ALS Warrior Cai Lei Partners with Ractigen Therapeutics: A Profound Pursuit of Science, Life, and Hope

丨Compiled by the PharmaHunter Club Research Team

Recently, the ALS field has once again played the song of ice and fire.Amylyx Pharmaceuticals AnnouncesRelyvrio to Be Withdrawn from Market Due to Disappointing Phase III Clinical Trial Results; andFamous ALS Fighter Mr. Cai Lei, Former Vice President of JD Group, Has Been Fighting ALS for Five Years and Continues to Seek New Hope for Himself and Many Fellow Patients on the Frontline of the "Counterattack" Against ALS.

On April 23, Ractigen Therapeutics and the rare disease care platform "Jianyu Mutual Aid Home" founded by Mr. Cai Lei jointly established a drug development joint laboratory for ALS. The two parties aim to further pool advantageous resources in the field of ALS research and treatment, share scientific research achievements, accelerate the research and development of ALS drugs and their clinical application, and open a new chapter.

At the signing ceremony, Mr. Song Tao, representative of the Gradual Healing Mutual Aid Home, and Dr. Li Longcheng, founder/CEO of Ractigen, signed a strategic cooperation agreement and jointly unveiled the joint laboratory, witnessing this important historical moment. Subsequently, the invited media...Drug Hunter ClubAndPharmaCube interviewed Mr. Lei Cai and Dr. Longcheng Li on their collaboration experiences and respective efforts in the ALS field.

From the "Ice Bucket Challenge" to scientist Hawking, and then toFormer Vice President of JD Group, Cai Lei,ALS, often labeled as an "incurable disease," is now seeing a new chapter as Mr. Cai Lei joins forces with Ractigen Therapeutics, a small nucleic acid drug development company dedicated to conquering ALS. Caught between despair and hope, can the fate of ALS, known as the foremost of the "five major绝症," be rewritten?

Figure: Pathogenesis of ALS and Related Genes

Fig. Trends in orphan drug designations and FDA approvals for amyotrophic lateral sclerosis. a, By product type and designation year; b, By therapeutic product type; c, By proposed mechanism of action and therapeutic product type.

• Riluzole (1995): Reduce motor neuron damage by lowering glutamate levels,But the patient's survival period was extended by only 2-3 months;

• Edaravone (2017): Scavenge free radicals, protect neurons by inhibiting excessive oxidative cellular damage,But only effective in a small portion of early-onset ALS;

• AMX0035（Relyvrio，2022）: An HDAC inhibitor and GPBAR1 agonist that targets pathways of ER- and mitochondria-dependent neurodegeneration, reducing neuronal death and dysfunction;But it has only been proven in clinical trials to delay the decline in functional scores, with no data yet on extended survival;

• Tofersen（2023）: Antisense oligonucleotide, targeting SOD1 mRNA, for the treatment of ALS caused by SOD1 gene mutations,However, the efficacy was not ideal, failing to reach the primary endpoint of improving motor function., the FDA granted accelerated approval based on biomarker data; andHigh IT dosing frequency (28 days) brings great inconvenience to patients.

The long cycle of new drug development has left many ALS patients anxiously waiting. However, small nucleic acid drugs act upstream of proteins and have significant advantages and enormous market potential compared to traditional drugs. In treating ALS, which has complex pathology, small nucleic acid drugs have shown unprecedented promise.

• Small nucleic acid drugs are aDisease-modifying therapies, theoretically, have an unlimited number of targets.As long as the known sequences can be used as its targets, enabling information-based and rational drug design;
• With multiple drug-forming mechanisms，It can activate at the transcription level, suppress at the post-transcriptional level, or alter its splicing, and also affect protein translation, achieving upregulation, downregulation, and splicing changes of genes.
• With the advantages of a short development cycle and high success rateAccording to data from Alnylam Pharmaceuticals, a leader in the RNA interference (RNAi) therapy field, the development success rate of its siRNA drugs in clinical stages is as high as nearly 60%, while the clinical development success rate of traditional targeted drugs is only10%；
• The toxic side effects are mild and controllable.；

• Compared with gene/cell/macromolecule therapy,The production process of small nucleic acid drugs is simple and low-cost.。

Under the leadership of Dr. Li Longcheng, Ractigen Therapeutics has become a leading small nucleic acid pharmaceutical company in China and even the world. AsThe world's only small nucleic acid drug development company utilizing three mechanisms of action (saRNA, siRNA, ASO), Two years ago, Ractigen, with deep concern for ALS patients and a strong sense of social responsibility, invested tens of millions of yuan into the research and development of ALS drugs, building on multiple drug development pipelines.

