Abstract A035: Pharmacokinetics and pharmacodynamics of the immunotherapeutic TLR-9 agonist MGN1703 – conclusions by comparison of data from clinical trials with healthy volunteers and cancer patients
Authors: Schmidt Manuel , Kapp Kerstin , Oswald Detlef , Schroff Matthias , Wittig Burghardt , Zurlo Alfredo 
Published: May 2016

Abstract
Background: The synthetic DNA-based immunomodulator MGN1703 is a member of the new dSLIM® family of TLR-9 agonists, comprising covalently closed dumbbell-like DNA molecules which consist entirely of natural DNA with two single-stranded CG-containing loops separated by a double-stranded stem. MGN1703 exerts its function by activating the innate and both arms of the adaptive immune system. MGN1703 has already shown a good safety profile and benefit for patients compared to placebo in maintenance therapy of metastatic colorectal carcinoma (mCRC) after fist-line induction therapy in a phase 2 clinical trial (MGN1703-C02, IMPACT).
Methods: Following preclinical studies in mice and monkeys, a human clinical program was performed, including a phase 1 trial (MGN1703-C01), on a variety of solid tumors, and the double-blinded, placebo-controlled phase 2 IMPACT trial with mCRC patients. Additionally, a single dose crossover, placebo-controlled phase 1 cardiac safety trial, MGN1703-C04, was conducted to assess cardiac and general safety, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy volunteers (HV). Fourteen HV were randomized and 13 subjects completed the study receiving a subcutaneous dose of 60 mg MGN1703 during one treatment period and a single dose of placebo during the other.
Results: After single dose administration of MGN1703 standard PK parameters were determined in the MGN1703-C04 trial: mean Tmax (14h), AUC0-t (5000 ng•hr/mL) and shape of the curve of MGN1703 concentration in serum. These were similar to single dose data obtained from cancer patients, where a mean Tmax of 10h and a mean AUC0-t of 5340 ng•hr/mL have been observed. Notably, multiple doses resulted in similar levels in serum of cancer patients, without accumulation of MGN1703.
PD was mainly evaluated by analyzing levels of the chemokine IP-10 in serum of the HV as an equivalent of innate immune activation. Elevated IP-10 levels in the serum of HV were shown peaking at 24-48 hours after dosing with MGN1703. This is clearly in line with expected time frame of immune activation subsequent to MGN1703 appearance in the serum of the HV. Timing and levels of IP-10 elevation are in keeping with data from the peripheral blood of cancer patients, where in addition to IP-10 also the subsequent activation of innate immune cells – especially the up-regulation of CD169 on monocytes – as a consequence of MGN1703 administration was observed.
Conclusions: The data show obvious similarities between healthy volunteers and cancer patients with respect to PK and PD and also confirm the appearance of the appropriate immunomodulatory signature downstream of MGN1703 appearance. This supports the twice weekly application scheme of current immunotherapy studies with MGN1703, e.g. the ongoing phase 3 IMPALA trial in mCRC patients. Further data will allow for evaluation of a possible association with clinical parameters in cancer patients.
Citation Format: Manuel Schmidt, Kerstin Kapp, Detlef Oswald, Matthias Schroff, Burghardt Wittig, Alfredo Zurlo. Pharmacokinetics and pharmacodynamics of the immunotherapeutic TLR-9 agonist MGN1703 – conclusions by comparison of data from clinical trials with healthy volunteers and cancer patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A035.