A new drug approval for the vanguard of RNA-targeted small molecules

A few years ago, at Arrakis Therapeutics, we set out to conquer a strange new territory, drugging RNA structures with small molecules. We have overcome many obstacles on this mission, inventing new concepts and methods where necessary and re-engineering known concepts and methods where possible. But we have not been the only people on this mission.

In addition to the early work of Matt Disney at the Scripps Research Institute and others in the academic community showing that this was even possible, a number of pharmaceutical companies have made important advances towards drugging RNA structures to discover new therapeutics. In fact, it was these early pharmaceutical successes that gave us the confidence that we would ultimately succeed in systematically drugging a wide range of RNA structures.

In early August, risdiplam, an orally available small molecule that binds to a stem-loop structure in the SMN2 pre-mRNA, received FDA approval for the treatment of spinal muscular atrophy, a devastating genetic disease. After an early collaboration with PTC Therapeutics, the team at Roche optimized, developed, registered, and will now market risdiplam as Evrysdi™.

Unraveling the genetic mechanism of SMA

Spinal muscular atrophy (SMA) is the most common monogenic human genetic disease and derives from the loss of a functional SMN1 gene, leading to impaired expression of a protein called ‘survival motor neuron’ (SMN). SMN is indispensable for normal neurodevelopment and motor function. Some SMN protein is expressed by a second gene, SMN2, but the splicing of this gene often skips exon 7, yielding an isoform of the mRNA that expresses a truncated, non-functional protein. The efficiency of exon 7 inclusion in the mature SMN2 mRNA varies significantly among patients and poor inclusion efficiency correlates with higher disease severity. In less severe disease, patients will reach adulthood and suffer from motor function deficiencies. In severe disease, patients suffer from poor neurodevelopment, failing to reach rudimentary developmental milestones such as sitting or standing or walking, with further deterioration leading to death at a young age.

Oligonucleotide drugs lead the way

Motivated by the prevalence and severity of this disease and, armed with a clear understanding of the genetic mechanism, several groups pursued new therapeutic agents to treat these patients. Ionis, building on discoveries out of Adrian Krainer’s lab at Cold Spring Harbor and later working with Biogen, developed an oligonucleotide that binds to the SMN2 pre-mRNA in the intron region downstream of exon 7, where that binding enhances exon 7 inclusion in the splicing event, affording full-length mRNA and expression of full-length SMN protein. This oligonucleotide, nusinersen, is administered intrathecally and exhibits a remarkably long half-life in the cerebrospinal fluid. As intended, administration to patients elevates SMN levels, leading in turn to significant improvements in motor function and neurodevelopment. The public reports of this drug’s clinical benefits were thrilling to everyone – patients, physicians, and researchers. On the strength of those findings, nusinersen was approved by the FDA at the end of 2016 for the treatment of SMA, marketed under the commercial brand Spinraza™.

A different therapeutic modality was pursued by Avexis, working with Novartis. Using gene therapy, their approach was beautifully straightforward – “Missing an important gene? We will replace it.” This gene therapy introduces a fully functional SMN1 gene which expresses corresponding full-length, functional SMN protein. The agent, onasemnogene abeparvovec, was approved by the FDA in 2019 and is marketed as Zolgensma™.

Dramatic discoveries of small molecules targeting SMN2

Prior to those outstanding therapeutic achievements, in 2015, a group from Novartis published an important paper in Nature Chemical Biology. This group also had SMA in their sights and wanted to find small molecules that elevated SMN2 exon 7 inclusion by any mechanism that achieved that end. They developed a gratifyingly simple, even brutal strategy: Screen a large library (ca. 1.5M compounds) against a cellular reporter assay designed to identify small molecules that selectively modulate the splicing of SMN2 pre-mRNA, favoring the isoform that includes exon 7 in the resulting mRNA. They found a few molecules that accomplished this nifty trick, and one of them, called NVS-SM1 in the Nature Chemical Biology paper, also achieved the same results in animal models. You’ll have to ask your friends at Novartis for the inside scoop, but as I understand it, it took some time for the team to accept the idea that this small molecule impacted the splicing of the SMN2 pre-mRNA by directly binding to that pre-mRNA. But the 2015 paper revealed that NVS-SM1 binds directly to a stem-loop structure in the SMN2 pre-mRNA, enhancing the residence time of the U1-snRNP, which promoted the desired inclusion of exon 7 into the final spliced mRNA. This was remarkable as there were no small molecule drugs proven to operate via direct binding to a human pre-mRNA or mRNA. This compound, since renamed ‘branaplam’, is in clinical trials in SMA patients.

About the same time as this publication, Arrakis Therapeutics was being formed, and the existence of a molecule that achieved biological activity by binding directly to mRNA featured prominently in our presentations to potential investors. Branaplam served as a clear “reason to believe” that our broad mission could be achieved. In the course of building Arrakis and pursuing our mission, we became aware of another molecule, RG7916 (aka RO7034067), emerging from a collaboration between PTC Therapeutics and Roche. Available information suggested that RG7916 achieved a similar outcome as branaplam by a similar molecular mechanism.

The team at Roche made this abundantly clear in 2018 with the publication of a paper in the Journal of Medicinal Chemistry describing the structure and mechanism of RG7916, renamed ‘risdiplam.’ Like branaplam, risdiplam enhanced exon 7 inclusion and raised the levels of the SMN protein in cells. At the time of that publication risdiplam was also in clinical trials for the treatment of SMA patients.

For, at the time, risdiplam represented reproducibility, doubling down on the initial promise of branaplam: two separate teams, using two completely different discovery strategies each identified drug-like small molecules that bound the same stem-loop on the same target, SMN2 pre-mRNA, yielding the same enhanced inclusion of exon 7. It even lent a certain air of inevitability to the discovery of RNA-targeted small molecules (rSMs) against well-formed, functionally significant RNA structures.

In the clinical trials assessing risdiplam, the infantile-onset cohort, after two years of treatment, 80% of the patients were alive and not on ventilators and the cohort of older patients experienced significant improvements in motor function. Based on these and related clinical benefits, risdiplam was approved a few weeks ago on August 7^th as an oral treatment for SMA in adults and in children above two months of age. Any marketing approval of a new chemical entity is a remarkable achievement for patients and drugmakers, but the novelty of the molecular mechanism – a small molecule targeting a functional RNA structure – makes this approval especially validating and inspiring for the emerging community of researchers pursing RNA with small molecules, especially my colleagues at Arrakis.

Many paths to the same destination of helping patients

There are potential advantages in attacking SMA with multiple therapeutics, even if all targeting the same gene. It is outstanding that patients, in a span of less than four years, have gone from zero to three disease-modifying therapeutic options with more on the way. It is certainly premature to check off SMA as a solved problem, but the therapeutic options available to patients are now drastically improved, lengthening life and improving the quality of that life.

This is our salute to our predecessors who, undaunted by the unusual molecular mechanism of action, found a promising new drug to improve and, in some cases, save the lives of patients. Here’s to the trailblazers! Many thanks for all of your efforts on this target and on behalf of SMA patients. And now, we will now get back to work on more RNA targets on behalf of many more patients.