Beyond Achondroplasia

Growing together with Clara

October 20, 2017
by inesp.alves
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Recruitment in clinical trials

The following document shared by BioMarin in September 2017, is a clarification on the ongoing clinical trials for achondroplasia and was released for associations and families:

BioMarin Achondroplasia Programme Update 20Sept17

Is important to mention that families interested in having their children enrolled in BioMarin ongoing observational study (111-901) and interventional clinical trial (111-301), have to contact directly the centers that are conducting the clinical trial, listed here.

Pharmaceutical companies DO NOT recruit patients for clinical trials. The companies, as BioMarin, select the clinical centers (hospitals) in which their trial will take place and is the trial coordinator of that clinical center (usually a chief clinician), that recruits patients and who must be contacted for recruitment.

August 29, 2017
by inesp.alves
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13th International Skeletal Dysplasia Society meeting

From the 20th to the 23rd September 2017, it will take place in Bruges, Belgium, the ISDS meeting.

The ISDS is registered as a non-profit organization and the principal aim of the Society is to promote scientific progress in the field of skeletal dysplasias and dysostoses. To this aim, the society organizes meetings on a two-year basis.

The focus of the meeting will be on the clinical, radiographic and molecular aspects of rare and genetic disorders of the skeleton with special attention to the newest discoveries within this field.
Clinicians and researchers with interest in rare bone disorders will attend this meeting, as representatives from industry and patient groups.

The themes related to achondroplasia that will be presented during the course of the three days meeting will be:

  • Longitudinal bone growth velocity assessment by near-infrared imaging in a murine model of achondroplasia, by Florence Authier
  • Achondroplasia natural history: the power of a multi-center clinical study, by Julie Hoover-Fong
  • Disruptive, targeted emerging therapies in skeletal dysplasias, by Robin Forbes
  • Oral administration of meclozine for the treatment of short stature in achondroplasia, by  Hiroshi Kitoh
  • FLAG-sFGFR3 treatment prevents the metabolic deregulations in achondroplasia, by Celine Saint-Laurent

And also, in a specific session “Treatment: ready for patients?”, Adrian Quartel, from BioMarin Corporate, will present “Who we are, what we do”.

There will also be posters presentation, with more than 50 posters submitted. The most relevant titles by now for achondroplasia are:

  • How occupational therapy intervention within a multidisciplinary bone dysplasia clinic can promote functional independence for children with skeletal dysplasia, by Jennifer Robin
  • Patient and public involvement (PPI) in designing clinical trials for rare diseases – the achondroplasia experience, by Emma Glass.

Insights of the meeting will be presented here after.

 

August 25, 2017
by inesp.alves
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Research on ARQ 087, a Tyrosine kinase inhibitor

 

In 2016, the research team led by Dr. Pavel Krejci published the following article:

Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes. Gudernova I, Vesela I Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P.

Turning this title comprehensible, the researchers said that the 5 agents/products (SU5402, PD173074, AZD1480, AZD4547 and BGJ398), known as TKIs (Tyrosine kinase inhibitors) showed great results in blocking FGFRs tyrosine kinases in dish cells (plates where the researchers put specific cells into a culture to be tested). The image below is an example of a cell culture plate.

Tissue culture. Credits: Ferentis

There are 4 kinds of Fibroblast growth factor receptor (FGFRs): FGFR1, FGFR2, FGFR3 and FGFR4 and their action (called signaling) are distinctive and involved diverse and multiple biological processes, including cell proliferation, survival, differentiation, migration, and apoptosis (means death of cells) during embryonic development and adult tissue homeostasis. 5,7

FGFR 3 is the receptor where is the mutation of achondroplasia in chondrocytes and knowing that TKIs can block FGFR3, they also block the other FGFRs. This means that TKIs target in not just FGFR3 but all or almost all FGFRs.

FGFR3 is a major physiological negative regulator of bone growth, and therefore a safe and effective FGFR3 inhibitor would undoubtedly revolutionize the treatment of short-stature syndromes in general, possibly including many that are unrelated to FGFR3. 3

Credits: Khan Academy

So,  in 2016, the team concluded that the 5 FGFR TKIs evaluated were poor candidates for therapy for achondroplasia, mainly because TKIs exhibited significant off-target activity. What does this mean? TKIs lack specificity for FGFR3, attack the other FGFRs, and show cell toxicity and this would compromise TKIs use for treatment of achondroplasia. 3

Although Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, and these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. This occurs because tyrosine kinases are widely distributed with specific functional roles in different organs. 2

Recently, in August 2017, the same team published:

ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations, in FGFR1, FGFR2, and FGFR3.

ARQ 087 is a tyrosine kinase inhibitors, that was tested in cultured chondrocytes (dish cells), and the team observed that ARQ 087 efficiently rescued all major effects of pathological FGFR3 activation as inhibition of chondrocyte proliferation, loss of extracellular matrix and induction of premature senescence. This means that in the cultured chondrocytes with the achondroplasia mutation and with ARQ 087, chondrocytes could grow and multiply as they do in a typical growth plate. Unfortunately, ARQ 087 has an off-target action too and blocks FGFR1, FGFR2 and FGFR3.

The main conclusion of the study is the following:

“The off-target effects of ATP-competitive TKIs represent a major obstacle compromising their use in the clinic, despite the fact that even serious side-effects may be tolerated in cancer, where the main objective is patient survival. In contrast, the side effects might not be acceptable in ACH or craniosynostoses, where the main treatment objectives are to increase stature height and correct disproportionate cranial development, respectively.” 4

This research proves that TKIs are not appropriate selection to treat achondroplasia.

