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Angel or devil? It has always been the subject
of controversy over JAK inhibitors.
In the eyes of pharmaceutical companies such as AbbVie, JAK inhibitors are naturally angels
.
As an important product in the field of autoimmune diseases, AbbVie's Rinvoq sales reached $695 million in the third quarter of this year, and the growth rate was as high as 59.
3%.
Against this backdrop, AbbVie has high hopes
for Rinvoq as one of Humira's successors.
But while AbbVie is optimistic, the European Medicines Agency's Safety Committee has issued a recommendation to restrict the use of JAK inhibitors
in 4 high-risk groups.
Among the restricted categories is AbbVie's Rinvoq
.
Side effects have long been an uncertain factor
for JAK inhibitors.
Before the European Medicines Agency, the FDA introduced corresponding measures last year to postpone the priority of JAK inhibitors in treatment, and the application of a wider
range of people.
The advantages and disadvantages are equally prominent, making the future of JAK inhibitors uncertain
.
So, will JAK inhibitors become "angels"?
/ 01 /
/ 01 /A generalist in immunity
A generalist in immunityAbbVie is right to see Rinvoq as one of Humira's successors
.
In a way, the two are extremely similar
.
Humira can become the "medicine king" for two reasons:
First, it is applicable to a wide
range of people.
In 2012, when Humira reached the top of the "medicine king", a total of 9 indications were approved; Today, there are more than 10 models
.
Second, the particularity of autoimmune diseases leads to a relatively long
medication cycle.
For example, in areas such as psoriasis, patients need to take it for life until the drug does not control the disease
.
It is based on these two characteristics that Humira has endured, and sales have climbed until the
patent expires.
Perhaps, Rinvoq also has this possibility
.
JAK kinases, which are targeted by JAK inhibitors, are at the heart of
the entire JAK-STAT signaling pathway.
The JAK-STAT signaling pathway is one of
the few immunomodulatory pathways that has been demonstrated.
Many diseases, such as rheumatoid arthritis, psoriasis, and hematological diseases, have been shown to need to be transmitted
through the JAK-STAT signaling pathway.
This also means that, like Humira, Rinvoq has the potential
to expand its indications.
Indeed, just a while ago, the FDA approved a new indication for Rinvoq for end-line therapy in adult patients with non-radiology axial spondyloarthritis (patients who have failed multiple lines or are not suitable for tumor necrosis factor inhibitors such as Humira).
This is the sixth indication for Rinvoq to be approved for marketing
.
As far as AbbVie's clinical development strategy for Rinvoq is concerned, its indications have the potential
to continue to expand in the future.
At the same time, the indications targeted by Rinvoq are also concentrated in the field of self-exemption, which has the characteristics of long medication cycle and high frequency, and the potential ceiling is also not low
.
This can also be seen through its sales performance
.
In the third quarter of 2022, Rinvoq sales reached 6.
95
US$100 million, with a year-on-year growth rate of 59.
3%.
It's not hard to see why AbbVie has high hopes
for Rinvoq.
/ 02 /
/ 02 /Constant "suppression" of regulation
Constant "suppression" of regulationHowever, JAK inhibitors not only have AbbVie's optimism, but also constant warnings and pressure
from regulators.
Just on 28 October 2022, the European Medicines Agency's Safety Committee (PRAC) issued recommended measures:
Due to the serious side effects of currently approved JAK inhibitors, including cardiovascular disease, blood clots, cancer and serious infections, their use
is restricted to individual populations.
PS: Restricted JAK inhibitors, including AbbVie's Rinvoq, Pfizer's Cibinqo and Xeljanz, Eli Lilly's Olumiant, Gilead's Jyseleca, and more
.
According to the committee's recommendations, people who are not eligible for JAK inhibitors include patients over 65 years of age, patients with high cardiovascular and cerebrovascular risks, and patients
with high risk factors for tumors such as smoking.
In addition, for patients with higher risk factors for thrombosis, although the use is not restricted, the committee has also made recommendations
to reduce the dose.
