ALXN1850 for Hypophosphatasia

(MULBERRY Trial)

Recruiting at 45 trial locations

Overseen By Alexion Pharmaceuticals, Inc. (Sponsor)

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Alexion Pharmaceuticals, Inc.

Disqualifiers: Cardiovascular, Respiratory, Hepatic, Renal, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to evaluate the efficacy of ALXN1850 versus placebo on radiographic outcomes in pediatric participants with HPP who have not previously been treated with asfotase alfa.

Do I need to stop my current medications for the ALXN1850 trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug ALXN1850 for hypophosphatasia?

Research shows that asfotase alfa, a component of ALXN1850, is effective in treating hypophosphatasia by improving bone and dental health, and enhancing quality of life in patients. It has been shown to normalize mineralization and improve survival in severely affected individuals. ^{1 2 3 4 5}

Is ALXN1850 (Efzimfotase alfa) safe for humans?

Asfotase alfa, a similar enzyme replacement therapy, has been studied for safety in treating hypophosphatasia. Over five years, it was generally well-tolerated, but some patients experienced changes in thyroid function tests, which should be monitored. ^{1 2 3 5 6}

How is the drug ALXN1850 different from other treatments for hypophosphatasia?

ALXN1850, also known as asfotase alfa, is unique because it is an enzyme replacement therapy specifically designed to address the underlying cause of hypophosphatasia by replacing the deficient enzyme, tissue-nonspecific alkaline phosphatase, which is crucial for bone mineralization. This makes it different from other treatments that primarily focus on managing symptoms rather than addressing the root cause of the disease. ^{1 3 4 6 7}

Eligibility Criteria

This trial is for children with Hypophosphatasia (HPP) who haven't been treated before. They must have a documented ALPL gene variant, high plasma PLP levels, be in early puberty or less, and show signs of HPP-related rickets on X-rays. Kids can't join if they've had recent fractures, allergies to the study drug ingredients, other bone diseases like hyperparathyroidism or hypoparathyroidism (unless due to HPP), or any major health issues that could affect the study.

Inclusion Criteria

I have HPP with rickets shown in X-rays and low ALP levels for my age and sex.

You have a specific gene variant or high levels of plasma PLP, or are in Tanner stage 2 or less.

Exclusion Criteria

I have been diagnosed with hyperparathyroidism.

I do not have any major health issues that could affect how my body handles medication.

I am not planning any surgery that could affect the study's results.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Randomized Evaluation Period

Participants receive either ALXN1850 or placebo every 2 weeks via subcutaneous injection

24 weeks

12 visits (in-person)

Open-label Extension (OLE) Period

Participants receive ALXN1850 every 2 weeks via subcutaneous injection

Up to 132 weeks

Up to 66 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ALXN1850 (Monoclonal Antibodies)
• Placebo (Placebo)

Trial Overview The trial tests ALXN1850 against a placebo to see how well it works on improving bone problems seen on X-rays in kids with HPP. It's designed to compare changes between those who get the real medicine and those who get a dummy pill without active ingredients.

Participant Groups

Group I: ALXN1850 Experimental Treatment 2 Interventions

Starting at Day 1 of the Randomized Evaluation Period, the ALXN1850 group will receive bodyweight dependent doses of either 20mg, 35mg or 50mg of ALXN1850 once every 2 weeks (q2w) via SC injection, for 24 weeks. Participants will enter the OLE Period and continue q2w dosing with ALXN1850 for up to 132 weeks.

Group II: Placebo Placebo Group 1 Intervention

Starting at Day 1 during the Randomized Evaluation Period, participants will receive placebo q2w for a total of 24 weeks. Participants will enter the OLE Period and continue q2w dosing with ALXN1850 for up to 132 weeks.

Who Is Running the Clinical Trial?

Alexion Pharmaceuticals, Inc.

Lead Sponsor

Trials

267

Recruited

141,000+

Dr. Alberto R. Martinez

Alexion Pharmaceuticals, Inc.

Chief Medical Officer since 2010

MD from University of Sao Paulo

Marc Dunoyer

Alexion Pharmaceuticals, Inc.

Chief Executive Officer since 2021

PhD in Molecular Biology

Alexion

Lead Sponsor

Trials

247

Recruited

38,600+

Marc Dunoyer

Alexion

Chief Executive Officer since 2021

PhD in Molecular Biology, University of Brussels

Christophe Hotermans

Alexion

Chief Medical Officer since 2021

MD, University of Leuven

Findings from Research

In a 13-week study involving 27 adults with pediatric-onset hypophosphatasia, asfotase alfa, an enzyme replacement therapy, demonstrated increased exposure and consistent bioavailability across different body mass index categories, supporting its use at a recommended dose of 6 mg/kg/week.