Developing new studies for achondroplasia can be very demanding and time-consuming, but patients trust that researchers do the best they can to deliver results that, ultimately, can be converted in a treatment and reduce the complications originated by achondroplasia: limbs and trunk disproportionality, neurologic, respiratory issues, orthopedic complications, negative social image, among others issues are concerns and raise problems during all life.

Not every study will originate a new medicine, but most studies will help to decide researchers which ways to go and which don´t.

 

Author Comment: The title and text of this post was amended after reconsideration of previous content.

 

Bibliography

  1. http://www.tuftsctsi.org/about-us/what-is-translational-science/
  2. Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy.Drug Saf. 2013 Jun;36(6):413-26.
  3. Gudernova I, Vesela I, Balek L, Buchtova M, Dosedelova H, Kunova M, Pivnicka J, Jelinkova I, Roubalova L, Kozubik A, Krejci P. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.Hum Mol Genet. 2016 Jan 1;25(1):9-23.
  4. Balek L, Gudernova I, Vesela I, Hampl M, Oralova V, Bosakova MK, Varecha M, Nemec P, Hall T, Abbadessa G, Hatch N, Buchtova M, Krejci P. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2, and FGFR3. Bone. 2017 Aug 18. pi: S8756-3282(17)30311-3.
  5. Kai Hung Tiong, Li Yen Mah, and Chee-Onn Leong. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis 2013; 18(12): 1447–1468
  6. http://www.the-scientist.com/?articles.view/articleNo/10487/title/The-Pressure-To-Publish-Promotes-Disreputable-Science/
  7. Ornitz D, Itoh N. The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015 May; 4(3): 215–266.

July 31, 2017
by inesp.alves
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Exercises and postural education for children with achondroplasia – OSCAR 2016

In 2014, several Centres of Reference in France dedicated to diseases involving the same organs, created OSCAR, the French network of rare diseases of bone, calcium, and cartilage.

Citing Dr. Geneviève Baujat (Necker-Enfants Malades hospital,  Paris) “The aims are to expose various resources (people, hospitals, e-structures) and to make people working all together with “axes”: to develop concrete tools…such as the “Follow-up schedule” or video tutorials (on YouTube) for achondroplasia and some others rare conditions”.

Although all information is only in French, is very valorous and must be shared worldwide.

Video tutorial

Child placement for the for exercises:

  1. Use a semi hard surface
  2. Do the exercises between meals
  3. The child wears little and comfortable clothes
  4. Distract the child during the exercises as like a playing moment
  5. Do soft massage during the exercise

Exercise 1: the child is placed stomach down

This exercise is to strengthen and reinforce the hip extensor muscles

 

Image credits: AQSpeed

Exercise 2: Lying on the side

While keeping the hips steady, work on the upper limb, producing a slight traction. And change limbs after. Repeat 10 times.

Exercise 3: Lying on the back

Produce gentle stimulation for the child to respond with active abdominal contractions. Repeat 10 times.

To remember:

  1. Do these exercises during 2 to 3 minutes every day.
  2. Encourage the child to do the exercises himself/herself
  3. Avoid extended sitting positions
  4. Keep doing the exercises throughout the child growth

Dr. Geneviève  Baujat ends saying:

These postural exercises are very important for children with achondroplasia and must be done in a very precise way. Also, the exercises should be done during all the child early development and more, this exercise time can be a very privileged moment between parent and child, done in a pleasant and playful way“.

All credits: OSCAR.

June 25, 2017
by inesp.alves
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Therachon heading to Phase 1 clinical trial

Therachon´s medicine in development for achondroplasia, TA-46, was granted Orphan Drug designation by the medicines agencies FDA and EMA.

TA-46 is a type 3 fibroblast growth factor receptor antagonists addressing achondroplasia. This medicine is an inactive form of the receptor that binds to available fibroblast growth factors (FGFs) and with this stops the abnormal receptors from working. Through its action as a decoy, the medicine is expected to reduce the activity of these receptors, thereby helping to restore normal patterns of growth (EMA, 2017).

To understand the evolution of the process, this are the latest known timelines:

  • 27 Feb 2017 –  TA 46 received Orphan Drug status for Achondroplasia by the European Medicines Agency, EMA

Captured image – EMA documents library

 

  • 2 Jun 2017 TA 46 received Orphan Drug status for Achondroplasia by the US Food and Drug administration, FDA

Captured image in Access Data FDA

  • 15 Jun 2017 Therachon signed an agreement with Catalent Pharma Solutions, to support the preclinical and clinical development of TA-46, heading for plan of clinical trials in paediatric patients with Achondroplasia
  • 20 Jun 2017 Press release of Therachon receiving orphan drug designation for TA-46

About Orphan Designation

FDA: The Orphan Drug Act (ODA) provides for granting special status to a drug or biological product (“drug”) to treat a rare disease or condition upon request of a sponsor.

EMA: The European Medicines Agency is responsible for reviewing applications from companies /pharmaceutical industry, who intend to develop medicines for rare diseases, known as ‘orphan drugs'(EMA, 2017). When a Orphan Drug designation is granted, EMA provides incentives in the drug development as:

  1. Market exclusivity:  10 years with no competition by similar products,after  the drug is approved for sale
  2. Protocol assistance:  The agency provides scientific advice to optimize development and guidance on preparing a dossier that will meet European regulatory requirements /US
  3. Fee reductions
  4. EU-funded research

Designation as an orphan medicinal product does not indicate that the product has already satisfied the efficacy, safety and quality criteria necessary for the granting of a marketing authorisation. As with any medicine, these criteria can only be assessed once the application for marketing authorisation has been submitted.

