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Inventory of failed clinical projects of global big pharmaceutical companies in recent years

 Last Update: 2023-01-05
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The world's top Big The overall level of Pharm cannot escape the iron rule
of 10% success in new drug development.
Starting from the failed clinical projects and pipeline strategies of big pharma, look at the research and development
of domestic innovative drugs.

It is also difficult to escape the iron rule of 10% success in new drug research and development

The success rate of innovative drug research and development of big pharmaceutical companies

Pfizer updated the company's 5-year clinical trial success rate at the beginning of 21 (only counting the 5-year rolling average of the new molecular entity NME project, Phase 2 and Phase 3 clinical trials, and the 3-year rolling average of Phase 1 study), as well as the comparison of industry averages (Industry includes 12 companies including AbbVie, Eli Lilly, Gillaid, Johnson & Johnson, BMS, Merck, Novartis, Pfizer, Roche, Sanofi, Allergan, Bayer
).
We can see that even the world's top big The overall level of Pharm cannot escape the iron rule
of 10% success in new drug development.

It is also difficult to escape the iron rule of 10% success in new drug research and development

The clinical success rate of new drugs is not only linked to the R&D capabilities of pharmaceutical companies, but also affected by many factors such as clinical development strategy (conservative or radical), the number of pipelines and clinics, the technical direction involved, and the field of drug use
.
This also leads to large differences in clinical success rates between major companies (this article is mainly discussed from the perspective of clinical failure projects).

We sort out the failed projects of Eli Lilly, Roche, AbbVie, Merck, AstraZeneca, BMS, Sanofi, and 7 large pharmaceutical companies in the past 5 years according to the statistical information available, and analyze them one by one according to market capitalization
.

Clinical development strategy pipeline and number of clinical trials, technical direction, drug field

Eli Lilly

Lilly's pipeline focuses on the four major drug fields of diabetes, tumor, immunity and nervous system, and only one page of PPT summarizes the clinical projects under development, which belongs to the simple and refined high-quality route
.
At the same time, Lilly is also one of the few companies in the big pharmaceutical companies whose pipeline is not tumor-first, and has a relatively even layout in various fields, such a strategy has allowed Lilly to keep a low profile and move forward
steadily.

It belongs to the simple and refined high-quality route

Although the market for pemetrexed and insulin with patent expiration has seriously declined in the short term, the strong growth of abecilide, eccilizumab, empagliflozin, and dulaglutide has also kept revenue stable, and more importantly, Tirzepatide and Donanemab, the two blockbusters have broad prospects, and will bring considerable revenue after commercialization, helping the company bring new growth
.

Figure 1 Lilly clinical pipeline reserve (Source: Eli Lilly)

From 2017 to 2022Q3, a total of 53 projects were terminated or failed by Eli Lilly, of which more than 50% were terminated in Phase 1, while less than 20% were failed in Phase 3 and above, which is partly related
to the relatively small proportion of Lilly's tumor pipeline 。 Important late-stage program failures included the missed OS endpoint in the KRAS mutation NSCLC in a phase III clinical trial; Ramolurumab challenges 1L line gastric cancer failure; Phase 3 clinical failure of JAKi baricitinib SLE; Failure of the expansion of empagliflozin type 1 diabetes; and Abecili HER2+BC, which was abandoned due to fierce competitive pressure in the market Phase III clinical trial, IL23 monoclonal antibody mirikizumab psoriasis sBLA
.
In addition, it acquired ARMO for $1.
8 billion Bioscience's IL-10 program, pegilodecakin, is no longer moving forward
after the first phase III clinical failure.

