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The domestic IBD market is expected to exceed 10 billion next year, and drug research and development is still in the early stages

 Last Update: 2023-02-03
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Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC) is a recurrent and inflammatory disease
characterized by intestinal inflammation and epithelial injury that affects the digestive tract.

Crohn's disease (CD) ulcerative colitis (UC)

The etiology of IBD is not fully understood, but it may be related to
a variety of factors such as genetics, environment, intestinal microbiome, and enteric immunity.

Source: Guilherme Piovezani Ramos, et al.
Mayo Clin Proc.
2019 January; 94(1): 155–165.

The burden of IBD varies globally

China has entered a period of accelerated onset

There are currently approximately 6 million to 8 million people
with inflammatory bowel disease worldwide.

In terms of epidemiology, the disease evolution of inflammatory bowel disease presents four epidemiological stages: disease emergence, disease acceleration, disease progression, and disease balance
.
Among them, Western developed countries are in the third epidemiological stage (exacerbation stage) and are expected in the future Equilibrium will
be reached within 30 years.

Disease emerges, accelerates, worsens, and balances
.
Among them, Western developed countries are in the third epidemiological stage (exacerbation stage) and are expected in the future Equilibrium will be reached within 30 years

Newly industrialized countries in Asia and Latin America are in an accelerated phase of the evolution of inflammatory bowel disease
.
For example, some regions in China and India have published rates that are very close to the cumulative range of incidence in Western countries (e.
g.
, the incidence of ulcerative colitis is 6-11/105）
。 In the next decade, the incidence in these regions is likely to be close to that of Western countries
.

Source: Gilaad G.
Kaplan & Joseph W.
Windsor, 2020, Nature Reviews

In recent years, the number of IBD patients in China has shown a continuous upward trend, with the number of CD patients growing at a compound annual growth rate between 2014 and 2018 15.
2%, from 68,000 to 120,000, and will reach 188,000 in 2023 and 283,000 in 2030
.

The number of IBD patients in China is on the rise

It is expected that the scale of China's IBD drug treatment market will maintain a continuous growth trend in the next five years, and is expected to exceed 10 billion yuan by 2024, with an average annual compound growth rate of 5.
5
%.

The size of China's IBD drug treatment market is expected to exceed RMB 10 billion in 2024

Source: Frost & Sullivan

In 2020, the UC drug market was approximately $7.
5 billion worldwide, accounting for 10%
of the total immunology market.
It has grown at a compound annual growth rate (CAGR) of 10% over the past 4 years The increase was mainly due to the improvement in diagnostic rates, the introduction of newer therapies, and the increased
use of biologics in patients with moderate to severe disease.

Treatment is gradually transitioned

Forwarding biologics is the trend

IBD It is an immune-mediated systemic disease, and the main treatment mode is drug treatment, including aminosalicylic acid, corticosteroids, immunosuppressants, antibiotics, and biological agents
.

The main treatment drugs include aminosalicylic acid, corticosteroids, immunosuppressants, antibiotics, and biological agents

The choice of treatment regimen is based on a thorough assessment of the condition, and the treatment plan is adjusted at any time during the treatment
process according to the response to treatment and tolerance to the drug.

In terms of treatment goals, appropriate adjustments will also be made over time, from clinical response and clinical remission to transmural healing, histological healing, and STRIDE-II updated in 2021 Consensus aims for endoscopic mucosal healing, normalization of quality of life, and
disability-free outcomes.
The IBD Blue Book: A Report on Physician-Patient Cognition and Quality of Life for Inflammatory Bowel Disease in China is available on CD In the patient's survey, patients believe that "long-term maintenance of the disease in remission" is the most important factor
in CD therapy.

Source: Turner D, et al.
STRIDE II,Gastroenterology 2021; 160:1570-1583

At present, biologics are the mainstream products in the domestic IBD drug market and are approved for moderate to severe disease that is ineffective with conventional therapy IBD
。 At present, there are only four major categories of biologics approved for marketing: infliximab, adalimumab, ustekinumab, and vedelizumab
.
Among them, adalimumab and ustekinumab have been approved by the FDA Approved for use in UC, however they are not yet approved for UC indications
in China.

