Small Molecules and Gene Therapy Muscle Out Oligonucleotide Therapeutics

Over the last two days, breathtaking data were reported for the treatment of two severe, inherited muscle-wasting diseases affecting children.  The investigative agents were a small molecule splicing modulator and a gene therapy both of which appear to achieve superior results compared to approved Oligonucleotide Therapeutics agents. 

The developments highlight the risk that while gain-of-function changes (here by splice modulation) may have proved to be low-hanging fruits for Oligonucleotide Therapeutics, they, unlike gene knockdown approaches, face increased challenges from other technology platforms.

Small molecule splicing modulation for Spinal Muscular Atrophy (SMA)

In 2011, Roche started collaborating with PTC Therapeutics on small molecule splice modulators for the treatment of SMA.  The idea is to screen small molecules for their ability to bring about changes in RNA processing that would hopefully be gene-specific enough so as not to cause widespread off-targeting.

I had always considered this to be a monumental, if not insurmountable task.  This is because a given splicing event brings together a set of proteins that each in turn also function at other genes.  So surely a small molecule that may bias splicing from SMN1 to SMN2, as does antisense oligonucleotide SPINRAZA from Ionis and Biogen through highly specific base pairing, would also affect a range of other genes.

If that were not enough of a challenge, a small molecule carries the extra baggage of being more widely available across tissue types such that off-targeting is a risk to not just the CNS as with SPINRAZA, but many other cell types where there may be no benefit from SMN upregulation.

Accordingly, the first compound in the PTC-Roche collaboration to enter clinical development, RG7800, had to be discarded last year due to retinal tox concerns.  Another small molecule competitor, branaplam from Novartis, had similarly been put on hold due to tox concerns although this compound has resumed development late last year.

It was therefore amazing to see updated results from the FIREFISH study of the follow-on compound RG7916 in type I SMA infants.  They show that 90% of children had an improvement in the CHOP-INTEND measure of physical functioning after 6 months on the drug.  The results are particularly impressive considering that treatment had been initiated relatively late compared to the new standard of care with SPINRAZA and the soon-to-be-approved gene therapy by Novartis (àAvexis).   

Not only that, there had been no treatment discontinuations due to safety issues with RG7916.

Given that SPINRAZA has to be given intrathecally while RG7916 can be given orally, and given that both the gene therapy and the orally available RG7916 appear to be somewhat more efficacious than the oligonucleotide, the focus of Biogen and Ionis should now be on testing combinations of SPINRAZA with both modalities.  Ideally, there is added efficacy from using the agents together either because due to higher achievable SMN protein levels and/or due to complementary biodistribution (note: the value of SMN increases outside motor neurons is debated).  If not, the SPINRAZA franchise may have a limited shelf-life.

Fake-it-‘til-you-make-it Sarepta with gene therapy breakthrough

The other piece of great news for families dealing with neuromuscular disease came yesterday at the Sarepta Therapeutics R&D Day. 

To wit, Sarepta had used dubious data and a lot of political lobbying to get the controversial exon skipper eteplirsen approved under accelerated approval.  While delaying the confirmatory study that is supposed to be part-and-parcel of an accelerated approval, Sarepta has been raking in billions in sales and added market capitalization.  This has allowed the company to build a veritable DMD powerhouse with a number of candidates that look much more promising than ordinary PMO-based eteplirsen.  They include peptide-conjugated PMOs and especially gene therapies.

If you are involved in drug development, better get used to the dubious morals of the industry.  If things go well, you behave like the paragon of virtue, if things don’t go so well you fake it until you get another chance at succeeding.  I digress…

Before the initial gene therapy data were to be presented by Jerry Mendell from Children’s Nationwide of SMA fame, I had dreaded the thought of having a hyped-up R&D Day being about divining the meaning of a biopsy slide or two on the barely-above-background expression of the microdystrophin transgene.

However, what was presented was anything but borderline.  Unlike with eteplirsen where we were dealing with debatable 1%-type absolute expression levels, there was robust microdystrophin expression: ~75% of cells expressed the transgene (by IF) with roughly 30% absolute expression of microdystrophin relative dystrophin from a normal person (by Western blot).

Not only this, the microdystrophin was functional at the molecular level as judged by restoring dystrophin-related protein complexes serving to protect the muscle from damage by acting as shock absorbers.  Accordingly, CK levels in the blood, a marker of muscle damage and elevated in children with DMD, were robustly (9x) and uniformly lowered in all 4 boys between the ages of 4 and 7.  Add to this the obligatory before-and-after videos and there is little doubt already at this relatively early stage already (~1-3 months after gene transfer) that AAVrh74.MHCK7.microdystrophin is a powerful agent applicable to essentially all types of DMD.

On the safety side, there were considerable, but transient and manageable increases in liver enzymes.  This was to be expected, however, considering the very high doses of AAVRh74 needed to achieve widespread transgene expression in muscles throughout the body and treating physicians know to look for it.

If the safety holds up and expression continues to be long-lived, AAVrh74.MHCK7.microdystrophin could render many exon-specific oligonucleotide splice modulators obsolete. The duration of action is the most concerning issue to me at this point given the attendant cell turnover and attendant risk of losing episomal gene therapies in patients with muscle damage.