To some extent, this is related to the relatively small proportion of Lilly's tumor pipeline

Figure 2 Failed late-stage clinical projects from 2017 to 2022Q3 (Source: Eli Lilly, compiled by Fengshuo Venture Capital)

Roche

Roche is currently in a critical period of "alternation of old and new" product pipeline, and the "old troika" of tumors in the pharmaceutical business has been impacted by biosimilars, with total revenue falling by more than 30% in the past two years, leaving sales pits
of up to $7 billion and $4 billion in 2020 and 2021 respectively.
In recent years, Roche has also continued to expand its pipeline reserves, of which NME has reached 51/21/10 clinical studies in phase 1/2/3; There are also 65 clinical indications for listed products, including 46 phase 3 clinical trials
.

In 2020 and 2021, there were sales holes of up to $7 billion and $4 billion, respectively
.
There are also 65 clinical indications for listed products, including 46 phase 3 clinical trials
.

Figure 3 Roche clinical pipeline reserve (source: official website)

Roche's clinical projects account for half of the tumor drugs, so most of the failed projects in phase 2 and 3 also occur in the field of
tumors.
Due to the earlier missed opportunity of IO treatment, K drug O drug has occupied most of the market, Roche had to accelerate the indication expansion of atezumab and rebet on TIGIT targets to regain the market
.
Perhaps the clinical development was too radical, which led to the setback
of multiple Phase 3 studies of the IM series and Skyscraper series.
GIREDESTRANT, a major variety in the breast cancer field, also missed the primary endpoint of PFS in a Phase 2 clinical trial
.
In addition, the field of nervous system is also a subdivision of Roche second only to tumors, with many targets and a wide range of indications in the product pipeline layout, and Roche has also failed
in the late clinical trials of many popular drugs such as Aβ monoclonal antibody, Tau protein, and α-Syn monoclonal antibody.

Oncology drugs in the field of nervous system

In the past year, TIGIT monoclonal antibody, SERD, and Aβ monoclonal antibody, which were originally the most promising to bring large-scale sales growth, have successively failed in phase III clinical trials, which undoubtedly made Roche's loss of heavy varieties worse
.

TIGIT monoclonal antibody, SERD, and Aβ monoclonal antibody failed one after another in phase III clinical trials

Figure 4 Failed clinical projects of Roche from 2017 to 2022Q3 (Source: Roche, compiled by Fengshuo Venture Capital)

AbbVie

After AbbVie's acquisition of Allergan in 2019, it added ophthalmology and medical beauty pipelines in the fields of immune diseases, tumors and nerves
.
AbbVie's Humira patent expires in 2018 (the European market has begun to decline), and the most important US market patent will expire
next year.
In the field of immune diseases, which is AbbVie's core market, Humira once again launched two "supernovas" - JAK inhibitors Rinvoq and IL-23 Inhibitor Skyrizi
.

Figure 5 AbbVie's clinical pipeline reserve (Source: AbbVie)

From the perspective of clinical development, AbbVie's failed late-stage clinical projects are concentrated in the fields of
oncology and immunity.
Oncology, primarily including the PARP inhibitor Veliparib in multiple solid tumors Phase III clinical failures, as well as EGFR acquired through an early $5.
8 billion acquisition ADC failed
.
Most of the self-exempt field failure projects stopped at the phase 2 study, and the phase 3 clinical failure was rare, which proved that AbbVie played a relatively more stable
role in the field of strengths.

Figure 6 AbbVie's failed clinical projects (Source: AbbVie, compiled by Rich Ventures)

Merck

K drugs supported 40% of Merck's pharmaceutical revenue in 2021 and will also usher in a patent cliff
in 2028.
Merck's existing pipeline reserves are slightly thin, which is difficult to supplement the volume of the 10 billion market of K drugs, and in the past two years, the company has also continued to "buy, buy, buy" to find the growth momentum
after K drugs.
As Merck's core market, although there are CTLA-4, TIGIT, and LAG-3 candidates after K drugs, the CPI track is now overcrowded, and Merck's existing tumor pipeline is not superior
.
The plan to acquire Seagen at the beginning of the year is also Merck's intention to strengthen its tumor layout
through ADC drugs.
In addition, Merck acquired Acceleron's expansion of the company's cardiovascular product pipeline for $11.
5 billion last year, and the lead drug candidate Sotatercepept lived up to expectations in the Phase 3 clinical trial of pulmonary hypertension in October this year
.

