Future AATD therapies

Advances in the treatment of alpha-1 antitrypsin deficiency and future therapies

In June 2024, the meeting of the Spanish Network for Research on Alpha-1 Antitrypsin Deficiency (REDAAT) took place, during the 57th SEPAR Congress that took place in Valencia from June 6 to 8.

Review of new strategies for future AATD therapies

On this occasion, Francisco Casas presented during the REDAAT meeting the “Advances in the treatment of DAAT and future therapies”.

During his presentation he reviewed the new strategies for the treatment of AATD, such as:

1. Neutrophil elastase inhibitors
2. Increasing exogenous AAT (existing IV replacement therapy with human AAT, advances in replacement therapy with human AAT and recombinant AAT (rAAT) by IV or inhaled route)
3. Increasing endogenous AAT (liver transplant and increasing AAT release by the hepatocyte)
4. Gene therapy
5. Treatment of liver disease.
6. Other strategies such as reducing lung inflammation with antioxidants or hyaluronic acid, and promoting alveolar regeneration with all-trans retinoic acid have failed.

Neutrophil elastase inhibitors (NE)

They offer an alternative to AAT augmentation therapy that does not rely on intravenous or nebulized routes.

One such drug is alvelestat (Mereo), which has recently completed a phase 2/3 trial, known as ASTRAEUS, of reducing the biomarkers desmosine and Aα-val360, in urine.

Another NE inhibitor, PHP-303 (pH Pharma) has completed phase 1 trials, with a promising safety profile.

AAT Increase

It is based on the derivation of human plasma donations.

It is an effective and safe treatment, but it depends on human donors, it is expensive and its administration is intravenous in a day hospital, and requires about 2 hours for its infusion.

The synthetic production of AAT or NE inhibitors could reduce this limitation; in addition, the treatment until now has been intravenous, but only a minority of the infused AAT reaches the lung.

On the other hand, an inhaled route can improve efficiency, while its administration is less invasive to administer. In addition, dosing escalation strategies vary in the literature, with equivocal evidence between regimens [5,14,17].

Finally, this therapy only addresses lung disease, that is, approaches aimed at treating liver disease are required if we want to treat all patients adequately.

The current status of drug development for AATD is summarized in the following table.

SPARTA Trial

The SPARTA trial of 60 mg/kg versus 120 mg/kg human AAT is awaiting results, which are anticipated to be available in 2026.

Another novel strategy is the administration of human AAT subcutaneously (ClinicalTrials.gov Identifier: NCT04722887), which will allow for home administration via infusion pump.

Given the limited availability of human AAT, research is underway to synthesize functional AAT, called recombinant AAT (rAAT).

This also increases the potential to create a maximally efficient AAT protein.

INBRX-101 (Inhibrx) is a rAAT Fc fusion protein that has completed Phase I trials showing normal serum levels of AAT in 24 patients with AATD, with an acceptable safety profile.

Inhaled AAT

Eliminates the need for intravenous access and allows for administration directly to the site of interest, which is the lung.

Less drug is needed to achieve the same lung tissue concentration.

An inhaled human AAT product (KAMADA-AAT, Kamada), has completed Phase 2 trials.

Results included significantly higher functional AAT levels in epithelial lining fluid (ELF) at doses of 80 mg and 160 mg.

Corrective drugs

AAT-correcting drugs aim to change the shape of the misfolded dysfunctional AAT protein, thereby improving its function.

In addition, they also prevent the polymerization of AAT in the liver, which is the main cause of AATD liver disease.

Trials of these drugs are in the early stages [33–35]. VX-864 (Vertex) showed a significant improvement in functional AAT levels versus placebo.

(Mean difference +2.2 to +2.3 μmol/L across 3 doses, p < 0.0001 in all 3 cases) in a phase 2 trial of 44 participants.

ADVANCE Research

Gene therapy has the potential to act by altering DNA or RNA to produce functional AAT instead of misfolded proteins.

The ADVANCE study is a phase 1/2 trial of ADVM-043 (Adverum), which uses a viral gene transfer vector to deliver a functional gene to the liver of 6 patients.

Functional human AAT is thus expressed, but serious adverse events have been reported.

Nucleotide editing therapies

The development of nucleotide editing therapies is a very active area: BEAM-302 (Beam) is described as a “liver-targeted lipid nanoparticle formulation of base editing reagents.