Next steps – clinical trial Phase 1

At the time of submission of the application for orphan designation in EMA, the evaluation of the effects of the
medicine in experimental models was ongoing (EMA, 2017).

Phase I trial (short video)

Is the first in a series of four stages in testing new therapies in humans. The primary goal of these studies is to determine whether the therapy can be given safely, so one of the main evaluations is to watch for harmful side effects that may be caused by the treatment. The doctors who lead the clinical trial also will try to determine the best way to give an experimental drug (e.g., by mouth, IV drip, or injection) and how often and how much should be given, which is called dosing (John Hopkins Medicine, 2017).

Phase I clinical study for TA-46 is scheduled for the beginning of 2018

In further phases of the clinical trial, TA-46 will be evaluated in children that will receive 1 single subcutaneous (under the skin) injection per week to reduce the effects of achondroplasia.

June 3, 2017
by inesp.alves
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BioMarin updates the Multicenter and Multinational Clinical Study 111-901

The “Multicenter, Multinational Clinical Assessment Study for Pediatric Patients With Achondroplasia” is a prospective observational study. This study code name is 111-901.

The aim of this study is to collect systematic growth measurements of the children in order to collect data to better understand the natural history of achondroplasia.

Children between 2 and 13 years old can be enrolled in the 111-901 study and the measurements take place at each 3 months and can go for up to 60 months (or 5 years).  BMN-111 will not be administered in this study. But for any children to be enrolled in the drug study (with administration of BMN-111)

BMN-111 will not be administered in this study. Yet, only children that participate in the study 111-901 can be enrolled in the drug study after, code study 111-301, in which BMN-111 will be administrated to 50% of participants while the others will receive placebo.

Credits: Brakefield R. Observational Studies and Experiments, 2015

The 111-901 study is now being conducted at 21 clinical centers around the globe, and new centers have been added in the USA and centers in Spain and Turkey have been included. All centers are currently recruiting patients.

Locations
United States,

 

Harbor-UCLA Medical Center
Los Angeles, California, United States, 90048
Contact: Nathalia Patritti Cressey, Study Coord    310-781-3682 ext Office
Contact    310-597-1960 ext Cell
Principal Investigator: Patti Dickson, MD
Children’s Hospital and Research Center Oakland
Oakland, California, United States, 94609
Contact: Jacqueline Madden, Study Coord    510-428-3885 ext 5745
 jmadden@mail.cho.org
Children’s Hospital Colorado
Aurora, Colorado, United States, 80045
Contact: Laurel Ware, BSN    720-777-5378

laurel.ware@childrenscolorado.org

Principal Investigator: Gary Bellus
 
Nemours/Alfred I. duPont Hospital for Children
Wilmington, Delaware, United States, 19803
Contact: Cassie Brown, Study Coord    302-298-7930

cassondra.brown@nemours.org

Contact: Michael Bober, MD
 
Emory University
Decatur, Georgia, United States, 30033
Contact: Elizabeth Smith, Study Coord

Elizabeth.d.smith@emory.edu

Contact: William Wilcox, MD

William.wilcox@emory.edu

 
Ann and Robert H Lurie Children’s Hospital of Chicago
Chicago, Illinois, United States, 60614
Contact: Victoria Sanders, Study Coord    312-227-6120
 
Indiana University, Riley Children’s Hospital
Indianapolis, Indiana, United States, 46202
Contact: Susan Romie    317-278-6650

sromie@iu.edu

Principal Investigator: David Weaver, MD
 
Johns Hopkins McKusick- Institute of Genetic Medicine
Baltimore, Maryland, United States, 21287
Contact: Adekemi Alade, Study Coord

aalade2@jhmi.edu

Contact: Kira Lurman, Study Coord

Kmarant1@jhmi.edu

 
University of Missouri
Columbia, Missouri, United States, 65201
Contact: Vicki L Jones, Study Coord    573-882-7583

umhsorthoenroll@health.missouri.edu

Contact: Daniel G Hoernschemeyer, MD    573-882-1351
Principal Investigator: Daniel G Hoernschemeyer, MD
 
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Contact: Racheal Powers    800-647-4805
Principal Investigator: Howard Saal, MD
 
Vanderbilt University
Nashville, Tennessee, United States, 37232
Contact: LeeAnna Melton, Study Coord    615-343-6761

leeanna.melton@vanderbilt.edu

 
Baylor College of Medicine
Houston, Texas, United States, 77030
Contact: Catherine Loffredo, Study Coord

catherine.loffredo@bcm.edu

 
Seattle Children’s Hospital
Seattle, Washington, United States, 98105
Contact: Tressa Mattioli-Lewis

tressa.mattiolilewis@seattlechildrens.org

Contact: Klane White, MD

klane.white@seattlechildrens.org

Principal Investigator: Klane White, MD
 
Medical College of Wisconsin, Children’s Hospital
Milwaukee, Wisconsin, United States, 53226
Contact: Paula Engelking    414-266-3289

pengelki@mcw.edu

Contact: Donald Basel, MD

dbasel@mcw.edu

Principal Investigator: Donald Basel, MD

 

Australia, Victoria
Murdoch Children’s Research Institute
Parkville, Victoria, Australia, 3052

 

France
Institut Necker
Paris, France, 75015
Contact: Kim-Hahn Le Quan Sang, MD    33 1 44 49 59 51

kh.lequansang@nck.aphp.fr

Principal Investigator: Valerie Cormier-Daire, MD

 

