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Adapted from iStock, Drypsiak Vertex may have pivoted away from the space, but candidates in development by Arrowhead/Takeda, Wave, Korro and others could address the damage underlying alpha-1 antitrypsin deficiency and make today’s treatments a thing of the past. Alpha-1 antitrypsin deficiency is a genetic disorder that affects the liver and/or lungs. Approximately 1 in 3,500 people have two abnormal SERPINA1 genes for the alpha-1 antitrypsin (AAT) protein and are at risk of serious organ damage due to AATD. While M-AAT is produced in healthy humans to inhibit neutrophil elastase in the lungs, AATD patients produce Z-AAT, which does not inhibit neutrophil elastase as effectively. If too much neutrophil elastase builds up in the lungs or liver, the result is inflammation which, untreated, can lead to lifelong complications. The only currently approved treatment option for AATD is augmentation therapy , which entails delivering normal alpha-1 antitrypsin collected and purified from blood donors through weekly intravenous administration. But this treatment does not reverse pulmonary damage or stop the progression of liver damage. Multiple companies are developing candidates that would prevent or reverse this damage, and despite some setbacks in the field, in the next 5 to 10 years we could see augmentation therapy become a thing of the past. In August 2024 , Vertex Pharmaceuticals announced that the company would cease research into both of its investigational small molecules for AATD. While Vertex had hoped that VX-634 and VX-668 would treat the disease by correcting the AAT protein, the efficacy was not transformative enough. Along with Vertex’s November 2023 discontinuation of the development of VX-864 for AATD due to reports of rashes and elevated liver enzymes, these setbacks highlight some of the challenges associated with researching new treatments for AATD. Meanwhile, Arrowhead Pharmaceuticals and Takeda are recruiting for three Phase III trials for fazirsiran, an investigational subcutaneous first-in-class investigational RNA interference (RNAi) therapy for AATD-associated liver disease. While Phase II AROAAT-2002 results indicated that fazirsiran led to significant reductions in Z-AAT, the evidence for pulmonary efficacy and improvement is murky because the Phase II trial did not have a placebo arm and the median FEV1 and mean DLCOhbg—markers of pulmonary function—were stable over time in all subjects receiving experimental treatment compared to baseline. While these data do not show any signs of pulmonary decline, there is no sign of overall pulmonary improvement either. In addition, Sanofi is working on SAR447537, an AATD asset acquired from Inhibrx. Formerly known as INBRX-101 , SAR447537 is a fusion protein currently in the recruitment stage for Phase II trials involving AATD emphysema. In Phase I results, safety and pharmacokinetic data supported the intravenous use of SAR447537 every three or four weeks. However, efficacy data related to the liver are not available. In the in vivo base editing space, Beam Therapeutics is investigating the use of BEAM-302 to treat AATD. BEAM-302 is a liver-targeting lipid nanoparticle formulation that is currently undergoing Phase I/II trials and is formulated to be a one-time intravenous injection of an adenine base editor. When tested in rat and mouse models , toxic liver protein levels decreased. Finally, Wave Life Sciences, AIRNA and Korro Bio are competing in the early phases of preclinical/clinical research to develop AATD-targeting subcutaneous RNA-editing oligonucleotides. On Oct. 16, Wave reported positive proof-of-mechanism data from a Phase Ib/IIa trial of WVE-006 in AATD, while Korro Bio released preclinical data this month for its AATD investigational treatment, KRRO-110 . AIRNA had yet to release its adenosine deaminase acting on RNA (ADAR) preclinical data publicly as of July 2024. With all these investigational treatments aiming to transform the way AATD is treated, augmentation therapy could soon be obsolete. If efficacy data for RNA-based oligonucleotides is significant and points to clinical success, RNA-based oligonucleotides could hit the market as soon as four to five years from now. In the meantime, at the current trajectory, fazirsiran could reach the market as early as two to four years from now if all goes well. Given these developments in the AATD space, competition could heat up within the next decade as more efficacy data are released from therapies currently at earlier stages of development.

