Clinical Trials

Date: 2018-09-19

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the 12th Annual Conference of the International Liver Cancer Association

Company: Mina Therapeutics (UK)

Product: MTL-CEBPA

Action mechanism:

  • RNAa (RNA activation). MTL-CEBPA consists of a double stranded RNA formulated into a SMARTICLES® liposomal nanoparticle and is designed to activate the CEBPA gene. By restoring CEBPA expression to normal levels, MTL-CEBPA has been demonstrated to attenuate or reverse liver disease in a range of pre-clinical studies including models of liver cancer, liver cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • The potential for MTL-CEBPA to enhance the benefits of other cancer therapies is supported by emerging pre-clinical research. In a chemically induced model of cirrhotic hepatocellular carcinoma in rats, treatment of MTL-CEBPA for one week followed by sorafenib for one week demonstrated a significant improvement in anti-tumour activity compared to either two weeks of sorafenib alone or two weeks of MTL-CEBPA alone. Durable activity of MTLCEBPA for several weeks after treatment was previously demonstrated in pre-clinical models of liver disease.

Disease: advanced liver cancer

Therapeutic area: Cancer - Oncology

Country: Singapore, Taïwan, UK

Trial details:

  • OUTREACH is a First in Human study of a new single agent (MTL-CEBPA) in patients with advanced cancer of the liver. The study is in two parts: dose escalation followed by a dose expansion; both parts of the study will recruit advanced hepatocellular carcinoma patients with cirrhosis. All participants will be refractory to or ineligible for loco-regional therapy including surgery, radiofrequency tumour ablation, transarterial chemoembolisation or sorafenib. (NCT02716012)

Latest news:

  • • On September 19, 2018, MinaTherapeutics provided an update from the ongoing Phase I study of small activating RNA (saRNA) candidate MTL-CEBPA in advanced liver cancer patients. The Chief Investigator of the trial reported observations of tumour responses in three patients when administered approved liver cancer therapies subsequent to treatment with MTL-CEBPA. These responses corroborate emerging pre-clinical research on the potential for MTL-CEBPA to enhance the benefit of other cancer therapies and to modulate the tumour immune microenvironment. The update from the MiNA clinical trial was presented at the 12th Annual Conference of the International Liver Cancer Association in an oral presentation titled "First-in-Human, First-in-Class Phase I Study of MTL-CEBPA, a Small Activating RNA (saRNA) Targeting the Transcription Factor C/EBP-? in Patients with Advanced Liver Cancer" in the Novel Targets and Markers session held on Sunday, September 16, 2018. "Although these instances are anecdotal, complete responses of tumours are a rarity in primary liver cancer," said Dr. Debashis Sarker, the Chief Investigator of the study and Principal Investigator at the National Institute for Health Research Clinical Research Facility at Guy’s and St Thomas’ and King’s College London. "Observing two patients responding in this manner to approved cancer therapies subsequent to treatment with MTL-CEBPA is very encouraging. I am pleased that MiNA is seeking to modify its ongoing trial to include investigations on the combination in additional patients and I look forward to the opportunity to further evaluate MTL-CEBPA."
  • In three patients investigators initiated off-study treatment with tyrosine kinase inhibitors, 0 – 3 months after completion of on-study treatment with MTL-CEBPA. Two patients administered with sorafenib experienced confirmed complete tumour responses together with marked decreases in alpha-fetoprotein tumour marker. One of these two patients also experienced resolution of both lung and peritoneal metastases. One patient administered with lenvatinib experienced a partial tumour response. In a published Phase III study of sorafenib as a single agent, complete responses were observed in 0% of patients and partial responses were observed in 2% of patients1. In a published Phase III study of lenvatinib as a single agent, complete responses were observed in 0% of patients and partial responses were observed in 18% of patients based on RECIST 1.1 criteria. Mina Therapeutics is now in active discussions with the regulatory authorities to amend its ongoing Phase I trial to include further studies of MTL-CEBPA in combination. Enrolment has been completed evaluating MTL-CEBPA as a single agent. Enrolment is expected to begin in Q4 2018 evaluating MTL-CEBPA in combination with sorafenib.
  • • On June 4, 2018, Mina Therapeutics announced preliminary results from its ongoing Phase I study of  MTL-CEBPA in advanced liver cancer. In the study, MTL-CEBPA was generally well tolerated in patients with both healthy and impaired live function and provided evidence of anti-tumour activity. MTL-CEBPA was also found to mediate RNAa activity in white blood cells. The data are being presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in a poster titled "Preliminary results of a first-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-a in patients with advanced liver cancer" in the Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics poster discussion session being held on June 4, 2018.
  • MTL-CEBPA was evaluated in the dose escalation part of a Phase I clinical trial in patients with advanced liver cancer. As of the data cut-off date of March 31, 2018, 23 patients had been treated once weekly at six dose levels (ranging from 28 mg/m2 to 160 mg/m2) and 5 patients had been treated twice weekly at 70 mg/m2. MTL-CEBPA was well tolerated in patients at all doses and no Maximum Tolerated Dose was identified. The large majority of adverse events (AEs) reported by investigators were mild to moderate in severity. 12 (43%) patients experienced AEs no higher than Grade 2. AEs of Grade 3 or higher included hyperbilirubinaemia (11%), elevated GGT (11%), hypophosphataemia (11%), anaemia (7%) and hypertension (7%). Only 3 (11%) patients discontinued treatment with MTL-CEBPA due to possible drug-related toxicities including acute coronary syndrome, hyperbilirubinaemia, and elevated GGT.
  • Pharmacokinetic data from this study showed that Cmax (peak plasma concentration of drug) and AUC (area under the curve) were dose proportional with no evidence of drug accumulation.
  • CEBPA gene expression was analysed in white blood cells of 10 patients across multiple dose levels and timepoints. The level of CEBPA gene expression was significantly higher on treatment than at baseline, supporting target engagement of MTL-CEBPA. Consistent with up-regulation of CEBPA, which has a role in myeloid differentiation, significant and repeated increases in neutrophils were observed after dosing MTL-CEBPA.

Is general: Yes