A Basket Study of Vosoritide in Children with Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome with Inadequate Growth During or After Human Growth Hormone Treatment

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Biomarin Pharmaceutical Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

25 Mar 2025 → ongoing

Decision date (initial)

2025-02-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

BioMarin Pharmaceutical Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Others, Safety, Efficacy, Pharmacodynamic, Dose response

To evaluate the effect of 3 vosoritide doses on AGV after 6 months of treatment

Secondary objectives 13

1. 1. To evaluate the effect of 3 vosoritide doses on linear growth after 6 months of treatment
2. 2. To evaluate the safety and tolerability of vosoritide
3. 3. To evaluate the effect of vosoritide on cardiac parameters as measured by echocardiography
4. 4. To evaluate the effect of the therapeutic dose of vosoritide on growth
5. 5. To evaluate the effect of vosoritide body proportions
6. 6. To evaluate the effect of the therapeutic dose of vosoritide on growth up to FAH
7. 7. To evaluate pubertal development with vosoritide
8. 8. To evaluate the PK profile of vosoritide
9. 9. To evaluate the effect of vosoritide on PD and bone growth biomarkers
10. 10. To evaluate the effect of vosoritide on bone age/chronological age
11. 11. To evaluate the effect of vosoritide on bone quality
12. 12. To evaluate changes in HRQoL with vosoritide
13. 13. To monitor cognitive development with vosoritide

Conditions and MedDRA coding

Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Participants must be ≥ 3 years old, and < 11 years old (females) or < 12 years old (males), at the time of signing the informed consent form.
2. 2. A genetically confirmed diagnosis of Turner syndrome, SHOX deficiency or Noonan syndrome.
3. 3. A height assessment corresponding to a height Z-score of ≤ -1.28 SDs (below the 10th percentile in height) in reference to the general population of the same age and sex.
4. 4. Tanner Stage 1, at time of signing the ICF.
5. 5. Previous or current hGH for the treatment of short stature associated with their condition
6. 6. Inadequate growth confirmed with an AGV that is less than age- and sex-matched average stature AGV determined using median heights from CDC growth charts

Exclusion criteria 8

1. 1. Participants with Turner syndrome known to have Y-chromosome material unless they have undergone gonadectomy and have fully external female genitalia.
2. 2. Diagnosis of systemic disease or condition that may cause short stature other than Turner syndrome, SHOX deficiency, or Noonan syndrome, eg, renal, neoplastic, pulmonary, cardiac, gastrointestinal, immunologic and metabolic disease.
3. 3. Bone age advanced beyond chronological age by more than 2 years.
4. 4. Uncorrected congenital heart disease which places the participant at increased risk ofadverse cardiac outcome in the setting of hypotension.
5. 5. Have an unstable condition likely to require surgical intervention during the study.
6. 6. Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of at least 6 months and growth plate closure assessed using bilateral lower extremity X-rays.
7. 7. Previous limb-lengthening surgery, or planned or expected to have limb-lengthening surgery during the study period.
8. 8. Planned or expected bone-related surgery (ie, surgery involving disruption of bone cortex, excluding tooth extraction), during the study period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in AGV at 6 months

Secondary endpoints 14

1. 1. Change from baseline in height and height Z score at 6 months
2. 2. Incidence of treatment-emergent adverse events, and results of laboratory and imaging assessments, over the course of the study
3. 3. Incidence of new diagnosis of hypertrophic cardiomyopathy in children with Noonan syndrome; Incidence of cardiac conditions requiring discontinuation of study treatment
4. 4. Change from baseline in height, height Z-score, and 12-month internal AGV over the course of the study
5. 5. Change from baseline in upper to lower body segment ratio over the course of the study; Change from baseline in arm span to height, ratio over the course of the study
6. 6. Change from baseline in height at each visit up to FAH; Change from baseline in height Z-score at each visit up to FAH; 12-month interval AGV summarized by age and sex up to FAH
7. 7. Tanner stage over the course of the study
8. 8. PK parameters (eg, Tmax, Cmax, AUC0-t, AUC0-inf, t1/2, CL/F, and Vz/F)
9. 9. Change from pre-dose at prespecified timepoints in urine cGMP; Change from baseline at prespecified timepoints in serum CXM
10. 10. Change from baseline in bone age/chronological age at prespecified timepoints
11. 11a. Change from baseline in bone mineralization based on the following, as measured by DXA: • total body (less head) BMD Z-score, • lumbar spine BMD Z-score, • total body (less head) BMC, • lumbar spine BMC, • lower extremity BMD/BMC
12. 11b. Change in the growth plates (ie, monitoring for closure), long bone growth and bone morphology in X-rays of the lower extremities (bilateral, whole length); Incidence of bone-related events of special interest (fracture, slipped capital femoral epiphysis and avascular necrosis or osteonecrosis)
13. 12. Change from baseline in the physical domain score and total score of the QoLISSY; Change from baseline in the physical and social domain scores and total score of the PedsQL; Change from baseline in PGI-S and CaGI S item scores; PGI-C and CaGI-C item scores; Change from baseline in PROMIS-SF Physical Activity score
14. 13. Change from baseline in KABC-II NVI scores

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Biomarin Pharmaceutical Inc.

Sponsor organisation

Biomarin Pharmaceutical Inc.

Address

105 Digital Drive

City

Novato

Postcode

94949-8703

Country

United States

Scientific contact point

Organisation

Biomarin Pharmaceutical Inc.

Contact name

BioMarin Pharmaceutical Inc.

Public contact point

Organisation

Biomarin Pharmaceutical Inc.

Contact name

BioMarin Pharmaceutical Inc.

Third parties 11

Locations

4 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 116 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications