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Disease-Modifying Therapeutics for Pulmonary Arterial Hypertension Inhibikase.com : IKT
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MULTI-THERAPEUTIC PIPELINE OF KINASE INHIBITOR THERAPEUTICS Developing
innovative medicines across the therapeutic spectrum Multi-therapeutic pipeline across cardiopulmonary disease, neurodegenerative disease and cancer. IkT-001Pro: Prodrug of imatinib mesylate to be evaluated in Pulmonary Arterial
Hypertension (PAH). Clinical 1 studies completed to quantify imatinib delivery. PAH has a $7B+ global addressable market. IND filed August 9, 2024, Study May Proceed' Letter received from FDA September 9, 2024 Phase 2
interim safety readout anticipated 4Q25/1Q26 Phase 2 top line results anticipated 4Q26 Robust patent portfolio: compositions to 2033, with extensions to 2039, PAH use to 2044 Risvodetinib (IkT-148009): Selective c-Abl
inhibitor. Phase 2 results expected November, 2024 measuring disease modification in untreated Parkinson's disease. FDA Phase 3 meeting planned December, 2024. Phase 3 entry anticipated 2 2025. $12B+ global addressable market. Orphan
designations: IkT-001Pro in pulmonary arterial hypertension under review. Highly-experienced management team, consultants, Board of Directors and Scientific Advisory Board. 1 2 From Biomedtracker (Citeline Commercial), 2024
(https://www.biomedtracker.com/indicationreport.cfm?indid=245#PipelineChart) ; Vision Research, 2022 Inhibikase.com : IKT 3
IkT-001Pro for Treatment of Pulmonary Arterial Hypertension IIn nh hiib
biik ka as se e..c co om m :: IIK KT T 4 4
1 PULMONARY ARTERIAL HYPERTENSION: A COMPLEX DISEASE WITH MORTALITY ON
PAR WITH CANCER PAH mortality on par with many Complex disease etiology leading to narrowing 2 1 Cancer Indications of lung microvasculature Dysfunctional Pulmonary Epithelium Vasodialators and vasoconstrictors working against one another
COMPERA: Comparative, Intermediate Risk Dysfunctional Vascular Smooth Muscle Sustained vasoconstriction Prospective 20% 3 yr mortality Registry of Newly Initiated Therapies for Pulmonary Hypertension; FPHR: French Persistent inflammation and
immune Pulmonary High Risk dysregulation Hypertension 40% 3 yr mortality Excessive infiltration of inflammatory Registry; mediators REVEAL: The Perivascular inflammatory cell Registry to infiltration Evaluate Early and
Long Term PAH Disease Management. 1 Humbert et al. Lancet Respir Med (2023); 11:804-819 2 Chang et al., JAHA (2022); 11:e024969 Inhibikase.com : IKT 5
1 NEW TREATMENT OPTIONS FOR PULMONARY ARTERIAL HYPERTENSION REMAIN A
HIGH UNMET NEED Only 1 approved Disease Modifying drug: Sotatercept (Merck). No oral disease-modifying therapies approved 1 2023 Sales ($B) for existing therapies that only treat symptoms $1.9 Projected sales by 2026 $2.6 for first approved disease
modifying 1 therapy $1.3 1 Currently a $5B market in the US alone; $.7.6B globally 1 From Biomedtracker (Citeline Commercial), 2024 (https://www.biomedtracker.com/indicationreport.cfm?indid=245#PipelineChart) ; Inhibikase.com : IKT
CURRENT STANDARD OF CARE AND THE POTENTIAL ROLE OF IMATINIB 1 Imatinib
inhibits the Platelet-derived growth factor receptor (PDGFR), blocking cell signaling that drives 2 proliferation. Shown to be disease-modifying Sotatercept Anti-prostacyclin ERAs Sotatercept blocks a different proliferative pathway. imatinib 3
Shown to be disease-modifying and approved. PDE5i PDGFR 1 1 Adapted from Tuttle, et al., Curr Opin Nephrol Hypertens 2024, 33:494-502 2 3 Hoeper et al. Circulation. 2013;127:1128-1138; Hoeper et al. New Engl. J. Med.(2023); 16:1478ff
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HISTORY OF IMATINIB THERAPY IN PAH 2010: Small proof-of-concept trial
demonstrates 2013: P3 IMPRES trial -> Imatinib hits stat 2005: Off-label use of imatinib elicits disease that Imatinib improves hemodynamics and sig on primary endpoint of 6MWD as well 1 control in advanced PAH patient 2 3 6MWD in PAH patients.
