Beyond Achondroplasia

Growing together with Clara

July 13, 2018
by inesp.alves
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A new step forward for TherAchon: the Dreambird study on Achondroplasia

TherAchon is a Biotechnology company that was established in 2014 and focuses on rare diseases. It is developing a drug for achondroplasia in particular: TA-46, which is planned to go onto phase I clinical trials in 2019 [1].

In order to prepare for the clinical trial with TA-46, TherAchon needs to capture many parameters on achondroplasia, as for example, establish how much children with achondroplasia grow each year, or understanding the baseline growth.

Image adapted from Brain for the cure

TherAchon has announced at the end of June that they have started a Natural History study on achondroplasia, called Dreambird.

The Dreambird study will follow-up 200 participants from several sites in Europe, USA and Canada which will evaluate and measure children growth, disease progression, the potential risk of complications related to ACH and protection factors, among other biological parameters for a specific period [2]. Which parameters will be measured, exactly, have not been disclosed yet, but the full details of this study will be available in the Clinical Trials website very soon.

Is important to emphasize that, because the Dreambird study is an observational study, the experimental drug TA-46 will not be administered at any time in this study.

Nevertheless, since one of the objectives of this study, besides providing a better understanding of pediatric achondroplasia, is to establish the baseline growth rates and to identify biomarkers for achondroplasia, it will be mandatory for children to participate in the Dreambird study before being enrolled in the future interventional studies, namely: the phase 2 and 3 of the TA-46 clinical trial.

The age of children to be enrolled in the Dreambird study is from 0 to 10 years old.

 

References

June 30, 2018
by inesp.alves
1 Comment

Vosoritide is now in study in children under 5 years old

BioMarin announced on the 14th June 2018, the first administration of BMN 111 to young children with achondroplasia under 5 years old. (1)

This is the BMN 111-206 study, a phase 2 study in Infants and Toddlers.

 

BioMarin Pharmaceutical logo (PRNewsfoto/BioMarin Pharmaceutical Inc.)

 

What happens in a Phase 2 study?

The participants have the disease or condition to be treated and can last up to 2 years. The purpose of this phase is to evaluate efficacy and side effects of the drug. On average, just approximately 33% of the drugs in evaluation in phase 2, move to the next phase. (3)

The 111-206 is a randomized, double-blind, placebo-controlled study of vosoritide in approximately 70 infants and young children with achondroplasia for 52 weeks or 1 year. This means that participants have an equal chance of receiving either placebo (an inactive treatment that looks the same as, and is given in the same way as, the investigational therapy but in just saline) or the investigational product BMN 111. It is not known whether placebo or investigational therapy is being administered to prevent bias. (2)

The study will be followed by a subsequent open-label extension. This means that at this time, both researchers and participants will know if they are getting vosoritide or placebo, and at what dose. (1)

Important information

Children in this study will have completed a minimum three-month baseline study to determine their respective baseline growth prior to entering the Phase 2 study. This differs from the phase 2 study, BMN 111-202, that requested at least 6-month of pretreatment growth assessment in Study 111-901 before study entry, and one standing height at least 6 months prior to screening for 111-202. (4)

This trial is opening in Australia, Japan, the United Kingdom and the United States and participants
must remain a resident of the country they enrolled in throughout the trial period. (2)

Main goals of this 111-206 study

The main objectives of the study are to evaluate the safety, tolerability, and the effect of vosoritide on height Z-scores, which is the number of standard deviations in relation to the mean height of age-matched, average stature children.

Credits (5)

 

The company also plans to augment the height Z-score data with assessments including proportionality, functionality, quality of life, sleep apnea, and foramen magnum dimension, as well as the advent of major illnesses and surgeries. (1)

One of the major goals to achieve in a treatment for achondroplasia is exactly what said in the previous paragraph, but rationally, this is a big challenge. Let’s wait for the next results and data publication on Vosoritide in children under 5 years-old, in whom effects of the drug are expected to be more evident.

 

Sources:

June 9, 2018
by inesp.alves
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A way to contribute to the knowledge on achondroplasia

An ongoing study on pediatric achondroplasia conducted by the Brod Group is still enroling participants

Call for participation – USA residents

  • Parents of children with achondroplasia under 18 years-old
  • children and adolescents with ACH, with ages between 9 to 14 years-old

You can get more information about this study in this post.

