OXC-201

Oxcia is a pioneer in the new and exciting research area that explores the role of oxidative DNA damage in inflammation and fibrosis and how this can be used in novel treatments. OXC-201 (TH5487) is a new type of DDR treatment that blocks inflammation and fibrosis by inhibiting an enzyme, OGG1. OXC-201 is in the preclinical phase with the potential to become a “first-in-class” treatment for interstitial pulmonary fibrosis (ILD) disease, which includes idiopathic pulmonary fibrosis (IPF). In addition, there are several other promising indications, e.g. sepsis and acute respiratory distress syndrome (ARDS).

The problem

Idiopathic (which means of unknown cause) pulmonary fibrosis is a severe fibrotic disease with elements of chronic inflammation. It is associated with the formation of permanent fibrotic scars, significant loss of organ function, increased mortality and high costs for society. The cause is unknown but several risk factors include  age, gender, smoking and genetic factors. Pulmonary fibrosis can also develop as a complication of inflammatory disease such as rheumatoid arthritis.

Today, there is no medical treatment that cures pulmonary fibrosis. Two approved drugs, Esbriet and Ofev, are given to these patients. They slow the rate of disease progression but fail to treat the underlying causes of disease and have a number of side-effects and contraindications. The only treatment that can prolong life is a lung transplant. Average survival is 3-5 years after diagnosis (Swedish Pulmonary Medicine Association 2019). The unmet need is enormous.

The solution

The goal of Oxcia’s OXC-201 is to inhibit a DDR enzyme, OGG1, gaining both anti-inflammatory and anti-fibrotic effects. The disease is attacked in a new way, blocking the onset of inflammation and fibrosis, potentially halting the disease.

Mechanism of action

In inflammation and fibrosis, the tissue is exposed to oxidative stress, which causes oxidative damage to DNA. OGG1 is a protein that binds to these damaged bases and plays an important role in the transcriptional regulation of gene expression in conditions of inflammation and fibrosis. OGG1 binds to DNA and mediates the assembly of transcriptional protein complexes including the transcription factor NF-κB.

The result is an upregulation of inflammatory and profibrotic substances, such as chemokines, cytokines and extracellular matrix proteins e.g. collagen leading to activation of the immune response and eventually tissue repair. Severe inflammatory and fibrotic diseases are often associated with an exaggerated immune response and impaired tissue repair. Through inhibition of OGG1 we can modify the dysregulated immune response and inhibit the development of fibrosis and the tissue damage.

“At Oxcia, we are proud to follow in the footsteps of Prof Tomas Lindahl, who won the Nobel Prize for discovering the base excision repair pathway including OGG1. We have developed the first and most advanced OGG1 inhibitor.

— Christina Kaldéren, Preclinical Director
Christina Kalderén

Key supporting data

OXC-201, has been evaluated in disease models and shown to exhibit a combination of anti-inflammatory and anti-fibrotic effects, inhibiting the production of inflammatory mediators such as TNFα and inhibiting the major hallmarks of fibrogenesis such as TGFβ and collagen1.

OGG1’s implication in fibrogenesis, combined with its role in inflammation, highlights this enzyme as a good therapeutic target for ILD, e.g., IPF treatment. Oxcia’s OGG1 inhibitor has preliminary data showing that it protects from acute lung inflammation and pulmonary fibrosis. It has furthermore potential to become a promising future treatment of pulmonary fibrosis as a consequence of viral infection (e.g. Covid 19).

Benefits

Compared to current standard of care treatment, OXC-201 affects not only the inflammation but also the subsequent development of fibrosis, with potential to halting the disease altogether.

Intellectual property

The OGG1 inhibitor is protected by patent in the major countries.

Status and plan

Further research of OCX-201 is ongoing, investigating whether it is a suitable clinical drug candidate.  Studies on selectivity, ADME (Absorption, Distribution, Metabolism and Elimination), PK-PD (pharmacokinetics-pharmacodynamics relationships) are performed with the goal of initiating safety pharmacology in 2022.

