Nature's latest report reveals: 4 popular target organs, TOP10 adaptation certificate

On January 25th researchers from the University of Oxford in the UK systematically analyzed clinical trials of AAV gene therapy in an analysis published in the Nature Reviews Drug Discovery.
AAV gene therapy trial analysis Of the 149 characteristic clinical trials analyzed by the authors, 94 were completed and another 51 reached the end of efficacy.
number of trials initiated each year increased from 5 in 2010 to 26 in 2017 (Figure 1a).
most of the preliminary completion studies are clinical Phase I/II studies that end in safety and effective, and more than 80 percent of the studies are supported by companies in the industry (Figure 1b).
Figure 1 | Clinical trial trends in AAV gene therapy.
a. Number of studies initiated each year; b. number of studies at various clinical stages; c. Type of AAV shell for each period; d. Use of starters for each period.
EoY, end of year.
addition, the average length of clinical trial studies appears to have decreased over time, which may reflect improvements in trial design and increased regulatory satisfaction with this treatment (Figure 2).
2 | 2003-2019 trial duration by year of start-up and clinical phase, in months (n s 51, A samp; B in both).
(Source: Nature Reviews Drug Discovery) The authors analyzed evolutionary trends in the use of AAV enclosures (based on 144 in 149 disclosure shell studies) and initiaters (based on 104 in 149 disclosure initiated sub-studies).
results show that the most used in clinical trials is still AAV2 serotype (Figure 1c), AAV2 serotype safety and ability evidence is also the largest, more than 40 completed trials.
since 2015, the number of drug trials delivered using AAV8 and AAV9 casings has continued to increase, reflecting the gradual increase in the use of gene therapy in central nervous system diseases.
other new types of clothing, such as AAV-LK03, SPK-100 and AAV-HSC15, have also made progress, but there is limited evidence of safety and effectiveness.
, the most clinically used promoters have long been ubiquitous promoters, such as CBA, CAG, and CMV (Figure 1d).
between 2015 and 2019, 45 percent of clinical trials in open starters used one of the three.
in clinical trials in recent years, there have been three new trends in the use of starters.
first, more than 25 clinical trials have used tissue-specific strong initiaters, such as albumin and synapses, to achieve gene expression in specific tissues.
Second, gene cassette's design and manufacturing capacity for larger doses of AAVs have been improved and enhanced, with AAV doses as high as 2×1014 vg/kg tested in patients without serious side effects, which allows the original initiaters of therapeutic genes to be used.
recent studies in animal models have shown that the high number of copies of AAV9 can cause severe toxicity, and it is not clear whether the use of raw initiaters that rely on high vector copies remains stable.
Biogen recently announced the termination of the development of the research SMA1 gene therapy BIB089, the reason for the termination is a similar toxicity problem.
third, in animal studies, synthetic initiaters used to target specific cell subse groups were successful, but none of the clinical trials in which such initiaters were used were initially completed until the deadline for this analysis.
Safety Researchers analyzed all studies with available safety data (n s 101) and classified safety events as drug-related events, i.e., adverse events that occurred within 28 days of administration, or adverse events in drug treatment, i.e. adverse events caused by the role of GM itself, the presence of the garment, or the response of the patient's immune system to GM or the garment (Figure 3).
3 | a. Serious adverse events associated with drug use (aSAE; n = 96）。
b. Serious adverse events in treatment (TESAE; n = 91）。
Of the 3,328 patients treated during the period selected in this analysis, 9 severe adverse events (SAEs) of magnitude 4 or 5 were considered serious adverse events (TESAEs) in treatment and did not die directly from GENETICs or clothing.
until the deadline for this analytical study, no studies were terminated for safety reasons, and all completed studies reached a safe end (n s 51).
