LMI070 (former NVS-SM1) is an oral drug that works by increasing the amount of functional SMN protein produced by the “back-up” gene, SMN2, by modifying its splicing. The therapy is being developed by Novartis as a treatment for spinal muscular atrophy type 1.

How LMI070 works

LMI070 was first discovered after about 1.4 million compounds were tested in a nerve cell model. After identification, LMI070 was tested in mouse models of SMA, and shown to result in the production of greater amounts of the SMN protein, leading to improvements in the body weight and survival of the SMA mice.

The study showed that LMI070 is able to enhance the recruitment of molecules needed to correctly read and process the SMN2 gene. By doing so, LMI070 is able to increase the amount of full-length SMN protein made by the SMN2 gene.

The selectivity of the interaction drug-DNA sequence is found in a limited number of genes, reducing the chances of the drug causing severe side effects in humans. These positive pre-clinical results led to a Phase 2 trial.

Clinical trial of LMI070

The open-label, multi-part, Phase 2 study of oral LMI070 in infants with type I SMA study is ongoing (NCT02268552), but not recruiting.

In May 2016, Novartis paused enrollment for the LMI070 study for the treatment of Type I SMA. Animal studies being conducted in parallel to the trial showed unexpected injuries to the peripheral nerves and spinal cord, testes, and blood vessels in the kidney. All patients currently enrolled are being closely monitored, and teams at the sites worked with families and health authorities to determine appropriate next steps.

When the enrollment was paused, patients already in the study were switched to a lower dose of LMI070. Some showed worse motor skills about eight weeks after the reduction, Novartis announced in a trial update, and one patient died following an upper respiratory infection due to increasing respiratory muscle weakness. Novartis then decided, “with the approval of the Data Monitoring Committee (DMC), a team of independent experts who monitor the trial’s safety results,” to offer patients’ families the option of returning to the original dose.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy after 13 weeks and to estimate the maximum tolerated dose and optimal dosing regimen of administered LMI070 in patients with Type 1 SMA. The completion date is estimated to be August 2017.

Next steps for LMI070

Novartis hopes to resume enrollment in the study after full evaluation of the new toxicology findings, the additional monitoring of patients, and feedback from regulatory authorities, investigators, and data monitoring committee members.

Read the latest LMI070 news on SMA News Today.

Follow the latest developments for all experimental spinal muscular atrophy treatments on the SMA Therapy Tracker.

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