment early 0 (0%) 1 (11%) 1 (11%) 2 (11%) Discontinued study early 0 (0%) 1 (11%) 0 (0%) 1 (6%) Overall TEAEs 3 (50%) 7 (78%) 8 (89%) 15 (83%) Drug related TEAEs 1 (17%) 5 (56%) 5 (56%) 10 (56%) Serious adverse events 0 (0%) 0 (0%) 0 (0%) 0 (0%) VK0214 Phase 1b Study: Discontinuations and Adverse Events 53 ● No SAEs reported ● Discontinuation rates low; treatment emergent adverse events (TEAEs) reported as mild to moderate Note: Study safety population, defined as all patients who were randomized and received at least one dose of study drug.
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Common GI related TEAEs Number of subjects reporting (%) Placebo (n=6) VK0214 20 mg (n=9) VK0214 40 mg (n=9) VK0214 Combined (n=18) All GI disorders Mild 2 (33%) 2 (22%) 0 (0%) 2 (11%) Moderate 0 (%) 0 (%) 0 (%) 0 (%) Severe 0 (%) 0 (%) 0 (%) 0 (%) Upper abdominal pain 1 (17%) 0 (0%) 0 (0%) 0 (0%) Constipation 0 (0%) 1 (11%) 0 (0%) 1 (6%) Dyspepsia 1 (17%) 0 (0%) 0 (0%) 0 (0%) Nausea 0 (0%) 1 (11%) 0 (0%) 1 (6%) VK0214 Phase 1b Study: Tolerability Summary 54 ● GI adverse events slightly higher among placebo (33%) vs. VK0214 (11%) ● Consistent with VK2809 experience; excellent overall tolerability though small n Note: Study safety population, defined as all patients who were randomized and received at least one dose of study drug.
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Takeaways From VK0214 Phase 1b in AMN Patients Study 55 ● Patients receiving VK0214 demonstrated progressive improvement in plasma levels of very long chain fatty acids (VLCFAs) in the relatively brief treatment period evaluated in this study (28 days) ● VK0214 continued to show benefits on broader plasma lipids, such as LDL-C, important for overall cardiometabolic health ● Consistent with prior clinical results in healthy volunteers, VK0214 was shown to be safe and well-tolerated in this 28-day study
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VK0214 – Summary and Current Status 56 ● Potential to be best in-class oral, small molecule TRβ therapeutic for X-ALD ● Encouraging in vivo efficacy with rapid (6 weeks) and progressive (up to 25 weeks) VLCFA reductions in plasma, brain, spinal cord and liver ● Phase 1 data in healthy volunteers demonstrated promising safety, lipid- lowering effects ● Phase 1b proof-of-concept study in adults with AMN showed significant VLCFA and lipids reductions in plasma after 28 days of treatment ● VK0214 has received Orphan Drug status from the FDA
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Financial Summary 57 ● Capital structure and summary financials Capital Structure1 In ‘000s Financials Sept 30, 2024 ($’000s) Shares outstanding 111,435 Cash burn YTD $158,673 Options, RSUs 7,585 Cash and ST Investments $930,440 Total shares, options, RSUs 119,020 Notes: 1) As of September 30, 2024
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Investment Highlights ● Developing novel therapeutics for metabolic and endocrine diseases ဝ Multiple clinical programs demonstrate best-in-class efficacy data ● Metabolic Disease Programs ဝ VK2735: GLP-1/GIP dual agonist for obesity VENTURE Phase 2 obesity study successfully achieved primary, End of Phase 2 mtg planned 4Q24 ဝ VK2735 Oral: GLP-1/GIP dual agonist for obesity Phase 1 study demonstrated positive PoC, reduced in body weight; Phase 2 planned 4Q24 ဝ VK2809: Selective thyroid receptor-β agonist for NASH/MASH VOYAGE Phase 2b trial successfully primary, secondary endpoints, data at AASLD 4Q24 ● Rare Disease Program ဝ VK0214: Selective thyroid receptor-β agonist for X-ALD Phase 1b in patients demonstrated PoC in reducing key biomarkers of disease 58
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Corporate Presentation December 2024