A recent study describes how the compound was discovered from a large screen for SMN2 modulators in a nerve cell model, followed by several rounds of chemical optimization to increase potency and brain-targeting capacity while minimizing toxicity.
The approval of Biogen‘s Spinraza (nusinersen) was a breakthrough for SMA patients, and it remains the only approved treatment for the disease. However, other pharmaceutical companies are developing alternative approaches, such as gene therapy, or compounds that work on the same principle as Spinraza but with improved pharmacological properties (e.g. better route of administration, improved potency or fewer side effects).
DNA is first transformed into pre-messenger RNA (pre-mRNA), which is then processed to create a mature mRNA molecule. This process is called RNA splicing. Once mRNA molecules are produced, a process called translation begins and gives rise to proteins.
During splicing, introns (the part of the pre-mRNA that does not code for proteins) are removed and exons (the part that does) are joined together. This phenomenon allows for a single gene to give rise to many different proteins.
By altering this mechanism, LMI070 enables the SMN2 gene to produce more copies of a full-length functional survival motor neuron (SMN) protein, the faulty protein in people with SMA.
LMI070 was discovered by Novartis after screening some 1.4 million compounds for those that could increase the production of SMN protein in a nerve cell model in vitro (in a laboratory dish).
The present study describes how this screening was done and how the lead compound was developed. Starting from the best hit identified in the screening, called pyridazine, researchers at Novartis initiated an optimization program where they performed small chemical changes to the molecule to see if they could optimize its properties.
Their efforts were focused on “maximizing cellular potency, improving in vivo exposure through reducing [body] clearance and increasing permeability” of the compound, in particular its ability to reach the brain.
One of their main goals was to reduce the compound’s toxicity. Researchers observed that the initial molecule (pyridazine) was toxic because it bound to a protein important for heart function (called hERG); as such, they tried to alter its chemical structure to reduce its affinity with this protein.
After several rounds of chemical testing and the creation of multiple modified drug versions, one lead compound — LMI070 — was taken forward for efficacy studies in a mouse model of SMA with early-onset and severe disease.
LMI070 was the candidate that better balanced low toxicity with greater potency and a favorable pharmacokinetic profile (uptake, distribution, metabolism and clearance by the body), in particular an improved ability to enter the brain.
Importantly, mice with severe SMA that began receiving oral treatment with LMI070 a few days after birth began to produce greater amounts of SMN protein in the brain, which translated into weight gain and extended lifespan.
“[S]plicing modulation via oral administration of small molecule SMN2 splicing modulators was a viable therapeutic strategy for the treatment of SMA,” researchers said.
These promising preclinical results supported the progression of LMI070 into clinical trials.
The study aims to evaluate the safety, tolerability, pharmacological properties and efficacy of LMI070 after a 13-week treatment period; and to estimate the maximum tolerated dose and identify a regimen considered safe for long-term use.
The trial is recruiting and estimates to enroll 44 children. After a two-year pause because of safety concerns, on Sept. 20, 2017 Novartis announced that the company was resuming enrollment in Europe, where different doses of LMI070 are being tested.
The company has also modified the trial design, giving participants a choice of receiving their weekly dose of branaplam orally, instead of via a feeding tube, which was the only option when the trial began.