However, after the end of the study, 3 of the 17 patients who received higher doses of experimental gene therapy AT132 for X-series small-tube myopathy died from regenerative liver and bile disease and subsequent sepsis and gastrointestinal bleeding.
the potential role of the immune response to the shell is being studied.
in all trials, an average of 21 per cent had severe adverse events (aSAE) associated with level 1-5 dosing.
intravenous and intravenous dosing is safer than most other methods of administering drugs (Figure 3a).
intracranial dosing is comparable to other methods in terms of the rate of severe adverse events, but the serious adverse events experienced tend to be of a higher level and have greater clinical significance.
, the most common adverse effects associated with dosing are nausea, injection site reactions, and headaches.
in all the trials analysed, an average of 35 per cent of severe adverse events were classified as serious adverse events in treatment and were not directly related to drug treatment.
note that gene therapy uses intramuscular injections to cause the lowest number of serious adverse events associated with treatment (Figure 3b).
data show that for the most commonly used AAV1 and AAV2, there is no significant difference between the severe adverse events associated with the treatment of the most commonly used AAV1 and AAV2, while AAV1 may be slightly more safe than AAV2 in the treatment of related severe adverse events (Figure 4).
4| serious adverse events occurring in drug-related and therapeutic events classified by shell type.
A. Number of trials associated with serious adverse events associated with the dissopassion of different shell types.
percentage of trials associated with severe adverse events associated with the disso handling of different shell types.
number of trials involving severe adverse events in treatment of different shell types.
percentage of trials with severe adverse events in treatment of different shell types.
of the 94 completed trials for analysis (Source: Nature Reviews Drug Discovery) were mostly concentrated in the four organs/tissues of the eye, liver, muscles, and central nervous system (Figure 5).
intravenous gene therapy used to treat metabolic and blood diseases, Parkinson's disease, type A and type B haemophilia for the liver has been the top 3 adaptations in clinical trials.
5 shows | target organization and adaptation certificate.
number of clinical trials in major target tissues, by time period.
B. Adaptation certificate for the cumulative number of clinical trials TOP 10.
(Source: Nature Reviews Drug Discovery) Overall clinical success rates are affected by the small number of gene therapies.
based on data from 11 new drug applications (NDA) stages, there is a 36% chance of progressing from research new drug (IND) applications to NDA, with a medium time of 86 months from IND to NDA.
the probability of success of gene therapy was higher than the historical average in all five therapeutic areas that had been tested (Table 1).
1 Probability of conversion of gene therapy at different stages Source: Nature Reviews Drug Discovery And gene therapy has the highest overall probability of success in blood diseases (56% progress from IND to NDA).
, however, the number of trials completed is still very small, and the closest to the listing of the research product valoctocogene roxaparvovec has not been approved by the FDA, which requires longer-term efficacy data.
based on an analysis of clinical data from more than 3,000 patients over 20 years, the authors believe that AAV gene therapy is a safe, well-to-use and effective treatment.
But there are also several issues that need to be addressed: First, the durability of gene therapy is uncertain due to the lack of lifetime follow-up to patients, and the role of steroid use and immune response in response persistence remains unresolved.
in diseases such as haemophilia and retinal genetic disorders that do not have rapid physiological decline, regulatory opposition will lead to drugs requiring longer, critical studies to collect stronger follow-up data.
life-saving products for diseases such as spinal muscular dystrophy may still benefit from shorter trials and rapid approval, but only if the drug shows convincing evidence of sustained improvement in the disease.
, the average dose of AAVs used in clinical trials has increased since 2015 as manufacturing processes have improved.
although higher doses of vectors can be used in diseases that require large numbers of transducting cells in the body, most vectors are eventually present in the liver and can cause potential toxicity in the liver and other areas.
need better gene box engineering to reduce viral load in the future.
, this analysis shows that the proportion of gene therapy trials outside the eyes, liver, muscles, and central nervous system is very low (n=11/94).
major organs such as the heart, kidneys and lungs, there is little AAV gene therapy.
In order to further improve the clinical significance of AAV gene therapy, it is necessary to constantly switch to engineered casings and synthetic promoter, so that the therapy avoids the liver, evades immune supervision, and enables GM to play a role only in a small subseology of cells.
: The clinical landscape for AAV gene therapies (Source: Nature Reviews Drug Discovery)