as key secondary endpoint PVR. 40m 1 Ghofrani et al, N Engl J Med. 2005;353:1412-1413 2 Ghofrani et al., Am J Respir Crit Care Med. 2010;182:117 3 Hoeper et al. Circulation. 2013;127:1128-1138 Inhibikase.com : IKT 8
IMATINIB AND SOTATERCEPT HAVE COMPARABLE EFFICACY Imatinib data from Ph3
IMPRES has comparable efficacy to Sotatercept from Ph3 STELLAR 1-5 data PULMO NA RY VASCULA R RESISTA NCE 6-MINUTE WA LK DISTAN CE 0 50 Placebo Adjusted Values -50 45 40 -100 35 -150 30 -200 25 -250 20 -300 15 -350 10 -400 5 -450 0 I M A T I N I B P
H 2 I M A T I N I B P H 3 I M A T I N I B P H 3 S O T A T E R C E P T S O T A T E R C E P T I MA T I N I B P H 2 I M A T I N I B P H 3 I M A T I N I B P H 3 S O T A T E R C E P T S O T A T E R C E P T Placebo Adjusted Values 2 0 0 M G * 4 0 0 M G *
P H 2 P O O L E D P H 3 2 0 0 M G * 4 0 0 M G * P H 2 P O O L E D P H 3 * Patient spent majority of trial at this dose * Patient spent majority of trial at this dose 4 Sotatercept only improved disease in 30% of STELLAR participants. There remains a
significant unmet need. 1 2 Humbert et al, J Engl J Med. 2021; 384:1204-1215; Ghofrani et al., Am J Respir Crit Care Med. 2010;182:117 3 4 Hoeper et al. Circulation. 2013;127:1128-1138; Hoeper et al. New Engl. J. Med. (2023); 16:1478ff 3 No
head-to-head trials have been conducted leading to the results shown. As a result no cross-trial comparisons can be made. Inhibikase.com : IKT 9 Meters Dynes Sec CM-5
Why imatinib failed to be approved IIn nh hiib biik ka as se e..c co om
SERIOUS ADVERSE EVENTS IN THE IMPRES STUDY Imatinib was not approved
because of high discontinuation rate in IMPRES Ph3 1-2 AEs mimicked disease symptoms as such mimicry could suggest clinical worsening Adverse Events included: Subdural Hematoma Edema and Fatigue may mimic symptoms of disease
GI: Gastrointestinal AEs including nausea and diarrhea 1 Hoeper et al. Circulation. 2013;127:1128-1138. 2 Frost et al., J. Heart Lung Transplantation 2015; 34:1366-1375. Inhibikase.com : IKT 11
SOLVING THE PROBLEMS WITH IMATINIB: SUPPRESSION OF SUBDURAL HEMATOMA
ALL patients with subdural hematoma treated with old-style anti-coagulants 1-2 Subdural hematoma didn't occur in the absence of anti-coagulants Imatinib significantly increases exposure of the anti- coagulants used in these patients via Cyp
inhibition. Subdural hematoma incidence: 1 2/103 patients in the core study (1.9%) 2 6/144 patients in the extension study (4.2%) 1. Anti-coagulant use no longer standard-of-care in PAH. 2. Imatinib has significant DDI with older anti-coagulants
used in IMPRES DDI with newer anti-coagulants like Eliquis thought to be modest. 3. Subdural hematoma is a known AE associated with Imatinib therapy in cancer, occurring in <1% of patients with CML on 3 chronic imatinib Anti-coagulant
use will be prohibited in the upcoming trial with IkT-001Pro 1 2 3 Hoeper et al. Circulation. 2013;127:1128-1138; Frost et al., J. Heart Lung Transplantation 2015; 34:1366-1375; Druker et al, N Engl J Med 2001 Apr 5;344(14):1031-7 Inhibikase.com
SOLVING THE PROBLEMS WITH IMATINIB: PROPERLY ANALYZING ADEVERSE EVENTS
LIKE EDEMA 1-2 From IMPRES manuscript GI and edema adverse event rate on Imatinib is similar in IMPRES and contemporary CML trials. However, discontinuation rate was AEs largely similar to those much higher in IMPRES. seen in other imatinib studies.
AE frequency and discontinuation rate across 3 Imatinib studies 70% Imatinib induced edema 60% mistaken for worsening of 50% PAH. 40% 30% 20% High discontinuation rate 10% likely driven by lack of physician experience with 0% drug. Nausea rate Edema
rate Diarrhea rate Vomiting rate AE-related discon rate IMPRES core and extension Blended CML trials Hoeper et al. Circulation 2013 Clinical worsening will be adjudicated by Data Monitoring Committee in planned trial 1 2 3 Hoeper et al. Circulation.
