Can Bojian ASO's new drug fail to perform Alzheimer's disease drug "miracle" again

Is the immediate failure a failure? Everyone has a different answer

In the eyes of some multinational companies, acknowledging failure may be a good way to stop losses; in the eyes of Biogen, even if failure is in front of them, the story has not yet reached the end

Recently, Biogen announced the results of a failed clinical trial in a positive and optimistic manner: the phase III VALOR study of Tofersen, an investigational drug for the treatment of ALS (amyotrophic lateral sclerosis) targeting SOD1, did not meet the primary endpoint.

"The results of the VALOR study are encouraging.

Since having the experience of "turning defeat into victory" for the Alzheimer's disease drug Aducanumab, Biogen has adopted a "let the bullets fly for a while" attitude towards failure, and is not in a hurry to put an end to the drug's development

"After discussing with researchers and bioethicists and listening to the opinions of patient advocacy groups, we will expand our access plan to allow all eligible SOD1-ALS patients to join the study

Bojian is also "actively engaging with regulatory agencies to determine the next step

01 CP of Bojian Group: ALS+ASO

Bojian’s challenge to neurological diseases can be said to be more courageous and never give up

The story of the well-known physicist and cosmologist Hawking's illness but a strong life and the world-famous "Ice Bucket Challenge" have given the public a certain understanding of ALS

ALS is a progressive neurodegenerative disease.

In order to overcome ALS, Bojian has successively launched multiple pipelines, including BIIB067 (Tofersen), BIIB078 (IONIS-C9RX), BIIB100 (XPO1 inhibitor), BIIB105 (ATXN2 ASO) and so on

In 2018, Biogen paid Ionis US$35 million to obtain Tofersen’s license to take over the development of the drug

It can be seen that Biogen's obsession with ASO (antisense oligonucleotide) therapy, these four pipelines are almost all related to ASO drugs

BIIB078 (IONIS-C9RX) is another ASO therapy introduced by Biogen from Ionis, which targets the C9orF72 gene

BIIB078 can target the mRNA from the C9orf72 gene and degrade it, preventing the production of the abnormal protein it encodes

BIIB105 (ATXN ASO) is also an antisense oligonucleotide (ASO) drug, which can bind to ATXN2 mRNA and mediate its degradation.

It can be seen that Bojian is very optimistic about the future of ASO therapy in the treatment of ALS
.

02 The past and present of ASO therapy

More than 40 years ago, scientists first proposed the concept of antisense oligonucleotides (ASO), which are short chemically modified RNA strands
.
The base sequence of ASO is complementary to the specific target RNA sequence.
After entering the cell, it combines with the target sequence to form a double-stranded structure according to the principle of base complementary pairing, thereby hindering the translation process of the target RNA and ultimately preventing the production of pathogenic proteins
.
Antisense oligonucleotides can be used for gene silencing, and most ASO drugs are inhibitors of target genes
.

The application of ASO in the industry generally began in the late 1980s, and it emerged at the same time as DNA therapy.
However, the mainstream view in the industry at that time believed that RNA was not druggable, so the research and development of RNA therapy belonged to a relatively niche school at the time.
The company has given up continuing research and development, and there are many star pharmaceutical companies among them
.
For example, Gilead, which is now a multinational pharmaceutical company, once positioned its focus on the research and development of ASO drugs after its establishment in 1987, but in the mid-1990s it decisively sold all the intellectual property rights of ASO drugs to ISIS Pharmaceuticals.
And devote himself to the research and development of small molecule antiviral drugs
.

ISIS is the predecessor of the current star ASO company Ionis.
In 1989, 40-year-old Stanley Crooke gave up the position of chief scientist of SmithKline (SmithKline, later part of GSK) and founded ISIS
.
ISIS focuses on the development of ASO drugs.
This company, in conjunction with Novartis, launched the world's first ASO drug, Fomivirsen, to the market in 1998, and also pioneered RNA therapy
.

This was supposed to be Ionis' most glorious moment, but everyone knew that "danger" was already lurking
.

In 1999, the gene therapy industry fell into a trough due to fatal cases in clinical trials, and RNA therapy was also not optimistic
.
That year, ISIS’s long-awaited Crohn’s disease drug failed to be significantly different from placebo in a key trial of 300 patients.
Within a few days, the company’s stock price fell from $16 to $5
.
At the juncture, ISIS had to lay off 40% of its staff to maintain the company's operations.
At that time, the cash on the account was only enough to last for a year, and it was on the verge of bankruptcy
.
At that time, most of the few developers in the industry also ceased operations in the early 20th century
.

