On Friday, September 25, we met with EMEA (the European regulatory agency) to begin dialogue about accelerating exon skipping. The Steering Committee met on Thursday to rehearse. A small group of us presented and/or analyzed each presentation. We wanted to strike the right tone, provide detailed information about exon skipping and we wanted them to understand this urgent need. At the end of the day, we were energized and ready to go!

We are all aware that both companies Prosensa and AVI are working on exons 51 (Prosensa- 44, AVI -50). What happens next? Will the next exons to be skipped take as long? What about the more rare mutations? Will every chemistry for each exon have to go through the common path of taking new drugs into the clinic? If this is the case for each individual exon, it may threaten the viability of exon skipping. And for our sons, it will take too long. They have no time to wait.

We stayed at a Hilton Hotel on the Thames River. We met at 8 AM and boarded the ferry, crossing the Thames. In fact, it seemed rather symbolic. We were entering new territory. When PPMD was organized 15 years ago, we could only dream about this day.

The meeting went very well. Francesco opened the meeting, introducing AON (exon skipping) as a potential therapy for DMD. Elizabeth Vroom presented the parent’s perspective. Two videos were shown – one of Justus at 4 years old. The video was actually a commercial – the first DMD commercial, donated by a PR firm 15 years ago and filmed on the beach in S. Africa. The second was done several months back. Justus as an adult, talking about outcomes – what would make a difference in his life today. It was striking in so many ways, more than I am able to describe in this short blog. It hit home. The impact, the need, the urgency.

Additional talks included delivery to tissue, results to date, toxicology, regulatory issues, backbone chemistry, trials with small populations and conditional approval.

I wrapped up with this:
The need is urgent.
Doing nothing increases risk for our sons.
Boys, all boys have little time. For the young, we need to save what they have. For the adolescent, we need to protect/preserve what they are losing and for the young adults, we need to hold on and work to restore what is lost in order to improve their quality of life.
We recognize that laws (regulatory and otherwise) are made to protect the masses, but in certain cases, in emergencies (for instance) laws are suspended. The example Elizabeth described was that of an ambulance. Speeding limits are designed to protect all drivers. In event of an emergency, the ambulance is granted permission to ignore the laws in order to protect the individual(s), help with the emergency.
In our lives, DMD is the emergency. Regulatory agencies need to consider what ‘sirens, sounds, lights’ – modifications can/should be deveoped to expedite AON as a potential therapy.

Skipping exon 51 serves only 13% of the boys with Duchenne.
Skipping exon 44 served only 6% of the boys.
Skipping exon 50 serves only 4% of the boys.
Exon skipping has the potential to help approximately 85% of all boys, but to do that in a timely way, we need to expedite the path.

The EMEA was open, interested and willing to consider how to move forward. They ‘got it’. Elizabeth McNeil, MD (orphan products/FDA) was present as well. I am certain she will help us deliver the message in the US.

Progress! We indeed crossed the river.

Ryan has posted the briefing document. We are making small revisions and the final document will be posted.

Download Briefing Document:
Muntoni EMEA introduction.pdf


Download image:
dystrophin exons EN.pdf

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Staff
Comment by Pat Furlong on October 4, 2009 at 8:26pm
Deb, I think we need to get these folks talking. I think it is critical to have the ability to measure subtle changes Deb.
Comment by Deb Robins on October 4, 2009 at 8:22pm
I understand about the rings. Doug won't wear braclet or watch anymore - even a long sleeved shirt is more difficulty than short sleeved. He won't use iphone but the slimmest and lightest little nokia he could buy on his lanyard. Thank you for seeing the little things as well as the big things!
Comment by Deb Robins on October 4, 2009 at 8:18pm
I should have known you would have more eggs in baskets Pat! One of my AB sons used video overlays in multiple windows in sports software 10 yrs ago now to compare his own javelin throwing with the olympian's technique so he could modify his angles and pace etc, so maybe sports institutes have software your people could modify?

