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Corporate Presentation June 2019 Disclaimer Some of the statements contained in this presentation constitute forward-looking statements. Statements that are not historical facts are forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as “may”, “will”, “expect”, “intend”, “estimate”, “anticipate”, “believe”, “continue” or similar terminology. These statements are based on the Company’s current strategy, plans, objectives, assumptions, estimates and projections. Investors should therefore not place undue reliance on those statements. The Company makes no representation, warranty or prediction that the results anticipated by such forward- looking statements will be achieved, and such forward-looking statements represent, in each case, only one of many possible scenarios and should not be viewed as the most likely or standard scenario. Forward-looking statements speak only as of the date that they are made and the Company does not undertake to update any forward-looking statements in light of new information or future events. Forward-looking statements involve inherent risks and uncertainties. The Company cautions that a number of important factors could cause actual results to differ materially from those contained in any forward-looking statement. 2 Well Diversified Mid-to-Late Stage Metabolic Pipeline for Large Market Opportunities Global partnerships secured for late stage clinical program in type 2 diabetes • Imeglimin: First in class oral drug candidate targeting mitochondrial dysfunction – Partnered with Sumitomo Dainippon Pharma and Roivant Sciences – Phase 3 results for TIMES 1 in Japan met primary and key secondary endpoints; U.S. trial in T2D patients with CKD 3b/4 ongoing – Total potential deal value >$900M plus royalties; partners funding Ph 3 & commercialization Two clinical stage NASH programs targeting underlying root cause of disease which can be developed as monotherapy and/or as combination therapy • PXL770: Direct AMPK activator for NASH – Pathway targeting steatosis, inflammation, and fibrosis – Phase 2a program underway • PXL065: MPC inhibitor for NASH – Deuterium-stabilized R-pioglitazone – Pioglitazone (racemate) demonstrated resolution of NASH without worsening of fibrosis – Phase 1b planned initiation Q2 19; Pivotal Ph 2 program initiation expected Q4 19/ Q1 20 • Preclinical studies underway for additional metabolic and rare diseases • Euronext listed (POXEL); strong cash position 3 – EUR 59.0 million (USD 66.3 million) cash & equiv. 3/31/19; runway into 2021 Leadership Team Highly Experienced Management Team Noah Beerman Christophe Arbet-Engels Thomas Kuhn Anne Renevot (MBA) (MD, PhD, MBA) Chief Financial Officer (Pharm D, MBA) Executive VP, CMO and EVP Late CEO and Co-founder Business Development Development & Medical and President, US Affairs Operations Sébastien Bolze Jonae Barnes (Pharm D, PhD) Sophie Bozec Pascale Fouqueray (MD, PhD) Senior Vice President Executive Vice President, (PhD) Investor Relations & Non-Clinical Development, Senior Vice President, Executive Vice President, Public Relations Co-founder R&D Pharmacology, Early Development & Co-founder Translational Medicine, Co-founder 4 Metabolic Pipeline Well-diversified Pipeline with Mid-to-late-stage Programs Indication MOA Preclinical Phase 1 Phase 2 Phase 3 Partner/ Rights Next Steps • Phase 3 TIMES Imeglimin completion Type 2 Mitochondrial Ph Japan/ • Target JNDA Diabetes Bioenergetics 3 Asia* submission 2020 • Manufacturing Imeglimin drug for Phase Type 2 Mitochondrial US/ EU/ Ph 3 3 Diabetes Bioenergetics Other** • Study in T2D patients w/ CKD • Complete NASH/ Direct AMPK Phase 2a PXL770 metabolic Ph 2 activator program in diseases NASH • Complete PXL007 Hepatitis B Phase 1 FXR agonist Ph 2 (EYP001) NASH program by Enyo Pharma • Complete PXL065 Phase 1, tox, (formerly NASH MPC Inhibitor Ph 2 CMC DRX-065) • Initiate Pivotal Phase 2 study Poxel/ Metabolic Direct AMPK • Complete DeuteRx (AMN/ALD, activator/ MPC Ph 1 preclinical programs NASH, etc.) Inhibitor studies 5 Open arrow designates expected development status in 2019 *including: China, South Korea, Taiwan, Indonesia, Vietnam, Thailand, Malaysia, the Philippines, Singapore, Myanmar, Cambodia, and Laos. **countries not covered in the Sumitomo Dainippon Pharma agreement Key Value Drivers Japan is a Phase 3 TIMES 1 met primary Target JNDA * ~$5B+ market and key secondary endpoints; submission opportunity for TIMES 2 and 2020 T2D with strong TIMES 3 results during 2019 growth Approx. 