。

Figure 7 Merck clinical pipeline reserve (Source: Merck)

Merck's website is relatively simple for clinical disclosure, so we do not make complete statistics on its failed clinical projects, and record the failed clinical projects
of some important pipelines as much as possible.
After the approval of K drug, it has obtained more than 30 indications, opened clinical programs and covered many indications, and inevitably experienced some failed phase 3 studies, and the recent failure of lenvatinib in first-line HCC is surprising
.
In addition, the early attention of tumor immunotherapy IDOi and AD drug BACE1 two products "folded" is also quite regrettable
.

Figure 8 Merck's failed clinical projects (Source: Merck, Abundance Ventures)

AstraZeneca

AstraZeneca's pipeline reserves are in Big As of 2022H1, there are 184 R&D pipelines, and the estimated number of product launches in the short term has shocked the big pharmaceutical companies here
.

Figure 9 Expected approval of AstraZeneca pipeline (Source: AstraZeneca)

AstraZeneca has a wide pipeline but the company is also good at "slimming" pipelines, with more than 70 clinical trials removed since 2018 (including clinical failures and strategic cleanups), but more than half
of the Phase 2 and 3 projects 。 Although AstraZeneca's pipeline products this year have performed very well (DS-8201, oral SERD), it is impossible to ignore the failed clinical projects in recent years: including two phase III clinical folds of IL-5R monoclonal antibody, the abandonment of the synthetic lethal Wee1 drug developed for nearly 10 years, and the early death CTLA-4 monoclonal antibody tremelimumab - which has experienced multiple failed phase III clinical trials in combination with durvalumab.
Dapagliflozin in the cardiovascular field failed in 2 phase III clinical trials
.

Figure 10 AstraZeneca's failed clinical projects (Source: AstraZeneca, compiled by Fengshuo Venture Capital)

AstraZeneca's advantage lies in the large pipeline and balanced development, supported by 5~7 varieties, and the future market prospects of supplementary products are very impressive
.
It is worth mentioning that the layout of AstraZeneca in the two major indications of breast cancer and lung cancer, breast cancer by ADC drug DS-8201, oral SERD, AKT inhibitor capivasertib to form a net layout, lung cancer has EGFR osimertinib, PD-L1 monoclonal antibody, cMET inhibitor, Trop-2 ADC multi-target coverage
.

Bristol-Myers Squibb

After BMS acquired Celgene in 2019, its business focuses on oncology, hematology, cardiovascular and immunology, with immune checkpoint inhibitors as the main line, cell therapy and cytokines as supplementary branch IO therapy is the core component of BMS pipeline, and other key pipelines include "doamidine" and anticoagulant series products
.

Figure 11 Bristol-Myers Squibb clinical pipeline layout (Source: Bristol-Myers Squibb)

In the past two years, BMS's most regrettable clinical project was to obtain the IL-2R agonist Bempeg for $3.
6 billion in 18 years as a strong complement to the company's immunotherapy pipeline, but after two consecutive clinical missed endpoints, it had to terminate the cooperation
with Nektar.
And in the process of expanding the indications of O drugs and Y drugs, they have also experienced many failed phase III clinical trials, especially in the large indication of lung cancer, and O drugs have frequently failed
.

IL-2R agonist Bempeg

Figure 12 Bristol-Myers Squibb's failed late-stage clinical project (Source: BMS, compiled by Harvest Ventures)

Sanofi

As a large pharmaceutical company, Sanofi has always been criticized for its high dependence on partner Regeneron
in its R&D drive.
From 2017Q4 to 2022Q3, Sanofi terminated up to 73 clinical projects (of which phase 2 and 3 accounted for about 65%)
.
In 2018, Sanofi hired John, a former Roche executive Reed revamped its R&D operations and directly cut 38 research pipelines, including 13 clinical-stage programs
.
In 2019, it spun off its diabetes and heart disease business, focusing on specialty drugs (immunology, rare diseases, blood, nerves, oncology), vaccines, general medicines (diabetes, cardiovascular and mature drugs), and M&A/introduction investment of nearly 15 billion US dollars from 2020 to 2021 to enrich its own pipeline
.