Staff
Comment by Pat Furlong on October 4, 2009 at 8:07pm
Hi Deb, The are using the SAM (step activity monitor) ini the PTC124/Ataluren trial. Craig McDonald did some early studies with the SAM, using DMD boys and healthy peers. Data suggested DMD boys take 30% steps than their healthy friends. We are working with a group out of California to develop hand/arm technology using the iphone. It is still in the testing phase, but it would be able to detect subtle movements. In the FA trial (idebenone) they utilized computer technology with weekly testing at home. I think we have to be more creative with the non-ambulatory population with regard to outcome measures. Small subtle differences could /must be utilized for proof of concept and could potentially improve the qualty of life for our young adults.
One story comes to mind. One young man (actually not so young -38) used to wear rings on several of his fingers. I saw him not long ago, no rings. When asked why - he said the rings made it impossible to move his fingers. Technology could enable precise measurements.
Comment by Deb Robins on October 4, 2009 at 7:54pm
Sorry for all spelling mistakes but I just thought of another reason for low impact outcome measures like hidden video. The effects of placebo and the effect of wanting to please the doctor (whom parents and child can almost love) could be controlled. I know if the stakes are high my own children will use more effort than they have natural gift to conquor - we all do. Can we not work on outcomes measures to take into account some of these effects and 'see' the miniscule strength that every boy is so grateful for, even if someone else can hardly notice it.
Comment by Deb Robins on October 4, 2009 at 7:48pm
Thanks Pat, the case in writing and as you describe it seemed to be put so forcefully and I dont' think i have ever read the hope of the non-ambulatory expressed as strongly by a group of parents albeit medically proficient ones as you, Elizabeth Vroom and company. Is there no plans to skip exon 53 - I thought it was next most common? And something that I wonder about is the advanced technology used to develop this therapy is not matched in the comaratively primitive outcome measures. Surely the sporting industry can help our scientist clinicians to develop highly technological ways (using video softward perhaps that can measure effort like the cardiologist measures our sons heart wall thickness and function in a scan) and with these outcome measures the benefit to youths with advanced necrosis of muscle will reinforce the urgency for all? Not an expert but the measures seem very old fashioned to me considering all that man can do today with technology.
Comment by Ofelia Marin on October 1, 2009 at 12:50pm
Thanks Pat.

Staff
Comment by Pat Furlong on October 1, 2009 at 11:03am
Ofelila, FDA and EMEA have approved drugs after a Phawse II/III. There are also times when conditional approval has been given with post marketing studies. There is little doubt that post marketing studies will be required in order to understand long term effects of these therapies.
To be quite honest, my opinion is not useful it would be only a guess and as a parent, I often would hang my heart of opinions of others. While it may be possible, I'm not sure if it is probable. I understand this is very frustrating, but these next 6-9 mo. should provide answers.
Comment by Ofelia Marin on October 1, 2009 at 10:18am
Hello Pat,

I have been thinking about this for a while and decided to ask your opinion. I am trying to understand how this path to market approval could be for AVI (assuming that the drug show efficacy!). Looking at Prosensa’s PRO51, I see that they had Phase I/IIa in Europe and now preparing Phase II/III with sites in more countries including US. Could the drug be approved by the FDA as well as EMEA (IF it works!) after this phase? If the answer is yes, then why doesn’t AVI do the same thing? Phase I/IIa in the UK now, then Phase II/III in US as well as other countries, then market approval both in Europe and US? This way no time would be “lost” in the US due to the clinical hold imposed by the FDA. (I do not think the time is lost since the UK trial is attempting to pinpoint the therapeutic dose levels…just thinking in terms of timing until market approval).

Thank you.

Staff
Comment by Pat Furlong on September 30, 2009 at 5:50pm
Hello Ofelia, FDA /AVI discussions are ongoing. You are right, the hold is based on the tox package. I think we all want to see things progressing in the US as they seem to be in the UK. Keep in mind, Prosensa's systemic trial was in Belgium, not the Netherlands, because the Dutch will not allow biopsies on children. Each system has its quirks that need to be ironed out. This is very frustrating I agree, but I feel certain both companies have recruited leadership teams (execs are from Genzyme) that have considerable experience and understanding to cut through the current bottlenecks.
Tina - there are many factors involved in the decisions related to what exons. While some make more sense from the perspective of frequency, AVI/Procensa make these decisions based on application, specific chemistry, toxicity, investment and other factors.
EMEA was a dialogue, nothing more. We did not expect decisions because regulatory agencies need to respond to a specific application. Rather we made the case that
exon skipping is a promising strategy for 85% (approx) of individuals
that the need is great and doing nothing increases risk for individuals with dmd
that the older boys/young men with DMD have less time
that it is important to consider streamlining the process (for instance, modified tox package, approval for backbone chemistry, small populations for clinical trials)
insure access to all individuals who could potentially benefit
recognize that status quo in a progressive debilitating condition IS benefit
Listen to the young men regarding outcome measures and impact on quality of life.
This will be an ongoing dialogue with regulatory agencies.

Ian, like you I find words such as 'these things take time" frustrating and patronizing. At the same time, I understand the need to 'do no harm'. I think we have to find the middle ground, develop a sliding scale of sorts with regard to risk (how much risk are parents/individuals) willing to take? Sliding scale would perform a risk/benefit analysism, weighing disease burden, disease severity, potential benefit and risk.
I know it is frustrating because there is time involved, but to be honest, it is a good thing that we are able to have the discussions.
For the last too many years, we had nothing to discuss, nothing to put on the table.

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