Alpha1-Proteinase Inhibitor for Alpha-1 Antitrypsin Deficiency

Recruiting at 5 trial locations

Overseen By Beatriz Garcia Castro

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

Trial Summary

What is the purpose of this trial?

This trial tests if Alpha-1 protein injections are safe and tolerable for people with Alpha1-Antitrypsin Deficiency. The treatment aims to protect their lungs by giving them extra Alpha-1 protein. Alpha-1 proteinase inhibitor, a human-derived blood product, has been used for over 20 years to treat individuals with Alpha1-Antitrypsin Deficiency.

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.

What data supports the idea that Alpha1-Proteinase Inhibitor for Alpha-1 Antitrypsin Deficiency is an effective treatment?

The available research does not provide specific data supporting the effectiveness of Alpha1-Proteinase Inhibitor for Alpha-1 Antitrypsin Deficiency. The first article mentions that the use of this treatment for emphysema related to the deficiency is debated, but it does not provide specific outcomes or data. The other articles focus on different topics, such as receptor agonists and antagonists, and do not address the treatment's effectiveness for Alpha-1 Antitrypsin Deficiency. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Alpha1-Proteinase Inhibitor for Alpha-1 Antitrypsin Deficiency?

The research on alpha-1-antitrypsin replacement therapy suggests that it is used to treat emphysema (a lung condition) related to alpha-1-antitrypsin deficiency, although its effectiveness is debated. This indicates that the drug may help manage symptoms of this genetic condition, but more studies are needed to confirm its benefits. ^{1 2 3 4 5}

What safety data exists for Alpha1-Proteinase Inhibitor treatment for Alpha-1 Antitrypsin Deficiency?

The safety data for Alpha1-Proteinase Inhibitor treatment primarily involves plasma-derived versions, which are used for augmentation therapy in Alpha-1 Antitrypsin Deficiency. These treatments are delivered via intravenous infusion and have been used in both hospital and home settings. While effective viral clearance steps are part of the manufacturing process, there remains a potential risk of contamination with new and unknown pathogens. Efforts are ongoing to develop recombinant versions to address these safety concerns. The treatment is generally considered safe, but the potential risks associated with plasma-derived products and the need for alternative recombinant options are noted in the literature. ^{6 7 8 9 10}

Is Alpha1-Proteinase Inhibitor safe for humans?

Alpha1-Proteinase Inhibitor, derived from human plasma, is used to treat Alpha-1 Antitrypsin Deficiency and is generally considered safe, though there is a potential risk of contamination with unknown pathogens. Efforts are being made to develop recombinant versions to address safety and supply concerns. ^{6 7 8 9 10}

Is the drug Alpha-1 15% a promising treatment for Alpha-1 Antitrypsin Deficiency?

Yes, Alpha-1 15% is a promising drug for Alpha-1 Antitrypsin Deficiency because it helps replace the missing protein that protects the lungs from damage, potentially slowing down the progression of lung disease. ^{6 8 9 10 11}

How is the drug Alpha-1 15% different from other treatments for Alpha-1 Antitrypsin Deficiency?

Alpha-1 15% is unique because it is administered subcutaneously (under the skin), unlike traditional treatments that are typically given intravenously (through a vein). This method can offer more convenience and potentially fewer side effects for patients. ^{6 8 9 10 11}

Eligibility Criteria

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).

I haven't increased my steroid dose above 5 mg/day prednisone in the last 4 weeks.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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-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 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]

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]

References

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

Alpha-1-antitrypsin replacement therapy: current status. [2007]

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

Transurethral resection of the prostate: failure patterns and surgical outcomes in patients with symptoms refractory to alpha-antagonists. [2013]

3. Japan pubmed.ncbi.nlm.nih.gov

[Alpha1-adrenoceptor subtypes and alpha1-adrenoceptor antagonists]. [2019]

4. United States 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. [2005]

5. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Phenotypes of the alpha-1 proteinase inhibitor in septic diseases and leukemia in children]. [2006]

6. Austria pubmed.ncbi.nlm.nih.gov

Recombinant human alpha-1 proteinase inhibitor: towards therapeutic use. [2006]

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

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

8. Germany pubmed.ncbi.nlm.nih.gov

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

9. England pubmed.ncbi.nlm.nih.gov

Alpha 1-antitrypsin deficiency: an overview. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

[Alpha 1-protease inhibitor deficiency. Diagnosis, follow-up and therapy options]. [2019]

11. United States 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. [2012]