So why did the committee restrict the use of JAK inhibitors?
The reason is that according to the clinical results of Pfizer's Xeljanz and Incyte/Eli Lilly, JAK inhibitors can induce side effects
such as cardiovascular and cerebrovascular, thrombosis, and serious infections.
Based on this, the Committee believes that these potential risks arise in all approved indications and therefore proposes restrictions
on use.
In fact, before the European Medicines Agency took action, the US FDA also restricted most JAK inhibitors based on Xeljanz's safety concerns:
The use of JAK inhibitors in the United States is limited to patients who have tried at least TNF inhibitor therapy but failed
.
That is, the FDA postponed the prioritization of JAK inhibitors in treatment; At the same time, the FDA has added a black box warning
to drugs.
Compared with the European Medicines Agency's policy, the FDA's policy applies to all patients, the scope of the crackdown is broader, and the impact will be more far-reaching
.
It is under the influence of FDA policies that Pfizer's Xeljanz sales have experienced a big decline:
In the first half of 2022, Xeljanz sales plummeted by 29%.
The reason for Xeljanz's decline in sales is precisely the significant reduction
in demand in the United States.
Although the safety question mainly came from Xeljanz, there are indications that JAK inhibitors, including Rinvoq, may also be affected
accordingly.
/ 03 /
/ 03 /Opportunities and risks come together
Opportunities and risks come togetherWhat is the ceiling of JAK inhibitors, it must also be a concern of
domestic pharmaceutical companies.
As a class of innovative drugs with high market popularity, domestic pharmaceutical companies are naturally indispensable
.
On October 16, 2022, Zejing Pharmaceutical's marketing application for jacktinib was accepted by the NMPA, and its indications are the treatment of medium- and high-risk myelofibrosis
.
If jacktinib is successfully approved for marketing, it is expected to become the first domestic JAK inhibitor
.
At the same time, including the JAK inhibitor SHR0302 developed by Hengrui Pharmaceutical, etc.
, are also close to the market
.
To some extent, some domestic JAK inhibitors may also have the risk of side effects of overseas products, which is determined by their
mechanism.
At present, some JAK inhibitors approved for marketing have greater side effects because of low selectivity
.
A total of four members of the JAK family have been found:
JAK1: mainly associated with acute lymphoblastic leukemia, acute myeloid leukemia, solid organ malignant tumors;
JAK2: mainly related to polycythemia vera, myelofibrosis, essential thrombocythemia and other diseases;
JAK3: mainly associated with acute megaloblastic leukemia, T-cell leukemia and lymphoma;
TYK2: mainly associated
with cutaneous lymphoproliferative diseases and T-cell leukemia.
Each member of the JAK family plays a variety of roles, so when JAK drugs inhibit other members of the JAK family, there are multiple side effects
.
According to the mechanism, the selectivity of some domestic JAK inhibitors is also not high
.
For example, Zejing Pharmaceutical has a significant inhibitory effect
on JAK1, JAK2, JAK3 and TYK2.
This also means that it may also encounter corresponding troubles
.
Of course, not all JAK inhibitors face this problem
.
Referring to the R&D process of overseas pharmaceutical companies, differentiated structural design can obtain selective JAK inhibitors, thereby opening the ceiling
.
For example, after layers of transformation and optimization, Bristol-Myers Squibb finally got a successful TYK2 inhibitor
.
In patients treated with this drug, no adverse reaction signals
related to JAK1, JAK2, and JAK3 were found.
A chase war for TYK2 inhibitors has begun, and domestic pharmaceutical companies have not been left behind
.
At present, pharmaceutical companies including Gaoguang Pharmaceutical, Jiayue Pharmaceutical, Qiyuan Biologics, InnoCare, Haisco, BeiGene and other pharmaceutical companies are carrying out the research and development
of TYK2 target drugs.
For products such as JAK inhibitors, which have equally outstanding advantages and disadvantages, there must be a coexistence
of risks and opportunities.
Whoever can solve the corresponding problems with technology will naturally get rich rewards
.
