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May 11, 2005

Hanging your heart in one place

The diagnosis of Duchenne muscular dystrophy is overwhelming. It takes weeks, months and for some, years to grasp the reality of the diagnosis. I admit, I am still overwhelmed by the complexity of Duchenne and the more I learn the more complex it seems.

For every family, on that day of diagnosis, a process of education begins. There is an immediate need for knowledge about the diagnosis, where it came from, why it happened in your family, what is actually happening on a cellular level, what interventions are available, where the best physicians are located and what promising research may change the predicted course of muscle degeneration.

Because there are no agreed upon standards for care, families begin a hunting expedition in order to determine the best path for their child. The ‘hunt’ is not just medical; it is also a ‘hunt’ for promising research – research that could potentially treat your son. You want to get out of this world of Duchenne and as quickly as possible.

I don’t want to belabor this to death, but it is important to identify a physician that you can trust to develop and implement a care regimen for your child as well as identify expert individuals capable of providing a sounding board to discuss interventions you hear about as you do your research or network with other families. You and others who love your son (parents, family friends) are vulnerable – they are likely to call with something they read or heard to suggest there is an answer. While your heart may take a leap, your brain needs to be grounded in reality.

When faced with this diagnosis, many (perhaps most) will consider what things they might do to slow muscle degeneration. One of the first considerations is nutrition and supplements. We hear so much from companies specializing in nutritional products suggesting most illness can be treated (or improved) by adding a supplement regimen. When Chris and Patrick were diagnosed, we consulted with nutritionists, herbalist, homeopaths and chiropractors. For several years, the boys were on a very specific diet –no refined sugar, no white flour, no red meat. It was very difficult to maintain but the entire family was onboard. They had a very specific nutritional regimen that included a long list of supplements such as Creatine, L-carnitine, CoQ10, Vitamin E and so on. I would buy these from a certain laboratory and three times a day, the boys would swallow a good number of supplements as recommended by experts in the field of nutrition. In a certain way, I had my heart set on these nutrients (keep in mind steroids were not recommended in 1990) and would fall apart if for whatever reason, they could not take all the recommended nutrients.

Clearly there are any number of nutritional “experts” that might suggest all conditions (genetic disorders, disease process, aging) are the result of a nutritional deficit. I think we might all agree that proper nutrition, vitamins, supplements are useful to maintain health and there have been a number of pilot trials as well as animal work in several laboratories that indicate trends suggesting a certain nutritional product may have benefit. But the real answer is we just don’t know – do not know dose, combinations and/or the potential effect. It is easy enough to read an article about another condition and extract the information and apply it to DMD, but we simply do not know.

What is largely unknown is the effect of combinations of nutrients – whether the effect is additive or whether certain nutritional products with similar mechanisms of action actually cancel each other. We have had conversations with Dr. John Wesley at Baxter Pharmaceuticals (a major interest of Baxter is nutritional support). Dr Wesley suggested that the body will utilize nutrients it requires/needs but adding nutrients does not and cannot drive a process. In other words, if there is a hole, increasing the supply will fill the hole. If there is no” hole to fill”, the body will degrade the product(s) and eliminate what is not needed. In Duchenne, we are just learning about potential ‘holes’ but we certainly do not know how many or how deep. In other words, we do not have information related to combinations and/or appropriate dose.

There is another consideration. Early in the diagnosis, the child ‘appears’ to improve. Muscle strength improves (and more with steroids). The child refines his/her small and large motor strength. For this reason, evaluating supplement regimens becomes very difficult because these early years are already referred to as the ‘golden years’, a time when the child appears to get better! Add steroids and there are moments when you can close your eyes and pretend you have ‘beat’ Duchenne. This makes it very difficult to identify improvement during these ‘golden years’ and certainly impossible to suggest the improved function is due to supplements.

Gillian Butler-Browne will be presenting during the conference. Her expertise is supplements – she works with the Muscle Community – works in DMD and with the muscle builders. Get your questions ready!

There is also the consideration of steroids and thankfully, the European Neuromuscular Committee (ENMC) and American Academy of Neurology (AAN) have published suggesting steroids are the ‘gold standard’ in DMD. What is unknown is the appropriate age for starting a steroid regimen, though many (experts and parents) now believe early (diagnosis 3-5 years) intervention provides the most significant benefit. There are many regimens out there but I think we would all agree, it comes down to trade offs – utilizing the most frequent regimen while limiting side effects. If the child is able to tolerate daily, it is a good thing, but some children simply cannot for reasons related to behavior and weight.

Once these major decisions are made, families turn to research. What are the current research strategies? How and who stands to benefit and WHEN. The most important question of all – WHEN. It is easy to imagine, after speaking with a brilliant researcher or physician, you decide to ‘hang your hat’ on a certain individual or certain approach. And, what else happens, in your head you calculate or approximate just when that strategy will occur and how your son will benefit. Maybe your heart makes this decision – that a certain approach in a certain year will get you out of the world of Duchenne.

