Abstracts - 2022 - Haemophilia

Beam's Gene Editor Achieves 'First Ever' Genetic Correction In AATD

Beam Therapeutics' investigational gene editor BEAM-302 can correct the disease-causing genetic mutation in patients with alpha-1 antitrypsin deficiency, according to preliminary findings from a Phase I/II study.

Patients with the deficiency commonly suffer from lung disease and damage, while a few—children in particular—will sustain liver injuries. There is currently no established cure for alpha-1 antitrypsin deficiency (AATD), and symptoms are managed as they arise.

Afflicting around 1 in 2,500 people, AATD is a rare and genetic disease characterized by no or insufficient expression of the AAT protein. AAT is made in the liver but functions in the lungs, working to protect them from damage caused by environmental stressors, such as dust, smoke and other forms of pollution.

Beam's answer to this disease is BEAM-302, a liver-targeted formulation of base-editing agents designed to target and correct the most common genetic mutation in AATD patients. According to the biotech, a one-time correction of this mutation can both lower the production and accumulation of a mutated form of AAT, while also boosting the expression of the normal, correctly folded protein. In turn, BEAM-302 increases the levels of functional AAT in circulation, thereby addressing the underlying pathway of AATD.

Monday's readout backs BEAM-302's mechanism of action. Results showed that in patients treated with a 60-mg dose of the gene therapy, total AAT levels jumped from 4.4 µM at baseline to 12.4 µM at 28 days. According to CEO John Evans, this therapeutic effect was "sustainable" and came "above the therapeutic threshold" for AAT.

Over the same time span, circulating concentrations of the mutant AAT protein dropped by 78% in patients treated at the same dose level.

The Phase I/II study also found BEAM-302 to be well-tolerated with an "acceptable" safety profile. All toxicities were mild or moderate in severity, with no serious side effects documented. As of data cutoff, none of the patients dosed with the gene therapy had experienced dose-limiting toxicities. There were instances of grade 1 elevations in liver enzymes (a "mild" elevation), though these were asymptomatic and did not necessitate treatment, according to Beam.

In a note to investors on Monday, William Blair analysts said these initial data for BEAM-302 "validates the safety and efficacy" of Beam's lipid nanoparticle and in vivo base editing platform, adding that the gene therapy's early AAT expression data are highly competitive in this space. "We are inclined to say BEAM-302 has set the bar for efficacy in this space," the analysts wrote.

Wave Life Sciences is also advancing an editing therapy for AATD, which in October 2024 elicited AAT levels of 10.8 µM. Unlike Beam, however, Wave's asset is an RNA editor, which would make its effects transient.

Mutated DNA Restored To Normal In Gene Therapy Advance

Researchers have corrected a disease-causing gene mutation with a single infusion carrying a treatment that precisely targeted the errant gene.

This was the first time a mutated gene has been restored to normal.

The small study of nine patients announced Monday by the company Beam Therapeutics of Cambridge, Mass., involved fixing a spelling error involving the four base sequences — G, A, C and T — in DNA. The effect was to change an incorrect DNA letter to the right one. The result was a normal gene that functioned as it should, potentially halting liver and lung damage of patients with a rare disorder.

"This is the beginning of a new era of medicine," said Dr. Kiran Musunuru, a gene therapy researcher at the University of Pennsylvania's Perelman School of Medicine.

He added that the method offers the hope of treating other genetic diseases precisely by fixing mutations — an alternative to current gene therapies, which either add new genes to compensate for mutated ones, or slicing DNA to silence genes.

Dr. Musunuru is a co-founder and equity holder of Verve Therapeutics, a gene therapy company, and receives funding from Beam Therapeutics for research, but not for this study.

Dr. Richard P. Lifton, president of Rockefeller University and head of its Laboratory of Human Genetics and Genomics, said the sort of gene editing Beam did, rewriting genes with an infusion, "is a holy grail" that "has the promise for being a one-and-done kind of therapy."