Honorarium for spent time

$125 honorarium for participating in a focus group and a $75 honorarium for participating in a telephone interview

 

If you are interested in participating, please contact Jane Beck, Senior Research Associate with The Brod Group:

e-mail: jane@thebrodgroup.net

telephone: (415) 317-3987

June 5, 2018
by inesp.alves
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A documentary on the lengthening process

The documentary  “The Lucas´s Journey“, by the film director Juan Enis, was produced by the mother of Lucas in 2015 and tells about the lengthening process of a boy with achondroplasia with 15 years-old, that had a total height of 1.25 meters. He decided to undergo this process, facing a long and painful postoperative time. Some images can be harsh to sensitive people.

The documentary wan now the Personal category of the 2018 ALPE Awards.

 

May 12, 2018
by inesp.alves
4 Comments

TransCon CNP for achondroplasia starts Phase 1 clinical trial

Ascendis Pharma announced on the 8th May it has dosed the first volunteers in a first-in-human phase 1 trial of TransCon CNP. (2)

Image 1: The TransCon technology. Credits: Ascendis Pharma Company Presentation. 8th May 2018 (1)

Ascendis TransCon technology includes the TransCon CNP that is a long-acting prodrug of a C-type natriuretic peptide (CNP) in development as a therapeutic option for achondroplasia and potentially for other fibroblast growth factor receptor (FGFR)-related skeletal disorders.

Phase 1 is taking place in Australia with healthy volunteers and is a double-blind, randomized and placebo-controlled phase 1 trial will evaluate single ascending doses of TransCon CNP in healthy adult subjects to assess 1. safety, 2. tolerability and 3. pharmacokinetics.

Understanding clinical trials

What is a phase 1?

Phase 1 is the first stage and usually involves small groups of healthy people, or sometimes patients. Phase 1 trials are mainly aimed at finding out how safe a drug is. (3)

Image 2: Medicines development process. Credits: EUPATI (5)

What is a double-blind trial?

In a blind trial, the people taking part are not told which group they are in. This is because if they knew which treatment they
were getting, it might influence how they felt or how they reported their symptoms. Some trials are ‘double blind’, which
means that the people taking part and the doctors treating them do not know who is getting the new treatment. (3)

What is a randomized trial?

When people are put in the trials treatment groups at random, usually by using a computer programme. This is done so that each group has a similar mix of people of different ages, sexes, and states of health.(3)

What is a placebo-controlled trial?

Controlled trials are designed to compare different treatments. Most controlled trials compare a new treatment with the standard
or usual treatment by setting up two groups of people. One group, known as the trial group or intervention group, are given the new
treatment. The other group known as the control group is given the standard treatment and in situations where there is no standard
treatment (as in achondroplasia), the control group may not be given any treatment at all or may be given a ‘placebo’ (a dummy drug). A placebo is designed to look very similar to the treatment being tested. So, in a drug trial the placebo looks exactly like the real drug, but does not do anything. By comparing people’s responses to the placebo and to the treatment being tested, researchers can tell whether the treatment is having any real benefit.(3)

What is pharmacokinetics?

The word is derived from the Greek words pharmakon (drug) and kinetikos (movement), is the study of the disposition of a drug after its delivery to an organism—in short, a study of “what the body does to a drug“. is used to describe the absorption, distribution, metabolism, and excretion of a compound. (4)

Figures 3-5: The TransCon technology. Credits: Ascendis Pharma Company Presentation. 8th May 2018 (1)

Expected timelines for the TransCon CNP clinical trial

 

Figure 6: adapted from Ascendis Pharma company presentation (1)

Jonathan Leff, M.D., Ascendis Pharma’s Chief Medical Officer. “TransCon CNP has been designed to provide continuous CNP exposure to optimize efficacy without cardiovascular risk in a convenient once-weekly dose. Data from this trial will help validate our target product profile, once again translating our promising preclinical results into clinical data.” (2)