2013;127:1128-1138; Frost et al., J. Heart Lung Transplantation 2015; 34:1366-1375; Druker et al, N Engl J Med 2001 Apr 5;344(14):1031-7 Inhibikase.com : IKT 13
SOLVING THE PROBLEMS WITH IMATINIB: FREQUENCY OF GI SIDE EFFECTS
DEPENDS ON DOSE Adverse Placebo Imatinib Adverse Imatinib Imatinib 1 2 2 Event (n=98) (n=103) Event 200-300mg 350-500mg % Occurrence % Occurrence Nausea 23 (24%) 57 (55%) Nausea 30% 50% Diarrhea 19 (19%) 36 (35%) Diarrhea 4% 33% Vomiting 13% 11%
Vomiting 10 (10%) 31 (30%) 1 2 Frequency of GI disturbance in IMPRES Lower frequency of GI disturbance at lower doses IkT-001Pro was developed to suppress GI adverse events and shown to achieve this in non-human primate studies 1 2 Hoeper et al.
Circulation. 2013;127:1128-1138; Druker et al, N Engl J Med 2001 Apr 5;344(14):1031-7 Inhibikase.com : IKT 14
Imatinib delivery by prodrug IIn nh hiib biik ka as se e..c co om m
SOLVING THE PROBLEMS WITH IMATINIB: MASKING THE CHEMICAL SURFACE
DRIVING GI AEs IkT-001Pro, a prodrug of imatinib, designed to mask imatinib at the gut wall 4-carbon atom linker imatinib linker gut wall + pH 2-6 pH 7 (blood) (stomach, ileum, duodenum) Lifetime in blood < 10 min Inhibikase.com : IKT
IkT- 001Pro IS A SMALL MOLECULE IMATINIB PRODRUG IkT-001Pro:
Anticipated lower GI toxicity alternative to imatinib Measurement of IkT-001Pro orally delivered once daily in Non-Human Primates RESULTS SUGGEST POTENTIAL No Adverse Event Level TO: Doses studied Cmax Tmax AUC 0-T (mg/kg/day) (mg/kg/day) (mean,
ng/mL) (mean, h) (mean, ng-h/mL) Achieve dose flexibility, NOAEL including use of higher dosing 176/206 4/3 1540/1960 Imatinib due to lower AEs 15 1 (91 days) (M/F) (M/F) (M/F) Suppress GI and other adherence-related adverse
400/318 5.3/3.7 IkT-001Pro 5220/3890 25, 75, 150 75 (28 days) (M/F) (M/F) (M/F) events NO A DVERSE EVENTS Up to 3.4x Up to 3.4x higher dose of imatinib increased exposure delivered as 001Pro 1 Imatinib data taken from FDA summary
data for approval #21-335 available at Drugs@FDA Inhibikase.com : IKT 17
C (ng/mL) max CLINICAL EXPERIENCE WITH IkT- 001Pro Bioequivalence and
Linear PK over the effective range Dose Linearity of 001Pro Bioequivalence of IkT-001Pro 60000 3500 established to cover a dosing y = 62.101x + 4087.3 range between 230 and 600 R = 0.9126 3000 50000 mg imatinib delivered No
clinically meaningful side 2500 40000 effects observed from single doses over this range. 2000 y = 2.7327x + 320.59 30000 No meaningful GI disturbance R = 0.9169 1500 observed from single doses over the range. 20000 1000 PK
analysis performed with two-period crossover studies 10000 500 over a total of 66 participants 0 0 200 300 400 500 600 700 800 AUC Cmax Linear (AUC) Linear (Cmax) Inhibikase.com : IKT 18 AUC (ng-h/mL) 0-inf
CHOOSING THE RIGHT DOSE OF IkT- 001Pro IKT-001Pro at bioequivalent dose
to 400 mg imatinib observed to Trough concentrations observed in human cancer have comparable exposures in humans patients or in PAH Oral Dose C Trough observed trough IMPRESS 1 1 2 (mg) (ng/mL) (ng/mL) 140 279 38 300 886 752 400 1216
750 125 to 1200 Projected trough need to saturate target: 200 to 250 ng/mL Projected Imatinib Equivalent Imatinib IKT-001Pro Dose 1 C Dose trough 300 mg QD 600 ng/mL 240 mg QD 500 mg QD 1100 ng/mL 380 mg QD 1 2 ACS Omega 2023,
8, 13741 13753; Renard et al., Br J Clin Pharmacol 2015; 80:75-85 Inhibikase.com : IKT 19
IkT- 001Pro POTENTIAL AS A BRANDED DRUG IN PAH Regulatory and IP
Status: IkT-001Pro is a New Molecular Entity for PAH Pre-IND Meeting with FDA April 5, 2024 IP protection out to 2039-2044+ Agency agreed that lower dosing, improved safety Composition of Matter profile in NHP studies may mitigate safety
