The Phase III

Posted Monday July 01, 2013 by Melissa

Our community has been waiting with anticipation for the next phase of this intrathecal trial to begin, that is, the Phase III clinical trial.

Last week, I became aware of some additional details. The following is my understanding of information so far, but it is as yet unconfirmed. The definitive source for this information will be Shire HGT and the principal investigators at each relevant site. I am sharing all of the information I have thus far, in hopes of dispelling any rumors and to provide clarity. I will update once I know more.

Sites: I would expect these to coincide with the locations of the current natural history study, noted below, but obviously, this could change.

3 U.S. – UNC, Chicago Lurie, Oakland

1 South America: Argentina

2 Europe: UK, Spain

Scheduled begin date:

Hopefully to begin screening as early as September.

Length of trial:

12 months.


10mg, every month.

Qualifying cognitive scores:

Floor of 55, not sure of ceiling. Speaking of cognitive testing, after many discussions with parents whose MPS II children have undergone cognitive testing, I will soon release a white paper discussing recommendations for psychological testing of severe MPS II children.

Qualifying Ages:

I have no idea here.

Treatment v. Control:

2 to 1 treatment ratio – what this means is that once a child qualifies, they will randomize and have a 2/3 chance to be decided to receive drug right away and 1/3 chance to instead receive no treatment for 12 months (but my understanding is that they would be eligible to receive drug thereafter).

Exclusionary criteria:

My unconfirmed expectation is that the same exclusionary criteria that applied during the Phase I/II trial will continue to apply here which means that a shunt or ICP over 30 would be an exclusion. It remains to be seen, however, whether they will continue to use the ICP criteria at the end of a no-treatment period to exclude a participant (sadly, as occurred during the Phase I/II). My personal belief, after discussion with researchers in the field, is that a shunt should not be an exclusion (and it is not an exclusion in the MPS I intrathecal trial) and I continue to hope that it will not, but I have received no reason to so hope.

Total enrollment:

I have no numbers here, although I personally would not expect the total to be over 30. I have been wrong before, however.


English and Spanish.

New Port:

As far as I know, we are still waiting for final FDA approval of use of the new port, both of us current participants in the extension study, as well as for Phase III trial participants. I personally am hopeful for a port surgery for Case sometime in the early part of the school year.

Clinical Endpoints:

These are the goals that the company is seeking to prove to the FDA as the sign that the drug works. (First of all, I want to bang my head against a wall because I watch evidence that the drug works walking around my house everyday, but then again, I understand that drugs may not work on everyone or every type of patient, so I need to be patient I guess). I don’t know what these are specifically yet.

Obviously, they would include some cognitive endpoint, such that those participants on treatment on average either improve, maintain, or lose cognition more slowly than those in the no treatment group. However, to me, the more significant effect of the drug was in overall improvement in Case’s behavior and independence. These domains were both measured in our trial with parent response tests so I understand why those alone would be difficult as endpoints, but if there were a way to have objective verification of these improvements or an improvement index that took into account the collective cognition, behavior, and independence skills, that would make a lot more sense to me. In addition, the reduction in ICP is also an important endpoint in and of itself given the prevalence of hydrocephalus or even non-shunted higher than normal ICP in Hunter boys.

Obviously, if they can achieve the use of a surrogate endpoint such as CSF GAG measurement or some other biomarker, that would be preferable as well. To that end, please review and support The EveryLife Foundation’s efforts to guide the FDA in applying biomarker endpoints to rare disease clinical trials (please see the relevant white paper).

Relationship to Natural History Study:

My expectation is that based on the familiarity that these sites have with those children already enrolled in the Natural History Study, the principal investigators at each site will call back those children to screen first. Again, they could choose to do something different, this is just my thought.

Time to Market:

Many of us are concerned with how long this IT drug will take to get to market for those who are excluded from the trial or for newly diagnosed children. My calculations are that when the trial begins, the soonest it is likely to get to market would be at least 3 years from that time. If you looked at best case scenario – 6 months to fully enroll (which would be fast), 12 months for the trial, 6 months to analyze data, 12 months for FDA approval. Now, of course, anything can happen, and my sincere goal is for this process to go as quickly as it can safely be done. I would hope that Shire seeks every opportunity to speed this process along (the FDA has such designations as Breakthrough designation, Accelerated Approval, and Fast Track which can each speed along parts of the process toward approval).

My Take:

My business sense understands many of the decisions, whether it be the cognitive or exclusion criteria, locations, numbers, etc. I understand it in the “overall MPS II community” sense, as one who is trying to get this to market in the fastest and safest way to benefit the community as a whole. But that doesn’t mean I embrace it from an individual or emotional sense. My mind and brain rage against the individual application of such arbitrary cognitive scores or narrow inclusions. My heart is already (and has been for the past 2 1/2 years) aching for those boys who do not qualify. I mean to make it my mission to find whatever treatment can be had for every MPS II child in their lifetime so that every mom and dad can receive the same gift we’ve been given.

That is all I know. Even with just this information, my brain is reeling, considering those families and boys that I know and love who will likely screen for this trial. I know the seriousness of this endeavor and the weighty result that hangs in the balance of a child qualifying or not. I pray for the protection of our boys and the wisdom, peace, and comfort for all of you parents who are seeking this information, whatever may be the result.

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