TransCon CNP is the third product candidate in Ascendis Pharma’s rare disease endocrinology pipeline to advance into clinic, developed using its innovative TransCon technology platform. The company anticipates top-line data from the phase 1 trial to be available in the fourth quarter of 2018. (2)

 

Sources:

  1. Ascendis Pharma Company Presentation
  2. Ascendis Pharma- Investors and News
  3. NHS”Understanding clinical trial booklet
  4. ScienceDirect “Pharmacokinetics
  5. EUPATI- Medicines development process

May 8, 2018
by inesp.alves
3 Comments

Study on achondroplasia – request for participation in the USA

The Brod Group, a health outcomes research, and consulting firm are currently conducting an international study of pediatric achondroplasia.

Purpose of the study

To get a better understanding of the experiences and daily life of children and adolescents with achondroplasia, as well as the experiences of parents who have children with achondroplasia.

The study findings

Will be used to help identify important outcomes to consider in future studies of achondroplasia and the results may also be a useful tool to address misconceptions of achondroplasia.

In this document, ACH Study Advertisement you can find additional study details.

Participants

This will be an international study and researchers are now looking for participants living in the U.S.A.

  • children and adolescents with achondroplasia with ages between 9 and 17 years old
  • parents of children with achondroplasia under 18 years of age  (one interview per family)

How will the study be conducted?

  • In a 1-hour telephone interview or a 2-hours focus group (location is to be determined but possibly in New York City)
  • All data will be kept confidential, and no individual will be identified in the study results
  • There is a $125 honorarium for participating in a focus group and a $75 honorarium for participating in a telephone interview

If you are interested in participating, adding value to this research with your personal real-life knowledge on achondroplasia, please contact Jane Beck, Senior Research Associate with The Brod Group:

e-mail: jane@thebrodgroup.net

telephone: (415) 317-3987

May 4, 2018
by inesp.alves
0 comments

The soluble FGFR3, Therachon´s TA- 46, may prevent early onset of obesity in achondroplasia

Obesity and metabolism are important topics related to achondroplasia but rarely discussed.

Developed especially during childhood, obesity is a common complication associated with achondroplasia, affecting more than 50% of people with this condition. The extra weight exacerbates many other complications associated with achondroplasia, such as lumbar lordosis and obstructive sleep apnea, and may play a role in the increased cardiovascular-related death observed in people with achondroplasia, making it a relevant medical complication in the management of this disease [1].

This complication is generally accepted as a risk factor for a number of complications, such as cardiovascular disease, diabetes, and hypercholesterolemia (excess cholesterol in the blood) in the general population. Although cardiovascular disease is higher in people with achondroplasia than in the general population [2], a few case studies suggested that achondroplasia related obesity doesn’t cause alterations in insulin and cholesterol levels [3-5].
This study was firstly presented in the 2017 International Skeletal Dysplasia Society meeting (report of ISDS 2017 here) by Dr. Celine Saint-Laurent, from Elvire Gouze research team, and the team demonstrated the existence of metabolic alterations in achondroplastic mouse model and in children with achondroplasia. Also, they showed how that the soluble FGFR3 (sFGFR3) therapy could revert these metabolic alterations in this mouse model.

To understand what happens to children witachondroplasiaia, the research team performed a longitudinal retrospective study. So what is this? 

In a longitudinal study, subjects are followed over time with continuous or repeated monitoring of risk factors or health outcomes, or both [6]. And retrospective is when a study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study [7].

They also evaluated anthropometric measures: body mass index – BMI, height, weight, etc, and blood parameter values were recorded and compared between children of 3 age groups: 0-3, 4-8 and 9-18 years old. After this, the researchers discovered that glucose (blood sugar) and insulin levels (a hormone made by the pancreas that allows your body to use glucose from carbohydrates in the food consumed for energy or to store glucose for future use. Insulin helps keeps your blood sugar level from getting too high (hyperglycemia) or too low (hypoglycemia) [8], were within normal, but these children had a tendency to have low cholesterol and triglyceride levels (fat), which is markedly different from what happens in obesity not associated with achondroplasia.

Key points:

1. The fact that obesity in achondroplasia is different at a metabolic level from obesity in the general population and that it is a relevant medical complication makes it a good indicator for the efficacy of a medication for achondroplasia.

