deuterated S-lisofylline (PCS499) / Processa Pharmaceuticals - LARVOL DELTA

Deuterated Pentoxifylline Analog in the Treatment of Necrobiosis Lipoidica: A Nonrandomized Clinical Trial. (PubMed, JAMA Dermatol) - P2 | "Necrobiosis lipoidica (NL) is a rare, chronic granulomatous skin disease for which no US Food and Drug Administration (FDA)-approved treatments exist. This nonrandomized clinical trial found that PCS499 was safe and well tolerated, with evidence of clinical and quality-of-life improvement, particularly in ulcerated NL; however, larger trials are warranted. ClinicalTrials.gov Identifier: NCT03698864."

Clinical • Journal • Dermatology • Diabetes • Inflammation • Metabolic Disorders

Adaptive Phase 2/3 Study for PCS499 (499) in Patients with FSGS (KIDNEY WEEK 2025) - "499 Background: Pentoxifylline (PTX) (FDA approved but not for PGD) has 7 active metabolites including its major metabolite, the S isomer of lisophylline (S-M1). ● What dosage regimen provides an approvable safety-efficacy profile? Results Phase 2-3 programs evaluated: ● Phase 2 study followed by a standard Phase 3 study with an interim analysis to evaluate sample size re-estimation ● Seamless Phase 2/3 study with interim analysis to evaluate safety, drop (or add) a dose, and/or sample size re-estimation Conclusion PCSA will share different Phase 2-3 programs that may improve the efficiency of clinically evaluating 499 in FSGS."

Clinical • P2/3 data • Chronic Kidney Disease • Diabetic Nephropathy • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Lupus Nephritis • Nephrology • Renal Disease

A Clinical Trial to Evaluate PCS499 in Treating Ulcerations in Patients Who Have Necrobiosis Lipoidica (clinicaltrials.gov) - P2 | N=4 | Terminated | Sponsor: Processa Pharmaceuticals | Trial completion date: Dec 2023 ➔ Apr 2023 | Active, not recruiting ➔ Terminated; lack of enrollment of this ultra rare disease

Trial completion date • Trial termination • Metabolic Disorders

A Clinical Trial to Evaluate PCS499 in Treating Ulcerations in Patients Who Have Necrobiosis Lipoidica (clinicaltrials.gov) - P2 | N=4 | Active, not recruiting | Sponsor: Processa Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=20 ➔ 4

Enrollment change • Enrollment closed • Metabolic Disorders

A Clinical Trial to Evaluate PCS499 in Treating Ulcerations in Patients Who Have Necrobiosis Lipoidica (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Processa Pharmaceuticals | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Aug 2022 ➔ Mar 2023

Trial completion date • Trial primary completion date • Metabolic Disorders

A Clinical Trial to Evaluate PCS499 in Treating Ulcerations in Patients Who Have Necrobiosis Lipoidica (clinicaltrials.gov) - P2; N=20; Recruiting; Sponsor: Processa Pharmaceuticals; Not yet recruiting ➔ Recruiting

Enrollment open • Metabolic Disorders

CoNCERT Pharmaceuticals: ROTH Conference (Concert Pharma) - Anticipated request for end of P2 meeting with the FDA for diabetic kidney disease in mid-2014

Anticipated FDA event • Renal Disease

Concert Pharmaceuticals’ CTP-499 for diabetic kidney disease selected as a top 10 project to Watch by Windhover (Concert Pharma) - Concert announced that CTP-499 has been chosen by Windhover as one of the Top 10 Autoimmune/Inflammatory Projects to Watch; Concert will provide an overview of CTP-499 during its presentation at the Windhover 2012 Therapeutic Area Partnership meeting being held at the Westin Copley Place Boston at 1:30 p.m. ET on Thursday, Nov 29, 2012 during Anti-Inflammatory/Autoimmune Projects to Watch session.

Clinical • Renal Disease

CoNCERT: Corporate Presentation (Concert Pharma) - "CTP-499 Benefit Greater in Patients with Higher Baseline UACR"; "48 Week Serum Creatinine Levels Rise More in Patients with Higher Baseline UACR"; "Higher UACR is known to correlate with more rapid disease progression"; "FDA supportive of enriched population in Phase 3 development"; "CTP-499: Statistically Significant Changes Observed in Biomarkers"; "CTP-499 benefit most evident in patients with actively progressing disease"

P2 data • Renal Disease

Concert Pharmaceuticals presents clinical results demonstrating CTP-499 is well-tolerated in patients with stage 3 chronic kidney disease (Concert Pharma) - P1b, N=33; P1b results in pts with CKD showed that CTP-499 was well-tolerated at doses that provide plasma levels of drug & active metabolites are believed to be desirable based on preclinical model; All pts succeeded in titrating to 600mg twice-a-day after 2 weeks of once-a-day dosing; All adverse events were mild in nature; No serious adverse events & no clinically significant laboratory abnormalities were reported, & no discontinuations associated with CTP-499 treatment; Expected to complete P2 study in 2013

Anticipated P2 trial completion • P1b data • Renal Disease

Concert presents phase 1 data for CTP-499 at ASN kidney week meeting (Concert Pharma) - P1, N=38; Results demonstrated that a controlled-release formulation of CTP-499 was well-tolerated at single doses up to & including 1800 mg; Concert expects to initiate a P2 clinical trial of CTP-499 in pts with diabetic nephropathy during the H1 '12

Anticipated P2 trial initiation • P1 data • Renal Disease

Concert Pharmaceuticals initiates phase 2 clinical trial evaluating CTP-499 for the treatment of diabetic nephropathy (Concert Pharma) - Concert Pharmaceuticals announced the initiation of dosing in a P2 clinical trial evaluating CTP-499; Concert expects to present findings from its safety & tolerability study in CKD pts in 2012

