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In 2021, COVID-19 continues to run rampant around the world, but the soldiers will come and go, the water will come and cover, and the related clinical trials have also achieved significant results. With the efforts of researchers, I believe that the just-coming 2022 will also be a fruitful year for clinical trials.
In this regard, Nature Medicine interviewed the "bigwigs" in the field. Let's take a look at what they see as the most important clinical trial results for the new year.
1. Universal influenza vaccine
The National Institutes of Health has begun the first human trial of the flu vaccine FluMos-v1 to assess its safety and immunogenicity.
In response, Neil P. King, an assistant professor at the University of Washington's Institute of Protein Design, said, "FluMos-v1, like existing seasonal influenza vaccines, produces antibodies against several different strains of influenza virus. Unlike existing influenza vaccines, FluMos-v1 vaccines use mosaic nanoparticle immunogens to jointly display antigens from multiple influenza viruses on the surface of the same nanoparticle. In our preclinical work, it was found that nanoparticle immunogens triggered a greater diversity of protective antibodies than current influenza vaccines. At the moment, we are very interested in how vaccines interact with previously exposed influenza viruses or the immune system of vaccines, and this pre-existing immunity may alter the performance of vaccines, which we did not yet understand before clinically."
（图源：European Pharmaceutical Review）
Second, antisense oligonucleotides for the treatment of Huntington's disease
Huntington's disease is a hereditary neurodegenerative disorder characterized by uncontrolled tremor (chorea), cognitive impairment, and psychiatric problems. Antisense oligonucleotides are a type of gene silencing therapy for Huntington's disease.
In March 2021, the antisense oligonucleotide treatment of Huntington's disease trial ended prematurely due to ineffectiveness. Despite this setback, the crucially complete outcome has yet to come out. This antisense oligonucleotide targets both mutant and wild-type huntingtin protein mRNAs, which is completely different from other antisense oligonucleotides on the market.
The results of this clinical trial will be the first time to truly understand the fundamental aspects of the RNA reduction strategy, including how the drug affects various biomarkers in hundreds of participants, and the results could change the clinical trial landscape for other diseases that can be treated with antisense oligonucleotides.
Table 1: Clinical trials in 2022
(Source: Nature Medicine)
CRISPR is used to treat amyloidosis
Amyloid is a factor contributing to the amyloidosis of the multiple neuropathy transthyroxine protein, and CRISPR-Cas9 gene editing eliminates the production of misfolded transthyroxine protein, which slows the formation of amyloid protein.
Julian Gillmore, a nephrologist at the Royal Free London Hospital, said: "For 25 years I have been studying patients with thyroxine-carrying protein amyloidosis until 5 years ago, when I observed a decline in their health. A few years ago, gene silencers came out and improved prognosis for patients, which is a very significant step forward. But patients taking gene silencing agents require lifelong recurrent therapy, and while most patients are stable, some continue to deteriorate. Preliminary data from the trial suggest for the first time that CRISPR-based gene therapies, which can edit specific genes in liver cells through intravenous infusion, are expected to have full results next year, and this new gene-edited therapy offers patients the prospect of meaningful clinical improvement after a single dose of the drug."
(Source: Acta Pharmaceutica Sinica B)
4. Oral treatment of kala-azar
Children in East Africa lack convenient, safe and effective treatments for kala-azar (also known as visceral leishmaniasis). Patients diagnosed with kala-azar can die if they do not receive treatment.
Today, the publication of the results of the Phase 3 clinical trial provides a better solution for the treatment of kala-azar. The trial tested a new combination of mitefoxin and paromycin in Ethiopia, Sudan, Kenya and Uganda in East Africa, with the aim of replacing the sodium gluconate sodium gluconate component currently used for injections of kala-azar with oral mitifucin, an improvement that is important for patients as oral treatment can be performed at local health centres. New, less toxic and easier-to-administer regimens will also benefit children.
Miltefosine plus paromomycin: an oral therapy for kala-azar
（图源：Science Photo Library/Alamy Stock Photo）
Targeting sigma 1 receptors for neurodegenerative diseases
The Sigma-1 receptor is a promising therapeutic target for the treatment of neurodegenerative diseases, because when it is activated by various ligands with neuroprotective properties, it stabilizes the function of several intracellular systems by acting as a companion.
