The Year for DMD - The Year for Hope for Gus - Part 1

2010 was a busy year – for Duchenne Muscular Dystrophy Research and for Hope for Gus.

I’ll talk about DMD research first – it was a year of disappointments and some hope of progress – ‘there’s good news and bad news…’ as the saying goes. Here are some highlights:

• In March, PTC Therapeutics and Genzyme Corporation announced that their drug Ataluren (also known as PTC-124) was not effective in Phase 2b trials: “The primary endpoint of change in 6-minute walk distance did not reach statistical significance within the 48 week duration of the study.”This was heartbreaking and scary for a bunch of reasons:

1. First, this drug offered a lot of families hope. It’s a long road, both in terms of time and money, to get a drug to phase 2b, and this drug seemed to be the one that was going to finish the journey. It may yet be a tool for treatment among many others, but it is not the silver bullet that we’d hoped for.
2. Even though only about 13% of the mutations that cause DMD would be addressed with this drug, the entire DMD community was rooting for it. It seemed to be the first real light at the end of the tunnel.
3. It’s a vague statement – people were left asking – did it help at all?
4. It was sobering and even a little surreal that a drug that had been in development for years and that experts had championed as treatment with tremendous potential could just vaporize in a press release. The DMD community is used to the boy-who-cried-wolf-dynamic. So many “cures” have come and gone over the years. But this one seemed different because so many major players (including Genzyme, a major pharmaceutical) were behind it. In the end, it was a lesson in the complexity of this disease. Nothing will be easy.

• In August, BioMarin announced the results of its phase 1 trial of the drug BMN-195. BMN-195 was a drug that would up-regulate utrophin. The drug “did not achieve plasma concentrations believed to be required to increase utrophin expression. Moreover, plasma concentrations of BMN 195 were even lower on repeat administration…” In response, BioMarin discontinued research into the drug. Again, we realized we know less than we think we know, but BioMarin’s press release also offered a view of the way forward from all of this. It said, “Given the limitations of BMN 195, we believe that other approaches to up-regulation of utrophin may be more possible, and we continue to believe that utrophin upregulation is a viable approach for the treatment of DMD. We are currently working on additional candidates to take forward into early human studies, and the new compound we are working on appears to overcome the limitations of BMN 195."

“We are currently working on additional candidates to take forward into early human studies, and the new compound we are working on appears to overcome the limitations…”

…and that is the nature of the ‘good’ news. We have learned this year – at times it has felt like the learning was mostly through failing – but even that is learning.

So now, some good news:

• A number of trials are underway. They include:

1. Sildenafil (also known as Viagra) – Phase II – This drug belongs to a class of drugs called phosphodiesterase 5 (PDE5) inhibitors. They relax the smooth muscles that line blood vessels, hopefully improving blood flow to skeletal muscles and the heart. Researchers have identified “an apparent strong therapeutic effect” of sildenafil on heart function in mice with a DMD-like disease.
2. ACE 031 – Phase II – This is a protein that is hoped to build muscle and increase the strength of skeletal muscles.
3. Epigallocatechin-Gallate (also known as EGCG – it’s the major polyphenol in green tea) – Phase II – This trial is based on EGCG’s neuroprotective effect and it’s effect as an anti-oxidant.
4. GSK2402968/PRO051 – Phase II – This is a compound that would induce exon 51 skipping, allowing for a partial dystrophin protein to be produced.
5. PRO044 – Phase I-IIa - This is a compound that would induce exon 44 skipping, allowing for a partial dystrophin protein to be produced.
6. AVI-4658 – Planning Phase II – This is a compound that would induce exon 51 skipping, allowing for a partial dystrophin protein to be produced.
7. Idebenone – Phase III – Through it’s anti-oxidant effect, this drug is hoped primarily to improve or delay the loss of respiratory function in patients. Additionally, researchers are interested in its impact on pulmonary function, motor function and muscle strength.

All of this is evidence of the pharmaceutical industry beginning to pay attention to Duchenne Muscualr Dystrophy. In September, Dr. Brian Tseng was hired by Novartis specifically to develop drugs for neuro-muscular disorders.

The year ended with some interesting research from Stanford. In that study, researchers asked why the Muscular Dystrophy Mice that are used for early testing of potential treatments often do far better than humans with DMD. As a result, many ‘promising’ treatments over the years have not fulfilled their promise in people.

Researchers determined that the difference is due to the fact that mice have longer telomeres in their muscle stem cells. As a result, they have a greater capacity for muscle cell regeneration after their cells have been destroyed due to a lack of dystrophin. There are two important implications from this research. First, there is a new mouse model that may more accurately reflect human DMD (it’s known as the Blau Mouse after Dr. Helen Blau, lead researcher). These are mice that lack both dystrophin and the enzyme, telemorase. Their phenotype of DMD is similar to human DMD.

There is a second, and more profound implication. The real cause of degeneration in DMD patients is that their bodies are exhausting their supply of stem cells prematurely. Any treatment regimen must ultimately address this in order to be effective. While other treatments will ameliorate the symptoms of DMD and may even slow the loss of stem cells in DMD boys, until we are able to restore their stem cell supply, our boy’s will ultimately experience muscle degeneration. This research seemed to fit right in with much of the year’s research. In pointing out where we have failed in the past, researchers may have moved us closer to a cure.

As the year turns to 2011, it has the feel of a huge chess board being set up for the game. We are finally getting the pieces in place, and, while we’re not there yet, soon we’ll be ready to play. When we eventually do start the game, we’ll win, we know that. It is excrutiating for families and kids with DMD to wait as we set up the board, but 2010 moved us a lot closer to checkmate.