ALXN1850 for Hypophosphatasia

(HICKORY Trial)

Recruiting at 75 trial locations

Overseen By Alexion Pharmaceuticals, Inc. (Sponsor)

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Alexion Pharmaceuticals, Inc.

Disqualifiers: Cardiovascular, Respiratory, Hepatic, Renal, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 78

124 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment called ALXN1850 to see if it helps adolescents and adults with HPP improve their ability to perform daily activities. The participants have not been treated with another common medication for HPP.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you have certain health conditions that affect drug absorption, metabolism, or elimination, you may be excluded from the trial.

Will I have to stop taking my current medications?

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 idea that ALXN1850 for Hypophosphatasia is an effective treatment?

The available research shows that ALXN1850, also known as asfotase alfa, is effective for treating hypophosphatasia. It is the only approved treatment that can normalize mineralization in patients, which is crucial for bone health. Studies have shown that it improves survival in severely affected infants and enhances the quality of life in children and adults. Additionally, when treatment was stopped in a group of adults, their condition worsened, but improved again once the treatment was restarted. This suggests that ALXN1850 is effective in managing the symptoms of hypophosphatasia. ^{1 2 3 4 5}

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

Research shows that asfotase alfa, a component of ALXN1850, is effective in improving bone and dental health in people with hypophosphatasia, a condition where bones and teeth don't harden properly. This drug has been transformative in improving survival and quality of life for patients, especially in severe cases. ^{1 2 3 4 6}

What safety data is available for ALXN1850 treatment in hypophosphatasia?

The safety data for ALXN1850, also known as asfotase alfa, includes findings from several studies. A five-year study (NCT01163149) evaluated the efficacy and safety of asfotase alfa in adults and adolescents with hypophosphatasia, showing significant changes in plasma PLP and PPi concentrations. Another study reported altered thyroid function tests in patients treated with asfotase alfa, indicating potential interference in ALP-dependent immunoassays. Additionally, a case series highlighted clinical deterioration upon discontinuation of asfotase alfa, suggesting the need for close monitoring if treatment is stopped. Overall, these studies provide insights into the safety profile of asfotase alfa in treating hypophosphatasia. ^{1 2 3 5 7}

Is ALXN1850 (Efzimfotase alfa) safe for humans?

Asfotase alfa, a treatment similar to ALXN1850, has been studied for safety in people with 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 7}

Is the drug ALXN1850, also known as asfotase alfa, a promising treatment for hypophosphatasia?

Yes, ALXN1850 (asfotase alfa) is a promising treatment for hypophosphatasia. It is the only approved drug that can improve bone and dental health in patients with this condition. It has been shown to enhance survival in severely affected infants and improve the quality of life in children and adults. The drug works by replacing a missing enzyme, helping to normalize mineralization in the body. ^{1 3 4 7 8}

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 (TNSALP). This approach is different from previous supportive care methods, as it directly targets the enzyme deficiency to improve bone mineralization and overall quality of life. ^{1 3 4 7 8}

Eligibility Criteria

This trial is for adolescents and adults with Hypophosphatasia (HPP) who have a documented ALPL gene variant, low serum alkaline phosphatase activity without other causes than HPP, high plasma PLP levels, and reduced walking capacity. They must not have been treated with asfotase alfa before. People with hypoparathyroidism unrelated to HPP, recent fractures or surgeries that could affect the study, allergies to ingredients in the treatment or placebo, or significant health issues affecting drug absorption or posing risks are excluded.

Inclusion Criteria

Must meet 1 of the following criteria:

My medical records show a diagnosis of HPP.

My test shows an ALPL gene variant from a certified lab.

Exclusion Criteria

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

I have hypoparathyroidism not caused by HPP.

History of allergy or hypersensitivity to any ingredient contained in ALXN1850 or the placebo comparator (Table 9)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Randomized Evaluation Period

Participants receive either ALXN1850 or placebo via subcutaneous injection every 2 weeks for 24 weeks

24 weeks

12 visits (in-person)

Open-label Extension (OLE) Period

Participants receive ALXN1850 via subcutaneous injection every 2 weeks for up to 132 weeks

132 weeks

66 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ALXN1850
• Placebo

Trial Overview The trial is testing the effectiveness of a new medication called ALXN1850 compared to a placebo on improving physical function in participants with HPP. It's designed to see if those taking ALXN1850 perform better on functional tests like walking distance than those taking an inactive substance.

Participant Groups

Group I: ALXN1850 Group 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 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 Group Placebo Group 1 Intervention

During the Randomized Evaluation Period, the placebo group will receive placebo on Day 1, followed by once every 2 weeks (q2w) via SC injection for 24 weeks. Participants will enter the OLE Period and receive bodyweight dependent doses of either 20mg, 35mg, or 50mg of ALXN1850 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

ADULT-ONSET HYPOPHOSPHATASIA: BEFORE AND AFTER TREATMENT WITH ASFOTASE ALFA. [2022]

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

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

8. England pubmed.ncbi.nlm.nih.gov

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