OXC-101 (Karonudib, TH1579)

The problem

One of the leading global causes of death is cancer and the number of patients with cancer is still increasing. This is devastating for patients and extremely troublesome for society. Despite new breakthroughs in cancer research with molecularly targeted therapies (ie therapy that attacks a specific oncogene / gene that causes the cancer) or immunotherapy, it is still chemotherapy, radiation and surgery that form the basis of how we treat cancer. Chemotherapy is effective, but also has severe side effects which often limit its use. The new therapies also have their limitations in lack of effect, development of resistance or therapy-related toxicity.

The solution

Oxcia aims to introduce oxidative stress and DNA damage to cancer cells, through targeted treatments and without harming healthy cells. 

The development of MTH1 inhibitors and OXC-101 is based on many years research at the Helleday lab at Karolinska Institute and in collaboration with academic groups worldwide such as Mayo clinic, University of Manchester, University of Sheffield, CNIO, NIH, Sanger institute, Uppsala University, and MIT.

Overwhelming evidence show OXC-101 (Karonudib) specifically introduces oxidative DNA damage to cancer cells, causing these to arrest and die, while sparing healthy cells

Mode of Action

OXC-101 is developed to inhibit the enzymatic activity of the MTH1 DNA repair protein, an enzyme that cleanses oxygen-damaged DNA building blocks in the cancer cell. OXC-101 also introduces additional oxidative DNA damage to the cell, pushing cancer dells above the threshold for repair.

Thus, OXC-101  fights cancer by taking advantage of the high oxidative stress and DNA damage that exist specifically in cancer cells. OXC-101 stops the division of the cancer cell by disturbing tubulin polymerization, further increases the oxidative stress and inhibits the MTH1 enzyme, resulting in additional oxidative DNA damage. This means that the cancer cell is no longer able to repair the DNA and oxygen damage. The cancer cell dies and the tumour cannot grow. The healthy cells remain largely unaffected (as they have limited DNA damage).

Mechanism of Action(1, 2, 3)

Notes:
(1) Gad et al Nature 2014 (1) Warpman Berglund et al Annals Oncology 2016 (3) Gad et al BioRxive 2019

Key supporting data

OXC-101 (Karonudib, TH1579) was developed at Karolinska Institutet in Prof. Thomas Helleday’s laboratory. In collaboration with KI and other national and international academic groups, extensive preclinical research has been performed. OXC-101 blocks tumour growth in many different human cancer models of both solid and hematological cancers. It shows similar or better efficacy when compared to many standard treatments. OXC-101 can also be combined with standard of care treatments showing additive/synergistic effects and is effective in chemotherapy resistant tumours. It is well tolerated in animals (mice, rat and dog) with no acute toxicity.

OXC-101 alters immune checkpoint markers on cancer cells and recruits cytotoxic T cells to the tumour. Thus, OXC-101 has potential to improve immune-oncology therapy by making cold tumours hot.

Ongoing phase I trials also show good tolerability.There are preliminary signs of OXC-101 (Karonudib) activity resulting in reduced target tumour size, elevation of biomarkers and infiltration of cytotoxic T cells.

Doctor patient meeting

Benefits

OXC-101 (Karonudib) has the potential to increase survival and has fewer adverse effects as compared to chemotherapy.

In various cancer disease models, OXC-101 (Karonudib) has been shown to have potential for a broad anti-cancer effect, can be given both alone and in combination with other approved anticancer treatment and can function in chemotherapy-resistant tumours.

OXC-101 has potential to increase the response of immuno-oncology treatment (making cold tumours hot).

Benefit summary:

Works on several cancer indications ✓
Works on heterogeneous cancers ✓
Healthy cells are not affected ✓
Less general cytotoxic side effects ✓
Potential to overcome existing chemotherapy resistance mechanisms ✓
Mono-, combination-therapy ✓
Oral treatment ✓

Intellectual Property

The patent protection for OXC-101 (Karonudib) is strong with large geographical coverage. The major patent covers pyrimidine-2,4-diamine derivatives for treatment of cancer. The patent portfolio also includes patents for other indications and patents for back-up compounds.

Status and plan

Oxcia has currently two ongoing phase I trials underway at Karolinska and Sahlgrenska University Hospitals.


Oxcia is also investigating other indications where OXC-101 (Karonudib) has therapeutic potential.