At present, biologics are the mainstream products in the domestic IBD drug market and are approved for moderate to severe disease that is ineffective with conventional therapy IBD
。

Biological agents are still dominating in China, or will they enter the "national procurement"?

In 1992, the first patient with Crohn's disease (CD) was treated with tumor necrosis factor antibodies at the Amsterdam Medical Center (AMC), with a specific clinical response and remarkable efficacy
.
Value, IBD A new era of treatment began
.
In fact, the medical community was already aware of the therapeutic potential and low adverse effects of the new treatment regimen, and began the fastest development and approval program
ever.

Subsequently, adalimumab, gorimumab and certolizumab were also marketed
.
Among the immunosuppressants, AbbVie's anti-TNF The drug adalimumab remains the industry's best-selling drug, generating nearly $20 billion in revenue in 2019, and Johnson & Johnson's infliximab earned more than $50 in 2019 billion dollars
.

Anti-TNF of AbbVie in immunosuppressants The drug adalimumab remains the best-selling drug in the industry,

Timing of approval for anti-TNF indications in Europe

Like rituximab, many varieties will be included in the conditions to meet the full competition of 3 companies, and it is the general trend
for biosimilars to be included in the national centralized procurement.
A number of domestic verified monoclonal antibodies may be included in the scope of centralized procurement in the future.
Such as adalimumab, infliximab, trastuzumab, etc.
, so the "forbidden area" of biosimilars must be broken
.

Source: CICC Research

The indications must not be extrapolated, this year may be the best time for TNF national procurement?

CDE The published Guidelines for Biosimilar Similarity Evaluation and Indications Extrapolation Technology pointed out that when direct comparison clinical trials prove that a drug candidate is clinically similar to a reference drug in at least one indication, scientific demonstration
of research data and information related to the pseudo-extrapolation indication may be possible.

Foreign IFX first biosimilar CP-13, from 2013 ECCO expressed concern about indication extrapolation to 2016 The year clearly states that the original study and similar are interchangeable, indicating that it is not appropriate to extrapolate to IBD through rheumatic disease-related data alone, and that some IBD may still need to be accumulated Relevant clinical efficacy evidence is more likely to be promoted
to domestic biosimilars.

Source: Gabbani T, et al.
Drug Des Devel Ther.
2017; 11:1653-1661

The IL-23 target is of interest and may replace TNF

Ustekinumab (abbreviation: UST) is a fully human IgG1k monoclonal antibody that binds to p40 Asia of IL-12/23, China in 2020 3 Approved for Crohn's disease indication, ustekinumab is indicated for adults with moderate-to-severe active Crohn's disease who have underresponded, lost response, or are intolerable to conventional treatments or tumor necrosis factor α (TNFα) antagonists (infliximab, adalimumab).
(CD) patients
.

In June 2022, Risankizumab (AbbVie) was approved by the FDA for marketing (600 MG/VIAL, intravenous), became the world's first interleukin-23 (IL-23) inhibitor
for Crohn's disease.
11 of the same year In January, Risankizumab was approved by the EMA for the treatment of moderate-to-severe active Crohn's disease
.

Interleukin-23 (IL-23) inhibitors of Crohn's disease with moderate to severe activity in Crohn's disease

Risankizumab for the treatment of Crohn's disease approved for marketing

Risankizumab is a humanized IgG1 monoclonal antibody evaluated in the Phase III study ADVANCE Efficacy and safety
of risankizumab for moderate to severe CD-induction.
A total of 850 patients were previously exposed to biologic agents in 490 cases on a 2:2:1 basis The proportion was randomized to receive IV risankizumab 600 mg, 1200 mg, or placebo
at baseline, weeks 4, and 8.
Section 12 Weeks, risankizumab outperformed placebo for all primary endpoints, including CDAI-based clinical remission, bowel frequency [SF], and abdominal pain, among others
.