In February 2024, "RAG-17 Injection" developed by Ractigen Therapeutics was submitted for clinical trial in China.。RAG-17 is an siRNA drug that targets and inhibits the expression of the SOD1 gene, used for treating ALS caused by SOD1 mutations. RAG-17 utilizes a proprietary technology independently developed by Ractigen Therapeutics.SCAD^TMDelivery Platform Technology, by conjugating double-stranded RNA with another single-stranded oligonucleotide aptamer, to achieve efficient and long-lasting delivery within the central nervous system (CNS). Previously,RAG-17 has received FDA Orphan Drug Designation (ODD).

Ractigen is one of the few global small nucleic acid pharmaceutical companies that simultaneously masters both intrahepatic and extrahepatic delivery, and has developed the proprietary SCAD technology.^TM，LiCO^TMAnd GLORY^TMDelivery Platform.Inspired by GalNAc, conjugating delivery modules to oligonucleotides via chemical bonds, without relying on formulation-based delivery systems, is an ideal approach for RNA drug delivery.Ractigen's SCAD^TMThe platform utilizes modifications and single-stranded nucleic acid conjugates to achieve extracellular liver delivery systems, efficiently delivering double-stranded nucleic acids to the central nervous system, eyes, lungs, and other tissues. It has been validated for delivery efficiency in multiple animal species, demonstrating good safety and simple preparation.It has currently entered the human trial stage.

Multiple preclinical studies have shown that RAG-17 can significantly delay the onset of disease, prolong the survival time of animals, and improve their motor function. Compared to other treatments targetingSOD1The small nucleic acid drug Tofersen, in the preclinical efficacy comparison of RAG-17 and Tofersen at equivalent mass doses:

1) At the same molar dose,RAG-17 vs. Tofersen in the Treatment of ALS MiceEfficacy+Excellent

2）RAG-17 Extends Median Survival by 101 Days in SOD1 Mutant Mice， AndTofersenPublished data，At the same dose, it can only extend the survival of SOD1 mutant mice by 37 days, and RAG-17 is more effective than Tofersen.

3) Preclinical data of RAG-17 support administration after ALS onset, with post-onset administration still significantly improving motor function. The 200 µg and 400 µg doses extended survival by 78 days and 128 days, respectively.This result was shown for the first time globally in this model mouse.Treatment After OnsetThe effect

4）Intrathecal administration shows pharmacological activity lasting at least 2 months in primates(Tofersen administered clinically once every 28 days)

Currently, RAG-17 has been administered multiple times in investigator-initiated clinical studies (IIT), demonstrating good safety and tolerability, as well as preliminary efficacy.Ractigen Therapeutics has submitted a Phase I clinical trial application to the CDE.

Ractigen believes that the successful experience of RAG-17 can be quickly extended to other ALS gene mutation targets, such as FUS, C9orf72, ATXN2, etc., to cover a larger population of ALS patients.With diverse drug-forming mechanisms and the globally leading, clinically validated central nervous system double-stranded RNA delivery technology SCAD^TM, which can flexibly develop therapeutic drugs based on different patients' gene mutation profiles and specific pathogenic mechanisms, and rapidly achieve clinical translation.

Suffering from the disease for 5 years,Cai LeiMr. Cai's condition is still deteriorating. At the signing ceremony, Mr. Cai Lei sat in front of the screen to deliver a speech for the inauguration of the laboratory, which gave us a more direct understanding of his real situation: although his eyes were sharp, his expression resolute, and his face kind, it was already difficult for us to clearly recognize his voice, and we had to rely on the assistant's help to understand.

But when it comes to RAG-17, Mr. Cai Lei "Far Ahead"Four Characters Leave a Deep Impression:

"At present, we cannot see any other drug for treating ALS in the world that has a median survival period of over 300 days in the SOD1 animal model G93A, except for RAG-17 from Ractigen Therapeutics."

That year, Mr. Cai Lei decided to "become a beam of light that can illuminate many people," and thus began a new venture. Amyotrophic lateral sclerosis (ALS), as a rare disease, has very limited medical data available. As an Internet veteran, he immediately took action to build a research data platform for ALS, helping scientists conduct targeted research and drug development. Currently, this data platform, "Jianyu Mutual Aid Home," has registered approximately 15,000 patients., which is the world's largest ALS research data platform.Based on the rare disease ALS research data platform, Cai Lei's team has made breakthroughs in patient demand aggregation, genomics analysis, proteomics, metabolomics, pathology library construction, iPSC, and rapid drug screening using organoids.