MASTIFFMAATEO
Clinical phasePhase 1Phase 1
TitleMTH1, A Phase 1, Study on Tumours Inhibition, First in Human, First in ClassA phase 1 study in patients with hematological malignancies to evaluate safety, tolerability and efficacy of Karonudib
StatusRecruitingRecruiting
IndicationSolid TumourLeukemia
LocationsKarolinska University Hospital, Solna, Sweden & Sahlgrenska University Hospital, Göteborg, SwedenKarolinska University Hospital, Huddinge, Sweden
Primary objectivesTo determine the safety and tolerability of OXC-101 (Karonudib, TH1579) in escalating doses for the treatment of patients with advanced solid malignant tumoursTo determine the safety and tolerability of Karonudid) in escalating doses for the treatment of patients with relapsed refractory AML, ALL, DLBCL, Burkitt’s lymphoma, MM, MDS
Secondary objectives– To define DLT and MTD
– To determine (i) a recommended phase Il dose (RP2D) and schedule, (ii) the pharmacokinetics, (iii) preliminary signs of clinical efficacy of OXC-101 (Karonudib)
– To define DLT and MTD
– To determine (i) a recommended phase Il dose (RP2D) and schedule, (ii) the pharmacokinetics, (iii) preliminary signs of clinical efficacy of OXC-101 (Karonudib)
Study designOpen LabelOpen Label
End dateDecember 2021Q2 2022

Publications

Co-expression of MTH1 and PMS2 is associated with advanced disease and disease progression after therapy in melanoma. , Das I, Tuominen R, Helleday T, Hansson J, Berglund UW, Brage SE. J Invest Dermatol. 2021 Aug 18:S0022-202X(21)01689-4. PMID: 34418425

MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells. , Karsten S, Fiskesund R, Zhang XM, Marttila P, Sanjiv K, Pham T, Rasti A, Bräutigam L, Almlöf I, Marcusson-Ståhl M, Sandman C, Platzack B, Harris RA, Kalderén C, Cederbrant K, Helleday T, Warpman Berglund U. Cell Death Differ. 2021 Aug 27. PMID: 34453118

MTH1 Inhibitors for the Treatment of Psoriasis. , Bivik Eding C, Köhler I, Verma D, Sjögren F, Bamberg C, Karsten S, Pham T, Scobie M, Helleday T, Warpman Berglund U, Enerbäck C. J Invest Dermatol. 2021 Aug;141(8):2037-2048.e4. PMID: 33676948

Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma. , Oksvold MP, Berglund UW, Gad H, Bai B, Stokke T, Rein ID, Pham T, Sanjiv K, Øy GF, Norum JH, Smeland EB, Myklebust JH, Helleday T, Våtsveen TK. Sci Rep. 2021 Mar 18;11(1):6317. PMID: 33737576

TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model. , Moukengue B, Brown HK, Charrier C, Battaglia S, Baud’huin M, Quillard T, Pham TM, Pateras IS, Gorgoulis VG, Helleday T, Heymann D, Berglund UW, Ory B, Lamoureux F. EBioMedicine. 2020 Mar;53:102704. PMID: 32151797

MTH1 Inhibitor TH588 Disturbs Mitotic Progression and Induces Mitosis-Dependent Accumulation of Genomic 8-oxodG. , Rudd SG, Gad H, Sanjiv K, Amaral N, Hagenkort A, Groth P, Ström CE, Mortusewicz O, Berglund UW, Helleday T. Cancer Res. 2020 Sep 1;80(17):3530-3541. PMID: 32312836

AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma. , Das I, Gad H, Bräutigam L, Pudelko L, Tuominen R, Höiom V, Almlöf I, Rajagopal V, Hansson J, Helleday T, Egyházi Brage S, Warpman Berglund U. Cell Death Differ. 2020 Jul;27(7):2081-2098. PMID: 31919461

MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. ,Scaletti ER, Vallin KS, Bräutigam L, Sarno A, Warpman Berglund U, Helleday T, Stenmark P, Jemth AS. J Biol Chem. 2020 Apr 10;295(15):4761-4772. PMID: 32144205

Karonudib is a promising anticancer therapy in hepatocellular carcinoma. , Hua X, Sanjiv K, Gad H, Pham T, Gokturk C, Rasti A, Zhao Z, He K, Feng M, Zang Y, Zhang J, Xia Q, Helleday T, Warpman Berglund U. Ther Adv Med Oncol. 2019 Aug 23;11:1758835919866960. PMID: 31489034

MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP. Jemth AS, Gustafsson R, Bräutigam L, Henriksson L, Vallin KSA, Sarno A, Almlöf I, Homan E, Rasti A, Warpman Berglund U, Stenmark P, Helleday T. Nucleic Acids Res. 2018 Nov 16;46(20):10888-10904. PMID: 30304478

Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity. , Narwal M, Jemth AS, Gustafsson R, Almlöf I, Warpman Berglund U, Helleday T, Stenmark P. Biochemistry. 2018 Feb 6;57(5):593-603. PMID: 29281266

A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma. , Einarsdottir BO, Karlsson J, Söderberg EMV, Lindberg MF, Funck-Brentano E, Jespersen H, Brynjolfsson SF, Olofsson Bagge R, Carstam L, Scobie M, Koolmeister T, Wallner O, Stierner U, Berglund UW, Ny L, Nilsson LM, Larsson E, Helleday T, Nilsson JA. Cell Death Dis. 2018 Jul 24;9(8):810. PMID: 30042422

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

Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space. , Rudling A, Gustafsson R, Almlöf I, Homan E, Scobie M, Warpman Berglund U, Helleday T, Stenmark P, Carlsson J. J Med Chem. 2017 Oct 12;60(19):8160-8169. PMID: 28929756

