This web site uses cookies. Do you accept the use of external cookies? Yes No Know more x
Survey about achondroplasia
We have designed a questionnaire with the purpose to better know the population connected to achondroplasia.
The questionnaire is optional and anonymous. The data obtained will be used for statistical purposes and to better understand the natural history of achondroplasia. Please consider answering.
If you would like to take the survey later, you can click on the link at the top "Register at BA"

LP Doc Talk is a project of Growing Stronger, a foundation based in S. Francisco, California and founded by Amer and Munira Haider, parents of  Ahmin, a boy now with 7 years-old, born with achondroplasia.

On the 8th May, 2016, Prof. Ravi Savarirayan answered a series of questions about BMN-111 clinical trial.
Next, is the transcription of the most important parts of the audio recording:

1.The first question I have here is regarding the availability of BioMarin, and it'€™s from Jenny from Russia. She talks about it would take a few years to register the medication in Russia. So she'€™s asking about the availability.

At the moment it's very hard to know the availability because we'€™re still in very early, early stages of the trial. So at the moment the drug is only available in the context of the trial because all of the drug trials so far are about to test the safety of this medication; because it'€™s the first time this medication is being used in children. It'€™s going to be some time before we'€™ve closely established its safety and hopefully then establish its effect and efficacy in this condition, and then basically we have to wait on the company and the regulatory authorities strategy on whether it will be available in every country.

But certainly one of the things that I'm very passionate about is making sure that new genetic therapies and new technology can be available to all people and all children who may need this medication and who may benefit from this medication. So I'€™ll certainly be working with the company and with regulatory authorities regarding that.

2. The next question comes from Spain and it'€™s about if giving this medication can correct the curving of the shin bones and the curving of the spine.

Again, we hope theoretically the medication may have benefits on all the bones including the spine because of its mechanism of action but it's still really early days. At the moment we really only have one year's data on the medication at a specific dose, and we do know that that'€™s increasing growth velocity, as was released recently by the company on the Research and Development Day in New York, but it'€™s really too early to tell the other effects at this time. So we really do have to wait. Although it is very exciting at this time, we'€™re still in the early steps of this journey to understanding exactly where this drug may have a place.

3. The next question is from New York, asking about leg lengthening and about surgery for leg lengthening and also surgery on the jaw for teeth.

Really, I think at the moment if your dental surgeon or ENT doctor is not familiar with achondroplasia then he or she will need to reach out to doctors who are. Really the mainstay of treatment will not be different to any other conditions and the bone healing will be the same, but often dental crowding is the problem in achondroplasia. So really your orthodontist would be best to speak to; a practitioner who has been familiar with the condition. And if your son is still a child he might be able to go to one of the major children'€™s hospitals in your area there in New York and maybe their dental department would have had much more experience with children with achondroplasia and other conditions, where sometimes because of changes in the way the craniofacial skeleton is formed dental crowding can be a problem.

That would be my advice, and specifically as a general rule it'€™s always good to make sure that if you have a child with a relatively rare condition like achondroplasia who needs some sort of management, it'€™s really important that you can canvas opinions from people who have seen many different cases and understand a little bit about the condition because it'€™s not quite the same as operating or managing a child without the condition. So thanks for your question there.

4.The next question is, what is the appropriate age to start the medication? How does the treatment work and how long does it go for? And finally, when could it be released?

We still don'€™t know what the appropriate age to start the medication is, and that'€™s why one of the trials is occurring. Currently the trials involved children aged 4 ½ to 14 ½ years, because it was thought that that would be safest age group to trial the medication in. But obviously a lot of growth is done before age 5 years so there are plans for a study to occur in children younger than 5 years, and at the moment that is being planned and possibly may start this year.

The treatment works because in achondroplasia there is a fault in a gene, or a genetic instruction packet called FGFR-3, and basically what that does is the gene is overactive which decreases growth. It'€™s a little bit paradoxical and it'€™s a bit like overwatering a plant. If you leave the tap on and overwater the plant, the plant doesn'€™t grow very well. This medication doesn'€™t turn the tap off but it puts a kink in the hose so that growth can resume as previously. So that'€™s really how it works.