Spain
Institut Catala de Traumatologica I Medicina de l’Esport
Barcelona, Spain, 08028
Contact: Miriam Perez    +34 932 05 43 62 ext 21148

miriam.perez@icatme.com

Contact: Ignacio Ginebreda    +34 619 21 35 77

ignacio.ginebreda@icatme.com

Principal Investigator: Ignacio Ginebreda
Hospital Sant Joan de Deu Barcelona
Barcelona, Spain, 08950
Contact: Jose Maria de Bergua    +34 650 80 60 71
Contact: Rosendo Ullot    +34 650 80 60 71

rullot@hsjdbcn.org

Principal Investigator: Rosendo Ullot
Hospital Universitario Virgen de la Victoria
Málaga, Spain, 29010
Contact: Antonio Leiva    +34 646 56 87 89
Contact: Felipe Luna    +34 607 85 81 22
Principal Investigator: Felipe Luna

 

Turkey
Acibadem University School of Medicine
Istanbul, Turkey, 34752
Contact: Beyzanur Gonenc    +90 532 300 09 13

beyzanur.gonenc@acibadem.edu.tr

Contact: Burcu Menderes    +90 555 313 40 86

burcu.menderes@acibadem.edu.tr

Principal Investigator: Yesemin Alanay, MD
Sub-Investigator: Selda Karaayvaz

 

United Kingdom
Guy’s and St. Thomas NHS Foundation Trust Evelina Children’s Hospital
London, United Kingdom, SE1 9RT
Principal Investigator: Melita Irving, MD

Information available on Clinicaltrials.gov

May 14, 2017
by inesp.alves
3 Comments

BioCentury published the article “Competing for growth”

BioCentury´s Senior writer Mike Leviten wrote a substantial article about the current  medicines in research and development for achondroplasia. The article was published on the 7th April.

This competition between pharma companies is very positive once it stimulates industry to develop best medicines and in faster pace. The investment in research and development of medicines is tremendous and the best possible outcomes for the companies in this race is when the company provides the most effective medicine in reducing achondroplasia associated medical complications, produces less side effects and substantially increases the quality of life of the patient and family.

When a chef is creating a new recipe, the best product is discovered sometimes after countless attempts but the chef will never achieve the goal without tasting what is being created. And in drugs discovery, “tasting” is when pharma works in the way to gather all efforts to know who the patient is and what the patient lives and need.

The following excerpt is available on Biocentury page:

With little in the clinical pipeline for achondroplasia beyond BioMarin Pharmaceutical Inc.’s late-stage vosoritide, startups Therachon AG and BioClin Therapeutics Inc. are rethinking how to tackle the disease. By targeting FGFR3 directly, the two companies think they can block a signal vosoritide misses, and produce compounds that have better efficacy and require less frequent dosing.

The field appears poised for an uptick of activity, triggered by BioMarin’s positive Phase II data and recent publications that validate the FGFR3 biology underlying the disorder.

Achondroplasia is the most common form of short-limb dwarfism, and is caused by a single point mutation in FGFR3 that constitutively activates the receptor and inhibits bone growth. The treatment landscape involves either painful limb-lengthening surgery or, typically, a one-year course of human growth hormone, which has limited benefit.

BioMarin’s approach is to block a downstream mediator in the FGFR3 pathway that is responsible for chondrocyte growth. Its candidate, vosoritide, is a stable analog of the peptide agonist CNP that acts via the cell surface receptor NPR2 to inhibit a ras-driven cascade downstream of FGFR3. In December, BioMarin initiated a Phase III trial of vosoritide in patients aged 5-14.

Ascendis Pharma A/S is taking a similar approach with its TransCon CNP, a sustained-release prodrug of CNP. The company plans to submit an IND this year (apply for an “Investigational New Drug” at the FDA and EMA).

By contrast, Therachon and BioClin are targeting FGFR3 activity directly, which allows them to block chondrocyte proliferation as well as growth.

May 12, 2017
by inesp.alves
3 Comments

Phase 3 trial for achondroplasia – BioMarin Study 111-301

The following information is fully available at the European Union Clinical Trials Register. Some sections will be here highlighted:

1.

Full title of the trial
A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia

What does PlaceboRandomized, Double-Blind mean?

Placebo: an inert substance that has no action or effect and can produce the placebo effect, that is the response that follows the administration of a placebo [1].

Randomized: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. In this particular case, a placebo will be compared with BMN-111 [2].

Double-Blind: when the patient and the investigator are blind in knowledge. This mean that neither the patient or the investigator know which patients are getting the drug and the ones that are getting placebo [3].

2.

Sponsor’s protocol code number 111-301

This is the designation of the phase 3

3.

IMP Role Test

The goal is to test an Investigational medicinal product (IMP)

4.

The IMP has been designated in this indication as an orphan drug in the Community Yes

Any medicinal product that aims to treat a rare disease is designated orphan drug

5.

Description of the IMP
D.3.1 Product name modified recombinant human C-type natriuretic peptide- CNP
D.3.2 Product code BMN 111
D.3.4 Pharmaceutical form Lyophilisate for solution for injection
D.3.4.1 Specific paediatric formulation Yes
D.3.7 Routes of administration for this IMP Subcutaneous use

CNP, is expressed as a 126–amino acid protein precursor (preproCNP), and is then processed to an active 53–amino acid cyclic peptide and further processed to a 22–amino acid peptide.  Native CNP (CNP22) has a short half-life inside the body of less than 2 minutes in mice and humans. BioMarin modified this CNP for a 39–amino acid CNP variant (BMN 111) and is produced in the bacteria Escherichia coli [4].