Anticipated P1 data • P2 initiation • Renal Disease

CoNCERT Pharmaceuticals: ROTH Conference (Concert Pharma) - Anticipated data from P2 trial for diabetic kidney disease by YE 2014; Anticipated completion of P2 open-label trial for diabetic kidney disease by YE 2014

Anticipated P2 data • Anticipated trial completion date • Renal Disease

Concert: Annual Report 2014 (Concert Pharma) - Anticipated expiry of US composition of matter patent in 2029; Anticipated expiry of composition of matter patent in EU in 2029; Anticipated expiry of composition of matter patents in Japan in 2029 and 2030 

Anticipated patent expiry • Renal Disease

CoNCERT Pharmaceuticals: ROTH Conference (Concert Pharma) - "CTP-499: Potential Effect to Protect Kidney Function"; "Trial results did not achieve primary 24 week UACR endpoint: Urinary albumin has fallen out of favor in past several years as an endpoint; Several recent studies demonstrated that decreasing UACR beyond an AECi or ARB did not result in additional protection of kidney function"

P2 data • Renal Disease

A phase 2 study to evaluate the safety and efficacy of CTP-499 in type 2 diabetic nephropathy patients (clinicaltrials.gov) - P2, N=170; Not yet recruiting -> Recruiting

Enrollment open • Renal Disease

A phase 2 study to evaluate the safety and efficacy of CTP-499 in type 2 diabetic nephropathy patients (clinicaltrials.gov) - P2, N=170; Not yet recruiting; New P2 trial

New trial • Renal Disease

A phase 2 study to evaluate the safety and efficacy of CTP-499 in type 2 diabetic nephropathy patients (clinicaltrials.gov) - P2, N=170; Sponsor: Concert; Recruiting -> Active, not recruiting.

Enrollment closed • Renal Disease

Concert Pharmaceuticals announces successful end-of-phase 2 meeting with FDA for CTP-499 (Concert Pharma Press Release) - "Concert Pharmaceuticals...announced the successful completion of an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) for CTP-499....During the meeting, the FDA indicated general agreement with Concert's proposed Phase 3 development plan providing flexibility to conduct either two clinical trials with CTP-499 or a single trial evaluating two doses of CTP-499 compared to placebo. The Company currently plans to submit a request for a Special Protocol Assessment (SPA) to the FDA later this year."

Anticipated FDA event • FDA event • Diabetic Nephropathy • Renal Disease

Design and rationale for a randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of CTP-499 in patients with diabetic nephropathy (Kidney Week 2011) - P2, N=170; eGFR will be determined at each visit along with a biomarker panel incl. cytokines & markers of fibrosis & kidney function; Plasma conc. of CTP-499/metabolites will be assessed monthly; In a subset of pts, 24h plasma & urine conc-time profiles will be obtained after 1st & last doses;Study enrollment is expected to begin in late 2011; Top-line data are expected in 2013

Anticipated data • Anticipated P2 enrollment • Renal Disease

Safety, tolerability and pharmacokinetics of CTP-499 in a multi-center, double-blind, two-arm, placebo-controlled, randomized study in nondialysis patients with stage 3 chronic kidney disease (National Kidney Foundation Spring Clinical Meetings 2012(NKF 2012)) - P1, N=33; Preliminary blinded safety data indicate CTP-499 was well tolerated & no SAEs were observed; Pharmacokinetic data are being evaluated; These results support use of this CTP-499 dosing regimen (600mg BID) in a planned P2 study in diabetic nephropathy

P1 data • Renal Disease

Concert Pharmaceuticals reports year end 2014 financial results (Businesswire) - "Concert initiated its process to negotiate a Special Protocol Assessment (SPA) for CTP-499 with the FDA. Concert expects to complete the SPA process in 2015."

Special Protocol Assessment • Diabetic Nephropathy • Renal Disease

Concert Pharmaceuticals reports third quarter 2014 financial results and provides update on CTP-354 program (Businesswire) - "At the upcoming American Society of Nephrology’s annual Kidney Week meeting, the Company will present additional Phase 2 biomarker data relating to CTP-499...In addition, the Company intends to initiate a special protocol assessment discussion with the U.S. Food and Drug Administration (FDA) by year-end 2014 for potential future Phase 3 development of CTP-499. Concert intends to seek a partner to advance the development of CTP-499 in diabetic nephropathy."

Anticipated FDA event • Anticipated licensing / partnership • Anticipated P2 data • Diabetic Nephropathy • Renal Disease

Concert Pharmaceuticals reports year end 2013 financial results (Businesswire) - P2, N=170; Sponsor: Concert Pharmaceuticals; NCT01487109; " A preliminary analysis of the combined 48 week Phase 2 analysis showed that CTP-499 appeared to help protect kidney function in patients with rapidly progressing type 2 diabetic kidney disease. Concert plans to report results for the first 48 weeks of the Phase 2 trial in the second quarter of 2014."

Anticipated P2 data • Diabetic Nephropathy • Renal Disease

Concert Pharmaceuticals presents positive 48-week results from phase 2 clinical trial of CTP-499 in diabetic kidney disease (Businesswire) - P2, N=170; Sponsor:Concert Pharmaceuticals; NCT01487109; "Concert Pharmaceuticals...announced 48-week results of its Phase 2 clinical trial of CTP-499 in patients with diabetic kidney disease. The results suggest that CTP-499 has protective effects on kidney function in patients with type 2 diabetic kidney disease, a condition in which kidney function is progressively lost. In addition, an observed, statistically significant reduction of certain fibrotic biomarkers suggests that CTP-499 may act as an anti-fibrotic agent."

P2 data • Diabetic Nephropathy • Renal Disease