Alpha 1 MZ Medication
There is no cure (yet) for an Alpha 1 Antitrypsin Deficiency genotype MZ at this time. The root cause of the deficiency is an genetic variant of SERPINA1. This causes the liver to produce 50% of the correct Alpha 1 Antitrypsin (the M) and 50% of a defect Alpha 1 antitrypsin (the Z) This means that curing the root cause needs a genetic modification, by turning the Z into an M, such that your liver is again producing MM type Alpha 1 Antitrypsin.
One of the options is a liver transplant, changing the MZ liver with a MM liver, which is sometimes done, when the MZ liver is not functional anymore. So this is more of a last resort, in case there are very serous liver issues.
Another option is a weekly infusion of Alpha 1 Antitrypsin to keep your levels up. This is mainly done for individuals which have a severe lung issue and to protect their lungs from further damage. There are also individuals which are on Alpha 1 antitrypsin infusions to correct their immune system, and more and more medical research is pointing into that direction as well. Please note that Alpha 1 Infusions are not available in all countries.
This means that the options at this moment are very limited, and the best what you can do is to offload your liver, eat healthy, live a healthy life and take care of your lungs as good as you can.
There are however developments ongoing where the genetic variant, which is causing the liver to produce the Z protein, can be eliminated or even changed into the correct one.
Below a number of announcements of companies working on medications for Alpha 1 Antitrypsin deficiency.
Please note that medications are tested in different phases where:
-
Phase 1 tests safety of the drug in healthy volunteers.
-
Phase 2 tests safety and effectiveness in Alpha1 patients.
-
Phase 3 tests safety and confirms effectiveness in a larger group of Alpha1 patients
-
After Phase 3, regulatory agencies like the FDA or EMA decide if the drug may be prescribed
-
Phase 4 tests the drug’s effect in various populations and any side effects associated with long-term use after the drug is approved.
Arrowhead and Takeda (Jan 2023)
They announced in Jan 2023 good results from their Phase 2 study of Fazirsiran in patients with Alpha-1 Antitrypsin Deficiency-Associated Liver Disease. In May 2023 the Phase 3 study is started.
Fazirsiran is an investigational RNA interference (RNAi) compound aimed at reducing the production of Z-AAT, thereby giving the liver the opportunity to regenerate and recover.
The phase 3 trial is a randomized, double-blind, placebo-controlled trial of fazirsiran efficiency and safety in approximately 160 patients over age 18 who have stage F2 to F4 fibrosis of the liver.
Note: This medication is already a massive step forward for Alpha 1 MZ individuals, when made available, because it may reduce or eliminate the liver issues of an Alpha 1 MZ individual, including the by the liver induced second and third order issues.
Beam Therapeutics (June 2024)
They announced First Patient Dosed in the Phase 1/2 Study of BEAM-302 in Alpha-1 Antitrypsin Deficiency (AATD)
Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company developing precision genetic medicines through base editing, today announced the first patient was treated with BEAM-302, an investigational in vivo base editing medicine designed to precisely correct the underlying cause of severe alpha-1 antitrypsin deficiency (AATD), that is currently being evaluated in a Phase 1/2 clinical trial.
“Treating the first patient with BEAM-302 is an important milestone for Beam and the AATD patient community, who are in need of novel and more effective treatment options that can address the full spectrum of disease manifestations,” said John Evans, chief executive officer at Beam. “Using the power and precision of base editing technology, BEAM-302 is the first clinical program in the gene editing field designed to directly correct a genetic disease-causal mutation back to a normal functional gene sequence with a one-time in vivo therapy. We believe BEAM-302 has the potential to be a best-in-class treatment of both AATD-associated lung and liver disease through the correction of the PiZ allele, the most common gene variant associated with severe AATD. Advancing this Phase 1/2 study is a top priority for Beam, and we look forward to continued site activation, patient enrollment and dosing.”
BEAM-302 is being evaluated in an open-label, dose-escalation Phase 1/2 clinical trial that will investigate the safety, pharmacodynamics, pharmacokinetics and efficacy of BEAM-302. The study design includes a dose exploration portion followed by a dose expansion portion to identify the optimal dose to take forward in a pivotal study.
