Spotlight – Vertex flexes its dealmaking muscle

Vertex has been seeking collaborations in the rare muscular diseases Duchenne muscular dystrophy and myotonic dystrophy type 1 for some time, making deals with Crispr Therapeutics and Exonics Therapeutics in 2019 and Affinia Therapeutics a year later. 

In the past three months it has signed up two more partners, Entrada Therapeutics and Tevard Biosciences. But all Vertex’s collaborations remain at the research stage, and a look at the pipelines for these disorders show that the group is playing the long game. 

Under Vertex’s most recent agreement, the financial terms of which were not disclosed, it will work with Tevard to create new transfer RNA-based therapies to restore production of the full-length dystrophin protein in patients whose Duchenne muscular dystrophy is caused by nonsense mutations. This disorder is known as nmDMD, and it cannot be treated by Sarepta’s exon-skipping therapies, for instance.

Tevard and Vertex seem to be the only groups seeking to apply tRNA technology to DMD, with most other developers pitting tRNA against retroviruses, including Covid and HIV. When it comes to treating nmDMD patients, however, one company already has a marketed product.

PTC Therapeutics’s Translarna was approved in Europe in 2014, and last year brought in revenues of $289m. The company is finding the path to the US much more difficult. Translarna has twice been rejected by the FDA and, though PTC seems intent on filing a third time, no concrete plans have emerged.

So there might very well be room for another nmDMD therapy in Europe, and it is even possible that Vertex and Tevard manage to pioneer the US market. But no specific agent has even been identified under the collaboration yet, so investors should probably not hold their breath. 

Competition 

The market for myotonic dystrophy type 1 (DM1), the subject of December’s tie-up with Entrada, might be trickier still, because a handful of projects from other groups are already in mid or late-stage clinical trials.

DM1 is characterised by muscle weakness and wasting, prolonged muscle tensing, cataracts and abnormal heart function, and can be fatal. It is caused by extra copies of a repeating sequence of three nucleotides in the noncoding region of the DMPK gene.

Vertex and Entrada’s research focuses on ENTR-701, an oligonucleotide designed to block the matching repeats in mRNA transcripts, while leaving the normal DMPK coding transcript intact.

For this deal the terms were announced: Entrada got $224m up front, and Vertex made an equity investment of $26.3m. Milestones could reach $485m, and tiered royalties in the mid to high single digits will be payable if ENTR-701 is eventually approved. 

The oligonucleotide is in late-stage preclinical development, with an IND application expected in the second half of this year.

Several companies have more advanced candidates. Lupin’s sodium channel blocker NaMuscla is already approved in Europe for symptomatic treatment of myotonia in adults with nondystrophic myotonic disorders, and the company is trying to move it into both forms of myotonic dystrophy. A phase 3 study could report this year. 

Underlying

But NaMuscla is only a symptomatic treatment; another player, AMO Pharma, is aiming at DM1’s underlying cause. Its AMO-02 has a dual mechanism, disrupting the pathogenic RNA repeat and inhibiting glycogen synthase kinase 3 beta, excessive levels of which can cause muscle weakness. 

AMO-02 is in a pivotal trial, Reach-CDM, with adverse events as the primary outcome. The main efficacy measure is the congenital DM1 rating scale, which was incorporated into the trial on the advice of the FDA. The UK’s MHRA has also said this scale would be an approvable endpoint. Topline data are due in mid-2023.

Avidity Biosciences is not far behind. That group’s antibody oligonucleotide conjugate AOC 1001 generated preliminary phase 2 data at the end of last year. In the Marina trial the agent demonstrated a mean decrease of 45% in DMPK after a single dose of 1mg/kg or two doses of 2mg/kg. Early signs of clinical activity were also seen, with improvement in myotonia in some participants. 

But all is not straightforward with Marina. In September the FDA put the trial under partial clinical hold, pausing enrolment owing to a serious adverse event reported in a patient in the 4mg/kg cohort. All current subjects can continue, and further data will come this year.

Being late to market is a particular risk in rare diseases, where a tiny patient population can be hoovered up by the first developer past the finish line. And Vertex has a long path ahead of it.