6.

D.8 Placebo
D.8.1 Is a Placebo used in this Trial? Yes
D.8.3 Pharmaceutical form of the placebo Lyophilisate and solvent for solution for injection
D.8.4 Route of administration of the placebo Subcutaneous use

7.

E.2 Objective of the trial
E.2.1 Main objective of the trial
Evaluate change from baseline in mean annualized growth velocity at 52 weeks in subjects treated with BMN 111 compared with control subjects in the placebo group.
E.2.2 Secondary objectives of the trial
• Evaluate change from baseline in mean height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
• Evaluate change from baseline in mean upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
• Evaluate safety and tolerability of BMN 111 in children with ACH
• Evaluate the pharmacokinetics of BMN 111

This study will take 1 year to produce results. Upper:lower segment body ratio will be evaluated.

Upper to lower body ratio

The lower body segment is the measurement of the length from the pubic to the floor; the upper body segment is the height minus the lower body segment. The U/L ratio (upper body segment : lower body segment) at birth is about 1.7; at age 3 years it is 1.3; at greater than 7 years, it is 1.0 with the upper body segment and lower body segment being about equal. Higher U/L ratios are noted in short-limb dwarfism.

So the ideal is a ratio near 1.

Vitruvian man – Leonardo Da Vinci

8.

Principal inclusion criteria
1. Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of 18 are willing and able to provide written assent (if required by local regulations or the IRB/EC) after the nature of the study has been explained and prior to performance of any research-related procedure.
2. 5 to < 15 years old at study entry
3. Have ACH, documented by clinical grounds and confirmed by genetic testing
4. Have at least a 6-month period of pretreatment growth assessment in Study 111-901 immediately before study entry, and has one documented standing height at least 6 months (+/- 10 days) prior to the screening visit for Study 111-301
5. Females ≥ 10 years old or who have begun menses must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study
6. If sexually active, willing to use a highly effective method of contraception while participating in the study
7. Are ambulatory and able to stand without assistance
8. Are willing and able to perform all study procedures as physically possible
9. Caregivers are willing to administer daily injections to the subjects and complete the required training

All children that get this phase 3 study (111-301) have to take first for at least 6 months, the natural history/growth assessment study (111-901).

9.

End points
E.5.1 Primary end point(s)
The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV) at Week 52 (12- month).
E.5.1.1 Timepoint(s) of evaluation of this end point
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 29, Week 52
E.5.2 Secondary end point(s)
The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.

Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG, X-rays/DXA, clinical hip assessment, and anti-BMN 111 immunogenicity assessments.

PK sampling will be carried out over the 12-month study period in subjects randomized to BMN 111 or placebo.

E.5.2.1 Timepoint(s) of evaluation of this end point
Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 29, Week 52

Clinical labs (urinalysis, chemistry, hematology): Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54

Vital signs and AEs: Screen, Day 1, Day 2, Day 3, Day 10, Week 6, Week 26, Week 39, Week 52, Week 54 (follow-up)

Physical exam: Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

ECG: Screen, Day 1, Day 10, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

X-Ray/DXA: Screen, Week 26, Week 52

Clinical hip assessment: Screen, Week 26, Week 52

Anti-BMN 111 immunogenicity: Day 1, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

PK: Day 1 (full), Week 13 (partial), Week 26 (full), Week 39 (partial), Week 52 (full)

Endpoint: In clinical trials, is an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives.

Anthropometric measurements:  systematic measurements of the size, shape and composition of the body

PK: Pharmacokinetics is the study of ‘what the body does to the drug’ and includes:
•    the rate and extent to which drugs are absorbed into the body and distributed to the body tissues
•    the rate and pathways by which drugs are eliminated from the body by metabolism and excretion
•    the relationship between time and plasma drug concentration [5].

10.

E.8.5 The trial involves multiple Member States Yes
E.8.5.1 Number of sites anticipated in the EEA – Europe 10

11.

E.8E.8.6 Trial involving sites outside the EEA.
Australia
France
Germany
Japan
Spain
Turkey
United Kingdom
United States
E.8.7 Trial has a data monitoring committee – Yes
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial – LVLS

LVLS – Last visit, last subject/patient

12.

F. Population of Trial Subjects- Age Range
F.1.1 Trial has subjects under 18 Yes
F.1.1 Number of subjects for this age range (all world): 110
F.1.1.1 In Utero No
F.1.1.2 Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3 Newborns (0-27 days) No
F.1.1.4 Infants and toddlers (28 days-23 months) No
F.1.1.5 Children (2-11years) Yes
F.1.1.5.1 Number of subjects for this age range: 88
F.1.1.6 Adolescents (12-17 years) Yes
F.1.1.6.1 Number of subjects for this age range: 22
F.1.2 Adults (18-64 years) No
F.1.3 Elderly (>=65 years) No

13.

F.4.2 For a multinational trial
F.4.2.1 In the EEA 24
F.4.2.2 In the whole clinical trial 110
F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
Following completion of 52 weeks subjects in both treatment groups may be eligible to receive BMN 111 in an open-label extension study, to assess safety and efficacy of BMN 111 over a longer term.