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Beam Base Editing Therapy Gets 'proof Of Concept' In Rare Lung Disease

Preliminary results from a small clinical trial suggest that a cutting-edge genetic medicine developed by Beam Therapeutics can repair the damaged DNA that gives rise to a rare liver and lung disorder.

The data, from the first nine patients treated in the trial, are an important proof point for Beam, which specializes in a form of CRISPR gene editing that can precisely rewrite misspelled DNA sequences by changing individual nucleotides, or "letters." Although the biotechnology company has previously released data for other experimental editing medicines, Monday's findings are the first from a therapy designed to directly correct a disease-causing genetic mutation.

In this case, Beam aims to treat a genetic condition called alpha-1 antitrypsin deficiency, or AATD, by fixing the DNA misspelling at the disease's root. Delivered into the liver by tiny globules of fat, the base editing machinery of Beam's medicine swaps an "A" for a "G" in the SERPINA1 gene variant linked to the most severe form of AATD. 

While only a first look at the medicine's potential, the results Beam disclosed Monday suggest treatment is working as intended, without causing any alarming side effects that could derail testing. Still, in a sign of the difficulties currently facing developers of genetic medicine, shares in Beam fell by nearly 15% in Monday morning trading. 

AATD's damage to the liver and lungs is tied to a misfolded "AAT" protein that's produced by the mutant SERPINA1 gene. Normally, this protein is secreted by liver cells and travels to the lungs, where it protects healthy tissue from an enzyme released by white blood cells to fight infections. When it's misfolded, however, the protein mostly accumulates inside liver cells, eventually causing inflammation and cirrhosis. And left unprotected, the lungs are vulnerable to attack by the enzyme, called neutrophil elastase. 

Beam's medicine, dubbed BEAM-302, is meant to address both consequences of AATD. In theory, correction of the SERPINA1 mutation should restore production of correctly folded AAT protein, thereby easing the stress on the liver and rebuilding the lung's defenses against neutrophil elastase. 

The data released Monday give reason to believe in that promise. All nine of the treated patients had lung disease associated with AATD, and received intravenously one of three ascending doses of BEAM-302. One month after treatment, researchers running the trial measured increases in total AAT protein that were between 1.6 and 2.8 times baseline levels. This occurred alongside reductions in circulating misfolded protein, indicating the higher levels were the result of properly produced AAT protein.

In one patient treated with the highest of the three doses, circulating levels of misfolded protein were 78% lower than baseline after one month. And in the three patients on that dose, total AAT protein levels reached an average of 12.4 micromolars — above a threshold that's considered protective as it is seen in people with a "carrier" AATD genotype. 

"We believe BEAM-302 has the potential to be a transformative therapy that could treat the entire spectrum of disease manifestations in severely deficient AATD patients," said Beam CEO John Evans in a Monday statement.

Importantly, wrote Jefferies analyst Michael Yee in a client note, BEAM-302's "safety looks clean." Adverse events are always a particular focus in early testing of new kinds of medicine, but are especially so in genetic medicine, where unwanted side effects have hampered studies of other therapies. 

Beam plans to continue with testing higher doses of BEAM-302 in more patients, as well as to open a second phase of its study which will enroll AAT patients with mild-to-moderate liver disease. The company also expects to report additional study data at a medical conference later this year. 

Alongside the data, Beam announced the pricing of a stock sale that it anticipates will raise $500 million in gross proceeds. The biotech had $850 million in cash, cash equivalents and short-term securities at the end of last year, which it said last month will last into 2027. The new funds should extend that runway to 2028, according to analysts at Leerink Partners.

Beam has plenty of company in targeting AATD. Several companies, Wave Life Sciences among them, are working on an "RNA editing" approach to treatment, while Arrowhead Pharmaceuticals and Takeda have been studying a gene-silencing method known as RNA interference. However, one of Beam's gene editing competitors, Intellia Therapeutics, recently said it would stop work on its AATD therapy.

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