concerns of Protection to 2033/4 IMPRES; Agency was keen to see this proceed 2038/9 with Patent Term Extension Agency agreed 505(b)(2) is an appropriate approval Method of Use in PAH path for IkT-001Pro Protection
anticipated to 2044 (without Agency agreed NME exclusivity applies to IkT-001Pro including PTE) Orphan Drug designation already under review No blocking IP from NVS Unique dosing + novel compositions of matter and use
will extend patent exclusivity to 2044. Patent Pending Agency agreed special designations/accelerated Other layers of Protection approval could be sought (e.g. Breakthrough, Fast-Track, Dosing, DDI, etc. etc.). To be
Filed Other layers of protection available Drug-drug interactions Inhibikase.com : IKT 20
ADVANTAGES OF 001Pro in PAH Summary of why imatinib delivered by
IkT-001Pro could be impactful IkT-001Pro is a Phase 3 ready asset for PAH following IND clearance Imatinib is proven to be effective in PAH High unmet need to improve the lives of patients, sotatercept isn't enough
IP protection as an NME with exclusivity over the patent life, which we believe will run into 2044 Imatinib has well-understood, long-term safety/tolerability and patient management If IkT-001Pro is efficacious, safe and
tolerable, IkT-001Pro should be eligible for Breakthrough Designation Program has potential for simpler/faster path to approval on 505(b)(2) as an NME Inhibikase.com : IKT 21
OUTLINE OF IKT-001PRO DEVELOPMENT PROGRAM Ph2b Trial (Registrational?)
Ph3 Trial N=150 Primary EPs: Primary EPs: Placebo Placebo N~160 1:1:1 - PVR - 6MWD IKT001-Pro 300 mg 1:1 No anti-coagulants or - Safety >1 anti-platelet IKT001-Pro Selected Dose randomization IKT001-Pro 500 mg therapy Stratify
sotatercept No anti-coagulants or * 80% powered to show a 30m * 80% powered to show a 25% 50% PVR > 800 dyne- 5 >1 anti-platelet s/cm at entry reduction in PVR improvement in 6MWD Wk 24 Wk 24 therapy allowed. HYPOTHETICAL EXECUTION
TIMELINE 2H 2024 2025 2026 2027 2028 IND Ph2b Ph3 Anticipated Topline in 2026 Anticipated Topline in 2029 Estimated costs/burn for illustration + ~$105M USD ~$100M USD $205M only; actual costs may vary Inhibikase.com : IKT
LEADING CLINICAL SCIENTISTS IN PAH DEDICATED TO COMPANY'S PAH
PROGRAM Dr. Marc Humbert, MD Dr. Marius Hoeper, MD President of the European Respiratory Society, Marc Marius M. Hoeper, MD, is deputy director of the Humbert is Professor of Respiratory Medicine, Vice Dean Department of Respiratory Medicine at
Hannover for Research and Director of the Inserm Unit 999 at Medical School, Hannover Germany, where he is also in Universit Paris-Saclay, France. He is the Director of the charge of the pulmonary hypertension (PH) program and Department of
Respiratory and Intensive Care Medicine, senior attending physician at the intensive care unit. As Pulmonary Hypertension Reference Centre H pital Bic tre, clinician scientist, he has published more than 400 papers Assistance Publique
H pitaux de Paris, France. Marc in these areas. Professor Hoeper was a task force Humbert was the Chief Editor of the European Respiratory member/chair at the 3rd, 4th, 5th and 6th World Journal from 2013 to 2017 and he is currently Section
Symposia on PH. He was also an author and Section Editor for Pulmonary Vascular Medicine. He has received Editor of the 2009 and 2022 European PH Guidelines and distinctions. Since 2017, Marc Humbert is the vice- the senior author of the 2015
European PH Guidelines. In coordinator of the European Reference Network for rare 2014, Professor Hoeper received the distinguished and low prevalence respiratory diseases (ERN-LUNG). Since Lifetime Achievement in Pulmonary Arterial Hypertension