 

 

Bibliography

 

  1. Gupta U, Verma M. Placebo in clinical trials. Perspect Clin Res. 2013 Jan-Mar; 4(1): 49–52
  2. National Cancer Institute dictionary
  3. Misra S. Randomized double blind placebo control studies, the “Gold Standard” in intervention based studies. Indian J Sex Transm Dis. 2012 Jul-Dec; 33(2): 131–134.
  4. US national library of medicine
  5. IUPHAR Pharmacology Education Project
  6. EU Clinical Trials Register

 

April 9, 2017
by inesp.alves
1 Comment

The TransCon CNP, a prodrug for achondroplasia

 

 

A company based in Denmark and is applying its innovative TransCon technology that combines the benefits of prodrug and sustained-release technologies and developed the TransCon CNP for achondroplasia.

FGFR3 and CNP

Achondroplasia is caused by a gain-of-function mutation in fibroblast-growth-factor-receptor 3 (FGFR3). The increased activity of the FGFR3 reduces the growth of the long bones. The C-type natriuretic peptide (CNP) has the ability to antagonizes the FGFR3 action inside the chondrocytes by inhibiting the MAPK chain reaction (mitogen-activated protein kinase). MAPK signals slow bone growth are subject to downregulation by the signaling cascade activated by C-type natriuretic peptide (CNP), that has the ability of CNP to stimulate endochondral ossification in vivo. In “Achondroplasia: pathogenesis and implications for future treatment” Laederich M and Horton W, 2010.

In a more simple way to explain this, when the CNP connects with its receptor in the cell (NPR-B) it can block the FGFR3 cascade that takes place inside the chondrocyte, the same as stopping a chain reaction of dominoes pieces falling. And by this action, CNP can produce a positive effect in restoring growth in achondroplasia.

Several approaches have shown promise in preclinical studies for achondroplasia and one of them uses CNP. BioMarin Pharmaceuticals developed the CNP analog, BMN 111, which retains the biologic properties of native CNP but has an extended half-life due to its resistance to neutral-endopeptidase digestion, allowing for once daily subcutaneous administration. In “Advances in treatment of achondroplasia and osteoarthritis“. Klag K and Horton W, 2016

After this, what is a prodrug?

A drug is a small organic molecule introduced in to the body for cure, prevention, treatment or diagnosis of disease that generally binds to a specific site or organ/cell and activates or inhibits the function of the desired biomolecule. But drug administration is associated with certain problems like distribution of the compound throughout the body and undesirable side-effects.

Prodrug is the masked form of active drug capable to increase the efficiency of drugs and to decrease its associated toxicity. As in the following image, a prodrug is considered to be the combination of active drug and side chain/ligand (covalently linked) which helps in targeting the specific cell/tissue. The prodrug is then converted to the original drug once it reaches the site of action, followed by rapid abolition of the released derivatizing group without causing side effects. In “Cutting Edge Approach on Prodrug: Contrivance for Target Drug Delivery“. Varsha Y et al., 2011

Cutting Edge Approach on Prodrug: Contrivance for Target Drug Delivery”. Varsha Y et al., 2011

What is a sustained release technology?

From all drug delivery systems, oral drug delivery remain the most preferred option for administration for various drugs. Sustained Release is also providing promising way to decrease the side effect of drug by preventing the fluctuation of the therapeutic concentration of the drug in the bodyside-effects are reduced and cure of the disease is achieved. The principal goal of sustained release forms is the improvement of drug therapy… In “A review on sustained release technology“Gupta M and Brijesh U, 2012

The TransCon technology

It can be applied to previous therapeutical approaches to extend duration of a drug’s action in the body, and to enhance the overall benefit of a therapeutic.  This technology combines the benefits of conventional prodrug + sustained release technologies creating a platform technology that is broadly applicable to proteins, peptides and small molecules (Ascendis Pharma).

In sum, the TransCon is like a reservoir that hold the drug inside it. After this “reservoir” is injected into the body, it can release the drug in a predetermined frequency of time. So in the TransCon CNP case, the TransCon holds CNP inside

Image: Ascendis Pharma

The TransCon CNP

Ascendis Pharma stated that the TransCon CNP is a sustained-release prodrug of C-Type Natriuretic Peptide (CNP), for the treatment of achondroplasia and has shown the following relevant points:

  1. Is being investigated as a once-weekly prodrug to provide continuous exposure to CNP to potentially improve efficacy, safety and/or convenience over first-generation CNP analogues.
  2. It releases CNP via a non-enzymatic hydrolysis of the TransCon linker.
  3. It is designed to maintain the same mode of action and distribution as the continuous administration of CNP and could become an efficacious and safe therapy for patients with ACH, with a convenient subcutaneous weekly dosing profile.
  4. It minimizes binding of CNP to the NPR-C receptor to decrease clearance;
  5. Reduces binding of CNP to vascular NPR-B receptors to avoid hypotension caused by activation of this receptor. (There are receptors NPR-A, NPR-B and NPR-C being the B the specific receptor of CNP)
What is drug clearance?

Is the rate at which the active drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output. The university of Nothingham

Recent updates

Ascendis Pharma presented two posters at the ENDO 2017 (Endocrine Society Annual Meeting, 1-4 April 2017) on TransCon CNP, and the top conclusions were:

  1. Lack of adverse hemodynamic effects of TransCon CNP, allowing for the administration of high doses to facilitate optimal efficacy.
  2. Observation of a dose-dependent effect on tibia growth in juvenile monkeys with weekly TransCon CNP with results that demonstrated growth effects continued through six months.
  3. The effects of TransCon CNP in a mouse model of achondroplasia, included bone growth and the potential to ameliorate some of the more disabling achondroplasia traits, including stenosis of the foramen magnum.

So, with this, the bar stands higher for all the companies currently working in a potential treatment for achondroplasia. The key goal for patients of receiving a drug that can reduce the complications directly related to achondroplasia, as the stenosis of the foramen magnum, seems to start to catch the attention of the researchers, the industry and the investors.

