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The treatment of thalassaemia is a small test, and the future application of gene editing is beginning to appear Industry observation

 Last Update: 2022-10-20
 Source: Internet
 Author: User

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• Gene editing technology is gaining favor in the field of gene therapy for thalassaemia, which avoids the possible carcinogenic risks
of random integration compared to lentiviral therapy.

• Gene editing technology is gaining favor in the field of gene therapy for thalassaemia, which avoids the possible carcinogenic risks
of random integration compared to lentiviral therapy.
Gene editing technology in

• Off-target issues and the possible genomic instability caused by cleavage are the most concerned potential risks
in the field of gene editing.

• Editing cells in vitro is an important reason why
companies prefer to enter.
In the future, the weather vane will turn to in vivo gene editing with a wider range of applications, and its layout may develop from genetic diseases to common diseases
.

Recently, bluebird bio's lentiviral gene therapy Zynteglo for β-thalassemia was launched in
the United States.
R&D customers observed that most of the follow-up gene therapy products for thalassaemia are gene editing technology routes, and incomplete statistics know that there are currently 6 gene editing products for thalassaemia in the world that have entered the clinical research stage
.

CTX001, the fastest progress, has reached the phase III clinical stage
.
In June 2022, CRISPR Therapeutics released the latest data of CTX001, the study enrolled 75 patients, of which 44 were β-thalassemia patients, after 1.
2~37.
2 months of observation after injection of drugs, 42 patients did not need blood transfusion, and the blood transfusion volume of the other two patients decreased by 75% and 89%,
respectively.

In the field of thalassaemia, is gene editing a major trend in the future, and how is it different from lentiviral therapy? Compared with viral vectors, what are the development trends of gene editing, which has a shorter time to enter the field of new drug research and development, after jumping out of the field of hematopoietic stem cell transformation? These are the focus
of our attention.

Differences between the two treatments

In the opinion of industry experts, an important reason for the industry's attention to gene editing treatment of thalassaemia is to avoid the possible carcinogenic risk
caused by random integration of lentiviral (LVV).

Bluebird's Zynteglo is the insertion of the correct β-globin gene into LVV and transfection of human hematopoietic stem cells to express normal adult hemoglobin in the body to treat thalassaemia
.
The gene editing protocol is to edit hematopoietic stem cells in vitro, and the entire editing system is introduced into the cells by means of electroporation and transfection reagents, the most commonly used of which is electroporation
.
This method of delivery does not require lentivirus
.

Lentiviral gene therapy has always been overshadowed by the risk of
random integration.
In 2000, a retroviral gene therapy caused leukemia in five subjects, which had a rather negative impact
on the entire gene therapy field at the time.
Lentiviruses are born from retroviruses, and although they are safer than retroviruses, there are still random integration problems
.

In fact, Bluebird, which is dominated by LVV technology platforms, has experienced several clinical pauses
for products before and after.
In 2021 alone, its lentiGlobin was suspended for two clinical studies for the treatment of sickle cell anemia because two subjects developed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), respectively; Eli-cel, who treated adrenal leukodystrophy, was also stopped
due to suspected MDS in one patient.
The brief clinical recovery of lentiGlobin was suspended again, and eli-cel was recently approved for marketing and the clinical suspension
was lifted.
Although it has not been confirmed that the safety problems found in clinical practice are necessarily related to the random integration of lentivirus, this has always been regarded as a major hidden danger and has been a major concern
of the industry.

Wei Dong, CEO of Boya, said that LVV has a very strong promoter and a complete viral structure, which may be randomly integrated into thousands of sites, and if it is inserted in the wrong place, it may bring about more significant changes, and gene editing will not face such a problem
.
Because of this, the industry generally believes that products such as gene editing are less
potentially risky.
"Of course, there is no long-term clinical observation data yet, and we hope that the final data can better verify everyone's hypothesis
.
"

Li Dali, co-founder and vice president of Bangyao Biologics, talked about another feature of gene editing: compared with lentiviral vectors, gene editing is more efficient and accurate
.
To ensure efficient editing, it is necessary to ensure that a high proportion of edited cells exist in the patient's body
.
This is closely related
to the long-acting nature of gene therapy.