Commercially, the first ASO drug was used for the treatment of AIDS-complicated ocular cytomegalovirus infection.
However, due to advances in antiretroviral therapy, the number of patients was greatly reduced, and Fomivirsen was eventually delisted in 2009
.
However, Crooke never gave up, repeated defeats, and led ISIS to rise from the bottom.
Now it has 3 listed products, 7 clinical phase III projects, more than 20 clinical phase II projects, and revenue exceeds 1.
1 billion US dollars.
, The industry leader with a market value of nearly US$5 billion, and was renamed Ionis at the end of 2015
.

Although Fomivirsen was delisted, most of the early days in the industry used the direct chemical modification of ASO (reducing delivery efficiency in exchange for simpler druggability) for drug modification, which made it easier for companies that entered the industry early to form patents.
At present, most companies in the world The company's nucleic acid chemical modification patents are all authorized by Ionis
.

In the unremitting research and development, Ionis ushered in the peak period of product launch around 2017
.

At the end of 2016, Nusinersen, an ASO drug jointly developed by Ionis and Biogen, was approved by the FDA for the treatment of spinal muscular atrophy (SMA) in children, becoming the world's first SMA treatment drug.
The new drug is three years later.
Enter the Chinese market
.
The global sales of Nocina Senna also stimulated the industry's nerves on the development of ASO in the field of neurological diseases.
Data show that as of the end of 2019, its cumulative sales reached 4.
7 billion U.
S.
dollars, becoming a blockbuster
.

In July 2018, Ionis and its wholly-owned subsidiary Akcea's ASO therapy Inotesen was approved by the EMA for the treatment of hereditary transthyretin amyloidosis
.
In 2019, Akcea's other ASO therapy, Volanesorsen, was approved by the EMA as an adjuvant therapy in addition to diet control for adult patients with familial chylomicronemia syndrome (FCS).
.
.

Up to now, there are about 10 ASO drugs on the market worldwide, and the indications mainly cover CMV retinitis, adult hATTR, homozygous familial hypercholesterolemia (HOFH) rare disease, Duchenne muscular dystrophy (DMD), the treatment of spinal muscular atrophy (SMA), familial chylomicronemia syndrome (FCS), and so on
.
ASO product coverage indications in clinical trials include use in the treatment of neurodegenerative diseases, rheumatoid arthritis, psoriasis, renal transplant rejection, inflammatory bowel disease (Crohn’s disease), tumors, and rare genetics Disease and so on
.

In recent years, with the emergence of new delivery systems and the delivery efficiency of purely chemically modified ASO is still unsatisfactory, pioneer companies such as Ionis are innovating.
For example, Ionis combines chemically modified ASO with GalNAc delivery system
.
At the same time, a group of biomedical companies that take delivery technology as an entry point are entering the ASO field
.
In terms of market structure, in addition to Ionis and Novartis, ASO drug R&D companies also include Sarepla Therapeutics, Sanofi, Bojian and other companies
.

ASO drugs are now in a stage of rapid development
.
However, China has not yet had local drugs on the market, and the future market development space is broad
.

Suzhou Ruibo, established in 2007, is a company dedicated to the development of small nucleic acid innovative technologies and small nucleic acid drugs
.
The company has established a research and development platform including small nucleic acid sequence design and high-throughput screening, delivery technology, and stabilization modification technology
.

Among its research products, SR062 and SR063 are both ASO drugs
.

SR062 is an ASO drug for type 2 diabetes.
It is expected to be the first drug to act on the glucagon receptor (GCGR).
There is no similar target on the market
.
At present, the product has completed 1 phase I clinical study and 3 phase II studies worldwide, and 2 clinical phase II studies are currently underway in China
.

SR063, an ASO drug for prostate cancer, has inhibitory effects on androgen-dependent and androgen-independent AR pathway-related metastatic castration-resistant prostate cancer (mCRPC).
Currently, a phase I clinical study has been completed , A phase IIa clinical study will be launched in China soon
.

At present, there are not many startup companies focusing on ASO drugs in China, and they are still a blue ocean
.