100% functional improvement in Krabe's disease! A quick overview of the latest status of domestic research and development of AAV gene therapy

October 17, 2022 /eMedClub News/--Forge Biologics recently ranked No.
1 of the European Gene Therapy Association (ESGCT).
At the 29th congress, the latest clinical data
of RESKUE phase 1/2 of its AAV gene therapy FBX-101 for the treatment of Krabbe's disease were announced.

Krabbe disease is a rare autosomal recessive neurodegenerative disease caused by loss-of-function mutations in the lysosomal enzyme galactoseylceramisase (GALC) gene, which causes the accumulation of certain lipids (such as psychosine) in cells and causes the death of myelin cells in the brain and peripheral nervous system, resulting in loss
of motor function.
Infantile patients usually die before the age of 2, and those with late onset survive to about 10 years of age, and there is currently no cure for the disease
.

FBX-101 is an adeno-associated virus serotype rh10 (AAVrh10) gene therapy administered intravenously after hematopoietic stem cell transplantation (HSCT) to deliver functional copies of the GALC gene to cells of the central and peripheral nervous systems to encode the desired enzyme.

In animal models, FBX-101 has been shown to functionally correct central and peripheral neuropathy and significantly extend animal lifespan
.
The results also show that systemic AAV gene delivery after HSCT is expected to overcome the safety challenges of traditional AAV immunology and create a safer environment
for gene replacement.

Data from this trial showed that patients showed increased activity in plasma and cerebrospinal fluid (CSF) in plasma and cerebrospinal fluid (CSF) after 90 days and 9 months of treatment with FBX-101, normal white matter myelination, and all subjects also showed improved motor function and normal brain development
.
In addition, FBX-101 was well tolerated, there were no treatment-related serious adverse events, and no humoral immune response was
observed.
The efficacy and safety
of FBX-101 in the treatment of Krabbe disease has been preliminarily demonstrated.

Current status of AAV gene therapy research and development

Gene therapy is becoming one of
the outlets for new drug research and development because it is expected to achieve a "root cause" effect.
According to public information, the total investment in the gene and cell therapy industry reached $23 billion in 2021, of which nearly half went to developers
specializing in gene therapy.
Hundreds of millions of dollars in financing and transactions are common, such as the agreement signed between Roche and Avista in July 2022 to develop AAV gene therapy vectors with a potential value of more than $1 billion; In November 2021, Newforth completed a Series C financing
of nearly RMB 400 million.

At the same time, the research and development of gene therapies is also increasingly hot
.
At present, the commonly used vectors of gene therapy include AAV, adenovirus, retrovirus, lentivirus, herpesvirus, etc
.
Among them, AAV vector gene therapy has the largest pipeline under development, more than 50%.

▲ Status of AAV clinical trials

(Image source: Star Wealth Research Institute)

As of June this year, there are nearly 200 AAV gene therapy studies in clinicaltrials.
gov, and more than 70 clinical trials are still ongoing
.
From the perspective of indications, neurological, metabolic, ophthalmic, and blood diseases are the main areas
of AAV gene therapy.
From the perspective of AAV gene therapy that has been declared in China, ophthalmic diseases and rare diseases are two hot directions
.

Ophthalmic diseases

In the field of ophthalmic diseases, Newforth's launch pipeline NR082 (NFS-01) has made rapid progress, which uses rAAV2 as a carrier to deliver the engineered ND4 gene to the patient's damaged optic ganglion cells through intravitreal injection, repair the mitochondrial biological respiratory chain, and restore the vitality and visual function
of optic ganglion cells.
In September 2022, the Phase 3 trial of NR082 in China completed the dosing of the
first patient.

It is worth mentioning that in the world's first clinical trial with the longest follow-up record, 5 patients with ND4 site mutation LHON had a significant improvement in visual acuity, the best visual acuity was restored to 0.
8, and the average best corrected visual acuity of 9 patients improved by 0.
39logMAR (that is, an improvement close to the four lines of the alphabet).

Among them, 8 patients completed long-term follow-up for nearly 8 years without serious adverse events, and 5 patients have maintained visual improvement to this day
.

In July this year, Fangtuo Biologics announced the completion of a $160 million Series B financing, and its initial pipeline FT-001 has obtained FDA clinical trial approval, and in September it obtained CDE clinical model approval, and will expect phase 1/2 clinical trials
in China.
It is reported that FT-001 is an AVV gene therapy candidate carrying the hRPE65 gene, which can bind to the surface receptor of human retinal pigment epithelial cells into the cell through subretinal injection, so that retinal cells express hRPE65 protein with isomerase activity, thereby delaying disease progression
.

In addition, AAV gene therapy companies in the field of ophthalmic diseases include Langsheng Biologics, Tianze Yuntai, Kanghong Pharmaceutical, Zhongyin Technology, Jiutian Biotechnology, Xingyan Biotechnology, Paizhen Biotechnology, etc
.

Rare diseases

"Rare diseases are not uncommon", there are nearly 7,000 different types of rare diseases in China, and under the huge population base, there are more than 16 million
rare disease patients.
However, less than 10% of rare diseases have therapeutic drugs, and there are a large number of unmet clinical needs
.

At this point, the author is most deeply touched by the fact that readers often inquire about the progress of the research and development of innovative drugs for rare diseases in our community, including many patients and family members
.
Fortunately, there are also many domestic companies in the research and development of AAV gene therapy for rare diseases
.

Krabbe disease, including LIN-2004 of Lingnuo Pharmaceutical; In the field of hemophilia, drug candidates such as BBM-H901 injection of Faith Pharmaceutical, ZS801 injection of Zhishan Weixin, and VGB-R04 of Tianze Yuntai have entered the clinical trial stage; In the field of spinal muscular atrophy (SMA), Jiain Biologics' EXG001-307 has been approved for clinical trial as the first AAV gene therapy for the treatment of SMA in China.
.
.

In addition, companies such as Shutaishen, Jinlan Gene, Huayi Lejian, Lingyi Biologics and other companies have deployed AAV gene therapy
.

summary

AAV gene therapy is a very promising treatment method, and most of the domestic companies deploying gene therapy have adopted AAV as a vector
.
And with the development of various technologies, some "new" AAV therapies have emerged, such as combining with bispecific antibody technology
.

In the future, domestic AAV gene therapy will enter the harvest period, and more treatment options
will be provided for patients.

Resources:

1.
style="margin-right: 16px;margin-left: 16px;white-space: normal;max-width: 100%;line-height: normal;margin-bottom: 0px;overflow-wrap: break-word !important;box-sizing: border-box !important;">2.
Tianchao Capital: The current situation and imagination of AAV gene therapy

——List of recent popular events——