Alpha1-Proteinase Inhibitor for Alpha-1 Antitrypsin Deficiency

Recruiting at 5 trial locations

Overseen By Charlie Strange, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Grifols Therapeutics LLC

Must not be taking: Systemic steroids, Antibiotics

Disqualifiers: Lung or liver transplant, Severe disease, Smoking, others

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

Compensation: Varies

Number of Visits: Unknown

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called Alpha-1 15% (Alpha1-Proteinase Inhibitor) to determine its safety for individuals with Alpha-1 Antitrypsin Deficiency (AATD), a condition that can lead to lung problems. The trial includes two groups receiving different doses to evaluate the treatment's effectiveness as a single dose and then as weekly infusions over eight weeks. Individuals diagnosed with AATD and experiencing breathing issues that meet specific criteria may be suitable candidates for this trial. As a Phase 1, Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to early-stage research.

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

You must stop taking any Alpha1-PI augmentation therapy at least 25 days before the trial and remain off it during the study. Other medications are not specifically mentioned, so check with the trial team for guidance.

Will I have to stop taking my current medications?

If you are currently receiving Alpha1-PI augmentation therapy, you must stop it for at least 25 days before starting the trial and remain off it during the study. The protocol does not specify about other medications, but it is recommended to maintain a stable dose of systemic steroids if you are taking them.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Alpha1-Proteinase Inhibitor, a treatment for Alpha-1 Antitrypsin Deficiency (AATD), is generally safe and well-tolerated. In one study, participants experienced no safety issues over an eight-week period. This treatment uses a protein from human blood, carefully purified to ensure safety. While the specific phase of the studies isn't mentioned, treatments in early clinical trials undergo close monitoring, meaning any side effects are usually minor or well-controlled. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about the Alpha1-Proteinase Inhibitor treatments for Alpha-1 Antitrypsin Deficiency because they offer a potential new approach to managing this condition. Unlike standard treatments that typically involve regular intravenous infusions, these investigational treatments use both intravenous and subcutaneous delivery methods. This could make treatment more flexible and convenient for patients. Additionally, the study is exploring different dosing strategies, such as single and repeat-dose regimens, which might optimize effectiveness and safety. These innovative approaches aim to improve patient outcomes and provide better management options for those living with this genetic disorder.

What evidence suggests that Alpha-1 15% might be an effective treatment for Alpha-1 Antitrypsin Deficiency?

Research has shown that Alpha1-Proteinase Inhibitor, such as Alpha-1 15%, protects the lungs by blocking a harmful enzyme called neutrophil elastase. This enzyme can damage lung tissue if unchecked. People with Alpha-1 Antitrypsin Deficiency (AATD) face a higher risk of serious lung diseases, and using this inhibitor has been shown to help protect their lungs. In this trial, participants will receive different dosages of Alpha-1 15% to evaluate its effectiveness and convenience as a treatment option. Early studies of administering Alpha-1 15% under the skin suggest it might offer a more convenient and flexible treatment option. While the initial results are promising, more research is needed to confirm its effectiveness in larger groups. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with Alpha1-Antitrypsin Deficiency (AATD) who have low serum AAT levels and specific lung function measurements. Participants can be new or current on Alpha1-PI therapy but must stop it before the study starts. Pregnant women, those not using effective contraception, people with severe allergies to plasma-derived treatments, recent lung surgery patients, or those with certain health conditions are excluded.

Inclusion Criteria

I have been diagnosed with Alpha1-antitrypsin deficiency.

I am willing to stop my Alpha1-PI treatment for 25 days before the study starts.

My alpha-1 antitrypsin levels are below the required threshold.

Exclusion Criteria

I am not pregnant, breastfeeding, and if able to bear children, I agree to use effective birth control during the study.

You have a severe deficiency in Immunoglobulin A (IgA).

You have a serious other illness, a history of a severe lung reaction, or an ongoing lung condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Period 1

Participants receive a single weekly subcutaneous infusion of Alpha-1 15% at either 72 mg/kg or 180 mg/kg

1 week

Single-Dose Data Evaluation Period

Participants undergo a 21-day washout/serial pharmacokinetic phase followed by weekly intravenous infusions for up to 78 weeks

21 days washout + up to 78 weeks

Treatment Period 2

Participants receive repeat-dose weekly subcutaneous infusions of Alpha-1 15% for 8 weeks

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Alpha-1 15%

Trial Overview The study tests two doses of a medication called Alpha-1 15%, given as a subcutaneous infusion in participants with AATD. The first dose is administered once and then weekly over eight weeks to evaluate safety and how the body processes the drug.

How Is the Trial Designed?

Group I: Cohort 2: Treatment Period 2 (Alpha-1 15%, 180 mg/kg) Experimental Treatment 1 Intervention

Following treatment period 1 and single-dose data evaluation phase, participants in Cohort 2 will enter treatment period 2 (Repeat-Dose) and will receive Alpha-1 15% 180 mg/kg, for 8 weekly SC infusions.

