Which area do big drug companies prefer to invest in?

To date, the most advanced areas for nucleic acid-based drug development and application should be the treatment of rare diseases caused by specific gene mutations, and several drugs have been approved for the market, such as Biogen's Spinraza for spinal muscular dystrophy, and Sanofi/Alnylam's treatment of Onpattro for hATTR amyloid degeneration.
but the maturity of oligonucleotides and gene therapy, as well as the birth of the gene editing revolution, are stimulating innovations in cardiovascular and metabolic diseases.
Recent biotechnology trading flows indicate that nucleic acid-based drug development is shifting to cardiovascular and metabolic diseases by targeting genetic targets associated with disease risk, such as PCSK9, lipoprotein (a) (Lp(a)) and ANNGPTL3, for a wider patient population.
visible trend is a growing focus on platform technologies based on anthotic oligonucleotides (ASOs) and small interference RNA (siRNAs).
, Pfizer, AstraZeneta, Novarma nor Nordisk and Lilly all have active partnerships with biotech companies in the field, including six deals signed in the past two years (Table 1).
same time, the use of viral vectors and gene-editing techniques (such as CRISPR) for gene therapy in the field of cardiovascular and metabolic diseases is gaining momentum.
recent big deal in the cardiovascular sector was Novartis' $21 billion acquisition of The Pharmaceuticals Company in November 2019, which resulted in Novartis acquiring a SIRNA drug, inclisran, which targets PCSK9.
the candidate was in phase 3 trials of hexa-family hypercholesterolemia and atherosclerosis cardiovascular disease.
February 2019, Novart also acquired an ASO candidate therapy that is in phase 2 trials to reduce Lp(a) levels after investing $150 million in Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals.
October of that year, Pfizer also paid $250 million for an ASO therapy in Phase 2 trials from Akcea, which targets ANGTL3, the third-leading target for cardiovascular disease.
two big deals in the nucleic acid drug sector this year came from AstraZeneta.
March 2020, AstraZenecom partnered with Silence Therapeutics to develop siRNA therapies for cardiovascular, metabolic and other diseases, a partner that will focus primarily on liver targets but will also explore targets in other tissues.
January 2020, AstraZenecom announced a partnership with MiNA Therapeutics to develop small activated RNA (saRNA) therapies for metabolic diseases.
but the specific financial terms are not disclosed (Table 1).
Table 1: Partial Metabolic and Cardiovascular Disease Gene Drug Cooperation Deals 2018-2020 Although most of these partnerships are with biotech companies with ASOs or SiRNAs candidates, investors also support the development of nucleic acid drugs in other ways (Table 2).
such as Verve Therapeutics, a cardiovascular gene editing company, has raised $123m in two rounds of A-round funding since 2019, the most recent of which was led by former Google Ventures (GV).
Omega Therapeutics, which is developing metabolic and other disease-controlling drugs, raised $85 million in a July 2019 venture.
table 2: How some metabolic and cardiovascular disease gene drug companies are funding how to target the heart Although the number of patients with rare cardiovascular disease is small, these people are well-suited to nucleic acid drugs because they directly target clearly defined causes of the disease and help patients with significant medical needs that are not being met.
and in some cases, treatments for rare diseases can open the door to treating larger numbers of patients.
the past decade, a series of large-scale genetic studies have laid the groundwork for cardiovascular treatment because lipid metabolism is the cause of heart attacks.
biotech company Verve Therapeutics is developing a heart disease therapy that targets lipid metabolism in liver cells.
Verve's study has identified eight genes with three characteristics that indicate their potential as therapeutic targets (Figure 1).
, each gene is associated with at least one of the three risk factors for LDL cholesterol, triglycerides, or lipoprotein (a) in the cardiovascular cycle.
second, researchers have found in genetic studies that drug-resistant mutations can reduce the risk of myocardial infarction and cardiovascular disease without adversely affecting health, suggesting that inhibiting their function is safe.
1: Cardiovascular drug targets from human genetics.
"resistance mutations" in eight genes were associated with a reduced risk of cardiovascular disease, and showed pathways to related risk factors.
(adapted from Verve Therapeutics) ApoA/B, lipoprotein A/B; IDL, DL; LDL, LDL; Lp (A), lipoprotein (A); TRL, triglycerides; VLDL, very LDL.
third is accessability.
gene therapy needs to be done in cells, and they don't reach every tissue effectively, especially the heart.
found eight potential targets in liver cells.
liver is a key part of cholesterol metabolism and synthesis.
importantly, it is also possible to deliver siRNAs and ASOs specifically to the liver, mainly by binding to the N-acetyl semi-lactamine (GalNAc) pioneered by Allenylam.
Givosiran, of Allenylam, is the first approved liver-targeted oligonucleotide drug, a GalNAc-siRNA binding for acute hepatic rickets. "Our results suggest that people with gene mutations are at higher risk of developing disease, but there are also people with protective mutations that reduce gene function," said Sekar Kathiresan, ceo of
Verve and co-author of the study at Harvard Medical School.
opens up the possibility of developing treatments for patients with specific genetic risk factors that can be tested with unmnant genes in a wider population.
" two pathways to mRNA oligonucleotide drugs are designed to reach the liver on their own.
the only approved oligonucleotide therapy for cardiovascular disease is Kynamro (mipomersen), which directly targets genes in the liver that encode lipoprotein (Apo) B-100, lowering LDL cholesterol and Lp(a) levels in the blood.
