ALS global new drug research and development pattern: AAV, Treg, stem cells and other therapies into the clinic

January 8, 2023 / eMedClub News/-- Atrophyrosis lateral sclerosis (ALS), commonly known as ALS, is a rare progressive neurodegenerative disease that primarily affects motor neurons in the cortex, brainstem and spinal cord.
This ultimately leads to loss
of mobility, muscle control, speech, and breathing.
According to statistics, an estimated 168,000 people worldwide suffer from the disease
.

Most cases of ALS are sporadic, but in a small number of ALS patient populations, a clear familial genetic trait is exhibited, indicating that ALS may be associated with
a specific gene.
So far, nearly 30 genes have been confirmed to be associated with the pathogenesis of ALS, and the most common pathogenic gene mutations mainly include SOD1, TARDBP, FUS, OPTN, SQSTM1, DAO, DCTN1, VAPB, SIGMAR1, GRN, C9orf72, etc
.
However, at present, the industry still lacks a clear understanding of the pathophysiology of ALS, and it is speculated that its pathogenesis may be related
to phenoamino acid toxicity, oxidative stress damage, mitochondrial abnormalities, gene mutations, protein instability and neurotrophic factor deficiency.

Due to limitations such as pathological complexity, ALS is not yet curable, and patients face limited options
.
According to incomplete statistics, so far, the FDA has approved only three drugs for the treatment of ALS (Relyvrio, Riluzole and edaravone), but these drugs can only delay the progression of ALS and cannot completely cure ALS
.

▲ Approved drugs for the treatment of ALS (Source: Reference 1).

According to statistics, the market share of effective ALS drugs has been increasing year by year in recent years
.
According to a new report by Grand View Research, the global ALS therapeutics market size was approximately $540 million in 2018 and is expected to reach $890 million by 2026, growing at a CAGR of 5.
8%
during the period 2019-2026.

In recent years, with the development of cell and gene therapy technology, many companies have applied this new treatment model to the treatment of ALS, and have made positive progress, and have entered clinical phase
3 at the earliest.

▲Cell and gene therapy for ALS

(Source: Reference 2)

Stem cell therapy

◆ BrainStorm Cell Therapeutics：NurOwn

NurOwn is an autologous stem cell therapy derived from mesenchymal stem cells derived from the patient's own bone marrow, which are induced by differentiation medium in vitro to specifically differentiate into MSC-NTF cells
that secrete neurotrophic factors (NTFs).
The modified MSC-NTF cells are infused back into the patient, which can effectively deliver a variety of neurotrophic factors and immunomodulatory cytokines directly to the injury site, thereby causing corresponding biological effects and ultimately slowing or stabilizing the progression of
the disease.
The therapy has been granted orphan drug designation for ALS by the FDA and EMA
.

In a Phase 3 clinical trial evaluating the safety and efficacy of repeated use of NurOwn in patients with ALS, NurOwn achieved no statistically significant performance in either the primary and secondary endpoints of treating ALS patients: 33% of MSC-NTF patients and 28% of placebo patients met clinical response criteria (odds ratio = 1.
33, P = 0.
45) after the end of the study, with no difference between the two groups; Therefore, the primary endpoint
was not met.

Interestingly, although the primary endpoint was not statistically significant, significant improvements in neuroinflammation, neurodegeneration, and neuroprotective-related cerebrospinal fluid biomarkers were observed in patients treated with NurOwn, as well as positive factors
such as the treatment's well-tolerated performance.

In addition to NurOwn, another MSC cell therapy, lenzumestrocel (Neuronata-R), for the treatment of ALS, is currently being evaluated
in Phase III clinical trials.
It is worth mentioning that Neuronata-R therapy has been approved by the Korean Ministry of Food and Drug Safety for the treatment of ALS
in 2014.

ASO drugs

◆ Ionis/Biogen : Tofersen

Tofersen is an antisense oligonucleotide drug
developed by Ionis and Biogen for the treatment of SOD1-ALS.
Tofersen binds to the mRNA encoding SOD1, causing it to be degraded by RNase-H, thereby reducing the production
of mutant SOD1 proteins.

Based on the results of the key Phase III VALOR study published in October 2021, the trial did not meet its primary endpoint, which was the difference
in patient scores from baseline to 28 weeks of the trial according to the ALS Functional Rating Scale Revised (ALSFRS-R).
However, multiple secondary and exploratory endpoint analyses of biological activity and clinical function showed a tendency to slow disease
progression.
According to the latest 12-month integrated data released in June this year, early use of tofersen can help reduce the amount of neuromicrofilaments (ALS biomarkers) and slow the decline
of multiple efficacy endpoints.

On July 26 of this year, the FDA accepted Tofersen's new drug application and granted it priority review status
.
Meanwhile, on December 5, EMA also accepted a marketing authorization application (MAA)
for tofersen for the treatment of SOD1-ALS.