Figure 13 Sanofi's late-stage clinical pipeline (Source: Sanofi)

However, even the pipeline slimming plus "buy, buy, buy" can not hide that Sanofi's drug development is still embarrassing, and a number of promising varieties have been clinically broken: three clinical studies of the breast cancer "cornerstone" SERD drug amcenestrant have failed one after another, the biased IL2 antibody acquired by $2.
5 billion announced the cessation of clinical research, and the two BTKi drugs rilzabrutinib acquired by $3.
68 billion have failed in phase 3 clinical trials.
tolebrutinib was suspended by the FDA for two heavy Phase III studies, as well as multiple Phase 3 clinical terminations
of the early $1.
7 billion SGLT-1/2 inhibitor.

Figure 14 Sanofi's failed late-stage clinical project (Source: Sanofi)

9.
Thinking about the pipeline strategy of big pharma companies, how do big pharmaceutical companies deal with the blockbuster product patent cliff?

Blockbuster product patent cliff, how do big pharmaceutical companies respond?

Big pharmaceutical companies are at the forefront of the industry with blockbuster drugs, a "blockbuster" product is enough to achieve a company, but it will also leave a huge sales gap behind the patent cliff, and the pipeline reserve of pharmaceutical companies needs to have strong enough cyclical characteristics to form a replacement
of new and old products.
Let's take a look at the different performances
of the three representative companies of AbbVie, Merck and Roche, which are facing the patent cliff of heavy products.

When AbbVie faced the patent cliff of Humira and ibrutinib, AbbVie launched two potential products, Risankizumab and Upadacitinib, in the field of self-immunity, and at the same time acquired Allergan in 19 years to enter the two potential tracks
of ophthalmology and medical beauty.
AbbVie has successfully written a new chapter in the long-term development of the company, and the current market value has doubled from $130B in 2020 to $270B
.

Merck has been a unique situation of K drugs in recent years, and the early market value has been hovering around $200B, and Merck must get rid of the situation
of K drugs dominating if it wants to make a breakthrough.
However, it is not easy to create the next "PD-1" in the field of oncology, the immune checkpoint track is crowded, Merck's CPI monoclonal antibody differentiation advantage is not highlighted (the most interesting TIGIT field Roche bad news), plus the plan to acquire Seagen to enter the ADC track at the beginning of the year is also gone
。 Merck, determined to diversify its pipeline after acquiring Acceleron's $11.
5 billion last year, said at an investor conference in April that it would bet heavily on cardiovascular — with plans to launch eight drugs over the next eight years and expected to reach more than
$10 billion in sales in 2030.
There are still 5 years left before the expiration of the K drug patent, which also leaves a breather for the new growth after Merck builds K drug, and the next few years will be an important time point to determine the future development direction of Merck
.

Determined to diversify the pipeline, it said that it will bet heavily on the cardiovascular field

Roche's situation is difficult to say optimistic, because the "three carriages" patent expired but there is no super-heavy product to take over the baton (although the current sales performance of the new three carriages is good, it is still a little bit less meaningful in the long run), and the market value has hovered
in the range of $250~$300B in the past three years.
In 2021 and 2022H1, Roche's diagnostic business increased by 29% and 11% respectively, while the pharmaceutical business barely maintained 3%~4% growth
.
Relying on the diagnostic business, although Roche's overall revenue has maintained a certain growth, it is difficult to offset the failure of many blockbuster products this year, and the market value has fallen from the peak of $320B in 2022Q1 to the $250B level three years ago
.

Big pharma "buy, buy, buy" products frequently fail, what do you think?