Glioblastoma and glioblastoma stem cells are dependent on functional MTH1. , Pudelko L, Rouhi P, Sanjiv K, Gad H, Kalderén C, Höglund A, Squatrito M, Schuhmacher AJ, Edwards S, Hägerstrand D, Berglund UW, Helleday T, Bräutigam L. Oncotarget. 2017 Jul 20;8(49):84671-84684. PMID: 29156675

Validation and development of MTH1 inhibitors for treatment of cancer., Warpman Berglund U, Sanjiv K, Gad H, Kalderén C, Koolmeister T, Pham T, Gokturk C, Jafari R, Maddalo G, Seashore-Ludlow B, Chernobrovkin A, Manoilov A, Pateras IS, Rasti A, Jemth AS, Almlöf I, Loseva O, Visnes T, Einarsdottir BO, Gaugaz FZ, Saleh A, Platzack B, Wallner OA, Vallin KS, Henriksson M, Wakchaure P, Borhade S, Herr P, Kallberg Y, Baranczewski P, Homan EJ, Wiita E, Nagpal V, Meijer T, Schipper N, Rudd SG, Bräutigam L, Lindqvist A, Filppula A, Lee TC, Artursson P, Nilsson JA, Gorgoulis VG, Lehtiö J, Zubarev RA, Scobie M, Helleday T. Ann Oncol. 2016 Dec;27(12):2275-2283. PMID: 27827301

Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition. , Bräutigam L, Pudelko L, Jemth AS, Gad H, Narwal M, Gustafsson R, Karsten S, Carreras Puigvert J, Homan E, Berndt C, Berglund UW, Stenmark P, Helleday T. Cancer Res. 2016 Apr 15;76(8):2366-75. PMID: 26862114

hMYH and hMTH1 cooperate for survival in mismatch repair defective T-cell acute lymphoblastic leukemia. , Eshtad S, Mavajian Z, Rudd SG, Visnes T, Boström J, Altun M, Helleday T. Oncogenesis. 2016 Dec 5;5(12):e275. PMID: 27918552

Pathways controlling dNTP pools to maintain genome stability. , Rudd SG, Valerie NCK, Helleday T. DNA Repair (Amst). 2016 Aug;44:193-204. PMID: 27311542 Review.

Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. , Carter M, Jemth AS, Hagenkort A, Page BD, Gustafsson R, Griese JJ, Gad H, Valerie NC, Desroses M, Boström J, Warpman Berglund U, Helleday T, Stenmark P. Nat Commun. 2015 Aug 4;6:7871. PMID: 26238318

Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry. , Coskun E, Jaruga P, Jemth AS, Loseva O, Scanlan LD, Tona A, Lowenthal MS, Helleday T, Dizdaroglu M. DNA Repair (Amst). 2015 Sep;33:101-10. PMID: 26202347

Development and validation of method for TH588 and TH287, potent MTH1 inhibitors and new anti-cancer agents, for pharmacokinetic studies in mice plasma. , Saleh A, Gökturk C, Warpman-Berglund U, Helleday T, Granelli I. J Pharm Biomed Anal. 2015 Feb;104:1-11. PMID: 25459754

Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. , Huber KV, Salah E, Radic B, Gridling M, Elkins JM, Stukalov A, Jemth AS, Göktürk C, Sanjiv K, Strömberg K, Pham T, Berglund UW, Colinge J, Bennett KL, Loizou JI, Helleday T, Knapp S, Superti-Furga G. Nature. 2014 Apr 10;508(7495):222-7. PMID: 24695225

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. , Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Ström CE, Svensson LM, Schultz N, Lundbäck T, Einarsdottir BO, Saleh A, Göktürk C, Baranczewski P, Svensson R, Berntsson RP, Gustafsson R, Strömberg K, Sanjiv K, Jacques-Cordonnier MC, Desroses M, Gustavsson AL, Olofsson R, Johansson F, Homan EJ, Loseva O, Bräutigam L, Johansson L, Höglund A, Hagenkort A, Pham T, Altun M, Gaugaz FZ, Vikingsson S, Evers B, Henriksson M, Vallin KS, Wallner OA, Hammarström LG, Wiita E, Almlöf I, Kalderén C, Axelsson H, Djureinovic T, Puigvert JC, Häggblad M, Jeppsson F, Martens U, Lundin C, Lundgren B, Granelli I, Jensen AJ, Artursson P, Nilsson JA, Stenmark P, Scobie M, Berglund UW, Helleday T. Nature. 2014 Apr 10;508(7495):215-21PMID: 24695224

Cancer phenotypic lethality, exemplified by the non-essential MTH1 enzyme being required for cancer survival. , Helleday T. Ann Oncol. 2014 Jul;25(7):1253-1255. PMID: 24737777 Crystal structure of human MTH1 and the 8-oxo-dGMP product complex. , Svensson LM, Jemth AS, Desroses M, Loseva O, Helleday T, Högbom M, Stenmark P. FEBS Lett. 2011 Aug 19;585(16):2617-21. PMID: 21787772