Several clinical studies using pridlipidine for the treatment of neurodegenerative diseases are ongoing. Pridipotin is an oral small molecule therapeutic agent that selectively targets sigma 1 receptors and has shown good safety in previous human clinical trials. Pridlipidine is the only drug to be tested in a Phase 3 clinical trial that will assess clinical progression in Huntington's disease. An important phase 2/3 trial of priddomidine for amyotrophic lateral sclerosis is also underway.
The role of sigma 1 receptors in neurodegenerative diseases has been established over the past few years, and there are considerable promising preclinical data suggesting that pridlipidine has a protective effect on Huntington's disease and other neurodegenerative diseases such as amyotrophic lateral cord.
Vi. Exon jump therapy for muscular dystrophy
Exon jumping is one of the more promising treatment options for Duchenne muscular dystrophy (DMD). The idea is to use an antisense oligonucleotide to cut selected exons from the precursor mRNA at or next to the mutation site in order to generate a translatable transcript from the mutated dystrophin gene.
A small number of boys with Duchenne muscular dystrophy are caused by a duplication of exon 2 of the DMD gene, which encodes dystrophin. This exon duplication can be removed by using a adeno-associated virus 9-based vector that carries a non-coding copy of the small nucleus RNA U7, the sequence of which points to the spliced donor and recipient sites within the replicating exon.
This exon-jumping method is the first human trial to exclude a copy of the DMD exon 2 and the expression of full-length wild-type dystrophin. Preliminary data show that this viral gene therapy has successfully expressed full-length dystrophin for the first time.
There are also four gene therapies for Duhn's muscular dystrophy being tested, but each requires the transmission of genes encoding engineered micromyotrophin, which is expected to achieve significant functional improvements.
7. Psychedelic therapy
Psychedelic therapy (sometimes called psychedelic assisted psychotherapy or PAP) is a psychiatric practice that involves the use of psychedelic substances as part of the psychotherapeutic process. In psychedelic therapy, the use of psychedelics is often combined with talk therapy.
David Nutt, professor of neuropsychiatric pharmacology, said, "Psilocybin is a psychedelic agent derived from fungi that shows great promise in treating mental health conditions. I'm excited about this psilocybin experiment for three main reasons. First, it addresses the problem of depression's resistance to existing therapies. Second, it's a multicentric and multinational trial that will allow researchers to test psychedelic therapies in different populations. Finally, it will also give some readings of the dose-effect relationship as they are testing three different doses of celoxibin."
（图源：David Buzzard / Alamy Stock Photo）
8. Oncolytic virus
Oncolytic virus is a virus that preferentially infects and kills cancer cells. When infected cancer cells are destroyed by oncolytic action, they release new infectious viral particles or virions to help destroy the remaining tumor.
A Phase 1 clinical study of intramutumular injection of ASP9801 in patients with advanced or metastatic solid tumors is underway. ASP9801 is a genetically engineered tumor-lysis virus that expresses two cytokines, IL-7 and IL-12, to help stimulate the anti-tumor immune response. ASP9801 is effective in a variety of immunocompetent mouse models and has shown promising results in both direct-treated and distant tumors. This study will be the first to assess the safety, tolerability and anti-tumor activity of this tumor-lysis vaccine virus in cancer patients.
Long-acting monoclonal antibodies to RSV
Respiratory syncytial virus (RSV) is the leading cause of severe respiratory infections in infants and children, but there is currently no vaccine.
Nirsevimab showed positive results in the phase 2/3 MEDLEY trial of respiratory syncytial virus (SV). Nirsevimab is a monoclonal antibody that targets the F protein on the surface of the virus with a YTE mutation on it, extending its half-life; this means that a single dose of the antibody protects infants against RSV.
(Source: Vejthani Hospital)
Title image source: Stand Cool Helo
End
Resources:
[1] Arnold C. 11 clinical trials that will shape medicine in 2022. Nat Med. 2021 Dec;27(12):2062-2064. doi: 10.1038/s41591-021-01601-5. PMID: 34893772.
[2] Behr M, Zhou J, Xu B, Zhang H. In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges. Acta Pharm Sin B. 2021 Aug;11(8):2150-2171. doi: 10.1016/j.apsb.2021.05.020. Epub 2021 May 26. PMID: 34522582; PMCID: PMC8424283.
[3] Vejthani Hospital. https://www.vejthani.com/about-us/