WVE-006 for Alpha-1 Antitrypsin Deficiency

(RestorAATion-2 Trial)

Recruiting at 5 trial locations

Overseen By Clinical Operations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Wave Life Sciences Ltd.

Must not be taking: AAT augmentation therapy

Disqualifiers: Multiple drug allergies, Recent infections, Alcohol use, others

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

Compensation: Varies

Number of Visits: Unknown

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this open-label study is to assess the safety, tolerability, pharmacodynamics, and pharmacokinetics of WVE-006 in participants with alpha-1 antitrypsin deficiency (AATD) following Period 1 single ascending dose (SAD) and Period 2 multiple ascending doses (MAD), respectively.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on AAT augmentation therapy during the study or within 30 days before it starts.

What data supports the idea that WVE-006 for Alpha-1 Antitrypsin Deficiency is an effective drug?

The available research does not provide any data on WVE-006 for Alpha-1 Antitrypsin Deficiency or its effectiveness. The studies listed focus on shoulder treatments and surgeries, which are unrelated to WVE-006 or Alpha-1 Antitrypsin Deficiency. ^{1 2 3 4 5}

How is the drug WVE-006 unique for treating Alpha-1 Antitrypsin Deficiency?

WVE-006 is unique because it potentially offers a novel approach to treating Alpha-1 Antitrypsin Deficiency by using a retroviral vector to insert normal human alpha 1-antitrypsin cDNA into cells, which may lead to the production of physiologically normal alpha 1-antitrypsin, unlike traditional augmentation therapy that uses protein infusions. ^{6 7 8 9 10}

Research Team

Cynthia Caracta, MD

Principal Investigator

Wave Life Sciences

Eligibility Criteria

This trial is for individuals with a genetic condition called Pi*ZZ Alpha-1 Antitrypsin Deficiency (AATD). Participants should be healthy or have mild to moderate AATD-related lung disease with an FEV1 of at least 50%, or stable liver disease. They must not have smoked for at least one year.

Inclusion Criteria

I am healthy or have mild to moderate lung or stable mild liver disease due to AATD.

I have not smoked for at least 1 year.

My genetic test shows I have the Pi*ZZ genotype.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single Ascending Dose (SAD)

Participants receive single ascending doses of WVE-006 to assess safety, tolerability, pharmacodynamics, and pharmacokinetics

4-6 weeks

Multiple Ascending Dose (MAD)

Participants receive multiple ascending doses of WVE-006 to further assess safety, tolerability, pharmacodynamics, and pharmacokinetics

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• WVE-006

Trial Overview The study tests WVE-006's safety and effects in people with AATD. It has two parts: first, they'll receive a single dose of the drug, then multiple doses over time to see how their body reacts and processes it.

Participant Groups

Group I: WVE-006 (Dose 3) Experimental Treatment 1 Intervention

Group II: WVE-006 (Dose 2) Experimental Treatment 1 Intervention

Group III: WVE-006 (Dose 1) Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Wave Life Sciences Ltd.

Lead Sponsor

Trials

14

Recruited

630+

Findings from Research

In a case series of 10 patients who experienced complications after shoulder arthroplasty, arthroscopic evaluation and treatment led to significant improvements in patient outcomes, with 3 excellent, 4 good, and 5 fair results based on the Hospital for Special Surgery (HSS) scores.

The study demonstrated that arthroscopy is a safe and effective method for diagnosing and treating complications, with no infections or major complications reported, although one patient experienced a periprosthetic fracture during the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arthroscopy for failed shoulder arthroplasty. Hersch, JC., Dines, DM.[2004]

The Weaver-Dunn procedure for chronic acromioclavicular joint dislocation showed good shoulder function in patients, with no significant difference in outcomes between those treated with a temporary hook plate and those with a braided PDS loop suture.

Patients who received the hook plate experienced more pain during movement compared to the PDS group, and the hook plate did not provide any functional advantage, leading to the conclusion that it may not be necessary and adds the risk of requiring an additional surgery for removal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical treatment of chronic acromioclavicular dislocations: a comparative study of Weaver-Dunn augmented with PDS-braid or hook plate. Boström Windhamre, HA., von Heideken, JP., Une-Larsson, VE., et al.[2016]

In a study of 31 patients who underwent Alvik's modification of the Eden-Hybbinette operation for recurrent shoulder dislocation, the majority reported good outcomes after an average follow-up of 5 years, with only one patient dissatisfied.

The procedure demonstrated a low rate of reoperations and no complications from the bone block fixation, indicating its safety and effectiveness compared to other surgical methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent dislocation of the shoulder. The Alvik modification of the Eden-Hybinette operation. Schrøder, HA., Fristed, PB.[2019]

In a study of 14 shoulders (13 patients) with failed total shoulder arthroplasty and intact rotator cuffs, conversion to hemiarthroplasty with glenoid bone grafting resulted in significant pain reduction and functional improvement, with VAS pain scores decreasing from 6.4 to 1.6 and ASES scores improving from 33 to 72 over an average follow-up of 44 months.