We still don'€™t know how long treatment should go for. Obviously there comes a point for all girls and boys when growth stops and that'€™s when the growth plates, which are the growing parts of the bone, fuse and obviously any time that that happens the drug will not be effective. So again, we still don'€™t know when the medication will be released but obviously we have a long way to go because we'€™re still in the early safety trials for the moment. So thank you for your question. I think that'€™s a question from my part of the world in Australia. [0:07:50]

5.The next question is from Romania, in Bucharest, and it'€™s a question about whether the medication BMN-111 can be administration for hypochondroplasia.

At the moment, the medication is only being used for achondroplasia. There may be theoretical reasons why it could be given to people with hypochondroplasia but that'€™s a very different condition, clinically, from achondroplasia. At the moment there are certainly no plans that I'€™m aware of in the world for that to be done, so the answer to that would be no, currently.

And the next question is again about treatment, which I'€™ve just covered so I won'€™t go over that again.

In the case of hypochondroplasia, yes if the medication or a medication like this medication were going to be used in a condition like hypochondroplasia, it would need to be in the setting of a ethically-approved clinical trial to make sure that firstly there'€™s no harm, and secondly that there is an effect that decreases medical complications. Again, it would be like any new drug being trialed but at the moment that is not in practical use.

6. The next question is from Western Australia. "When will Phase 3 of the BioMarin drug trial start?"

Again, at the moment it'€™s not known, but when we had the Research and Development Day in New York it was stated publicly that it would be hoped that Phase 3 trials would be beginning sometime in 2016. So basically that'€™s all I know at the moment, and typically any Phase 3 trials, speaking generically, would involve a larger group of patients to understand the medication more in larger numbers.

7. The next question was how to apply for Phase 3 trials. Well, that would depend on the sites chosen to lead the Phase 3 trial and when enrollment started, and it's too early to tell at the moment. But it'€™s hoped that Phase 3 may start sometime this year.

8.The clinical effects of BMN-111 in stage 2.

Well they'€™ve just been released very recently, and the 12-month data have been released showing that the medication most importantly is not showing any serious adverse events or side effects that has required stopping of the medication. And secondly, it appears to be having a promising effect on growth velocity at the 15ug/kg/day dose, with growth velocity on average increasing from 4 to 6 cm in a small number of children with achondroplasia. And this obviously needs to be further investigated and studied.

9. The next question is, do patients need to take the medication every day?

At the moment, it'€™s given as a subcutaneous injection, very much like an insulin injection, and currently it'€™s a daily injection. And again, it will probably take a lot longer to understand whether the medication needs to be taken every day or can be taken less frequently to get its maximum benefit. So unknown at the moment, that question.

10. And finally again, when will the drug be available?

That'€™s impossible to say at the moment. Things are going promisingly well but it'€™s still very early Phase 2 trials at the moment.

11. The next question is from London in the UK, talking about the effects of sustainable bone lengthening and if the trials lasted only a year so far and the final individuals is not yet known, is it possible that growth is accelerated but the final height will actually still be within the final achondroplasia range?

Well that'€™s a very good question and that'€™s why it'€™s very important that we'€™re very, very careful and that we don'€™t jump to too many conclusions, because it'€™s still early days and all of the initial studies, the Phase 2 studies, are really about assessing whether this medication is safe and tolerated, which it appears to be so far in the study.

The next things are about sustainable bone growth and bone length. Yes, many medications that have been tried in the past such as growth hormone have had a temporary effect but no final height effect.

The only thing that I would say, speaking personally as a scientist, is that this medication appears to be a precision medication in that it affects specifically the abnormality in achondroplasia whereas growth hormone therapy was never going to do that because children who have achondroplasia are generally not deficient in growth hormone. So we hope that it will have sustainable effects, but I completely agree with this caller that it'€™s too early to talk about sustainable effects on bone length.

12. Final questions, someone from Texas in the United States. Questions about the 30 microgram/kg/day cohort. Has there been evidence of catch-up growth?

