Only 3 drugs have been approved! Frozen life, and $1.16 million worth of drugs

Remember when the Ice Bucket Challenge went viral? From Bill Gates to Robin Li, from Jay Chou to Nicholas Tse... Countless celebrities have taken part in the challenge to raise awareness of ALS.

Perhaps most of the patients are unknown, but some are familiar, such as the famous British physicist and cosmologist Stephen Hawking, Zhang Dingyu, president of Wuhan Jinyintan Hospital, and CAI Lei, former vice president of JD.com.

According to current treatment methods, if you are unlucky enough to suffer from ALS, you will have only three to five years left in your life, and your beautiful life will be gradually frozen.

More regretfully, only three ALS drugs have been approved.

There are only three approved drugs,
The top price is $1.16 million

ALS, which has been discovered for more than 200 years, is a heterogeneous neurodegenerative disease characterized by degeneration of upper and lower motor neurons. Patients average life about 4 years, and our country has about 200,000 patients. The treatment of such a serious disease is basically helpless, and only three drugs have been approved for the treatment of ALS, with little effect.

In 1995, the first ALS drug, Riluzole, was approved, breaking a gap in ALS treatment. In clinical trials, riluzole was shown to extend survival by three months compared with placebo after 18 months, or three months for a year and a half of the drug. While the drug can provide some relief, it alone will not solve ALS. Riluzole price is a little more expensive, imported drugs about 4000 yuan per box, the annual cost of about 50,000 to 60,000 yuan.

Research on ALS is ongoing, but it's been 22 years.

In 2017, Edaravone, a second drug for ALS, was finally approved for sale. Clinical data showed that 24 weeks of Edaravone reduced functional decline by 33%. Edaravone price is close to the people, about 20,000 yuan per year.

In 2022, the FDA approved a third drug, AMX0035, to treat ALS. The first two drugs are small beer compared to the amazing journey AMX0035 took to get approved. Unlike other drugs, AMX0035 relies on phase 2 data to "muscle" its way to market. Initially, Phase 2 data on the drug didn't impress reviewers, so Phase 3 data was needed to get the drug approved. The FDA may have been swayed by patients' demands and companies' attitudes. First of all, if we wait for the results of the Phase 3 clinical trial, it will take until 2024, which is absolutely fatal for ALS patients who only have about five years to live. Secondly, company officials said that if AMX0035 did not show therapeutic effect in phase 3 clinical trials, AMX0035 would voluntarily withdraw from the market. Perhaps the above two factors contributed to the early approval of AMX0035, so FDA reviewers also have a "temperature".

According to clinical results, AMX0035 showed better results over a period of 24 weeks, with patients in the treatment group having an ALSFRS-R score (a rating of bodily function where higher is better) of 2.32 points higher than those in the placebo group, while AMX0035 had a monthly score decrease of 1.24 points compared to 1.66 points in the placebo group. So AMX0035 does provide some relief. Another study showed that patients treated with AMX0035 extended survival by about 6.5 months.

Although the drug can only prolong the survival of 6.5 months, it is expensive, about 160,000 to 170,000 US dollars per year, about 1.16 million yuan.

Can New treatments Break the ice?

The above three drugs can only be used in the early or middle stage, so as to temporarily prolong the survival of patients. Long-term use is ineffective, and the effect of late use is poor.

In addition to the above 3 drugs, which drugs are currently in clinical phase 2/3? The following table summarizes some ALS drugs in phase 2/3 clinical stage.

At present, ALS drugs under research are basically divided into antisense oligonucleotides, antibodies, anti-inflammatory and stem cell therapy.

Antisense oligonucleotide therapy

It is currently a promising method for the treatment of neurodegenerative diseases. This method mainly reduces the production of toxic proteins by inhibiting the binding of SOD1 messenger RNA, so as to reduce the toxicity of mutant SOD1 and prolong the survival of ALS patients.

At present, there are also a number of such drugs in the clinical stage, the representative drug is BIIB067, has advanced to the clinical phase 3.

Antibody therapy

It is represented by drugs such as ANX005. ANX005 is a C1q inhibitory antibody. When C1q is abnormal, it will accumulate around synapses and cause the mistaken killing of nerve cells. Therefore, inhibition of C1q can alleviate the disease process to a certain extent.

Anti-inflammatory therapy

Represented by Masitinib. Masitinib is a tyrosine kinase inhibitor that reduces microglial cell activation.

According to Phase 3 clinical data, this drug can significantly reduce the rate of ALSFRS-R decline. The drug could become the fourth approved treatment for ALS.

Stem cell therapy

Due to their own characteristics, such as the strong potential of self-renewal and multi-differentiation, stem cells are gradually gaining favor in the treatment of ALS, providing neurotrophic support to the central nervous system.

However, beyond a possible temporary positive effect, clinical trials have not yet shown a long-term benefit from stem cells.

The representative drugs for stem cell therapy are NurOwn, Reldesemtiv and Neuronata-R. Unfortunately, the Phase 3 clinical trials of NurOwn and Reldesemtiv failed, and Neuronata-R has also become the only clinical vaccine of ALS stem cell therapy in phase 3.

At present, several drugs on the market can only prolong the survival of ALS patients in the short term. Drugs that can prolong the survival of ALS patients in the long term have not appeared so far, and the hope of a complete cure is far away.

As of April 2023, there were 806 ALS trial studies registered on clinicaltrial.gov in the United States, and perhaps hope for ALS patients lies among them.

Difficulties in drug development for neurodegenerative diseases

When you look at neurodegenerative diseases, none of them have been solved yet, and there are multiple reasons for this. The first, and most important, is that neurodegenerative diseases are the result of the interaction of multiple factors, not a single one. So a drug that targets a single mechanism may have some efficacy, but it's very limited in terms of stopping the progression of the disease, prolonging life, improving ability to live and so on.

The second factor is that the number of patients with this kind of disease cannot form a "data pool" for clinical basic research, so the corresponding scientific research is limited. That's why CAI Lei, former vice president of JD.com, set up a big data platform called "Jianyu Mutual Aid Home".

Third, the high cost of drug research and development and the lack of scientific treatment programs and research and development policy support for such diseases aggravate the difficulty of funding related drug projects. The goal of the Ice Bucket Challenge is to raise money for ALS drug research and development.

For the above reasons, the research and development of drugs for neurodegenerative diseases has not been able to achieve a qualitative breakthrough so far, and it is difficult to prolong survival in some areas even in the short term.

summary

In view of the current drugs used to treat ALS, there is still only a limited short-term extension of patients' survival. With the rise of gene therapy, we look forward to the day when ALS patients will finally see the light of day.