Researchers at the non-profit n-Lorem discovered and developed a personalised ASO therapy to treat a rare neurological disease. Credit: SurfsUp via Shutterstock. A patient with a rare progressive neurodegenerative disorder receiving a personalised experimental antisense oligonucleotide (ASO) treatment developed by the non-profit n-Lorem has reported improvements in seizure severity and quality of life. The patient, named Susannah, has a rare condition called KIF1A-associated neurological disorder (KAND). US-based non-profit n-Lorem developed a personalised, experimental ASO medicine specific to Susannah’s genetic mutation. After receiving her first dose of the personalised medicine, her seizures fell to under 30 per week and she has remained stable. KAND is caused by mutations in the KIF1A gene, leading to progressive motor impairments, developmental delays, and cognitive difficulties. Management of KAND mainly focuses on addressing symptoms and improving quality of life through supportive therapies, like speech or physical therapy. There are no other therapies for KAND in clinical development, as per GlobalData’s Pharma Intelligence Center. GlobalData is the parent company of Pharmaceutical Technology . Following the ASO treatment, the patient’s ability to walk also improved after one month; compared to having an average of 26.2 falls per day before treatment, she now experiences up to seven falls daily, with many days without any falls. See Also: Eli Lilly boosts sales forecast by $3bn as diabetes and weight loss drugs propel revenue Recursion and Exscientia merge to form drug discovery company Data from the study published in Nature Medicine also detail notable advancements in speech, attention, group interaction, and motor functions, while the patient’s cognitive abilities have remained stable. Susannah has continued on the ASO treatment for 20 months, with a favourable safety and tolerability profile. ASO therapies work by using short, synthetic strands of nucleic acids to target and modify specific genes, reducing the production of harmful proteins or correcting genetic defects. The treatment developed by n-Lorem targets and corrects the harmful version of the KIF1A gene. Founded by former Ionis Pharmaceuticals ’ CEO Stanley Crooke, n-Lorem aims to bring ASO therapies to patients who are diagnosed with a disease that is found in less than 30 people. Research physicians submit an application to the non-profit, which examines if the patient’s genetic mutation is amendable to the ASO technology. More than 130 patient applications have so far been approved by the organisation for a range of different mutations. There has been an increase in the number of nonprofits developing rare disease medications where the patient population size is too small for commercialisation. Italian research charity Telethon Foundation manufactures and distributes Strimvelis, a gene therapy for rare disease adenosine deaminase severe combined immunodeficiency (ADA-SCiD). The non-profit took over development after it was dropped by its pharmaceutical company in 2022, allowing patients to receive treatment. ASO therapies have long been investigated in rare diseases because they target the cause of disease at the molecular level. Researchers have also developed candidates that are approved to treat conditions affecting larger patient populations. Biogen ’s ASO Spinraza (nusinersen) secured approval for treating the movement disorder spinal muscular atrophy in 2016, pulling in $610.5m in sales in 2023 as per the company’s financials. In the announcement accompanying the case study, n-Lorem’s CEO Stanley Crooke said: “Prior to treatment, Susannah’s disease had progressed to her being mostly in a wheelchair, approaching nonverbal with debilitating seizures that limited her and her family’s quality of life. Susannah has now been on treatment for more than 20 months and we continue to observe improvements in her mobility, neurological function, and quality of life.” The non-profit, which launched in 2020, is also conducting a KIF1A outcome measures, assessments, longitudinal and endpoints (KOALA) study to understand how KAND symptoms develop and change over time.

Dive Brief:RNA editing startup Airna is adding more funds to its Series A round, raising another $60 million as it develops genetic medicines for lung, cardiovascular, metabolic and blood diseases.The Boston- and Germany-based biotechnology company made its debut last September with $30 million, launching with a plan to develop a medicine for the rare inherited disorder alpha-1 antitrypsin deficiency.Proceeds from the round will help the company take its AATD drug candidate into the clinic as early as next year, said Kris Elverum, Airnas CEO.Dive Insight:Airna describes its drugmaking approach as a safer alternative to the direct editing of DNA, such as via CRISPR-based techniques.“DNA is like the hardware of the cell, with the foundation,“ Elverum said. “RNA I think of as the software of the cell, which makes and operates the machines.“Airna was co-founded by Thorsten Stafforst, a professor studying RNA editing at the University of Tbingen, and by Jin Billy Li, a longtime geneticist and professor at Stanford University. The companys science is based around enzymes called adenosine deaminase acting on RNA, or ADAR, which help modify and regulate genes.The companys lead program is trying to correct the mutation that causes AATD, which can affect either the liver or lungs, and leads to conditions such as chronic obstructive pulmonary disease. Researchers estimate up to 100,000 people in the U.S. have the deficiency.Treatment of AATD depends on symptoms and can involve bronchodilators, antibiotics and, in some cases, injections of replacement AAT protein. A subcutaneous injection that is administered infrequently and “can repair the underlying disease“ would be preferable, Elverum said.RNA allows us to go after targets and root cause biology, but also have a drug product with a cost benefit that is quite favorable for large diseases and for treating earlier in the disease course, Elverum said.Airnas Series A extension was led by European life sciences investor Forbion, and also involved Arch Venture Partners, Ono Venture Investment, Alexandria Venture Investments and ND Capital. Its board of directors is chaired by Rodger Novak, the co-founder of CRISPR Therapeutics.A handful of companies are working on RNA-modulating treatments for AATD, including Wave Life Sciences, which launched a clinical trial for its drug this year. Among the drugs farthest along in clinical testing is Sanofi's INBRX-101, which it acquired in January as it was being tested in a Phase 2 trial, as well as Arrowhead Pharmaceuticals' experimental liver disease drug in development with Takeda. '