The pharmacokinetics of asfotase alfa showed that its activity was dose-proportional and that steady state was achieved by approximately day 29, indicating effective dosing and potential for reliable treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia. Pan, WJ., Pradhan, R., Pelto, R., et al.[2022]

Enzyme replacement therapy (ERT) with asfotase alfa has been shown to reduce the severity of oral manifestations in children with hypophosphatasia (HPP), based on a review of 22 studies.

Earlier initiation of ERT is recommended for better oral health outcomes, although some studies reported cases of further primary tooth loss, highlighting the need for more detailed research on oral health improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of enzyme replacement therapy on the oral health manifestations of hypophosphatasia among children: a scoping review. Smart, G., Jensen, ED., Poirier, BF., et al.[2023]

Asfotase alfa, the only approved treatment for hypophosphatasia (HPP), can interfere with thyroid hormone measurements in certain immunoassays that use alkaline phosphatase (ALP) as a labeling enzyme, leading to falsely low levels of free triiodothyronine (FT3) and free thyroxine (FT4).

In a study of three HPP patients, normal thyroid function was confirmed despite low FT3 and FT4 readings from the AIA-2000 immunoassay, highlighting the importance for clinicians to choose appropriate testing methods to avoid misinterpretation of thyroid function in patients receiving asfotase alfa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Altered Thyroid Function Tests Observed in Hypophosphatasia Patients Treated with Asfotase Alfa. Kato, H., Hidaka, N., Koga, M., et al.[2022]

Asfotase alfa (AA), a bone-targeted enzyme replacement therapy, has significantly improved survival rates in severely affected infants with hypophosphatasia (HPP) and enhanced the quality of life for children and adults with the condition.

The review highlights the development of AA, including its design and clinical trial outcomes, while also addressing its limitations and potential adverse effects, establishing its critical role in the management of HPP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy. Bowden, SA., Foster, BL.[2023]

Asfotase alfa, an enzyme replacement therapy for hypophosphatasia, showed significant long-term benefits in 6 adults over 61-68 months, but clinical deterioration occurred after treatment was discontinued for 15-48 months.

Upon restarting asfotase alfa, patients demonstrated improvement, highlighting the need for close monitoring and clinical practice guidelines for managing treatment interruptions in hypophosphatasia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of discontinuing 5 years of enzyme replacement treatment in a cohort of 6 adults with hypophosphatasia: A case series. Rockman-Greenberg, C., Josse, R., Francis, M., et al.[2022]

In a study involving 19 adults and adolescents with hypophosphatasia (HPP), treatment with asfotase alfa significantly increased levels of pyridoxal 5'-phosphate (PLP) after 6 months, indicating its efficacy in normalizing TNSALP substrate levels.

Patients treated with asfotase alfa showed improvements in functional abilities, such as increased walking distance over 5 years, and the treatment was generally well tolerated with mild to moderate side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Kishnani, PS., Rockman-Greenberg, C., Rauch, F., et al.[2020]

Asfotase alfa, the only approved treatment for pediatric-onset hypophosphatasia, can interfere with certain immunoassays that utilize alkaline phosphatase (ALP), potentially leading to false positive or negative results in blood tests.

While asfotase alfa was detected in most ALP assays, it did not affect tests using alternative detection systems, and its interference could be eliminated through sample extraction, highlighting the importance of testing assays for this interference in treated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interference of Asfotase Alfa in Immunoassays Employing Alkaline Phosphatase Technology. Piec, ID., Tompkins, B., Fraser, WD.[2021]

References

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

Pharmacokinetics of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia. [2022]

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

The impact of enzyme replacement therapy on the oral health manifestations of hypophosphatasia among children: a scoping review. [2023]

3. Egypt pubmed.ncbi.nlm.nih.gov

Altered Thyroid Function Tests Observed in Hypophosphatasia Patients Treated with Asfotase Alfa. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Profile of asfotase alfa in the treatment of hypophosphatasia: design, development, and place in therapy. [2023]

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

Impact of discontinuing 5 years of enzyme replacement treatment in a cohort of 6 adults with hypophosphatasia: A case series. [2022]

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

Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. [2020]

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

Interference of Asfotase Alfa in Immunoassays Employing Alkaline Phosphatase Technology. [2021]