Therapeutic Focus - Roche ups big pharma stakes in spinal muscular atrophy

Roche’s $30m payment to PTC Therapeutics is the first big pharma-style licensing deal to emerge from the nascent pipeline of therapies for spinal muscular atrophy (SMA). Research into treating the rare genetic condition, which in its most severe form usually claims infants before they reach two years, has relied in large part on university and foundation funding, but with a batch of preclinical candidates in development more commercial activity may be in the works.

Trophos’ candidate olesoxime represents the most advanced drug in the pipeline for the degenerative disease, with phase II trials underway in 150 SMA patients in Europe. However, coming on strong is Repligen, which this year advanced RG3039 into phase I in healthy volunteers; several more companies are in some stage of preclinical development (see table). In the light of big pharma’s continuing interest in orphan diseases, further progress will be watched with interest.

Poor prognosis for many

SMA is a group of conditions resulting from defects in the survival motor neuron 1 (SMN1) gene, which codes for the SMN protein. Without this protein spinal motor neurones degenerate, leading to atrophy, most severely in the muscles closest to the spine but also leading to weakness throughout. Cognition, emotional development and sensory nerves are unaffected.

A gene called SMN2 also makes SMN protein, but produces less of it. The number of copies of SMN2 a patient has generally determines the severity of disease.

One in 50 people are carriers of the genetic defect; however, it only manifests itself when both parents have the gene. One in 10,000 children is born with SMA. With muscles so severely affected, complications include aspiration, respiratory infections and breathing difficulties.

In its most serious form, known as type I or Werdnig-Hoffmann disease, SMA onset occurs between birth and six months. Children with this form of the disease never sit up, and death usually occurs before age two. Sixty percent of those born with SMA have type I according to the SMA Foundation, a leading fundraiser and backer of research into the disease.

Onset in type II and III occurs between seven and 18 months and after 18 months, respectively; type II patients typically are never able to stand and frequently die in childhood. Type III patients are able to stand and walk, and can expect to survive to adulthood. In rare cases, there is adult onset, known as type IV.

Leading the way

The most advanced candidate in the disease, olesoxime, is being tested in type II and III patients only, which addresses around 86% of the living population with the condition. Trophos chief executive Damian Marron says the type I population may be difficult to treat as neuronal damage may be near-total to total at birth, giving developers few therapeutic options.

Trophos started its phase II trial of olesoxime in SMA in 2010; the study is substantially funded by the Association Française contre les Myopathies. Preclinical studies have demonstrated that olesoxime promotes the function and survival of neurons and other cell types through interactions with the mitochondrial permeability transition pore (mPTP), essentially by modulating dysfunctional mitochondria.

Final results are expected in 2013 from the 24-month randomized, double-blind trial comparing olesoxime with placebo in non-ambulant SMA patients aged from 3 years upwards. Recruitment of 160 patients finished in September, with an interim efficacy analysis expected in September 2012 after a full year of treatment, Mr Marron says.

The primary end-point of the study is the change from baseline in the MFM functional scale - a quantitative scale used to measure the functional motor abilities of a person affected by a neuromuscular disease.

Mr Marron says “compelling and robust” data from the trial could be sufficient to file for regulatory approval.

Olesoxime's lead indication is in amyotrophic lateral sclerosis (ALS); results are imminent from a phase III trial, which will determine whether Actelion wants to execute an option to buy out Trophos (Event- Actelion hoping for Trophos ALS success, September 23, 2011).

Looking for a partner

Already testing its candidate in healthy volunteers is Repligen with RG3039, a product targeting the SMN2 gene. Discovered and developed by another US-based support group, Families of Spinal Muscular Atrophy, the company licensed the drug in 2009.

The oral drug works by inhibiting an RNA processing enzyme which targets the gene SMN2, causing it to ramp up production of the SMN protein lacked by sufferers. The drug has been shown to improve mobility and lifespan in preclinical animal models of SMA.

No serious adverse events have been reported from the phase I study so far. The company said in October it is in talks with numbers companies to explore a partnership over the drug; PTC’s success shows there is interest.

Raising visibility

Roche’s deal with PTC meanwhile raises the visibility of the pre-clinical pipeline.

For $30m upfront and up to $460m in milestones, Roche has bought global rights to at least three of PTC’s compounds to treat SMA. These rely on a small-molecule technology that can enhance protein production by altering regulating control processes once messenger RNA has been transcribed from DNA.

Like many of the candidates in development, PTC has received funding from non-commercial sources – in this case, the SMA Foundation. Testing in patients could be several years away.

Next in the clinic?

Antisense researcher Isis could be the next to test a therapy in man; the company says on its website it is currently conducting IND-enabling studies on its candidate, ISIS-SMNRx.

The drug is designed to modulate the alternative splicing of the SMN2 gene to significantly increase the production of functional SMN protein; positive results have been achieved in mouse models.

The company recently highlighted a paper published in Nature last month that described a pre-clinical experiment in mice treated with ISIS-SMNRx, extending their life span more than 25-fold.

Strengthening SMN2

Généthon, meanwhile, is working on a gene therapy approach; its progress is unclear.

Much earlier stage research is going on within government agencies, universities and other not-for-profit research institutions, as well as commercial enterprise. And Roche is not the only big pharma company to show an interest - Novartis has an ongoing research project with the SMA Foundation, to investigate small molecule therapies. Candidates remain pre-clinical and the Swiss pharma giant has revealed little about its progress, suggesting a move into man remains some time away.

With the level of research work ongoing, there are good odds of seeing multiple compounds moving into clinical development in coming months and years. However, the model of non-profit funding cannot sustain pipeline development for long; more commercial partnerships will need to emerge.