Well, we don'€™t know at the moment. Those data are still being analyzed. It'€™s too early to tell and certainly that hasn'€™t been released at the moment. And again, talking about the drug coming to market. It'€™s very hard to tell and it will depend on how the Phase 2 and then the planned Phase 3 studies go.

13. The final question was, "€œDo the daily injections need to be given in a specific area for them to be effective?"

Again, that'€™s a good question. And at the moment, much like insulin, the injections are given with varying the sites of the injection. They can be given in the buttocks, around the thighs, in the upper arms, and in the abdomen as well. The injection sites are usually rotated so we don'€™t want to keep injecting the same site and causing irritation.

The other good thing is that really apart from a little bit of mild redness at the injection site there haven'€™t been any other significant reactions, which is great. But certainly any injection that delivers the drug into the subcutaneous tissue, which is just underneath the skin but not into the muscle, is the mode of administration currently of this medication.

I think they'€™re the main questions I had on my sheet and I hope that my answers have helped shed some light. I think the main thing to remember is that although there is a lot of promising data on the first 12 months use of this medication in children with achondroplasia, it'€™s really important to remember that this trial is all about making sure the medication is safe and then the next parts of the trial will be looking at effectiveness and the best way of using this medication.

The way I look at this is that this is a great new option for families and children with achondroplasia, and it'€™s certainly an option that wasn'€™t there previously and we'€™re hoping that it may well decrease the medical complications of the condition and keep healthy children healthy as adults. So it'€™s an exciting time but it'€™s very, very early days and we still need to learn a lot more and we'€™re working very hard to do so. The primary consideration is always the safety of our patients. Thank you very much.

14.  Are we going to be able to give the treatment to our six-month-old daughter in the near future? In your opinion what would be the best age to start the treatment?

I think again if the treatment is proved to be safe and effective then starting the treatment potentially as early as possible may have better long term effects, but it'€™s too early to tell.

Certainly there are plans, as has been already released on the website, for a study looking at children younger than 4  ½ years. So there may well be. There may well be potential to treat children as young as six months but at the moment it'€™s too early to give any more specifics. From a theoretical perspective, if the medication is safe then early treatment could result in better long-term effects in terms of medical benefit.

15. Question from Japan:  "€œI'€™m contacting you because of my son with achondroplasia. I feel that it is a real glory to send questions to you, as the greatest doctor in terms of international. My questions are: a) In phase 2, the first 26 patients from January 2014 and their extension, what about the interval after the first period? b) Is there anything to dose? c) In my understanding there is no dosing period after the first period finished until second period started. If they stopped daily dosing, even in a few weeks, I think something could go wrong. For example, the head is going to be bigger."€

Thank you for the question. At the moment with the studies they rolled over into each other so none of the children missed any doses of injection. So basically one study finishes and the next one starts immediately, so there'€™s not been any break.

But again, we don'€™t really know yet. If children start the medication and stop the medication we'€™re really not sure of those effects at the moment. But certainly if I'€™m hearing the question correctly, the children who started off in the six-month initial trial and then the 18-month extension, they just went straight into the extension and they didn'€™t miss any medication unless there was another issue.

16.  What do you think of cohort 5? I think the quantity seems too much because the result of cohort 3 showed around normal growth. The medium growth velocity among the subjects was 6.1 cm a year, according to the June 2015 data. I'€™m really interested in an expert'€™s opinion. If another Phase 2 about the cohort is needed, it will be much longer in terms of estimated study completion.

That'€™s a good question, but I don'€™t really have the answer because at the moment, as you know, there'€™s a cohort at 15 and there'€™s a very small cohort at 30 micrograms/kg/day, and at the moment there haven'€™t been any more plans for any further cohorts. There was always the option for another cohort, but that'€™s something that the company is internally considering at the moment. At the moment all we know is that Phase 2 is ongoing, nothing else has been confirmed. And certainly the fifth cohort for the initial study we don'€™t know anything about that at the moment.

17 .One last question from Japan. "€œDo you have any idea about final practical use stage in your country?"

Oh no, no. It'€™s way too early for that. We'€™ve just started. The children have only been on the medication for a short period of time and we'€™re just understanding the safety profile and just beginning to explore some of the early effectiveness profiles. It'€™s going to be sometime more before that.