In addition to the difference in delivery methods, the treatment ideas used by LVV and gene editing are also slightly different
.
Also modifying hematopoietic stem cells, LVV is equipped with the β-globin gene, which expresses the adult hemoglobin that is missing in the human body, and the idea of gene editing is to activate γ-globin (fetal hemoglobin) to replace the absence
of β-globin.
Whether it's viral vectors or gene editing, the mechanism of modifying hematopoietic stem cells is equally applicable to some other blood diseases, such as sickle anemia, so CRISPR Therapeutics' CTX001 and Editas Medicine's EDIT-301 are both being developed at the same time
.

The specific editing idea is mainly in two directions: one is for the BCL11A erythrone enhancer, which destroys the expression of BCL11A through gene editing, which can lift the inhibition of fetal hemoglobin and activate the reexpression
of fetal hemoglobin.
CRISPR Therapeutics, Sangamo Therapeutics, Burson-Marson, and BangYao Biologics all use this strategy
.
The other direction targets the site on γ-globin that binds to BCL11A, which can also be depressed
by gene editing to destroy this site.
Editas Medicine uses this strategy
.

For the difference in thinking, Wei Dong explained that there are nearly one or two hundred mutations in β-globin, and each mutation represents a very small patient population, and gene correction for these mutations is not particularly efficient, and the commercial value is limited, so basically few gene editing companies develop thalassaemia drugs
that directly correct β-globin genes.

"The different strategies used by lentiviruses and gene editing, although both increase hemoglobin levels and red blood cell function, still have some essential differences
.
Will these differences be reflected in different patient efficacy and responses, and whether gene editing reflects a higher safety profile than lentiviral strategies? These should be observed
in the future long-term follow-up and follow-up.
Gene therapy is also a process
that needs to be observed for a long time.
Li Dali told the R&D customer
.

Controlling off-target risks remains a top priority

Although the carcinogenic risk of LVV can be avoided, safety risks are also a core challenge
in the field of gene editing.

In 2021, ALLO-501/ALLO-501A, a gene-editing universal CAR-T product developed by Allogene, was suspended from clinical trial
because one subject had chromosomal abnormalities and potential carcinogenic risks.
In early August 2022, the IND application for BEAM-201, a CAR-T product developed by Beam Therapeutics, was suspended
by the FDA.
At present, it seems that the two suspended clinics are CAR-T products, and the editing techniques used are TALEN and single-base editing, respectively, not the most widely used CRISPR
.

Beam recently disclosed information that the FDA has asked the company to add, the first two of which are research and data involving safety of genome rearrangement and
off-target.
This partly confirms that off-target problems and the possible genomic instability caused by cleavage are the most concerned potential risks
in the field of gene editing.

"Small molecule or antibody drugs, there are on target desirable effect and on target undesirable effect, off target desirable effect and off target undesirable effect
.
In the field of gene editing, we also need to add a specific on target editing and off target editing
.
In this way, there will be a real concept of
gene editing therapeutic index.
This also requires companies to know how to manage potential off-target and possible adverse reactions
from R&D to production.
Wei Dong said
.

In fact, clinical pauses have more or less negatively affected
the field.
Wei Dong said that any early, cutting-edge technology field, after the leader has a problem, the later companies may be affected
.
Regulators worry about the entire technical level and suspend all related projects
.
Allogene was halted from
all 5 TALEN technology programs.

When Wei Dong previously worked in other companies, he also encountered two cutting-edge product problems, and all similar projects around the world were put on hold
.
Because of this risk, Burson-Ya chose to develop three different technology platforms - CRISPR/Cas9, CRISPR/Cas12 and the self-developed RNA base editing technology LEAPER
.
This is a way of
sharing risk at the decision-making level.

In Li Dali's view, there is uncertainty about the safety of any therapy in the initial stage, and the clinical suspension is not necessarily caused by the gene therapy technology itself, which requires more clinical research and detailed data to determine, verify and feedback
.
The reasons for the clinical suspension are under
further investigation.
"Maybe from the industry and the outside world, there will be different reactions
to this incident.
" At the same time, I think that early detection of problems, being able to solve them or explaining them, is actually a good thing
for this field.
”

Returning to the specific risk control, Li Dali said that the application of gene editing has a lot to do with the site, and the frequency of off-target and genomic instability caused by different sites will be very different
.
Cas9 does not produce random cutting, the site of the cleavage is very related to the corresponding sequence of sgRNA, and the sgRNA without off-target risk can be selected through in-depth study of sgRNA sites and sensitive detection methods, because the selection of sgRNA is not unique
in the treatment of many diseases.
This makes the off-target risk of CRISPR gene editing relatively easier to manage
.
Base editing may be caused by deaminase to cause the risk of random off-targeting, and the potential risk
can also be reduced through tool modification and evolution.