In the combing of the above-mentioned failed projects, it is not difficult to find that almost all large pharmaceutical companies have heavy mergers and acquisitions or license in the pipeline, and the early huge investment is like a mud cow into the sea
.
M&A, licenses IN has long been an important strategic means for big pharmaceutical companies to expand their pipelines, and the failure of some heavy transaction projects is also only a projection
of the "high risk and high investment" characteristics of innovative drug research and development.
Similarly, the "high return" characteristics of innovative drugs are also highlighted in the transaction projects, AbbVie's two major drug king Humela and ibrutinib, Merck's K drug, Sanofi BMS O drug, lenalidomide, Sanofi's dopilumab, AstraZeneca's big killer DS-8201 are all introduced
through mergers and acquisitions.

"High risk, high investment" and "high return"

Drug Discovery A 21-year study in Today magazine shows that 60% of the NME developed by 14 representative large pharmaceutical companies in the 20 years from 1999 to 2018 came from mergers and acquisitions and drug licensing, and 40% came from self-research, which shows that external innovation plays an important role
in the development of the pipeline of big pharmaceutical companies.
Big Pharma is limited to a stable but complex internal industrial system, and is not as efficient and flexible as Biotech in research and development in subdivided fields, but Big Pharma can use the advantages of resources and cash to help products maximize their commercialization potential
.
The focus of mergers and acquisitions and introduction should return to product value, and enterprises should combine pipeline development strategies and comprehensive consideration of product risk/return, and big pharmaceutical companies can neither buy all at once, nor should they cut off external introduction
by relying on "self-innovation" alone.

60% comes from mergers and acquisitions and drug licensing, which shows that external innovation plays an important role in the development of the pipeline of big pharmaceutical companies, and big pharmaceutical companies can neither buy all at once, nor should they cut off external introduction
by relying on "self-innovation" alone.

Figure 15 The origin of NME development by 14 representative large pharmaceutical companies between 1999 and 2018 (Data 1)

In the hands of big pharmaceutical companies, how to see the products that are quickly following in China?

We see some familiar figures in the failed clinical trials of big pharma: TIGIT monoclonal antibody, IL-2 cytokines, PD-L1/TGFβ dual antibody (German Merck) are all popular products
followed by domestic pharmaceutical companies.
Even individual varieties have become an important value component of the Biotech pipeline (such as TIGIT monoclonal antibody in BeiGene, I-Mab's CD47), and the clinical failure of big pharma has undoubtedly cast a shadow
over domestic Biotech R&D and stock prices.
However, we should also note some of the successful cases behind the big pharma folding projects:

Even individual varieties are an important part of the Biotech pipeline, but we should also note the success stories behind some of the big pharma folding projects:

The O drug of PD-1 for the treatment of first-line liver cancer BMS, Merck K drug + lenvatinib ace combination all failed in phase III clinical trials, while Innovent "Shuangda" combination, Hengrui "Shuangai" combination and BeiGene tirarelizumab were all successful
in phase III studies.
After the failure of drug K drug successively, Henlius splulimab became the first SCLC in the first line Phase III clinically successful PD-1 monoclonal antibody
.
The two breast cancer pipelines of Roche oral SERD and AKTi have failed, and not long ago, AstraZeneca has successfully contrasted with Roche in the above two projects, and Sanofi
has broken in the SERD project.

PD-1 treatment of first-line liver cancer first-line SCLC Phase III clinically successful PD-1 monoclonal antibody
.

There are many factors that cause clinical failure, and the failure of a drug cannot be described as a "failure" for similar products, and for fast-following projects, the latter should learn from previous experience and be more cautious
in the clinic.
The domestic strategy of fast following is not undesirable, as long as it follows fast enough or locates "Me.
" Better" products, what needs to be vigilant is the strategy
of blindly following the trend.

Just follow fast enough or locate "Me.
" Better" product

References

R&D efficiency of leading pharmaceutical companies – A 20-year analysis

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