Bayer's new drug is approved for clinical use. Can AAV therapy become a new hope for the treatment of Huntington's disease?

August 27, 2022/eMedClub News/--On August 23, 2022, Asklepios BioPharmaceutical (hereinafter referred to as AskBio), a wholly-owned subsidiary of Bayer, announced that it has obtained a license to conduct its clinical trials in France through its subsidiary BrainVectis.

BV-101 is a novel, specially designed adeno-associated virus (AAV) gene therapy vector that can directly deliver a gene of interest into a patient's brain, addressing metabolic dysfunction in diseased neurons while facilitating mutation Clearance of huntingtin

In preclinical studies, BV-101 demonstrated the ability to repair a defective essential cholesterol metabolism pathway in mice, providing neuroprotection and restoring physical performance by delivering CYP46A1, a protein that is reduced in the brains of Huntington's patients, which is the brain a key enzyme

What sets BV-101 apart from other attempts to treat Huntington's disease is that it is designed to restore cholesterol, according to Dr.

"The approval of this trial in France marks an important milestone that means there is hope for a treatment for one of the world's most devastating genetic diseases ," said Sheila Mikhail, CEO and co-founder of AskBio

The clinical trial of BV-101 will be an open-label dose-escalation study designed to evaluate the safety, tolerability and preliminary efficacy of BV-101 in adult patients with early-stage HD

AskBio, a wholly owned and independently operated subsidiary of Bayer AG, acquired BrainVectis in 2020, enriching its pipeline of treatments for HD and other degenerative diseases, and was acquired by Bayer in the same year
.

It is a fully integrated gene therapy company with a portfolio of clinical programs covering neuromuscular, central nervous system, cardiovascular and metabolic disease indications, with a clinical stage pipeline including Pompe disease, Parkinson's disease and congestive heart failure of therapeutic drugs
.

▲ Source of AskBio gene therapy pipeline map: company official website

The company's AAV capsid development platform integrates bioinformatics analysis, crystal structure analysis, in vivo/in vitro modeling and genome sequencing technologies, designed to extend the capabilities of AAV capsids and enable them to circumvent antibody neutralization, including Heparin- and heparan sulfate-binding chimeric vectors, domain swap-based Loop chimeric vectors, and diglycan receptor chimeric vectors are presented
.

AAV Gene Therapy: New Hope for the Huntington Field?

Currently, there are no disease-modifying therapies approved for the treatment of HD, a rare inherited neurodegenerative disease that affects approximately 60,000 patients in the European Union, according to the Committee on Orphan Medicinal Products (COMP)
.

The disease is caused by an abnormally repeated mutation in the huntingtin gene, which causes abnormal protein aggregation in nerve cells and causes a series of symptoms that usually begin between the ages of 30 and 50, but can also occur earlier It manifests itself at a certain age, eventually leading to complete physical as well as mental degeneration
.

Previously, antisense oligonucleotide (ASO) therapy was regarded as a new way to treat HD.
However, in March last year, the ASO drug tominersen developed by Roche and Ionis Pharmaceuticals stopped clinical phase 3 research, and Wave Life Sciences stopped WVE-120101 and WVE-120102, two ASO drugs in Phase 1/2 clinical trials, are administered by spinal injection
.

Of course, this does not mean that ASO does not have the potential to treat HD, and Wave Life Sciences is also actively promoting a third related drug
.

On September 7 last year, Roche subsidiary Spark Therapeutics and NeuExcell Therapeutics announced that they had reached a gene therapy cooperation agreement, using Spark's advanced AAV platform and NeuExcell neural regeneration gene therapy platform to develop new gene therapy for HD, demonstrating AAV to a certain extent The therapeutic potential of gene therapy in this area
.

In addition to AskBio's BV-101 mentioned above, the drug that is currently progressing faster is uniQure's AMT-130, which adopts a different treatment principle from BV-101
.

uniQure is a nearly 22-year-old gene therapy company focused on developing AAV gene therapies
.

AMT-130 is one of the company's candidate therapies that encapsulates artificially synthesized microRNAs through an adeno-associated virus type 5 (AAV5) vector
.

This artificially engineered microRNA fragment, synthesized based on the company's proprietary miQURE™ silencing technology, inhibits or silences the expression of Huntington's disease-causing genes, and is the first orphan drug-designated AAV gene therapy for Huntington's disease
.

The drug can be injected directly into the striatal region of the brain, which then spreads to other sites and reduces the expression of mutant huntingtin (mHtt)
.

Currently, the drug is undergoing Phase 1/2 clinical trials
.

In June of this year, uniQure published safety and biomarker data for the low-dose group of the trial within one year.
The data showed that AMT-130 was well tolerated, with an average 53.
8% reduction in mHtt in cerebrospinal fluid (CSF), which was not seen in the study.
Adverse events associated with gene therapy
.

Based on these data, experiments in the high-dose group were approved
.

However, on Aug.
8 the company reported its second-quarter financial results
.

After the report revealed that in a Phase 1/2 trial for Huntington's disease, 3 of 14 patients in the high-dose AMT-130 treatment group experienced serious side effects, the company said it was in agreement with the data safety monitoring committee ( DSMB) decided to suspend the administration of the high-dose group after consultation
.

The cause of the side effects has not yet been determined.
It is expected that the safety review will be completed in the fourth quarter of this year and the potential risks will be reduced in the next 2-3 months
.

uniQure said that since no serious adverse events related to AMT-130 were reported in the low-dose group, the high-dose group did not affect the ongoing Phase 1/2 low-dose study, nor did it affect the readout of its data.
, the relevant data will be released again in 2023
.

That is to say, regardless of the reasons for the side effects in the high-dose group, the safety and efficacy of AMT-130 in the low-dose group will not change
.

summary

At present, gene therapy is still the main means of HD treatment.
Correcting or compensating for diseases caused by gene defects and abnormalities by introducing exogenous normal genes into target cells is the theoretical basis for the treatment of such diseases
.

Among the two AAV therapies that are progressing rapidly, AskBio chose to deliver the CYP46A1 gene, while uniQure chose to silence the Htt gene to achieve therapeutic effects
.

At present, these two therapies are in the early clinical stage, and ASkBio has just been approved for clinical use
.

However, these two AAV therapies take different principles and provide patients with different options.
From the current trial results, AAV therapy is undoubtedly effective in the treatment of HD and is well tolerated.
With the advancement of clinical trials and more The disclosure and analysis of the data is believed to provide patients with more scientific and effective differentiated treatment plans
.

References:

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