2. Although sFGFR3 has already shown to increase body length and decrease mortality in an achondroplasia mouse model, the researchers also measured how this drug would affect these metabolic disturbances in the same mouse model and demonstrated that the soluble FGFR3 prevented the atypical abdominal obesity observed in untreated mice and that it normalized some of the blood parameters.

 

Image 2. Regions of interest (ROI) for obesity in children with achondroplasia and Android:gynoid fat ratio measurement in the three age groups. Credits: Saint-Laurent C, Garcia S et al., 2018. Android fat distribution describes the distribution of human adipose tissue in the trunk and upper body while Gynoid fat refers to the body fat that forms around the hips, breasts and thighs [10]

Background:
Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients and is associated with life-threatening complications including increased risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication.
Methods and findings:
To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0±3], [4±8] and [9±18] years old. Our results show unexpected results with the development of an atypical obesity
with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholesterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during a high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to
D22), the development of these metabolic deregulations was prevented in adult animals(between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals.

Conclusions:This study demonstrates that

  1. achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications.
  2. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation.
  3. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients.
  4. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulations.

We look forward in seeing how this compound, the soluble FGFR3 (the same as TA-46 from Therachon) will be effective in children with achondroplasia when the company presents phase 2 clinical trial results.

Sources
  1. Unger, S., L. Bonafé, and E. Gouze, Current Care and Investigational Therapies in Achondroplasia. Current Osteoporosis Reports, 2017. 15(2): p. 53-60. 
  2. Wynn, J., et al., Mortality in achondroplasia study: A 42-year follow-up. American Journal of Medical Genetics Part A, 2007. 143A(21): p. 2502-2511. 
  3. Collipp PJ, Sharma RK, Thomas J, Maddaiah VT, Chen SY. Abnormal glucose tolerance in children with achondroplasia. Am J Dis Child. 1972; 124(5):682±5.
  4. Pirgon O, Atabek ME, Sert A. Achondroplasia associated with metabolic syndrome: patient report. J Paediatr Child Health. 2008; 44(10):602±4.
  5. Alatzoglou KS, Hindmarsh PC, Brain C, Torpiano J, Dattani MT. Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochodroplasia due to FGFR3 mutations. J Clin Endocrinol Metab. 2009; 94(10):3959±63.
  6. https://www.bmj.com/about-bmj/resources-readers/publications/epidemiology-uninitiated/7-longitudinal-studies
  7. https://www.statsdirect.com/help/basics/prospective.htm
  8. https://www.endocrineweb.com/conditions/type-1-diabetes/what-insulin
  9. Saint-Laurent C, Garcia S et al.Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia, PLos One, 2018 Apr 13;13(4):e0195876.
  10. https://en.wikipedia.org/wiki/Gynoid_fat_distribution

March 4, 2018
by inesp.alves
3 Comments

5th Nordic Skeletal Dysplasia Symposium – full session dedicated to achondroplasia

The 5th Nordic Skeletal Dysplasia Symposium will be held in Copenhagen, on March 8-9, 2018.

As stated in the Welcome note of this symposium “Skeletal dysplasias are rare diseases and the annual symposium is important to share medical knowledge with colleagues in different countries. We hope to attract all medical professionals who are working in – or are interested in – the field of skeletal dysplasias. This includes both caregivers, clinicians, scientist, and students“.

On the day 2 of the event, a full session will be dedicated to achondroplasia, on the following topics:

13.30-14.30 Management and follow-up of achondroplasia, Irwing M/Osmund D
14.30-15.00 Cervical spine compression/instability: diagnoses, signs and symptoms, Borbjerg T
15.00-15.15 Achondroplasia: mechanical axis considerations. Orthosis – true or false, Hindsø K
15.15-15.30 Finnish quiz with focus on achondroplasia three-five questions, Valta H

We will try to gather and share some information that will be presented at this symposium.

 

March 2, 2018
by inesp.alves
1 Comment

FDA Advisory Committee Meeting on Achondroplasia – Call for patients input

On March 22, 2018, FDA, the US Food & Drug Administration, will conduct a public advisory committee meeting on achondroplasia. The purpose of this meeting to discuss the major objectives of a phase 3 drug development program indicated for the treatment of children with achondroplasia.