Many pharmaceutical companies, with the help of Mr. Cai Lei, are also accelerating the development of drugs for ALS.Only in the past 2023,Mr. Lei CaiCollaboration has driven the development of over 15 clinical pipelines for ALS drugs.RAG-17 is one of them.. Two years ago, Ractigen learned about Mr. Cai LeiMade every effort to promote the development of ALS drugs and contacted them.“We saw the stunning preclinical efficacy results of Ractigen's RAG-17 two years ago.”`, realizing RNA interference technology`Great hope for ALS treatment, both parties quickly launched preclinical animal experiments.

Cai Lei and Ractigen: A profound pursuit of science, life, and hope; a two-way dedication between a great "ALS fighter" and an outstanding innovative enterprise; and also a combination of efficient project execution and promising RNA interference technology.Powerful Combination。

"…We"Through collaboration with preclinical animal experimental bases, including cooperation with Ractigen Therapeutics, we advanced to complete the efficacy testing in animal experiments in just over 90 days. Normally, completing animal experiment collaborations requires nearly a year or more, involving business communication, negotiation, contract signing, mouse reservations, and waiting for the animal experiments to commence. However, our efficient and low-cost collaboration facilitates pharmaceutical companies in accelerating their progress."

The development of new drugs is a race against time.According to data provided by Cai Lei's team, from the second half of 2020 to the first half of 2023, China launched more than 27 ALS clinical pipelines, accelerating ALS clinical trials by approximately 20 times.A senior neuroscientist said that Cai Lei has pushed forward the research and development of ALS drugs by at least 10 years.

However, this is far from enough. The investment in gene drug development is enormous, and the current financing environment is concerning. After witnessing the significantly prolonged survival period of RAG-17 in animal models, Mr. Cai Lei called for the establishment of the Ractigen Joint Laboratory.

“Urgently requires the concern and support from all sectors of our society, including capital investment.I also hope that more people in the society can pay attention to rare diseases, such as opening green channels for drug development. We also hope to provide more policy support, including preclinical animal trials, IIT, etc., and give more policy preferences.。Rare diseases naturally receive insufficient attention and limited investment. In China, approximately 60 patients with ALS pass away every day. We hope that the patient community can become more united in participating and supporting drug development. We also hope that members of the media can advocate more for support and attention toward the treatment of rare disease patients.”

“ALS is not only a rare disease and a cruel terminal illness, but also belongs to the same category of neurodegenerative diseases as Parkinson's and Alzheimer's. There are more than 60 million patients worldwide, and as life expectancy increases, the number of patients with neurological diseases will continue to grow in the future.The breakthrough in ALS can provide a rapid model for the accelerated development of drugs for neurodegenerative diseases. Therefore, we hope to call on all sectors of society and the investment community to pay attention to ALS, neurodegenerative diseases, and other difficult diseases. This is a new era of hope in the field of life sciences. Focusing on the R&D of biopharmaceuticals means caring about the well-being and health of each of us.”

Mr. Cai Lei still believes in the power of "belief" and is also bringing faith to more patients with ALS and other difficult diseases. He is fighting against time, against terminal illness, and against impossibilities. Over the past four years of battling ALS, Cai Lei has been undertaking a superhuman workload every day to push forward the progress of efforts to conquer ALS, remaining ceaselessly active on the front lines as an "ALS fighter." It is our shared responsibility to continuously follow his struggle, understand ALS and other rare diseases, and support the development of innovative drugs.

Source:

[1] Ractigen:Mr. Cai Lei and Ractigen Establish Joint Laboratory to Collaboratively Tackle ALS

[2] First Finance:The World's First Targeted ALS Drug Arrives in China, So Why Does Cai Lei Still Say "No Major Breakthrough"?

[3] Peeling the Onionpeople：Cai Lei: A ALS Patient's Fight for Survival

[4] Kraft S, Mease C, Jillapalli D, Fermaglich LJ, Miller KL.Trends in drug development for amyotrophic lateral sclerosis. Nat Rev Drug Discov. 2023 Dec 12. doi: 10.1038/d41573-023-00199-2. Epub ahead of print. PMID: 38086894.

[5] Drug Hunter Club:RNA Drug Hunter | Wenkai Xie from Ractigen: RNA Activation, China's World-Class "Underlying Technology" in Small Nucleic Acids

Featured Article Recommendations

"Under Observation"Click 1