Group II: Cohort 2: Treatment Period 1 (Alpha-1 15%, 180 mg/kg) Experimental Treatment 1 Intervention

Participants will receive Alpha-1 15% 180 mg/kg, single weekly SC infusion in treatment-period 1 (Single-Dose) at Week 1.

Group III: Cohort 2: Single-Dose Data Evaluation Period (Liquid Alpha1-Proteinase Inhibitor 120 mg/kg) Experimental Treatment 1 Intervention

Following treatment period 1, participants in Cohort 2 will enter 21 days of washout/serial pharmacokinetic (PK) phase and then the single-dose data evaluation phase. During the single-dose data evaluation phase, Liquid Alpha1-PI 120 mg/kg, weekly IV Infusions will be administered from intravenous-dose Week 1 (single-dose Week 5) for up to Week 78, with the last IV dose given 1 week prior to the first repeat Alpha-1 15% SC dose.

Group IV: Cohort 1: Treatment Period 2 (Alpha-1 15%, 72 mg/kg) Experimental Treatment 1 Intervention

Following treatment period 1 and single-dose data evaluation period, participants in Cohort 1 will enter treatment period 2 (Repeat-Dose) and will receive Alpha-1 15% 72 mg/kg, for 8 weekly SC infusions.

Group V: Cohort 1: Treatment Period 1 (Alpha-1 15%, 72 mg/kg) Experimental Treatment 1 Intervention

Participants will receive Alpha-1 15% 72 mg/kg, single weekly subcutaneous (SC) infusion in treatment-period 1 (Single-Dose) at Week 1.

Group VI: Cohort 1: Single-Dose Data Evaluation Period (Liquid Alpha 1-Proteinase Inhibitor 60 mg/kg) Experimental Treatment 1 Intervention

Following treatment period 1, participants in Cohort 1 will enter 21 days of washout/serial pharmacokinetic (PK) phase and then the single-dose data evaluation period. During the single-dose data evaluation phase, Liquid Alpha1- Proteinase Inhibitor (PI) 60 mg/kg, weekly intravenous (IV) Infusions will be administered from intravenous-dose Week 1 (single-dose Week 5) for up to Week 78, with the last IV dose given 1 week prior to the first repeat Alpha-1 15% SC dose.

Who Is Running the Clinical Trial?

Grifols Therapeutics LLC

Lead Sponsor

Trials

59

Recruited

6,000+

Published Research Related to This Trial

Alpha 1-antitrypsin is crucial for protecting the lungs from damage caused by neutrophil elastase, and its deficiency can lead to emphysema, especially in smokers, highlighting the importance of avoiding smoking for affected individuals.

The abnormal Z-mutant form of alpha 1-antitrypsin can accumulate in the liver, leading to serious liver diseases, including cirrhosis and cancer, with liver transplantation being a potential treatment for end-stage liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha 1-antitrypsin deficiency: an overview. van Steenbergen, W.[2022]

Alpha 1-antitrypsin deficiency can lead to severe lung disease, but it is now treatable with alpha 1-proteinase inhibitor therapy, which is derived from human plasma and administered through intravenous infusion.

This infusion therapy can be given in both hospital and home settings, making it accessible for patients and highlighting the importance of nursing considerations for safe administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Principles and clinical management of alpha 1-antitrypsin deficiency. Scharnweber, KS.[2004]

Alpha-1-antitrypsin replacement therapy may help slow the decline in lung function (measured by FEV1) in individuals with alpha-1-antitrypsin deficiency, particularly those with moderate lung disease, based on several observational studies and one meta-analysis.

However, the evidence from large randomized controlled trials is lacking, indicating that more rigorous studies are needed to confirm the effectiveness of this therapy and explore new treatment options for this genetic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-1-antitrypsin replacement therapy: current status. Abusriwil, H., Stockley, RA.[2007]

In a study comparing 38 men who had failed alpha-antagonist therapy with 25 men who had not, those who previously used alpha-antagonists had poorer outcomes after undergoing transurethral resection of the prostate (TURP) for lower urinary tract symptoms due to benign prostatic hyperplasia (BPH).

The findings suggest that the reduced success of TURP in patients with prior alpha-antagonist failure may be linked to underlying comorbid conditions affecting voiding function, rather than the size of the prostate itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transurethral resection of the prostate: failure patterns and surgical outcomes in patients with symptoms refractory to alpha-antagonists. Blanchard, K., Hananel, A., Rutchik, S., et al.[2013]

Human alpha-1-proteinase inhibitor is crucial for preventing lung damage by inhibiting neutrophil elastase, and its deficiency can lead to severe emphysema, highlighting the need for effective therapies.

Current plasma-derived treatments may not meet clinical demand and carry risks of contamination, prompting research into recombinant versions of the inhibitor, which could offer safer and more abundant alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use. Karnaukhova, E., Ophir, Y., Golding, B.[2006]

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]

Alpha(1)-adrenoceptors, which have three main subtypes (alpha(1A), alpha(1B), and alpha(1D)), play crucial roles in various physiological functions and have different pharmacological profiles.