◆ WAVELife Sciences：WVE-004

WVE-004 is an ASO drug developed by WAVELife Sciences for ALS and frontotemporal dementia (FTD) caused by mutations in the C9orf72 gene, designed to selectively target transcriptional variants containing hexanucleotide repeat amplification (G4C2) associated with the C9orf72 gene, thereby preserving the C9orf72 protein
.
G4C2 amplification in C9orf72 is one of the most common genetic causes of sporadic and hereditary forms of
ALS and FTD.

Preclinical studies have demonstrated WVE-004's ability to strongly and durably knock out duplicate transcripts
contained in the spinal cord and cerebral cortex.
According to the test on motor neurons of patient cells and transgenic mice carrying the human C9ORF72 gene and repeated amplification results, it was shown that after 6 months, mRNA containing repetitive sequences in the spinal cord was reduced by 60-80% and in the cortex by 40-50%.

In addition, WVE-004 also reduced dipeptide repeat protein (DPR) in the spinal cord and cortex by about 90% without affecting normal protein levels
.
In simple terms, WVE-004 could be a drug
against genetic factors in ALS.

Currently, the company is conducting a Phase 1/2 safety study
of WVE-004 in 42 patients with ALS or FTD associated with C9ORF72.
The study is being conducted at two sites in Canada and the Netherlands and is expected to be completed
in February 2023.

AAV gene therapy

◆ Eikonoklastes Therapeutics:ET-101

ET-101 (SynCav1) is licensed by Eikonoklastes and pioneered by the lab of Dr.
Brian Head at the University of California, San Diego, for an AAV9 gene therapy that overexpresses Caveolin-1, which organizes and regulates synaptic receptors
necessary for neuromuscular signaling and function 。 The results showed that increasing Caveolin-1 can have a protective effect on nerve cells, allowing nerve cells to compensate for neurodegenerative processes caused by underlying diseases, and keeping cells healthy and improving their function
.
ET-101 can play a role in maintaining the health of nerve cells, making it an option
for a variety of neurodegenerative diseases.

In December 2022, ET-101 received FDA orphan drug designation for the treatment of sporadic and familial amyotrophic lateral sclerosis
.
At present, the therapy is still in the preclinical research stage
.

◆ Apic Bio:APB-102

APB-102 from Apic Bio is also a gene therapy candidate consisting of next-generation recombinant adeno-associated virus (AAV) capsid (rAAVrh10) and microribonucleic acid (miRNA) vectors designed to slow or reverse the progression of
SOD1 ALS.
The microRNA binds to SOD1 mRNA, thereby reducing the production
of mutant proteins in patients with this disease.
Reducing levels of mutant SOD1 protein may improve motor neuron survival and function and may provide therapeutic benefits
for patients with SOD1-associated ALS.
Preclinical conceptual studies have demonstrated that APB-102 inhibits mutant SOD1 gene activity
.

Previously, APB-102 was granted orphan drug designation and fast-track designation by the FDA for the treatment of SOD1 ALS
.
APB-102 is already in the IND phase, and in December Eikonoklastes also entered into an AAV manufacturing partnership with gene therapy manufacturer Forge Biologics to push ET-101 into clinical trials
.

Treg cell therapy

◆ Coya Therapeutics：ALS001

ALS001 is an autologous Treg cell therapy developed by Coya Therapeutics, primarily for the treatment of ALS
.
Its phase I clinical results showed that ALS001 could play a protective role on nerves and slow down the progression of
ALS.
In 2021, ALS001 received orphan drug designation from the FDA
.
At present, its phase IIa clinical trial has been completed, and a phase IIb trial
is planned.

Antibody drugs

◆ Implicit Bioscience：Atibuclimab

Atibuclimab is a CD14-targeting monoclonal antibody consisting of mouse variable regions and human IgG4 Fc regions that regulate pathogenic inflammatory responses
triggered by infection and injury.
Atibuclimab is currently in a Phase 2 clinical study to evaluate the safety and efficacy
of ALS.
In January 2021, the FDA granted Atibuclimab orphan drug designation
for ALS.

epilogue

For a long time, the treatment and reliever drugs for neurodegenerative diseases have been very limited and unsatisfactory, and the development of new drugs in this field has also repeatedly frustrated
the pharmaceutical industry.
Now, from the above successful development of ASO drugs for ALS diseases, AAV gene therapy and various types of cell therapies and good data obtained in clinical trial studies, especially this year, the third approved drug for the treatment of ALS, Relyvrio, all indicate that there is another big step
forward in the treatment of ALS.

ALS may be just the beginning, and with more involvement from pharmaceutical companies and regulators, it can be expected that more neurodegenerative diseases will receive public attention in the future, and such patients will have more effective and safer treatments
.