A new drug by Ionis Pharmaceuticals, CA, USA, has emerged as a novel and effective treatment for hyperlipidemia. IONIS-APO(a)Rx is an antisense therapy that lowers elevated lipid levels and reduces risk of cardiovascular disease in people who are genetically predisposed to this condition.
Results of the phase 2 clinical trial have shown promising results. This innovative treatment modality for hyperlipidemia has been carried out for the first time in human subjects.
The objective of the study was to assess the safety and efficacy of this avant-garde cutting edge technology. Unlike conventional treatment options — the statins, for example — the new treatment modality employs the use of antisense nucleotide sequence, a strand of nucleic acid, whether DNA or RNA, as a novel drug therapy that binds to and inactivates a messenger RNA responsible for encoding the message of a defective gene that acts as a causative agent for the disease and “turns off” the gene action.
The mRNA is the target site for the antisense therapy as it encodes the message for the production of defective proteins by translating it to the transfer RNA (tRNA). In case of hyperlipidemia, the antisense therapy targets the mRNA that encrypts the message of a defective gene responsible for production of large amounts of lipid levels in the blood.
This genetic therapy is a breakthrough development in the treatment and management of hyperlipidemia. The trial was conducted as two randomized, prospective, placebo controlled trials, employing varied number of participants and chemical moieties of antisense nucleotide sequence in each trial.
The study outcomes were reported in The Lancet by Nicholas Viney and colleagues.
The first trial was conducted as a phase-2 trial at multiple locations in different countries, namely Denmark, the Netherlands, Canada, Germany and the United Kingdom. The first trial included 64 participants, all with elevated levels of lipoproteins, which were further categorized in two groups .Group A had participants with lipoprotein levels in the range of 125–437 nmol/L while group B had participants with lipoprotein levels ≥438 nmol/L. The trial name of the antisense oligonucleotide sequence was IONIS-APO(a)Rx and was administered subcutaneously in a dose-escalating manner.
Both groups were randomly assigned the trial product in a different ratio. Group A received 1:1 ratio while group B received 4:1 ratio, implying that participants in group A received single dose while participants in group B received multiple doses. The total duration of the study was 12 weeks and the dosages employed were 100mg, 200mg and 300mg, each dose given weekly for a total of 4 weeks and then shifted to the next increasing dose.
An injectable saline solution was employed as a placebo for both the sample groups. The prime objective was to assess the safety, acceptability or tolerability and percentage decline in fasting plasma lipid levels at day 85 or 99.
The study inferred that the lipid levels significantly reduced in group B (71.6%) than in group A (66.8%), implying that multiple or increased doses corresponded in a linear manner in reducing the mean plasma lipid levels.
Moreover, the innovative therapy also had some auxiliary benefits such as reduction in bad cholesterol levels — the LDL-C and lipoprotein B levels, minimizing oxidation of phospholipids — a key factor in pathology of heart disease and monocyte movement towards inflammatory sites, thus attenuating inflammation.
The second randomized trial employed a different chemical form of the antisense oligonucleotide sequence with a similar trial name of IONIS-APO(a)-L Rx that was highly specific for liver cells.
In the second trial, a total of 58 participants were engaged in the study with lipid levels of ≥75 n mol /L and the dosages were assigned in a dose-dependent manner, meaning increased doses with the passage of time. The dose range was 10-120 mg of IONIS-APO(a)LRx. However, the participants were assigned varied pattern of dosing.
Like the first randomized trial, the participants in the second randomized trial were also further categorized into two groups: one group received single dose therapy and the other group received a dose therapy in ascending order.
A total of 28 subjects were engaged in the first group, receiving single dose therapy of either 10, 20, 40, 80 and 120 mg of subcutaneous IONIS-APO(a)-LRx and placebo in a 3:1 ratio while the second group, comprising of 30 participants, received multiple, ascending-dose therapy, 10, 20 and 40mg of IONIS-APO(a)-LRx in an 8:2 ratio. The results were to be inferred at day 30 in single-dose group and at day 36 in multiple-dose group.
Like the first randomized trial, the outcomes in the second randomized trial were also very promising. The results inferred that all participants in single-dose therapy with IONIS-APO(a)-LRx achieved significant reduction in mean plasma lipid levels by day 30 while the participants in multiple-dose therapy achieved mean lipid reduction in dose-dependent manner.
That is, with increasing doses from 10mg to 40 mg, the lipid reduction levels decreased in correspondence with the increased doses, implying that the maximal lipid reduction was attained in subgroup receiving 40 mg multiple dosage at day 36.
Both these randomized prospective studies concluded that the new breakthrough treatment holds a strong promise for managing hyperlipidemia irrespective of what dosage regimen is employed — single or multiple. Both dosage regimens proved highly fruitful in declining escalated lipid levels.
However, participants in both randomized trials experienced some critical adverse incidents in the form of myocardial infarction but these were considered to be not related to either of IONIS-APO(a)Rx or IONIS-APO(a)-LRx. However, the former was associated with reactions at the injection site.
This cutting edge therapy can now be considered as a ray of hope in the near future for hyperlipidemia since the condition is not merely restricted to increased lipid levels in the blood but paves the way for multiple heart diseases. It is also a major determinant of atherosclerotic heart disease that involves deposition of fat plaques in the heart vessels, thus reducing blood flow to the heart and elevating the risk of heart attack manifold in such patients.