Kynamro was originally developed by Ionis Pharmaceuticals and later licensed by Sanofi Genzyme as an ASO drug.
because the drug requires a large dose to be effective, it is at risk of liver toxicity and is only approved in the United States for patients with pure family high cholesterolemia with rare diseases.
, vice president of cardiovascular drug development at Ionis, said: "The company's next-generation ASO therapy is combined with galNAc in a connection.
the lithe to a specific cell surface subject, which reduces the dose of the drug (about 20 times) and achieves the same therapeutic effect.
the specific case, once the therapeutic drug enters the liver cells, the connection is cut, and a single-stranded ASO then targets specific messenger RNA (mRNA) to attract RNase H1 to degrade it.
this approach is similar to RNA interference (RNAi) therapies such as siRNA, in addition to double-stranded siRNA, which uses a different approach involving RNA-induced silent complexes to degrade targeted mRNA.
leading the way in siRNA-based cardiovascular disease treatment options is GalNAc-linked siRNA therapy inclisran, which is currently under review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
This drug lowers LDL cholesterol levels by targeting PCSK9, a protein involved in lipid metabolism and an important genetically validated drug target - a functionally obtained mutation in PCSK9 leads to familial hypercholesterolemia, while a functional deficiency mutation in PCSK9 lowers LDL cholesterol and prevents coronary heart disease.
convincing genetic evidence has led to the development of drugs targeted at PCSK9 on a variety of platforms, including early studies of the first generation of non-binding siRNA technology.
but the technology platform's candidates were overtaken by two monoclonal antibodies, the regenerative element Praluent and the evolocumab, which were approved by the FDA in 2015.
, however, the disadvantage of these antibodies is that they need to be given more frequently than siRNAs.
Anzolone, chief executive of Arrowhead Pharmaceuticals, said: "RNA interference drugs are generally better than antibodies because catalytic processes are often used.
"Drugs like inclisran can cut LDL cholesterol in half by only two injections a year, while Praluent and Repatha need to be injected every two to four weeks."
antibodies work faster than ASO therapy, but their drug concentration levels are also extremely high, and if you take an antibody that blocks proteins, it's everywhere.
, ASO drugs are a very precise method, which is why they are attractive.
two ASO drugs for PCSK9 are also potentially competing; Roche's investment in CiVi Biopharma is developing a GalNAc-combined ASO therapy, CiVi-007, which is currently in phase 2 trials; and on November 13th Ionis announced that it was working with AstraZeneca to develop a PC9 antisythetic therapy, ION449, which is in phase 1.
at the same time, another battle is brewing for a technology platform targeting ANGPTL3, which is developing antibodies evinacumab.
reducing ANGPTL3 improves high triglyceride and LDL cholesterol levels in patients with abnormal blood lipids, which affect tens of millions of patients in the United States.
after positive data from phase 3 trials, regeneratives have applied for regulatory approval for the treatment of pure family hypercholesterolemia, and the FDA and EMA will make a decision in the coming months.
2019, Ionis-owned Akcea licensed its GalNAc conjugate ASO therapy vpanorsen, which is in the second phase of trials of multiple cardiovascular diseases.
a permanent change ANGPTL3 may be the foothold of the next generation of gene drug "gene editing therapy".
a 2017 paper from the American College of Cardiology, Verve Kathiresan and University of Pennsylvania cardiologist and genetic researcher Kiran Musunuru and others found that a healthy family carried two copies of the broken ANNGPTL3 gene, showing lower LDL cholesterol levels and overall cardiovascular risk.
this study suggests that ANGPTL3 is a "standby gene" and that a one-off treatment could benefit from eliminating it," said Kathiresan, a professor at the university.
2018, Musunuru and others at the University of Pennsylvania used CRISPR gene editing technology to insert a fractured ANGPTL3 into a mouse model of pure familial hypercholesterolemia, resulting in significantly lower levels of triglycerides and LDL cholesterol.
study was published in the journal Circulation.
, gene editing techniques for ANGPTL3 and other targets that can lower LDL cholesterol, Lp(a) or triglycerides emerged.
Verve's study of ANGPTL3 in monkeys showed the benefits of gene therapy, with the main candidates including a specific configuration of a gene editor and a guided RNA.
drugs will be wrapped in lipid nanoparticles and delivered specifically to liver cells through a subject-mediated ingestion.
the advantage of nanoparticles is that they are faster than typical adeno-related virus (AAV) vector carrier delivery systems.
delivery stays, the more likely you are to deviate from the target edit.
gene editing is a good way to "restore enzymes lost in patients" and once the technology is established, the risk-benefit ratio advantage will ensure its use in rare genetic diseases.
, however, other drugs with more safety tests also seem to be effective in reducing certain gene expression in the liver, so using gene-editing drugs to target cardiovascular targets such as PCSK9 or ANGPTL3 may not be worth it.
the current research and development idea is to expand from rare diseases to common diseases.
the original group of patients was a small group of heart attack patients with familial hypercholesterolemia, not starting with 12.5 million heart patients in the United States.
to provide a gene drug for a genetic disease, which has since expanded to a larger population and developed treatments for targets that affect each risk pathway, such as LDL cholesterol, Lp(a) and triglycerides.
because the benefits are added up.
explore other ways, that is