Again I have to just mention that we want to go slow, and even though the primary results are promising we need to be meticulous and slow as we understand more about this medication. So the latest press release and the release from the company just recently is the latest information that we have and the latest information that I have as well.

18.  Here'€™s another question from Edinburgh, Scotland. "€œMy child was born three months ago and diagnosed with achondroplasia. Are there any trials planned for infants and toddlers in the future, and would it include children from the UK?"€

So, just to say again that there are plans for treatment of children under 4  ½ years. It will become more clear as time passes. Potentially if the caller'€™s child is in the UK, there is a site in London, in England. So potentially the answer would be yes but I would recommend that the caller contacts the company who could discuss that and give the name of the principle investigator in the United Kingdom.

19.  How can we follow up (perhaps with a call or appointment) later to see if your drug becomes indicated eventually, in time hopefully? Where are your U.S. centers for contact? What age will be the '€˜end times'€™ to try it? Do you suggest patients just wait, or will use of growth hormone knock off patients from any study trials?

Again, the best way to do things is to go through the company, the website, and to keep updated. At the moment it'€™s early days and the medication is still in trial. It'€™s a long way from being licensed and those types of things. The best way would be probably to keep updated with the website and I know that many patients have almost more information than us because they'€™re checking it every day.

The next thing is that if your child is on another trial medication or on growth hormone, that will preclude them from, I would expect, being in this trial as well. So we have to wait and see. But certainly with regards to updates, and the idea will be if this medication is indicated then obviously the idea would be to have access and that would be dependent on each country and the regulations there.

But there'€™s a long way to go before we need to do that. The first thing is to make sure that we have a safe medication that is working in the way we want it to work.

  20.  "Will there be any reason to consider this drug for other possible beneficial reasons -€“ hand and foot growth, et cetera - or will this likely just affect long bones?"€

Basically, this medication should affect all the growth plates, and there are growth plates in all of the bones including the spine. So we have to wait and see what the effect is on all of the bones. But obviously the most effects will be on the bones that grow fastest, which are the long bones. But it will, theoretically, have an effect on all of the bones that form by this method of bone growth, which is called endochondral ossification. From an academic point of view it'€™s a neat solution because it actually is looking at the condition at its source.

21.  Is there any potential for insurance coverage for this novel new drug?

Oh, I have no idea and that would vary from country to country. It would only be after the medication was licensed so again, we are about 20 steps from there.

22.  Are there any trials planned after Phase 3? Any on HCH, or will this perhaps requite off-label use?

Not that I know of. And again, with regards to other conditions there'€™s no plans that I know of at the moment but things change very rapidly so we'€™d have to wait and see. Five years ago we wouldn'€™t be having this conversation because there was no therapy for achondroplasia that had the potential for a trial. So things change very rapidly. We'€™re in an era of medicine and genetics where there are new treatments emerging, so we'€™ll just have to wait and see about all of that.

In fact, I'€™ve just written a paper on emerging therapies for skeletal dysplasias, which has just been published online in the American Journal of Medical Genetics, and can be downloaded by any of the listeners, which summarized just where we are with not just achondroplasia but other skeleton dysplasias as well.

23. I know that the doctor says that we are about 20 steps away from being licensed. I know it'€™s obviously hard to tell at this point, but do we know at least an estimate, more or less, of what 20 steps away looks like? Is it like two years away -€“ assuming everything goes well. Are we talking about two years away? Are we talking about 10 years away? What kind of timeframe, if we can even get an estimate? I don'€™t know if that'€™s possible but I'€™d be interested in knowing.

Thank you for your question but I would just be guessing. I have no idea. I'€™m probably the wrong person to ask that question, and it would really depend on what trials are done next and the results that are coming out. And so I have really no idea.

Obviously the idea would be to work towards it as quickly as possible, but only when all the information is present. But I really couldn'€™t give you a time and I think that question is also being asked to the company, who know more about it than I do, and they also aren'€™t giving a timeframe. So I really wouldn'€™t want to speculate at all.

All credits: Growing Stronger

To view this site you need Internet Explorer 8 (or a higher version)
or another internet browser.

Thank You.