Discussion
LNA-i-miR-221, HCV) infection, Alport syndrome, cancer, human malignancies, PD, hepatitis C, treatment-resistant, colon carcinoma, tumors
VIRUS, ALPORT SYNDROME, CANCER, ADVANCED CANCER, SOLID TUMORS, KIDNEY FIBROSIS, MAY, HEPATITIS C, COLON CARCINOMA, TUMORS
RNA-based therapeutics hold promise as a broadly applicable and adaptable way of targeting almost any protein or genome region. These attributes are exemplified by the rapid design and development of mRNA-based COVID-19 vaccines [As RNA-based molecules are negatively charged, which hampers uptake across cell membranes, and prone to degradation by a range of nucleases, a variety of chemical modifications have been proposed to enhance their PK and PD. Specifically, third-generation chemical modifications introduce changes to the furanose ring generating, for example, LNA ASOs. To date, the RNA therapeutics that have progressed to clinical testing make use of second- or third-generation chemical modifications. These investigational therapies include two anti-miR-122 inhibitors, RG-101 (an N-acetyl galactosamine-conjugated ASO) and miravirsen (SPC3649; a β-D-oxy-LNA), that have undergone clinical trials as novel therapeutics for hepatitis C virus (HCV) infection. In addition, anti-miR-92a (MRG-110) has been investigated as an anti-angiogenetic agent to improve wound healing (NCT03603431), and anti-miR-21 (RG-012) as a therapy for the prevention of kidney fibrosis in patients with Alport syndrome (NCT03373786). However, to our knowledge, no miRNA-targeting therapies have been investigated in cancer patients to date [In this first-in-human phase I study of LNA-i-miR-221, a novel 13-mer LNA inhibitor of miR-221, 4 consecutive daily-doses of 5 mg/kg, after dose escalation, was well tolerated. No clinically significant changes in vital signs, physical examination or ECG findings were observed, nor were any clinically significant changes from baseline noted in safety laboratory results. During the course of the study 37 AEs were reported by 15 patients, all of which were CTCAE grade 0–2, mostly without potential relationship to LNA-i-miR-221 administration. Therefore, no major safety concerns were noted in this trial, and we conclude that the MTD was not reached.Investigation of the PK profile of LNA-i-miR-221 in plasma revealed that, on average, LNA-i-miR-221 exhibited non-linear PK across the range of doses explored. Similar observations were reported during preclinical safety studies conducted in rats [Importantly, systemic exposure to LNA-i-miR-221 led to downregulation of miR-221 expression levels as well as increased expression of CDKN1B at mRNA and protein levels, and of PTEN, demonstrating that the infused naked LNA-i-miR-221 was active in producing a PD target modulation in circulating cells. These data prove that the injected investigational drug is biologically active on the canonical miR-221 relevant targets and that this activity indeed correlates with a PK increase in the higher dose patient cohorts. We have not assessed target modulation in patient’s tumors. However, in vivo pre-clinical data in rodents demonstrated high and persistent bioavailability of LNA-i-miR-221 in solid tissues [Of the 16 patients treated with LNA-i-miR-221 during this study who were evaluable for clinical response, the majority had SD (8 patients), as assessed through CT scan imaging of tumors over time. One 60-year-old metastatic colon carcinoma patient, treated with 5 mg/kg LNA-i-miR-221, exhibited a PR and received a further three cycles of treatment (4 cycles in total) on a compassionate use basis. Taken together, these findings suggest that LNA-i-miR-221 has anti-tumor activity. As of August 2022, 9 months after the last dose of LNA-i-miR-221, the patient who exhibited a PR was alive, with persisting symptomatic improvement and even with a more profound radiological response. At the end of May 2023, the patient is still alive with an excellent performance status (PS 0).Notwithstanding the limitations of this small study population and limited cohort sizes used in this first-in-human study, the results presented here provide the basis for further clinical investigation of LNA-i-miR-221 for the treatment of solid tumors. This study provides preliminary evidence of anti-tumor activity in treatment-resistant advanced cancer patients, and, to our knowledge, this trial represents the first clinical evidence of miRNA inhibition as a safe and effective treatment for human malignancies.