Vosoritide for Turner Syndrome

Overseen By Kimberly Boucher, RN

Age: < 18

Sex: Female

Trial Phase: Phase 2

Sponsor: Roopa Kanakatti Shankar, MBBS, MS

Must not be taking: Estrogen, GnRH analogs

Disqualifiers: Growth plate fusion, Malignancy, Y-chromosome, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests vosoritide, a medication that helps bone growth, in young girls with Turner syndrome who are short. It aims to see if vosoritide can help them grow taller, especially if they haven't responded well to other treatments.

Will I have to stop taking my current medications?

The trial requires that participants stop taking growth hormone or recombinant insulin-like growth factor-1 (IGF-1) at least one week before the screening visit. Other medications like estrogen, certain hormone analogs, and some steroids are also not allowed during the trial.

What data supports the idea that Vosoritide for Turner Syndrome is an effective drug?

The available research does not provide any data on Vosoritide for Turner Syndrome. Instead, it focuses on treatments for a different condition called transthyretin amyloidosis. Therefore, there is no information here to support the effectiveness of Vosoritide for Turner Syndrome. ^{1 2 3 4 5}

How does the drug Vosoritide differ from other treatments for Turner Syndrome?

Vosoritide is unique because it is specifically designed to target growth issues by enhancing bone growth, which is different from the standard hormone replacement therapies used in Turner Syndrome that primarily focus on estrogen for pubertal induction and managing ovarian insufficiency. ^{6 7 8 9 10}

Research Team

Roopa Kanakatti Shankar, MBBS, MS

Principal Investigator

Children's National Research Institute

Eligibility Criteria

This trial is for pre-pubertal girls under 11 years old with Turner Syndrome, either not treated with growth hormone or who had a poor response to it. They must be willing to follow study procedures and have a height significantly below average for their age. Girls with fused growth plates, Y-chromosome material without gonadectomy, significant unrelated health issues, allergies to the medication, or recent investigational drug use are excluded.

Inclusion Criteria

I am between 3 and 10 years old.

I have never used growth hormone or it didn't work well for me.

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. Subjects under the age of 18 are willing and able to provide assent if required

Exclusion Criteria

I have Y-chromosome material but have undergone surgery to have female genitalia.

I am currently taking growth hormone or IGF-1 treatment.

I have not used estrogen, GnRH analogs, aromatase inhibitors, or oxandrolone.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily subcutaneous injections of vosoritide for 12 months to assess growth velocity and safety

12 months

Monthly visits for safety monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Extension

Participants with a positive response to therapy may continue receiving vosoritide until growth cessation

Until growth cessation

Treatment Details

Interventions

• Vosoritide

Trial Overview The trial tests Vosoritide's effectiveness in increasing growth velocity over 12 months in girls with Turner Syndrome who have short stature. It compares their growth rate on Vosoritide against historical data from before treatment. Responders can continue receiving the drug after the initial study period.

Participant Groups

Group I: Vosoritide treatment arm Experimental Treatment 1 Intervention

Vosoritide will be administered daily via subcutaneous injection for 12 months using the FDA approved weight-based dosing band strategy for achondroplasia.

Vosoritide is already approved in United States for the following indications:

Approved in United States as Voxzogo for:

• To increase linear growth in pediatric patients with achondroplasia who are 5 years of age and older with open epiphyses
• to increase linear growth in pediatric patients less than 5 years of age with achondroplasia with open epiphyses

Who Is Running the Clinical Trial?

Roopa Kanakatti Shankar, MBBS, MS

Lead Sponsor

Trials

1

Recruited

20+

Roopa Kanakatti Shankar

Lead Sponsor

Trials

1

Recruited

20+

Findings from Research

Inotersen (Tegsedi™) is a second-generation antisense oligonucleotide that effectively inhibits the production of the misfolded transthyretin protein, addressing the underlying cause of hereditary transthyretin amyloidosis (ATTR).

In the Phase III NEURO-TTR study, inotersen demonstrated significant efficacy in stabilizing or improving peripheral neuropathy and enhancing quality of life for patients, marking it as a breakthrough therapy for this previously untreatable disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotersen (transthyretin-specific antisense oligonucleotide) for treatment of transthyretin amyloidosis. Benson, MD., Dasgupta, NR., Monia, BP.[2020]

Patisiran is the first approved RNA interference therapy that effectively reduces levels of the amyloidogenic protein TTR, showing a safe clinical profile in early phase studies and significant clinical benefits in a phase III trial involving patients with hereditary transthyretin-mediated amyloidosis (ATTRv).

The treatment led to substantial improvements in polyneuropathy scores and quality of life for patients, and it has been approved for use in Stage I and II ATTRv with polyneuropathy, while its effects on ATTRv with cardiomyopathy are still being studied.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of patisiran: a viable treatment option for transthyretin-related hereditary amyloidosis. Milani, P., Mussinelli, R., Perlini, S., et al.[2020]

In a study using a V30M TTR transgenic mouse model, TTR siRNA treatment effectively cleared TTR deposits from the meninges and brain blood vessels, suggesting a potential therapeutic approach for managing CNS-related complications in familial amyloid polyneuropathy (FAP).