About BEAM-302
BEAM-302 is a liver-targeting lipid-nanoparticle (LNP) formulation of base editing reagents designed to correct the PiZ mutation. Patients homozygous for this mutation (PiZZ) represent the majority of patients living with severe AATD disease. A one-time A-to-G correction of the PiZ mutation with Beam’s adenine base editor has the potential to simultaneously reduce the aggregation of mutant, misfolded AAT protein that causes toxicity to the liver and increase circulating levels of corrected and functional AAT protein, thus addressing the underlying pathophysiology of both the liver and lung disease. In addition, the reduction in circulating PiZ aggregates (i.e., polymers) has the potential to further minimize lung inflammation and dysfunction. Importantly, because the native AAT gene would be corrected in its normal genetic location, AAT levels are anticipated to increase physiologically in response to inflammation or infection. This is a critical aspect of AAT’s normal function to regulate the body’s inflammatory response, which does not occur with currently approved protein replacement therapies. Correction of the PiZ mutation is expected to be durable based on preclinical evidence.
INHBRX / Sanofi (Jan 2024)
IINHBRX announced that NBRX-101 has successfully completed a Phase 1 trial, demonstrating positive results in terms of safety and pharmacokinetics and is currently enrolling a Phase 2 clinical trial to further evaluate the potential of INBRX-101 as a treatment for AATD. If successful, INBRX-101 could offer a significant improvement in the treatment options and quality of life for AATD patients.
INBRX-101 is a human recombinant protein that holds the promise of allowing Alpha-1 Antitrypsin Deficiency (AATD) patients to achieve normalization of serum AAT levels with less frequent (monthly vs. weekly) dosing.
ATD is an inherited rare disease characterized by low levels of AAT protein, predominantly affecting the lung with progressive deterioration of the tissue. INBRX-101 may help to reduce inflammation and prevent further deterioration of lung function in affected individuals.
Dicerna Pharmaceuticals, Novo Nordisk (Update June 2024)
Belcesiran is a novel Dicer-substrate small interfering RNA oligonucleotide that is designed to silence the mutant SERPINA1 gene in individual’s with A1ATD.
Conclusion of the Phase 1 study of belcesiren in healthy volunteers showed that belcesiran was well-tolerated with dose-dependent and reversible effects on serum AAT levels in HVs.
The Phase 2 study is conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.
Vertex Pharmaceuticals Incorporated (Nov 2023)
The company is discontinuing its alpha-1 antitrypsin deficiency (AATD) therapy, dubbed VX-864, “due to non-serious rash events in some patients.
Wave Life Sciences (Dec 2023)
WVE-006 is uniquely designed to correct the disease-causing RNA mutation in AATD, thereby restoring circulation of wild-type M-AAT protein and reducing Z-AAT protein levels to address both lung and liver manifestations of the disease. Proof-of-mechanism data in individuals with AATD, as measured by restoration of M-AAT protein, expected in 2024.
In preclinical studies, WVE-006 led to potent and durable RNA editing and restoration of AAT protein up to 30 micromolar, underscoring the impact of our novel chemistry.
They announced the initiation of dosing in healthy volunteers in a clinical trial program, which is investigating WVE-006 as a potential treatment for alpha-1 antitrypsin deficiency (AATD)
Korro Bio (May 2024)
Korro Presents Additional Preclinical Data for KRRO-110 at the American Thoracic Society 2024 International Conference
-
KRRO-110 showed sustained editing efficiency of approximately 60% and increased total alpha-1 antitrypsin (AAT) protein levels to greater than 60uM at week 13 in an in vivo genetic Alpha-1 Antitrypsin Deficiency (AATD) mouse model
-
KRRO-110 showed 35µM of M-AAT one week post the first dose, with 0µM of M-AAT at baseline, increasing to 45µM of M-AAT at week 13
-
Phase 1/2 trial of KRRO-110 in ZZ AATD patients, anticipated in 2026