“The encouraging TransCon CNP preclinical data support the hypothesis that a CNP analogue can be an effective treatment for achondroplasia without dose-limiting hypotension”

Kennett Sprogøe, Ph.D., Senior Vice President of Product Innovation

Transcript of interview to CEO and CMO of Ascendis Pharma, on the Earnings Conference Call- March 22, 2017

“Our long acting CNP pro-drug, TransCon CNP, is designed to optimize the therapeutic index by allowing a CNP level high enough to be therapeutic, but without achieving levels that result in hypotension, which has limited current investigational therapies.

In relevant animal models, we have shown no change in blood pressure following once weekly administration of TransCon CNP. In contrast a daily administered CNP which did lead to hypotension.”

Scott Smith – Senior Vice President, Chief Financial Officer

“We expect to submit an IND (Investigational New Drug application) or similar filing for TransCon CNP during the fourth quarter of 2017 and initiate clinical development in early 2018.”

Jan Mikkelsen – President and CEO


In conclusion, this is a enthusiastic time for patients with achondroplasia, their families, clinicians and the researchers community, by having several drugs in research and development: Vosoritide, TA-46, Meclizine, RMB-007, B-701 and TransCon CNP. We will keep a close look in all these drugs aiming to treat achondroplasia.

February 13, 2017
by inesp.alves
0 comments

Foramen magnum growth in achondroplasia

What is the central nervous system (CNS)?

The nervous system has two parts: the central nervous system and the peripheral nervous system, due to their location in the body. The central nervous system (CNS) includes the nerves in the brain and spinal cord. It is safely contained within the skull and vertebral canal of the spine. All of the other nerves in the body are part of the peripheral nervous system (PNS). Pubmed Health

The central nervous system consists of two parts: the brain and the spinal cord.

The brain works like a central computer. It processes information that it receives from the senses and body, and sends messages back to the body. Brain tissue is made up of about 100 billion nerve cells (called neurons) and one trillion supporting cells which stabilize the tissue.

The spinal cord is the highway for communication between the body and the brain. When the spinal cord is injured, the exchange of information between the brain and other parts of the body is disrupted.

What is the foramen magnum?

Most anatomic designations have origen in Ancient Greek and Latin. Both words in foramen magnum come from Latin: foramen means “hole” and magnum “great”.

The foramen magnum represents a large oval opening in the occipital bone that exists in the base of the skull. It is one of the several oval or circular openings (foramina is the plural of foramen) in the base of the skull. The spinal cord, an extension of the medulla, passes through the foramen magnum as it exits the cranial cavity a natural opening or passage, especially one into or through a bone. Radiopaedia

View from inside the skull, looking from above. Case courtesy of OpenStax College, Radiopaedia.org, rID: 42751

Medulla oblongata and foramen magnum animation. Credits: Wikimedia commons. The medulla oblongata, or just medulla, is a transition between the lower part of the brain (the pons) and the spinal cord.

The foramen magnum is a fundamental component in the complex interaction of bony, ligamentous, and muscular structures composing the craniovertebral junction. Shape and size of the foramen are critical parameters for the manifestation of clinical signs and symptoms in craniocervical pathology.
Among developmental and acquired craniocervical junction disorders, achondroplasia is the most commonly reported. . Tubbs R. et al., 2010

et al. – from Latin et alii, meaning “and others” (used to refer an article written by more than 3 authors).

Pathology – from the Greek pathos “suffering” and ology “the study of something

Achondroplasia results in abnormal endochondral bone formation at the cranial base resulting in a narrow cervical spinal canal, foramen magnum (Mukherjee D. et al., 2014) and jugular foramina which further leads to ventricular dilatation and prominence of the emissary veins. Some degree of ventriculomegaly (increased volume of the ventricles) is present in almost all children with achondroplasia. Bosemani et al., 2014
The presence of prominent emissary veins and meningeal veins (the veins visible in the forehead of many children with achondroplasia) supports the role of collateral vessel formation to compensate for intracranial venous hypertension and increased CSF pressures. Bosemani T. et al., 2014

Credits: Bosemani et al., 2014

Age controls are in this study, children of similar age without achondroplasia. Credits: Bosemani et al., 2014The shape of the FM is variable and the size of the foramen magnum in patients with achondroplasia was small at all ages, particularly in those with serious neurological problems. Shepur M., et al., 2014

Babies with achondroplasia have significantly smaller foramen magnum diameters than unaffected babies, and this difference persists across the lifespan.  DelRosso L., Gonzalez-Toledo E., Hoque R., A Three-Month-Old Achondroplastic Baby with both Obstructive Apneas and Central Apneas, 2013

In the next image is possible to see the size of the foramen magnum (dark cycle) in a baby with achondroplasia.

Clinical case: a 3 months old baby with achondroplasia. Mild foramen magnum narrowing without evidence of cervicomedullary junction stenosis. DelRosso L., Gonzalez-Toledo E., Hoque R., 2013

The CT scan of foramen magnum of 200 non achondroplastic children of all ages and 100 adults, showed an average foramen magnum length of 35 mm (1,38 in) in adults and that of children reached the adult foramen magnun size by 3-4 years of age. Shepur M., et al., 2014

What is cervicomedullary junction (CMJ) compression?