FDA values patient perspective on the development of pharmaceutical treatments for achondroplasia and this meeting presents individuals with achondroplasia and their families a valuable opportunity to provide FDA with input on important topics. These topics include the types of clinical trial endpoints that would have a clinically meaningful impact on patients’ functional or psychological well-being and other considerations on the design of clinical trials involving people with achondroplasia.

The meeting’s open public session will take place on March 22, 2018, from 10:30 a.m. to 5:30 p.m. at our location in Silver Spring, MD, just outside of Washington, DC). Individuals, families, and others (patient organizations) may provide testimony in person at this meeting’s open public comment. Anyone interested in providing public comment at the meeting should register with  Marieann.Brill@fda.hhs.gov by March 7.

There are a limited number of speaking slots. In addition, individuals, families, and others can submit a written comment on the topic of achondroplasia and development of potential treatments to the public docket. Additional details can be found in the federal register notice of the meeting.

FDA is seeking to collect a rich and diverse set of patient perspectives on this topic.  We have developed a flyer, attached, with information relevant to this meeting and encourage you to disseminate it to any individuals or groups who may be interested in this meeting.

Preview of the information flyer. To read the flyer in full, click on the following link: AchondroplasiaAC

FDA link to the announcement

 

Beyond achondroplasia will participate in this call for contribution by sending a written comment.

The information here provided was kindly shared by Blake Bannister, Decision Support and Analysis Team, Center for Drug Evaluation and Research, FDA     

February 14, 2018
by inesp.alves
2 Comments

Therachon starts phase 1 clinical trial with TA-46 for achondroplasia

Therachon announced today, 14 February 2018, the beginning of Phase 1 for the clinical trial with TA-46 for achondroplasia.

This trial will take place in The Netherlands, with 70 adult healthy volunteers and it will be:

  • randomized – A study in which the participants are divided by chance into separate groups that compare different treatments or other interventions. Using the chance to divide people into groups means that the groups will be similar and that the effects of the treatments they receive can be compared more fairly. At the time of the trial, it is not known which treatment is best. Pubmed health
  • placebo-controlled – Studies of new drugs often compare the effects of an investigational drug with the effects of a placebo. The reason for using a placebo control is that the benefits of taking medications are not always due to the drug itself. These benefits are called “placebo effects.” An example is when an investigator’s enthusiasm about a new medication sometimes influences the patient’s response. In a double-blind, placebo-controlled research design, the doctors, nurses working directly with patients, and participants themselves involved in the study, will not know which group patients are in. PsychCentral
  • double-blind trial – is a trial where neither the researchers or patients/participants know what they are getting (the drug or the placebo). The computer gives each patient a code number. And the code numbers are then allocated to the treatment groups. Cancer Research UK

The number of participants vary significantly, depending on the study and if teh new medicine is for a more common condition or a rare condition. Credits: Global Medical Institutes

 

The trial is designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses of TA-46.

Luca Santarelli, Therachon´s CEO said that this is “an important milestone for the company,”.

Beyond Achondroplasia has published more information about TA-46 previously (read the first article). The company has high expectations that Ta-46 may show significant therapeutic impact in achondroplasia as may improve anatomical proportions and prevent complications related to achondroplasia, that start to occur in early life phases.

Next steps

Is important to know the timelines for this phase 1 trial, namely the duration of this trial as also the results of safety, tolerability and mechanism of the drug in these healthy volunteers and then, after positive results, know the expected dates of the beginning of phase 2, with children with achondroplasia.

How is expected TA-46 to work?

TA-46 acts as a ligand trap can reduce the superactivation of the mutated receptor FGFR3 (that is overworking in achondroplasia, which reduces the multiplication and development of chondrocytes, that the cells that give origin at the growth plate level, to the bone formation).

TA-46 is being developed as a weekly subcutaneous drug for children and adolescents living with the disease.

And this investigational therapy has received Orphan Drug Designation from the European Medicines Agency (EMA) on the 27th March 2017 and the U.S. Food and Drug Administration (FDA).

You can check Therachon´s press release here

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