Phase III Study ADVANCE No.
12 Weeks, risankizumab outperformed placebo for all primary endpoints, including CDAI-based clinical remission, bowel frequency [SF], and abdominal pain, among others
.

ADVANCE test results

Interleukin-23 (IL-23) plays an important role in the differentiation and maturation of Th17 cells, which can lead to intestinal inflammation and IBD
.
There is growing evidence of blocking IL-23 It is an effective and safe therapeutic target for CD and UC
.

Source: Journal of Crohn's and Colitis, Volume 16, Issue Supplement_2, April 2022, Pages ii64–ii72

JAK inhibitors: Upadacitinib is the most eye-catching, and the black box warning still needs to be vigilant

Many of the roles of cytokines involved in CD and UC pathology are the activation of signal transduction proteins and transcriptional activating factor (STAT) DNA by Janus kinase (JAK) molecules The result of
binding proteins.
Therefore, inhibition of the JAK–STAT pathway has become an attractive target for novel IBD therapeutics
.

Currently, according to the Insight database, a total of 23 JAK inhibitors worldwide have entered the clinical stage
in the field of IBD.

23 JAK inhibitors worldwide enter clinical phase

From: Insight (manual sorting, if there is a mistake, please correct)

Tofacitinib/tofacitinib is an oral non-selective JAK inhibitor approved by the US FDA in May 2018 for the treatment of UC.

However, compared with anti-TNF drugs, there is at least 1 Cardiovascular risk factors for RA over 50 years of age receiving tofacitinib 5 or 10 mg BID Patients are at increased risk of major adverse cardiovascular events, malignancy, venous thromboembolism, and death
.
So, for JAK As far as inhibitors are concerned, black box warnings are undoubtedly like a shackle, always reminding them of safety risks
.

For JAK As far as inhibitors are concerned, black box warnings are undoubtedly like a shackle, always reminding them of safety risks
.

In numerous JAK Among the inhibitors, Upadacitinib/uppatinib is undoubtedly the most eye-catching drug
.
Upatinib is an oral, once-daily, selective, reversible JAK Inhibitors, developed for the treatment of a variety of immune-mediated inflammatory diseases
.

In numerous JAK Among the inhibitors, Upadacitinib/uppatinib is undoubtedly the most eye-catching drug
.

In July 2022, the European Commission (EC) approved RINVOQ® [Upadacitinib 45 mg (induction dose) and 15 mg and 30 mg (maintenance dose)] is used in adults to treat moderately to severe active ulcerative colitis
that is inadequate in response to, unresponsive or intolerant to conventional medical therapy or biologic therapy.

In U-ACHIEVE and U-ACCOMPLISH, 36% and 44%, respectively, were observed in the RINVOQ 45 mg treatment group, at week 8 of patients achieved mucosal healing, compared with 7% and 8%
of patients treated with placebo.
In maintenance therapy studies, at week 52, RINVOQ was 15 mg and 30 mg Mucosal healing was observed in 49% and 62% of patients in the treatment group, respectively, compared with 14%
of patients treated with placebo.

In October 2022, the European Medicines Agency's (EMA) Safety Committee (PRAC) announced the initiation of a safety review for Janus kinase (JAK) inhibitors, including Rinvoq (Rifu, ® Upatinib), Cibinqo and Xeljanz (Shangjie ®, Tofacitinib), Olumiant, Jyseleca, etc
.

Prior to EMA's action, the FDA restricted
the use of most JAK inhibitors based on Xeljanz's ® safety concerns.
The FDA requires a response to the above 3 The boxed warnings for JAK inhibitors (Xeljanz®, Olumiant®, and Rinvoq®) have been revised to identify information about
serious heart-related events, cancer, blood clots, and risk of death.