As the name implies, CMJ is the region where the brainstem (the medulla) continues as the spinal cord. A lesion located in this region affects either the brainstem or cervical cord or both depending on its extent and pathology. Involvement of brainstem is manifested as cranial nerve palsies, decreased respiratory drive, long tract signs: clonus (series of involuntary muscular contractions and relaxations), muscle spasticity (stiffness) or bladder involvement that usually indicate a lesion in the middle or upper parts of the spinal cord or in the brain and hydrocephalus if there is obstruction of the fourth ventricle. Nair A., et al. 2014

Hydrocephalus – a disturbance of cerebrospinal fluid (CSF) formation, flow, or absorption, leading to an increase in volume occupied by this fluid in the central nervous system (CNS). Animation here

Impaired venous drainage in achondroplasia has been shown to be caused by deformation of the skull base that by its turn, results in stenosis of the foramen magnum and jugular foramina. Bosemani et al., 2014

The most serious neurological complication in patients with achondroplasia is cervicomedullary junction (CMJ) compression caused by a tight deformed foramen magnum. Compression at the foramen magnum can result in cervical myelopathy manifested as clonus and hyperreflexia, hypotonia, sleep apnea, and even sudden death. Due to the potentially lethal complications associated with symptomatic disease, neurosurgical decompression has been used to widen the foramen magnum and relieve the pressure on the emerging cervical cord. Fortunately, most children with achondroplasia do not suffer neurological symptoms and achieve normal motor and intellectual development without surgical intervention (Mukherjee D. et al., 2014).

 

Monitoring the growth of the Foramen magnum in achondroplasia

The foramen magnum size increases slowly in achondroplasia, but does increase with age. Sudden infant death has been described in achondroplastic individuals, but this usually occurs when this individuals are awake and is associated to marked hypotonia, large head size and cranial vein dilatation. … Almost all children will gain significant muscle tone by age 2 or 3 years old and catch up on all motor milestones. This is probably due to the fact the foramen magnum size increases faster than cervical cord volume, thus relieving pressure on the cord. Thus the severe hypotonia on achondroplasia is self limited. Only those with significant neurological impairment and increased intraventricular pressure should require surgery. Nicoletti B., et al., Human Achondroplasia: A Multidisciplinary Approach, Volume 48 of Basic Life Sciences, Springer US, 2012

Taken from a very old paper:

The fitted nonachondroplastic foramen magnum growth curves demonstrate that the maximum growth occurs in the first 18 months and slows thereafter. Indeed, the sagittal dimension (lateral plane that dives the head into left and right halves) almost doubles within the first 2 years, while the transverse dimension (horizontal plane that divide the head into top and bottom parts) enlarges by half the original dimension. Growth of this area is essentially complete by 5 years. Hetch J., et al.,1989

Foramen magnum growth chart

 

 

The achondroplastic foramen magnum is small at birth and the curves demonstrate that in achondroplasia, during the first year of life, the transverse dimension (fig1a) is the most severely impaired and that growth throughout life is negligible. These curves suggest that foramen magnum growth is more severely impaired than can solely be attributed to abnormal endochondral growth. In the foramen magnum area, the early growth spurt (vertical line in fig 1, around 12 months of age) is absent in the transverse dimension, suggesting that other disruptive processes in achondroplasia contribute to the abnormal development of the foramen magnum. There are a premature fusion and aberrant development of the posterior synchondroses, that should normally occur by 7 years but in achondroplasia premature fusion has been observed as early as 1 year. Hetch J et al., 1989

The development of the skull base occurs mainly at the growth centers called synchondroses: intersphenoid, spheno-occipital and intraoccipital synchondroses. FGFR3 mutation accelerates ossification of cartilages in these synchondroses and causes early closure. This early closure can be the main reason of hypoplasia of the skull base in ACH. Hetch J et al., 1989

Left: view from beneath the skull. Right: view inside the skull base. Credits: Al-Zubair N., 2013

The anatomy of the skull base. There are some synchondroses of the intra- or inter-bones of the skull base. Credits: Nakai Y., et al., 2015

In conclusion mode:

1. Despite stenosis of foramen magnum and jugular foramina, only 10–15% of children develop progressive hydrocephalus, requiring neurosurgical treatment. Bosemani T. et al., 2014

2. The absence of correlation between degree of ventriculomegaly and severity of foramen magnum or jugular
foramina stenosis suggests that the decision for neurosurgical intervention cannot be taken on the basis of individual neuroimaging findings alone. Bosemani T. et al., 2014

3. It is unclear whether the absolute dimension of the foramen magnum is helpful in determining which patient will benefit from decompression. The American Academy of Pediatrics recommends an initial evaluation with a thorough neurologic history, complete physical examination, neuroimaging, and polysomnography. DelRosso L. et al., 2013

4.”Only those with significant neurological impairment and increased intraventricular pressure should require surgery” Nicoletti B et al., 2012.” This conclusion is very important in the evaluation of young children with achondroplasia. Medicine and mathematics are not the same science and in medicine, “1 plus 1 is not equal two”. This example was used to say that there are many factors involved in assessing a baby with achondroplasia as well the individual singularity, that has to be taken in account when deciding for a decompression surgery in a child with achondroplasia younger than 2 years-old. Many neurosurgeons without experience in achondroplasia cases, that face for the first time a baby with achondroplasia with a MRI with a narrow foramen magnum, will encounter a huge challenge in evaluating the risk of cervical mielopathy and the exact need of the decompression surgery.

5. Foramen magnum dimension should be regularly evaluated during early pediatric ages, and this way, using the data to developing a better natural history for achondroplasia.

6. New medicines developed for achondroplasia should act directly at the foramen magnum area and reducing the synchondrosis early closure in achondroplasia.

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