All patients showed successful graft incorporation, and the procedure had a low complication rate, with only one case of postoperative infection, indicating that this approach is both effective and relatively safe for managing glenoid bone defects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of intermediate outcomes of glenoid bone grafting in revision shoulder arthroplasty. Schubkegel, TA., Kwon, YW., Zuckerman, JD.[2014]

Surgical treatment of acute acromioclavicular dislocations (ACDs) performed within three weeks post-injury showed slightly better outcomes in terms of coracoclavicular distance and percentage increase compared to chronic cases, suggesting that timely intervention may lead to better structural results.

Both acute and chronic ACDs resulted in similar pain and functional scores post-surgery, indicating that if surgery is delayed beyond three weeks, the modified Weaver Dunn technique can still provide good clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative Comparative Evaluation of Patients Undergoing Surgical Treatment for Acute Versus Chronic Acromioclavicular Dislocations. Storti, TM., de Paula, LB., Simionatto, C., et al.[2021]

A new method using monoclonal antibodies (MAbs) has been developed to specifically detect different variants of the alpha 1-antitrypsin (alpha 1-AT) protein, which is crucial for diagnosing alpha 1-AT deficiencies that can lead to emphysema.

This rapid and straightforward immunoblot assay allows for early diagnosis and treatment of alpha 1-AT deficiencies, enabling timely interventions such as augmentation therapy and lifestyle recommendations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of genetic variants of alpha 1-antitrypsin with site-specific monoclonal antibodies. Zegers, ND., Claassen, E., Gerritse, K., et al.[2019]

In a long-term study involving four Japanese patients with alpha1-antitrypsin deficiency, weekly intravenous infusions of 60 mg/kg Alpha-1 MP were found to be generally safe and well-tolerated over a period of 52 weeks, with most reported adverse events being mild.

The treatment did not lead to significant changes in pulmonary function tests or laboratory parameters, indicating that Alpha-1 MP does not adversely affect lung function or overall health in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency. Seyama, K., Suzuki, M., Tasaka, S., et al.[2022]

Researchers successfully integrated a normal human alpha 1-antitrypsin (alpha 1AT) cDNA into mouse fibroblasts using a modified retroviral vector, demonstrating a method to potentially treat alpha 1AT deficiency.

The produced alpha 1AT was biologically active, effectively inhibiting neutrophil elastase, and had a serum half-life comparable to that of normal human alpha 1AT, indicating its potential efficacy as a therapeutic intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Production of glycosylated physiologically "normal" human alpha 1-antitrypsin by mouse fibroblasts modified by insertion of a human alpha 1-antitrypsin cDNA using a retroviral vector. Garver, RI., Chytil, A., Karlsson, S., et al.[2019]

In a long-term study of seven patients with Alpha-1-Antitrypsin Deficiency, weekly intravenous augmentation therapy significantly slowed the decline in lung function (FEV1) compared to the three years prior to the program, indicating its efficacy in managing COPD symptoms.

The home care program, 'Alpha-1-Mobile', was found to be safe and well-accepted, with minimal hospitalizations due to exacerbations and no adverse events related to the augmentation therapy, highlighting its practicality for ongoing patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. Wilke, A., Semper, H., Gross, C., et al.[2022]

A genetic mutation in the alpha 1-antitrypsin (alpha 1-AT) gene, identified as 'nullHong Kong', leads to a total absence of functional alpha 1-AT protein in serum, which is crucial for protecting lung tissue from damage.

The mutation results in a truncated protein that cannot be secreted from liver cells, explaining the patient's deficiency and increased risk for emphysema due to unchecked neutrophil elastase activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. Sifers, RN., Brashears-Macatee, S., Kidd, VJ., et al.[2021]

References

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

Arthroscopy for failed shoulder arthroplasty. [2004]

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

Surgical treatment of chronic acromioclavicular dislocations: a comparative study of Weaver-Dunn augmented with PDS-braid or hook plate. [2016]

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

Recurrent dislocation of the shoulder. The Alvik modification of the Eden-Hybinette operation. [2019]

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

Analysis of intermediate outcomes of glenoid bone grafting in revision shoulder arthroplasty. [2014]

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

Postoperative Comparative Evaluation of Patients Undergoing Surgical Treatment for Acute Versus Chronic Acromioclavicular Dislocations. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Detection of genetic variants of alpha 1-antitrypsin with site-specific monoclonal antibodies. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term safety of Prolastin®-C, an alpha1-proteinase inhibitor, in Japanese patients with alpha1-antitrypsin deficiency. [2022]

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

Production of glycosylated physiologically "normal" human alpha 1-antitrypsin by mouse fibroblasts modified by insertion of a human alpha 1-antitrypsin cDNA using a retroviral vector. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

[Longterm Homecare Augmentation Program in Alpha-1-Antitrypsin Deficient Patients]. [2022]

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

A frameshift mutation results in a truncated alpha 1-antitrypsin that is retained within the rough endoplasmic reticulum. [2021]