Source: EMA website

S1P receptor modulator: Ozanimod or segmentable mild to moderate UC market

On November 23, 2020, BMS announced its S1P receptor modulator Zeposia (ozanimod) is approved by the European Commission (EC) for the treatment of patients
with moderately to severely active ulcerative colitis (UC) who do not respond or respond insufficiently and intolerant to conventional therapies or biological agents.

Moderately to severely active ulcerative colitis (UC)

In a phase 3 trial as induction and maintenance therapy for adults with moderate to severe ulcerative colitis, two primary endpoints were met, with induction therapy at week 10 entering clinical remission (clinical remission) and the results of maintenance therapy at week 52 were highly statistically significant (p<0.
0001).

NCT02435992 Clinical trial results

According to the Insight database, in the field of IBD, there are currently 9 S1P receptor modulators in the world that have entered the clinical stage, as shown in the table below
.

At present, 9 S1P receptor modulators worldwide have entered the clinical stage

From: Insight (manual sorting, if there is a mistake, please correct)

In addition, the recent TL1A monoclonal antibody results are also very eye-catching, and on December 7, Prometheus Biosciences announced the TL1A monoclonal antibody PRAO23 The latest data from 2 phase II clinical studies for Crohn's disease and ulcerative colitis showed excellent efficacy, and the company's stock price rose 165.
67%
on the day.
See Insight Previous reports>>> tens of billions of inflammatory bowel disease market dark horse has appeared, TL1A monoclonal antibody phase II data is eye-catching! Pfizer chasing and blocking layout next-generation products.
.
.

Also TL1A monoclonal antibody, Roivant Sciences today announced that it is developing RVT-3101 at 2b Positive results
were obtained in phase II clinical trials.
In a biomarker-screened patient population, patients treated with expected Phase 3 clinical trial doses achieved a clinical response rate of 40% (clinical remission) and 56% endoscopic improvement
.

RVT-3101 40% clinical response rate (clinical remission) and 56% endoscopic improvement
.

IBD drug therapies are developing rapidly, but the domestic market for anti-TNF drugs remains strong
.
With more IBD therapeutics approved next year, more players will enter the IBD market
.

But it's also important to note that sales of drug candidates may be lower than we expect
.
On the one hand, the reason is that the overall penetration rate of new drugs in China is not high, and it is difficult for new biological agents to distinguish anti-resistance TNF drugs, on the other hand, there is still a gap between the domestic drug launch time and the international market, and there is a situation
where the market share is squeezed by each other.

But it's also important to note that sales of drug candidates may be lower than we expect
.

References:

1.
Guilherme Piovezani Ramos, et al.
Mayo Clin Proc.
2019 January ; 94(1): 155–165.

2.
Gilaad G.
Kaplan & Joseph W.
Windsor, 2020, Nature Reviews

3.
Frost & Sullivan Report

4.
Walsh, G.
, Walsh, E.
Biopharmaceutical benchmarks 2022.
Nat Biotechnol 40, 1722–1760

5.
Source: Turner D, et al.
STRIDE II,Gastroenterology 2021; 160:1570-1583

6.
Inflammatory Enterology Group, Gastroenterology Branch, Chinese Medical Association, et al.
IBD Blue Book: Physician-Patient Cognition and Quality of Life Report for Inflammatory Bowel Disease in China.
2021

7.
Gabbani T, et al.
Drug Des Devel Ther.
2017; 11:1653-1661

8.
9.

9.
10.
Aliment Pharmacol Ther.
2022 Feb 15.
doi: 10.
1111/apt.
16785.
Epub ahead of print.
PMID: 35166398.

10.
Aliment Pharmacol Ther.
2022 Feb 15.
doi: 10.
1111/apt.
16785.
Epub ahead of print.
PMID: 35166398.

11.
Trends Pharmacol Sci.
2017 Feb; 38(2):127-142.
doi: 10.
1016/j.
tips.
2016.
10.
014.
Epub 2016 Dec 1.
PMID: 27916280.

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