PCS499

Diverse Pharmacology, Diverse Potential for Ulcerative Necrobiosis Lipoidica

PCS499 Targets NL

Our most advanced product candidate, PCS499, is an oral tablet and deuterated analog of a major metabolite of pentoxifylline (PTX or Trental®). PCS499 and its active metabolites have a diverse pharmacology profile and can act on multiple targets that play vital roles in the treatment of various conditions.

In particular, Necrobiosis Lipoidica (NL) has been selected as the lead indication for PCS499. NL is a chronic, disfiguring condition that affects the skin and subdermal tissue on the lower extremities of patients, such as the legs. Currently, there are no FDA-approved treatments for NL.

Developing effective treatments for this condition is difficult due to the various pathophysiological changes that contribute to the degeneration of tissue of NL lesions. However, PCS499 may provide a novel treatment solution for NL thanks to its metabolites, which affect many of the biological pathways that contribute to the physiological processes associated with NL.

License Agreement

In March 2018, we acquired exclusive rights from Concert Pharmaceuticals, Inc. to license, sublicense, develop, manufacture, use, and commercialize PCS499 worldwide.

A Promising New Option for an Orphan Disease

PCS 499 pipeline

Clinical Development

Previous History

On June 18, 2018, PCS499 was granted orphan-drug designation by the FDA for the treatment of NL, and on September 28, 2018, the IND for PCS499 in NL became effective, enabling us to move forward with a Phase 2A trial. The purpose of this multicenter, open-label prospective trial was to determine the safety and tolerability of PCS499 in patients with NL.

The data from this trial would later be used to design future clinical trials. The highest dose of PCS499 administered to NL patients was 1.8 grams/day, which is 50 percent greater than the maximum tolerated dose of PTX. Results from the study showed that the PCS499 dose of 1.8 grams/day appeared to be well tolerated with no serious adverse events reported.

Current Status & Clinical Trials

PCS499 is currently undergoing a randomized, double-blind, placebo-controlled study to evaluate its efficacy and safety in treating ulcerations of patients who have NL.

About This Trial

Why PCS499 for Ulcerative Necrobiosis Lipoidica

Numerous pathophysiological changes that contribute to tissue degeneration at the lesions make ulcerative NL difficult to treat. However, PCS499 and its metabolites simultaneously affect various biological pathways that can cause tissue degeneration, making PCS499 a promising novel treatment solution for NL.

Faster Time to Market

Before we acquired the rights to PCS499, Concert Pharmaceuticals completed many of the New Drug Application studies, thus enabling the expedited development of PCS499. Because NL is a serious orphan condition with no existing treatments, the FDA has stated that PCS499 approval may be possible with one pivotal trial if the statistical significance of the one trial has a p << 0.05.

Different from Other Treatments

Despite the lack of FDA-approved treatments for NL, high doses of PTX have seen off-label use to treat NL patients. However, this form of treatment is only successful in a small percentage of cases, as high doses are not well tolerated by most patients. As an analog of PTX, PCS499 and its metabolites deliver approximately twice as much of the functional compound as PTX and are better tolerated by patients.

Clinical Evidence Supports PTX and PCS499 for NL.

According to data collected from clinical experience and published case studies, it is possible for patients who can tolerate high doses of PTX to see significant improvement in ulcers within one to nine months. However, increasing PTX beyond its maximum dose (1.2 gm/day) to achieve a higher response rate can lead to dose-limiting side effects, including nausea, vomiting, and headaches. The Phase 2A study of PCS499 demonstrated that 1.8 gm/day is well-tolerated by patients and closed the ulcers entirely in the only two patients with severe ulcerative NL.

Benefits of PCS499

PCS499 breaks down into numerous active compounds, which may be ideal for treating NL.

PDE Inhibitor: Affects inflammation, collagen degeneration often found in NL
Anti-Fibrotic Effect: Counters the increase in Fibrosis from NL
Inhibits Cytokines (e.g., TNFα): Used to affect the cytokines increased from NL
Inhibits Platelet Aggregation: Counters a decrease in platelet survival from NL
Decrease Blood Viscosity: Opposes decrease in blood flow-oxygenation found in NL
Anti-Inflammatory: Along with the broad PDE inhibitor to impede inflammation

Market Landscape

Fewer Side Effects for Necrobiosis Lipoidica Patients

Necrobiosis Lipoidica (NL) is a chronic, disfiguring skin condition with no currently approved FDA treatments. This condition is more common in individuals with diabetes and women, with an average age of onset between 20 and 60 years. Patients with NL experience persistent rashes that develop into ulcerated lesions in about one-third of cases. Ulceration can cause severe complications, such as life-threatening infections and necrosis.

22,000 - 55,000

NL patients in the U.S.¹

150,000 - 400,000

NL patients worldwide²

^{1. Source: Muller SA, et al. Arch Dermatol. 1966; Jockenhöfer F, et al, J Dtsch Dermatol Ges. 2016; Company}

Publications

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Clinical Efficacy
- Braman V, Graham P, Cheng C, Turnquist D, Harnett M, Sabounjian L, Shipley A Randomized Phase I Evaluation of CTP-499, a Novel Deuterium-Containing Drug Candidate for Diabetic Nephropathy. Clin Pharmacol Drug Dev. 2013 Jan;2(1):53-66. doi: 10.1002/cpdd.3. Epub 2013 Feb 21. PMID: 27121560.
- Sabounjian L, Graham P, Wu L, Braman V, Cheng C, Liu J, Shipley J, Neutel J, Dao A First-in-Patient, Multicenter, Double-Blind, 2-Arm, Placebo-Controlled, Randomized Safety and Tolerability Study of a Novel Oral Drug Candidate, CTP-499, in Chronic Kidney Disease. Clin Pharmacol Drug Dev. 2016 Jul;5(4):314-25. doi: 10.1002/cpdd.241. Epub 2016 Feb 11. PMID: 27310332.

Bioanalytical
- Tang X, Bridson G, Ke J, Wu L, Erol H, Graham P, Lin CH, Braman V, Zhao H, Liu JF, Lin ZJ, Cheng Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jul 15;963:1-9. doi: 10.1016/j.jchromb.2014.05.043. Epub 2014 May 28. PMID: 24927417.

Necrobiosis Lipoidica (NL)

Overview of NL
- Muller SA, Winkelmann Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol. 1966 Mar;93(3):272-81. doi: 10.1001/archderm.93.3.272. PMID: 5910868.
- Wanat K, Rosenbach Necrobiosis Lipoidica. UpToDate Nov 2020.

MOA/Pathophysiology
- Antiinflammatory activities of PCS499
  - Fantin M, Quintieri L, Kúsz E, Kis E, Glavinas H, Floreani M, Padrini R, Duda E, Vizler C. Pentoxifylline and its major oxidative metabolites exhibit different pharmacological Eur J Pharmacol. 2006 Mar 27;535(1-3):301-9. doi: 10.1016/j.ejphar.2006.02.017. Epub 2006 Mar 20. PMID: 16545799.
  - Semmler J, Gebert U, Eisenhut T, Moeller J, Schönharting MM, Alléra A, Endres Xanthine derivatives: comparison between suppression of tumour necrosis factor-alpha production and inhibition of cAMP phosphodiesterase activity. Immunology. 1993 Apr;78(4):520-5. PMID: 8388363; PMCID: PMC1421886.
  - Sullivan GW, Carper HT, Mandell Pentoxifylline modulates activation of human neutrophils by amphotericin B in vitro. Antimicrob Agents Chemother. 1992 Feb;36(2):408-16. doi: 10.1128/aac.36.2.408. PMID: 1318681; PMCID: PMC188449.

Hemorrheological Effects of PCS499
- Ambrus JL, Stadler S, Kulaylat Hemorrheologic effects of metabolites of pentoxifylline (Trental). J Med. 1995;26(1-2):65-75. PMID: 7561532.
Metabolic Pathway
- Lillibridge JA, Kalhorn TF, Slattery Metabolism of lisofylline and pentoxifylline in human liver microsomes and cytosol. Drug Metab Dispos. 1996 Nov;24(11):1174-9. PMID: 8937849.

Epidemiology/ Clinical Course of NL
- Erfurt-Berge C, Dissemond J, Schwede K, Seitz AT, Al Ghazal P, Wollina U, Renner Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicentre study. Eur J Dermatol. 2015 Nov-Dec;25(6):595-601. doi: 10.1684/ejd.2015.2636. PMID: 26575980.
- Hashemi DA, Brown-Joel ZO, Tkachenko E, et al. Clinical Features and Comorbidities of Patients With Necrobiosis Lipoidica With or Without Diabetes. JAMA Dermatol. 2019;155(4):455-459. doi:10.1001/jamadermatol.2018.5635
- Jockenhöfer F, Kröger K, Klode J, Renner R, Erfurt-Berge C, Dissemond

Cofactors and comorbidities of necrobiosis lipoidica: analysis of the German DRG data from 2012. J Dtsch Dermatol Ges. 2016 Mar;14(3):277-84. doi: 10.1111/ddg.12749. PMID: 26972191.

Muller SA, Winkelmann Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol. 1966 Mar;93(3):272-81. doi: 10.1001/archderm.93.3.272. PMID: 5910868.
Treatment of NL
- Feily A, Mehraban Treatment Modalities of Necrobiosis Lipoidica: A Concise Systematic Review. Dermatol Reports. 2015 Jun 8;7(2):5749. doi: 10.4081/dr.2015.5749. PMID: 26236446; PMCID: PMC4500868.
- Reid SD, Ladizinski B, Lee K, Baibergenova A, Alavi A. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment J Am Acad Dermatol. 2013 Nov;69(5):783-791. doi: 10.1016/j.jaad.2013.05.034. Epub 2013 Aug 19. PMID: 23969033.
- Sandhu VK, Alavi A. The role of anti-tumour necrosis factor in wound healing: A case report of refractory ulcerated necrobiosis lipoidica treated with adalimumab and review of the literature. SAGE Open Med Case Rep. 2019;7:2050313X19881594. Published 2019 Oct 18. doi:10.1177/2050313X19881594
- Case reports of Treatment with Pentoxifylline
  - Basaria S, Braga-Basaria Necrobiosis lipoidica diabeticorum: response to pentoxiphylline. J Endocrinol Invest. 2003 Oct;26(10):1037-40. doi: 10.1007/BF03348204. PMID: 14759079.
  - Littler CM, Tschen Pentoxifylline for necrobiosis lipoidica diabeticorum. J Am Acad Dermatol. 1987 Aug;17(2 Pt 1):314-6. doi: 10.1016/s0190-9622(87)80338-9. PMID: 3624574.
  - Noz KC, Korstanje MJ, Vermeer Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline. Clin Exp Dermatol. 1993 Jan;18(1):78-9. doi: 10.1111/j.1365- 2230.1993.tb00977.x. PMID: 8440063.
  - Wee E, Kelly R. Pentoxifylline: An effective therapy for necrobiosis Australas J Dermatol. 2017 Feb;58(1):65-68. doi: 10.1111/ajd.12420. Epub 2015 Nov 12. PMID: 26559761.