It has reportedly been able to correct alterations in the SERPINA1 gene in mouse models, with increases in serum AAT and a reduction in liver polymers.

Similarly, Intellia has developed NTLA-3001, a CRISPR-mediated targeted gene editing therapy.

Wave Life Sciences and GSK have collaborated to develop WVE-006, an RNA editing oligonucleotide that offers to correct single nucleotide mutation at the mRNA stage.

Fazirsiran (Takeda)

It is described as an RNA interference therapy, which causes degradation of AAT RNA, thus reducing AAT production from hepatocytes, polymerization and subsequent liver disease.

In this case, in the phase 2 trials, liver biopsies were taken from 15 patients with PiZZ AATD and liver disease at baseline and at 12 weeks, with a median reduction of -83.3% in AAT.

Serum liver enzymes were also reduced in all patients, and fibrosis regression was observed in the majority. The safety profile is good.

Ongoing trials

Phase 3 trials in larger samples are ongoing.

Another RNA interference therapy, belcisiran (Dicerna), is also in phase 2 trials.

Future therapeutic therapies AATD

En la siguiente figura se resumen las diferentes dianas terapéuticas en la DAAT.

Key points

1. Currently, IV AAT therapy remains the only disease-modifying and well-tolerated pharmacological intervention available for AATD.
2. In the short term, the use of chaperones could be a promising treatment, as well as new molecules that interfere with RNA, inhibitors of AAT or neutrophil elastase, and inhaled AAT that may improve efficiency while being easier to administer.
3. In the long term, there is great potential for gene therapy:
   • The use of dual-function vectors that inhibit Z-AAT gene expression and promote M-AAT biological activity is a viable approach for the correction of pulmonary and hepatic manifestations related to AATD.
   • Co-administration of AAT viral vectors and capsid-specific Treg cells is a way to avoid immune responses, improving their efficiency and reducing adverse events resulting from their administration.
   • Gene editing strategies, including the use of RNA silencers and CRISPR-Cas9, are very promising for the correction of specific mutations in the SERPINA1 gene.
4. Strategies to recreate whole organs for transplantation, or repopulation with hepatocytes expressing corrected AAT would be very useful, as they would allow simultaneous treatment of lung and liver disease associated with AATD.
5. Homogeneous and robust evaluation criteria for all these therapies are needed, which assess the relationship between the biological activity of AAT:
   • Rate of progression of lung parenchymal and extracellular matrix degradation.
   • Inflammatory state of the lung.
   • Clinical, functional and imaging efficacy.
6. It is necessary to identify new biomarkers that evaluate the levels of disease progression and response to AATD treatments.

Reference sources

1. McElvaney NG, Burdon J, Holmes M, et al. Long-term efficacy and safety of alpha1 proteinase inhibitor treatment for emphysema caused by severe alpha1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med. 2017 Jan;5 (1):51–60. doi: 10.1016/S2213-2600(16)30430-1
2. De Soyza J, Pye A, Turner AM. Are clinical trials into emerging drugs for the treatment of alpha-1 antitrypsin deficiency providing promising results? Expert Opin Emerg Drugs. 2023 Dec;28(4):227-231. doi: 10.1080/14728214.2023.2296088.
3. Campos MA, Kueppers F, Stocks JM, et al. Safety and pharmacokinetics of 120 mg/kg versus 60 mg/kg weekly intravenous infusions of alpha-1 proteinase inhibitor in alpha-1 antitrypsin deficiency: a multicenter, randomized, double-blind, crossover study (SPARK). COPD: J Chronic Obstructive Pulmonary Dis. 2013 Dec;10 (6):687–695.
4. LLC GT. A study to evaluate safety, tolerability and pharmacokinetics of two different doses of Alpha1-proteinase inhibitor subcutaneous (human) 15% in participants with Alpha1-antitrypsin deficiency. 2021. Available from: https://classic.clinicaltrials.gov/ show/NCT04722887
5. Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α 1 -antitrypsin deficiency. Eur Respir J. 2017 Nov;50(5):1700610.
6. Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016 Jun 6;3(3):668–682. doi: 10.15326/jcopdf.3.3.2015.0182

Source: Centro Andaluz Alfa 1