On Saturday October 21, 2006, PTC Therapeutics released long-awaited preliminary data from the Phase IIa trial. Twenty-six boys with Duchenne muscular dystrophy (DMD) received PTC124 for a period of 28 days. PTC124 is a novel, orally-administered small molecule that targets a particular genetic alternation referred to as a nonsense mutation or premature stop.

What does it all mean? Is PTC124 a cure for boys with premature stop codons? What are the next steps? Is there anything on the horizon for the boys with other types of mutations?

First, the trial.

It is tempting to make the leap and believe that all boys with premature stop codons are in line for treatment or cure, but in fact, our role at PPMD is to help you understand exactly what this trial tells us, and not to project beyond these data. We will try to do just that. We are encouraged by the data from the Phase IIa trial. We feel very positive about the safety profile and the fact that all boys who participated in the trial tolerated PTC124 very well. Drs. Wong (Cincinnati), Finkel and Bönnemann (Philadelphia) and Flanigan (Utah) are all cautiously optimistic and feel quite confident that continuing to move forward is justified.

The preliminary finding of a decrease in CK levels is an encouraging sign but we do not know how much of a change in the CK is needed to be clinically meaningful. (The CK or CPK is a blood test that measures creatine phosphokinase, an enzyme found predominantly in the heart, brain, and skeletal muscle. In children without muscle disease, this value is typically in the range of 0-200, but in boys with DMD, the value is dramatically elevated, often 10-100 times the normal value. The CK level, therefore, is a useful “biomarker” for DMD).

Dystrophin Expression -- Demonstrating an increase in dystrophin in muscle tissue is the primary goal of this Phase IIa study. This is being evaluated in several ways. So far two methods of analysis have shown encouraging results and other methods are still in process of evaluation. Muscle tissue from several boys in this study, grown in a test tube setting (“in vitro”) and exposed directly to PTC124, demonstrated an increase in dystrophin production. Next, muscle biopsies (“in vivo”) obtained at baseline and after 28 days of treatment with PTC124 were stained for the dystrophin protein. Evaluation of the in vivo effects of PTC124 over the 28-day treatment course suggest an increase in dystrophin expression in muscle biopsies in a number of the boys participating in the trial, although quantitative analysis is not yet complete. The investigators feel that these preliminary qualitative findings of dystrophin expression in some of the boys are a positive sign, and in many ways confirms that things are changing for boys with Duchenne.

In addition, some parents and teachers of boys who participated in the trial reported positive changes. These anecdotal reports run the gamut from observations of improved behavior to functional improvement. The difficulty is how to evaluate or quantify ‘improvement’. In a certain way, the boys improved in their own space that is, relative to ‘where they had been’. This is wonderful news of course, but very difficult to prove, measure and quantify. Identifying improvement what it is, how to define and measure it is going to be critical in order to understand benefit in DMD.

We are all so anxious for news, especially good news such as this, that it is easy to let our minds run away and think ‘cure’ is right around the corner. PTC is working to address several additional questions: Will higher dosage or longer exposure to PTC124 be well tolerated? Will PTC124 improve function and maintain functional improvements over time? Will the heart muscle respond? Will all boys with premature stops respond equally?

First off, it is good news and not just for boys with premature stop codons but for the entire DMD community. This is the first time an oral medication has been shown to increase dystrophin production in boys with DMD, and as a community we can become believers. We now have our first glimpse that Duchenne can and will be treated. All of this makes us join together to say: God bless those 26 boys and their parents who were willing to participate. We, as the Duchenne community, are grateful for their contribution to science and medical advances. We will be anxiously waiting for news about next steps.

Second, in the week of World Series news flashes, the Phase IIa study is a base hit, maybe a double, but we have not won the game. We have a beginning, a light in the tunnel. We now need to conduct the additional studies that will provide more answers. We need to understand more about dose Is more better? Does an increased dose result in increased functional gain?

Finally, PPMD is here to field the team that will win not just this game, but the series. PPMD recognizes that PTC124 is specific for a subset of boys with DMD and it is certainly true, what we learn from this trial will have broad application. For the last three years, PPMD has been working with PTC Therapeutics on Project Catalyst our drug discovery program. In 2003, we identified 4 drug targets with the goal of developing small molecules to benefit all individuals diagnosed with DMD. We now have promising ‘hits’ on all identified targets and continue our work with PTC to optimize those compounds. We will continue to act as a catalyst, looking for every possible way to accelerate the development of treatments.

There is still much to do behind the scenes. Building the infrastructure that will be required to deliver care and treatment for every child, young adult or adult diagnosed with DMD is essential. With PTC124 we have entered the major leagues. Today we are on the field taking aim at Duchenne running for base hits, one at a time and will continue to do so until we have enough home runs to win the World Series.