Despite the significant reduction of TTR in the blood, cerebrospinal fluid levels remained unchanged, indicating that TTR siRNA does not disrupt the protective functions of TTR in the central nervous system, which is an important consideration for future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficiency of silencing RNA for removal of transthyretin V30M in a TTR leptomeningeal animal model. Gonçalves, P., Martins, H., Costelha, S., et al.[2017]

Up to 83% of patients with TTR amyloidosis (ATTR) experience lower urinary tract dysfunction, with voiding symptoms being the most common, affecting 34.8-87.5% of patients.

Over 40% of ATTR patients suffer from sexual dysfunction, with erectile dysfunction in men and sexual arousal disorder in women being the most prevalent symptoms, highlighting the need for comprehensive assessment and tailored management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis and treatment of urinary and sexual dysfunction in hereditary TTR amyloidosis. Bentellis, I., Amarenco, G., Gamé, X., et al.[2020]

Hereditary transthyretin-related amyloidosis (ATTRv) is a serious genetic condition that leads to severe nerve and heart problems, but treatments like patisiran and inotersen can significantly reduce the levels of the harmful transthyretin protein, improving patient outcomes.

Both patisiran and inotersen have been shown to slow the progression of neuropathy and enhance quality of life in patients, and they have been approved for use in Germany since August 2018 for specific stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene therapy options for hereditary transthyretin-related amyloidosis]. Schilling, M.[2022]

A survey of 155 North American endocrinologists and gynecologists revealed that while 87% felt confident in prescribing hormone replacement therapy (HRT) for adolescents and young adults with Turner syndrome, only half were aware of existing guidelines.

Provider preferences for HRT varied significantly by specialty, with gynecologists less likely to choose hormonal contraceptives and more likely to prefer a higher transdermal estradiol dose, highlighting the need for standardized, evidence-based treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormone Replacement Therapy After Pubertal Induction in Adolescents and Young Adults with Turner Syndrome: A Survey Study. Dowlut-McElroy, T., Kanakatti Shankar, R.[2023]

Turner syndrome, affecting 25-50 per 100,000 females, requires a multidisciplinary approach to care due to its impact on multiple organs throughout life, as highlighted by recent advances in treatment guidelines.

An international consensus meeting led to updated guidelines addressing key areas of care, including growth, cardiovascular health, and hormonal therapy, with formal evaluations of treatment efficacy for conditions like short stature and infertility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Gravholt, CH., Andersen, NH., Conway, GS., et al.[2022]

A study of 29 individuals with Turner syndrome (ages 15-26) showed that those receiving standard estrogen doses had normal uterine growth, with uterine length and volume actually larger than in a control group of 292 females without Turner syndrome.

The findings suggest that current international guidelines for estrogen dosing in Turner syndrome are effective, as they support adequate uterine development during pubertal induction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Recommended Estrogen Dosing for Pubertal Induction in Turner Syndrome Results in Normal Uterine Growth. Lindsay Mart, F., Gutmark-Little, I., Streich-Tilles, T., et al.[2023]

Turner syndrome, characterized by the absence of one X chromosome, leads to significant health risks, including small stature and ovarian failure, necessitating lifelong medical supervision and specialized care.

Recent advancements in treatment include improved fertility options like egg donation and vitrification, as well as enhanced monitoring for cardiovascular issues, particularly aortic dissection, through regular cardiac ultrasounds and MRIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical guideline 'Turner syndrome']. van den Akker, EL., van Alfen, AA., Sas, T., et al.[2022]

In a study of 31 adult patients with Turner's Syndrome, significant differences in final height were observed based on karyotype, indicating that genetic variations may influence clinical outcomes.

The analysis revealed that many patients had additional health issues, such as congenital cardiac and renal malformations, hypercholesterolemia, and abnormal liver function, highlighting the need for comprehensive management strategies for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Turner's syndrome in adult life: case-series and systematic review. Ros, C., Castelo-Branco, C.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Inotersen (transthyretin-specific antisense oligonucleotide) for treatment of transthyretin amyloidosis. [2020]

2. England pubmed.ncbi.nlm.nih.gov

An evaluation of patisiran: a viable treatment option for transthyretin-related hereditary amyloidosis. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Efficiency of silencing RNA for removal of transthyretin V30M in a TTR leptomeningeal animal model. [2017]

4. Germany pubmed.ncbi.nlm.nih.gov

Diagnosis and treatment of urinary and sexual dysfunction in hereditary TTR amyloidosis. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

[Gene therapy options for hereditary transthyretin-related amyloidosis]. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Hormone Replacement Therapy After Pubertal Induction in Adolescents and Young Adults with Turner Syndrome: A Survey Study. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Current Recommended Estrogen Dosing for Pubertal Induction in Turner Syndrome Results in Normal Uterine Growth. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

[Clinical guideline 'Turner syndrome']. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Management of Turner's syndrome in adult life: case-series and systematic review. [2023]