Oxcia is also exploring other indications where OXC-201 has therapeutic potential.

Publications

Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma. , van den Boogaard ML, Oka R, Hakkert A, Schild L, Ebus ME, van Gerven MR, Zwijnenburg DA, Molenaar P, Hoyng LL, Dolman MEM, Essing AHW, Koopmans B, Helleday T, Drost J, van Boxtel R, Versteeg R, Koster J, Molenaar JJ. Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2007898118. PMID: 34479993

Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects. , Baquero JM, Benítez-Buelga C, Rajagopal V, Zhenjun Z, Torres-Ruiz R, Müller S, Hanna BMF, Loseva O, Wallner O, Michel M, Rodríguez-Perales S, Gad H, Visnes T, Helleday T, Benítez J, Osorio A. Sci Rep. 2021 Feb 10;11(1):3490. PMID: 33568707

NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487. , Hanna BMF, Michel M, Helleday T, Mortusewicz O. Int J Mol Sci. 2021 Apr 27;22(9):4542. PMID: 33925271

OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions. , Hanna BMF, Helleday T, Mortusewicz O. Biomolecules. 2020 Oct 26;10(11):1483. PMID: 33114607

Targeting OGG1 arrests cancer cell proliferation by inducing replication stress. ,Visnes T, Benítez-Buelga C, Cázares-Körner A, Sanjiv K, Hanna BMF, Mortusewicz O, Rajagopal V, Albers JJ, Hagey DW, Bekkhus T, Eshtad S, Baquero JM, Masuyer G, Wallner O, Müller S, Pham T, Göktürk C, Rasti A, Suman S, Torres-Ruiz R, Sarno A, Wiita E, Homan EJ, Karsten S, Marimuthu K, Michel M, Koolmeister T, Scobie M, Loseva O, Almlöf I, Unterlass JE, Pettke A, Boström J, Pandey M, Gad H, Herr P, Jemth AS, El Andaloussi S, Kalderén C, Rodriguez-Perales S, Benítez J, Krokan HE, Altun M, Stenmark P, Berglund UW, Helleday T. Nucleic Acids Res. 2020 Dec 2;48(21):12234-12251. PMID: 33211885

Computational and Experimental Druggability Assessment of Human DNA Glycosylases. , Michel M, Visnes T, Homan EJ, Seashore-Ludlow B, Hedenström M, Wiita E, Vallin K, Paulin CBJ, Zhang J, Wallner O, Scobie M, Schmidt A, Jenmalm-Jensen A, Warpman Berglund U, Helleday T. ACS Omega. 2019 Jul 5;4(7):11642-11656. PMID: 31460271

Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. , Visnes T, Cázares-Körner A, Hao W, Wallner O, Masuyer G, Loseva O, Mortusewicz O, Wiita E, Sarno A, Manoilov A, Astorga-Wells J, Jemth AS, Pan L, Sanjiv K, Karsten S, Gokturk C, Grube M, Homan EJ, Hanna BMF, Paulin CBJ, Pham T, Rasti A, Berglund UW, von Nicolai C, Benitez-Buelga C, Koolmeister T, Ivanic D, Iliev P, Scobie M, Krokan HE, Baranczewski P, Artursson P, Altun M, Jensen AJ, Kalderén C, Ba X, Zubarev RA, Stenmark P, Boldogh I, Helleday T. Science. 2018 Nov 16;362(6416):834-839. PMID: 30442810

Germline variation in the oxidative DNA repair genes NUDT1 and OGG1 is not associated with hereditary colorectal cancer or polyposis. , Mur P, Jemth AS, Bevc L, Amaral N, Navarro M, Valdés-Mas R, Pons T, Aiza G, Urioste M, Valencia A, Lázaro C, Moreno V, Puente XS, Stenmark P, Warpman-Berglund U, Capellá G, Helleday T, Valle L. Hum Mutat. 2018 Sep;39(9):1214-1225. PMID: 29900613