Tradeoffs are part and parcel of how we think and how we work things out in our head. “My son is 7 years old. Viral gene therapy will do …. My son is 8 and Direct DNA injections will occur….. Phase I Plasmid DNA trials are complete and Phase II will happen…. Antisense oligonucleotide therapy trials begin … By (add in your own date) date, they will know something… By X date they will do systemic delivery … By X date my son will be…... he will be walking, he will be ‘fixed”. Myostatin Inhibition trials have started …. By X date they will have data, By X date they will expand to DMD… and so on. You will drive yourself crazy.

We always work on comparisons, on the ‘if - then theory’. If my son is X today, tomorrow he will be Y and then we will have a certain treatment with the assumption that whatever intervention we believe in will ‘fix’ Duchenne, will halt muscle degeneration.

The really good news is that there are a number of strategies are coming forward and they are all promising. The animal data compelling and certainly suggests strategies have sufficient maturity to initiate clinical trials. Several trials are in the planning stages:

1. Protease inhibitior BBIC
2. Calpain Inhibitor - Myodur
3. PTC124
4. AON trials (exon skipping) single muscle
5. Direct DNA injections
6. Myostatin inhibition (Becker, FSH, Myotonic)
7. Single muscle AAV/Microdystrophin

What is unknown is what I call the IF FACTOR- if the preclinical (animal) data that demonstrates benefit will be the same in our boys.

The bottom line is that our best strategy is not to ‘hang our heart’ on any one strategy or one approach or any one person. Rather to do whatever necessary to accelerate translation of ALL promising strategies with the goal that for some, perhaps one approach will be sufficient. For others, we may need to utilize a combination of strategies in order to buy a lifetime.

PTC124

Last week Kimberly and I met with individuals at PTC Therapeutics. Like you, we were anxious for news about the upcoming clinical trial. PTC is scheduled to meet with FDA on June 10. Of course, these meetings are ongoing and it is expected the protocol will be finalized at this time. Sites are identified for the upcoming clinical trials. They are: Children’s Hospital of Philadelphia (CHOP), Cincinnati Childrens Hospital Medical Center (CCHMC) and the University of Utah. The protocol is in the final stages and it is expected 24 children will participate. If you are hoping your son could be a candidate, you need to have his premature stop confirmed by the U. Utah/Dr. Kevin Flanigan. If your son has had a muscle biopsy, make sure you have this record available. If he has not, this would occur prior to starting the drug. Outcome measures of the trial are functional improvement and signal (*dystrophin expression). Pre and post biopsies will be required. This is a Phase II clinical trial. If (the IF FACTOR again) all goes well, the trial will expand into a Phase III trial. We expect the trial to begin in July (cross fingers and pray).

Albuterol/Clembuterol

Both are B2- agonists, both decrease the inflammatory response, both MAY have benefit in skeletal muscle. Results of the Albuterol trial suggest the 12 week treatment with extended release Albuterol MAY increase strength in DMD patients but recognize a larger, double-blind, randomized study is necessary before the results can be confirmed.

PPMD provided support for the first year of the clinical trial at UCLA. Drs. Melissa Spencer and Jim Tidball have had a longstanding interest in understanding the role of inflammation in DMD. You will hear a range of opinions from families who have either participated in the trial or gave their child Albuterol (from their own doctor) –from comments such as benefit, to maybe some benefit while some families suggest they saw short term benefit which then disappeared.

We have also had discussions with body builders who use Albuterol or Clembuterol. They suggested that they take these drugs intermittently, some suggesting 2 wk. on and 2 wk. off. Dr. Lee Sweeney thought this might be a better approach than daily use because Albuterol downregulates the B2 receptor which may account for short term benefit.

While Clembuterol is not on the market in the US, Dr. Simon Maybaum (heart transplant surgeon -Columbia U/NY) has been investigating Clembuterol and currently has it is trial with his ADULT heart failure patients. We met with him several months ago and he is now collaborating with Lee Sweeney.

So again, we have a ‘maybe’. Animal work is ongoing. There are recommendations for and interest in organizing another clinical trial. Some experts worry about Albuterol’s effect on the heart and all this needs to be considered as we move forward. There were no cardiac problems in the early trial.

PPMD has been interested in understanding potential benefit of anti-inflammatory agents and has provided support for this work in the laboratory of Andrew Hoey (Australia). Dr. Hoey is interested in drugs such as Enbrel, Remicade and other anti-inflammatory agents. He is very cautious about the potential risk to cardiac muscle.

In addition, PPMD is providing support for a meeting specifically focused on Anti-inflammatory agents. The meeting will involve experts in the DMD field as well as experts in the area inflammation, to include clinicians with experience treating Rheumatoid arthritis. Questions for the meeting involve the degree of inflammation present in DMD muscle, the impact of anti-inflammatory agents, the use of anti-fibrotic agents, discuss risk vs benefit of known anti-inflammatory agents and plan next steps in terms of accelerating translation into clinical trial.

Both Dr. Hoey and Dr. Spencer will be presenting during our annual conference.

Posted by ppmd at 04:12 PM | Comments (5)