Recent drugs like tamsulosin, naftopidil, and silodosin have been developed to specifically target these receptors to treat urinary obstruction in benign prostatic hyperplasia, highlighting their clinical relevance and subtype selectivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Alpha1-adrenoceptor subtypes and alpha1-adrenoceptor antagonists]. Muramatsu, I., Suzuki, F., Tanaka, T., et al.[2019]

Intrapleural administration of AAV5 vectors expressing human alpha1-antitrypsin (halpha1AT) in mice resulted in significantly higher serum and lung levels of alpha1AT compared to traditional intramuscular delivery, achieving levels 10-fold higher than AAV2 delivery.

At 40 weeks post-administration, the AAV5-halpha1AT vector maintained serum alpha1AT levels of 900 microg/ml, surpassing the therapeutic threshold of 570 microg/ml, suggesting that this method could be a promising gene therapy approach for treating alpha1-antitrypsin deficiency in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrapleural administration of a serotype 5 adeno-associated virus coding for alpha1-antitrypsin mediates persistent, high lung and serum levels of alpha1-antitrypsin. De, B., Heguy, A., Leopold, PL., et al.[2012]

A new compound has been developed that is a highly potent full agonist specifically targeting the alpha 1A adrenergic receptor subtype, which could have significant implications for treating conditions like benign prostatic hyperplasia.

This compound shows excellent selectivity for the alpha 1A receptor, which is important because it may lead to fewer side effects compared to less selective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist. Meyer, MD., Altenbach, RJ., Hancock, AA., et al.[2005]

Isoelectrofocusing techniques effectively identified rare phenotypes of proteinase alpha 1-inhibitor (p alpha 1i), highlighting the importance of using standard sera for accurate identification.

In children with acute leukemia and sepsis, there was a significant increase in p alpha 1i levels, suggesting a potential link between these conditions and the emergence of a rare Pi MM anode phenotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phenotypes of the alpha-1 proteinase inhibitor in septic diseases and leukemia in children]. Basis, VIu., Stakishaĭtis, DV., Bumialis, VV., et al.[2006]

Alpha-1 antitrypsin deficiency is a common hereditary condition, particularly among Caucasians, and is linked to about 2% of chronic obstructive pulmonary disease cases, leading to significant lung issues by age 30 to 45.

Diagnosis involves measuring serum levels of alpha-1 antitrypsin, and treatment options include intravenous augmentation therapy with purified alpha-1 antitrypsin, which can help prevent further lung function deterioration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Alpha 1-protease inhibitor deficiency. Diagnosis, follow-up and therapy options]. Köhnlein, T., Klein, H., Welte, T.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5529111/

Clinical utility of alpha-1 proteinase inhibitor in the ... Alpha-1 antitrypsin (AAT) functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic ...

2. grifols.com grifols.com/en/view-news/-/news/grifols-completes-cohort-1-in-clinical-study-of-alpha-1-15-evaluating-first-in-human-subcutaneous-dosing-option-for-patients-with-alpha1-antitrypsin-deficiency

Grifols completes Cohort 1 in clinical study of Alpha-1 15 ... Grifols has completed Cohort 1 in clinical study of Alpha-1 15% and moving forward into Cohort 2. This study evaluating first-in-human subcutaneous dosing ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04722887

NCT04722887 | A Study to Evaluate Safety, Tolerability ... The purpose of this study is to evaluate the safety and tolerability of 72 milligrams per kilogram (mg/kg) and 180 mg/kg Alpha-1 15%, administered as a single- ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2844046/

Alpha1-Proteinase Inhibitor (Human) - PMC Zemaira is a sterile, stable, lyophilized preparation of highly purified human alpha 1 -PI, also known as alpha 1 -antitrypsin (AAT), derived from human plasma.

5. rarediseaseadvisor.com rarediseaseadvisor.com/news/subcutaneous-aat-aatd-study/

Study on Subcutaneous AAT in AATD Completes Phase 1/2 If approved, Alpha-1 15% will drastically ease the treatment burden of AATD, giving patients greater flexibility and convenience. Read more ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04722887

NCT04722887 | A Study to Evaluate Safety, Tolerability ... The purpose of this study is to evaluate the safety and tolerability of 72 milligrams per kilogram (mg/kg) and 180 mg/kg Alpha-1 15%, administered as a single- ...

7. grifols.com grifols.com/documents/6155538/6172316/np-20221115-en.pdf/f4a0cf67-16fc-07eb-86ce-580a99627579?t=1703229828982

Grifols completes Cohort 1 in clinical study of Alpha-1 15%, ... In this multi-center, single-dose and repeat-dose study over eight weeks, Cohort 1 has been completed and demonstrated no safety issues with ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01983241

NCT01983241 | Efficacy and Safety of Alpha1-Proteinase ... This is a multi-center, randomized, placebo-controlled, double blind clinical study to assess the efficacy and safety of two separate dose regimens of ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1094553922000153

Comparative biochemical efficacy analysis of an alpha 1 Alpha1-proteinase inhibitor (A1PI) augmentation is the only specific treatment targeting the underlying deficiency in alpha1-antitrypsin deficiency (AATD).