Complex pricing

Since the first gene therapy was approved, its high cost has been the focus
of discussion.

Zynteglo is priced at $2.
8 million in the U.
S.
and €1.
575 million (approximately $1.
8 million)
when it launches in Europe in June 2019.
Later, due to price, Zynteglo withdrew from the European market
in 2021.
A month after Zynteglo was launched in the United States, Skysona (eli-cel) was approved in the United States for $3 million, once again setting a new record for
the most expensive drug.

Will the different technical ideas of gene editing have pricing implications? This may have to be seen
in two ways.

From the perspective of cost, according to Li Dali, the packaging and purification process of lentivirus is relatively complex and the investment is large
.
The application of gene editing systems is generally two ideas, one is to use recombinant Cas9 protein plus guide RNA (sgRNA); One is to replace recombinant proteins with Cas9 mRNA, plus sgRNA
.
The synthesis of sgRNA and Cas9 protein can be commercialized, and many companies can now provide clinical-grade Cas9 protein, and the cost will be further reduced
after localization.
Gene editing is much
less expensive than viral vectors.

However, Wei Dong said that pricing considerations are complex and not just tied to
cost.
In Europe and the United States, especially for the two types of innovative drugs, First-in-class or Best-in-Class, it is not priced according to cost, but needs to consider the profit after the manufacturer must recover the R&D investment and the pharmacoeconomic value of
the product.

European regulators asked Zynteglo to drop from $1.
8 million to $930,000, and Bluebird did not accept it
.
For Bluebird, if it drops to $930,000, the total profit will be reduced in the case of higher costs, which will not support research and development and commercialization
.
So in the end, Bluebird opted out of the European market
.
"Most foreign innovative drugs are actually more inclined to enter the US market
first.
Bluebird Zynteglo was first launched in Europe because β-thalassaemia drugs have a strong market demand in Europe, and European regulators granted them the qualification
to accelerate review.
Wei Dong said
.

"They tried a different pricing system in each country, with multi-year in Europe and one-time payments
in the U.
S.
This provides a good reference
for our own future business planning in China and other countries.
The final pricing is not necessarily the same
for each country and patient group.
Wei Dong said
.

Whether it's $930,000, $1.
8 million or $2.
8 million, it's unrealistic in China — that's the consensus
of the two experts.

The entry point for gene editing in vivo

Modifying hematopoietic stem cells and developing CAR-T can be said to be two major tickets
to enter the field of gene editing.
These two directions are to edit cells in vitro, the risk is more controllable, and the product development route is short and promising, which is also an important reason why
enterprises prefer to enter.
The future weather vane will turn to gene editing
in vivo.

Li Dali believes that the future trend is on the one hand the layout and application of in vivo therapy; On the other hand, gene editing is currently mainly treated by destroying some genes or causing small base changes, and will develop
in the future in the direction of functional acquisition of genes and fixed-point modification of long sequences.

According to Wei Dong's observation, in the early days, because of the insufficient understanding of off-target and some potential risks, basically all companies will start
with in vitro therapy.
With more and more clinical data, various types of analysis and production processes becoming more and more mature, many emerging companies in the field have no longer been developed in vitro on certain platforms, but directly into in vivo gene editing
.
In vivo gene editing has a broader range of applications and potential
.

The layout of gene editing in vivo may show a trend
of transformation from genetic diseases to common diseases.
For example, there have been some advances
in the field of cardiovascular.

Verve Therapeutics is developing a base-editing therapy, VERVE-101, and in July announced its first patient dosing
in New Zealand.
VERVE-101 targets PCSK9 and the first indication is heterozygous familial hypercholesterolemia (HeFH).

There are already many different drugs targeting PCSK9, including antibodies and siRNA
.
Wei Dong told the developers that antibodies are injected once every two weeks or a month, and siRNA is injected once
every six months.
Gene therapy sounds attractive
to complete the treatment in one injection.
If VERVE-101 works well in HeFH, safety data can be obtained, and the subsequent 20 million patients with cardiovascular diseases caused by high cholesterol can also be treated
by this method.
Therefore, cardiovascular disease has become one of the important directions of gene editing therapy in vivo, and may realize the application
from genetic diseases to non-genetic diseases.

"In the future, there may be more gene-editing technologies that are more suitable for muscle, cardiovascular or nervous system applications
.
" The particularity of gene editing technology combined with the particularity of delivery tools can lead to a more colorful
gene editing therapy in vivo.
”

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