2.4 million Study in T2D patients with Phase 3 initiation Imeglimin patients in the US CKD and manufacturing expected with drug for Phase 3 program in T2D patients T2D have CKD ongoing with CKD stages 3b/4 stages 3b/4 Unique opportunity PXL770 Complete for NASH and other direct AMPK activator Phase 2a PoC chronic metabolic Phase 2a program program In NASH PXL770 diseases underway expected 1H 2020 PXL065 (d-R- Initiation Potential for expedited pioglitazone) a potent of pivotal Phase 2 development in NASH MPC inhibitor study In NASH and orphan metabolic advancing to Phase expected PXL065 diseases 1b Q4 19/1Q 20 Focus on metabolic Conducting Additional metabolic diseases; specialty and preclinical studies in and rare orphan indications metabolic and rare opportunities Preclin 6 diseases * Decision Resources, September 2014 Imeglimin First in a New Class of Potential Anti-diabetic Treatments with a Differentiated Mechanism of Action Imeglimin Global Partnerships Combined Potential Total Deal Value >$900 Million Development Partner Imeglimin Rights Deal Value Status • Upfront payment: $42M • Phase 3 TIMES • Future potential Development and program (TIMES 1, development milestone commercialization TIMES 2 and TIMES rights in Japan, China, payments and sales-based 3) in T2D patients South Korea, Taiwan payments of up to • Target JNDA and 9 other Southeast approx. $257M submission in Japan Asian countries* • Double digit escalating 2020 royalties • Upfront payment: $35M1 Development and Equity Investment: $15M commercialization in at €8.5/share • Ongoing study in the U.S., Europe, and • Future potential T2D patients with other countries** development and CKD regulatory milestone • Pending successful Poxel and Roivant will payments and sales-based decide on a potential completion and post- co-promotion prior to payments of up to $600M FDA meeting, goal is commercialization • Double digit escalating to initiate Phase 3 royalties *including: Indonesia, Vietnam, Thailand, Malaysia, the Philippines, Singapore, Myanmar, 8 Cambodia, and Laos. **countries not covered in the Sumitomo Dainippon Pharma agreement 1. Poxel contributing $25M (~€20M) to development program over a 2-year period Imeglimin Development Strategy for Japan Targeting a JNDA Submission in 2020 for T2D Mechanism of action relevant for Asian T2D patients Phase 3 TIMES program fully enrolled with over 1,100 patients Phase 3 TIMES 1 trial met its primary and key secondary endpoints 2015 2016 2017 2018 2019 2020 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Phase 2b PMDA TIMES 1: Monotherapy vs placebo JNDA Phase 1 N=300 EOP2 N= ~200; 6-month treatment Subm. TIMES 2: Long term safety Mono & Add-on to oral therapy (Open label) N=~700; 12 months TIMES 3: Long term safety add-on to insulin N=~200; 12 months Non-pivotal trials in renal impaired population Sumitomo Dainippon Pharma is development and commercialization partner for Japan 9 Phase 3 TIMES 1 Trial in Japan Met Primary and Key Secondary Endpoints (n=213) A 24-week Phase 3, randomized, double-blind, placebo-controlled, monotherapy trial to assess the efficacy, safety and tolerability of Imeglimin administered orally in Japanese patients with type 2 diabetes Placebo Screening Wash-out Double-blind treatment period Follow-up If necessary run-In 1 - 2 weeks 8 weeks 4 weeks 24 weeks 1 week Imeglimin 1000 mg bid Placebo bid • TIMES 1 trial in Japan met its primary endpoint of a reduction in HbA1c and secondary endpoints, including fasting plasma glucose • Similar tolerability profile observed compared to placebo • TIMES 1 results are consistent with the Phase 2b results observed in Japan TIMES 1 Trial Met Primary Endpoint of HbA1c Reduction Placebo Imeglimin Patients (n) 107 106 HbA1c (%), mean (SD) 7.93 (0.684) 7.99 (0.764) • Statistically significant HbA1c reduction with demonstrated LS mean (SE) efficacy and an observed = -0.87% (0.09) tolerability profile similar to placebo (n=213) • TIMES 1 results are consistent with Phase 2b results observed In Japan p < 0.0001 Japan: Accessible T2D Market with Solid Growth $5B+ Anticipated to Grow to $6B in 2020 • 2nd largest diabetes market Global Type 2 Diabetes Market (Sales in $B) outside of US/EU $60.0 • ~$5B+ (/year) • Estimated sales in Japan $50.0 $14.7 expected to grow to $6B by $13.3 EU/ROW 2020; Imeglimin’s target $11.9 $40.0 $10.7 Japan date for JNDA submission $9.6 6.1 $8.5 5.7 US 5.4 5.2 • Sitagliptin: ~$1.1B+ annual $6.5 $30.0 4.9 sales in 3 years* 4.6 4.5 • We believe there is clear $3.8 development path defined $20.0 4.4 34.4 32.8 by PMDA: all recent new 29.8 31.3 27.0 28.4 23.8 agents approved with $10.0 18.3 ~1,000 patients in Phase 3 • Asia: significant opportunity $0.0 in China 2013 2014 2015 2016 2017 2018 2019 2020 * Decision Resources, 2015 Report Source: Oppenheimer & Co. estimates 12 Roivant Development Focus for Imeglimin • Roivant to develop Imeglimin first specifically to treat patients with type 2 diabetes with chronic kidney disease (CKD)
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  • Exploration and Development of PPAR Modulators in Health and Disease: an Update of Clinical Evidence

    Exploration and Development of PPAR Modulators in Health and Disease: an Update of Clinical Evidence

    International Journal of Molecular Sciences Review Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence Hong Sheng Cheng 1,* , Wei Ren Tan 2, Zun Siong Low 2, Charlie Marvalim 1, Justin Yin Hao Lee 2 and Nguan Soon Tan 1,2,* 1 School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore; [email protected] 2 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; [email protected] (W.R.T.); [email protected] (Z.S.L.); [email protected] (J.Y.H.L.) * Correspondence: [email protected] (H.S.C.); [email protected] (N.S.T.); Tel.: +65-6904-1294 (H.S.C.); +65-6904-1295 (N.S.T.) Received: 30 September 2019; Accepted: 10 October 2019; Published: 11 October 2019 Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner.