2022 inventory: Top 10 failed clinical trials, Roche, Merck, Pfizer...

There is a famous "double ten" law in the field of medicine, that is, it takes ten years and one billion dollars to invest a "new drug"
.

The difficulty of new drug research and development is full of thorns and bumps on the road to success
.

Progress
in failure.
This article summarizes the top 10 clinical failures in 2022 from the aspects of drug impact and unmet clinical needs, and tries to draw inspiration
from these cases.

Indications: First-line treatment of extensive-stage small cell lung cancer; First-line treatment of PD-L1 high-expression non-small cell lung cancer

On March 30, 2022, Roche announced that the Phase 3 clinical trial (SKYSCRAPER-02) of tiragolumab + atezolizumab (TIGIT+PD-L1) for the treatment of extensive-stage small cell lung cancer (ES-SCLC) did not meet the primary endpoint
of PFS.

The SKYSCRAPER-02 study was designed to compare the safety and efficacy of atezolizumab + chemotherapy (carboplatin + etoposide) with or without tiragolumab in patients with untreated ES-SCLC (n=490), with the primary endpoints PFS and OS
.

Subsequently, at the 2022 ASCO meeting, Roche first announced the SKYSCRAPER-02 clinical data of Tiragolumab for ES-SCLC, which is also the first TIGIT monoclonal antibody phase III results
.
Results showed no additional benefit of PFS or OS in the combined Tiragolumab group compared with the control group, with median PFS of 5.
4 months and 5.
6 months (95% CI: 5.
4-5.
9) and OS of 13.
6 months and 13.
6 months
, respectively.
The company believes that the final analysis results are also difficult to achieve statistical significance
.

In May, Roche's TIGIT antibody was folded again, and on the 11th, the phase 3 SKYSCRAPER-01 study data of tiragolumab + atezolizumab combined with first-line treatment of PD-L1 high-expressing non-small cell lung cancer (NSCLC) was announced, and numerical improvements were observed in the two common primary endpoints, but PFS was not reached, OS data was immature, and the specific data was not announced, but Roche's stock price fell by nearly 8% on the day
。

Tiragolumab is a novel TIGIT inhibitor with an intact Fc region, and by selectively binding to TIGIT, tiragolumab blocks TIGIT interactions with a polio virus receptor (PVR, or CD155) protein that inhibits the body's immune response, enhancing the body's immune response
.

TIGIT is a novel inhibitory immune checkpoint, which is an inhibitory receptor shared by T cells and NK cells, which can inhibit the killing effect of NK cells and T cells on tumor cells, and become a hot emerging immune checkpoint
.
From the results of clinical studies, TIGIT is expected to form a combination with PD-1/PD-L1 inhibitors to block the TIGIT signaling pathway, enhance the body's immune response to cancer cells, and improve anti-tumor activity
.

The successive failures did not make Roche abandon Tiragolumab, and Roche's three quarterly reports showed that several clinical trials of Tiragolumab 1L NSCLC are still ongoing, including SKYSCRAPER-01
.

At present, there is no TIGIT antibody approved for marketing in the world, in addition to Roche, BMS, MSD and other international giants have a layout for this target, who will become the first TIGIT antibody field to eat crabs we still need to wait and see
.

Indications: advanced urothelial carcinoma; Advanced liver cancer

The exploration of K drug pembrolib, which is expected to become the global drug king, in combination with lenvatinib (cola combination) has also encountered Waterloo in 2022
.

In February 2022, at the Genitourinary Cancer Symposium (ASCO GU22), Yohann Loriot presented the Phase 3 clinical study (LEAP-011) of pembrolizumab combined with lenvatinib first-line treatment in patients with advanced urothelial carcinoma who are not candidates for platinum-based chemotherapy, with two endpoints of PFS and OS
。 The results showed that the mPFS of patients treated with pembrolib and lenvatinib was 4.
5 months, and the mPFS of pembrolib + placebo was 4.
0 months, with no significant difference between the two groups; the OS performance of the pembrolib + lenvatinib group was even worse than that of the control group (11.
8 months vs 12.
9 months).

In August, "cola therapy" was hit hard again, and Merck announced that the two primary endpoints of PFS and OS in the Phase 3 LEAP-002 study of pembrolib combined with lenvatinib for the first-line treatment of advanced liver cancer were not met
。 The results showed that the OS and PFS of patients treated with pembrolib + lenvatinib showed an improvement trend compared with lenvatinib alone, but the results were not statistically significant, and the detailed data of the LEAP-002 study were presented at the subsequent ESMO meeting, and the mOS of the cola combination was 21.
2 months and the control group was 19 months, but the preset statistical difference
was not achieved.
The mPFS of the cola combination and control group were 8.
2 months versus 8 months
, respectively.

It is a pity that the LEAP-002 study did not get positive results, first the mOS in the lenvatinib group exceeded expectations, reaching 19 months, far exceeding the 13.
6 months in the REFLECT study, and then the interim analysis consumed the OSα value, resulting in the final P exceeding the threshold of 0.
0185 ((initially 0.
023)), which did not reach the statistical endpoint
.

If more patients with HBV etiology liver cancer were included at the time of enrollment, if there was no interim analysis, if sorafenib was selected as the control group, the outcome might be different, but the research and development of innovative drugs is so cold and cruel, both judgment and life and death
.

Indications: post-exposure prophylaxis; Standard population therapy

Paxlovid was approved for EUA in the United States and the European Union in December 2021 and in China in February 2022
.

After the listing, Paxlovid occupied the dominant position of antiviral drugs, becoming one of the fastest selling drugs in history, achieving a total revenue of $9.
6 billion in the first half of 2022, and the full-year revenue guidance was as high as $22 billion.

In April 2022, Pfizer announced that the phase II/III clinical trial (EPIC-PEP) of the new crown oral drug Paxlovid for post-exposure prophylaxis did not meet the primary endpoint of reducing the risk of infection (confirmed) in adults exposed to the new coronavirus through household contact, and the results showed that adults who received Paxlovid for 5 days and 10 days had a 32% and 37% lower risk of infection, respectively, compared with placebo, which was not statistically significant
.

Soon after, Paxlovid failed clinically again, and on June 15, Pfizer released the results of the Phase 2/3 clinical trial of the EPIC-SR study, in which the primary endpoint of sustained remission of all symptoms for 4 consecutive days was not met, and the secondary endpoint was not statistically significant although the risk associated with hospitalization or death was reduced by 70
%.

After the two clinical failures, Pfizer said the company will focus on generating further data on Paxlovid in vulnerable populations, including giving immunocompromised people longer treatment periods and exploring potential applications in hospitalized severe care
.

Indications: Alzheimer's disease

AD treatment has always been the "old difficulty" in the medical community, the root cause and mechanism of AD has not yet been clear, the current drug development is based on a variety of hypothesis theory, of which the β-amyloid (Aβ) hypothesis is the most recognized
.

In June 2021, the FDA approved Biogen's Aducanumab based on the β-amyloid hypothesis, which is also the first new AD drug approved by the FDA in nearly 20 years.

The two Aβ antibody drugs in the Roche pipeline, Crenezumab (crecilizumab) and Gantenerumab, have been developed for more than ten years, and the funding investment is bottomless, and the clinical failure of both drugs has been encountered
.

In June 2022, Roche's highly anticipated crenezumab Phase II (NCT01998841) failed in a study designed to evaluate Crenezumab's potential to
slow or prevent AD in cognitively impaired people carrying specific gene mutations that cause early-onset AD.

Unfortunately, none of the common primary endpoints assessing the rate of change in cognitive ability or episodic memory function were ultimately met, and at the Alzheimer's Association International Conference (AAIC) in August, researchers presented preliminary data showing that patients taking crenezumab experienced a 20% slower decline in FCSRT than in the placebo group; On the composite index, the decline was 23 percent slower, but not statistically significant
.
Safety data showed no cases of ARIA-E in the eight-year trial
.

Roche announced the results of two Phase 3 clinical studies (GRADUATE I, II) of its Gantenerumab, which unfortunately did not meet the primary endpoint of slowing clinical decline, showing that gantenerumab reduced clinical decline by 8% and 6%, respectively, compared to placebo, which was not statistically significant, and that gantenerumab removed Aβ levels in the brains of AD patients in two studies were lower than expected
.

Crenezumab and gantenerumab failed clinically one after another, like two smacks that made Roche have bitter words, and at the same time, in the face of a huge market and unmet clinical needs, countless companies entered the "swamp" in the biological science jungle of the AD field with the spirit of exploration, but could not extricate themselves, Pfizer, Biogen and now Roche
.

Unlike Roche, Eli Lilly ushered in its own breakthrough in the field of AD treatment, and on December 7, 2022, Lilly announced that the first head-to-head study of donanemab for early symptomatic AD had positive results, and a 6-month analysis of the primary outcome of the Phase 3 clinical trial TRAILBLAZER-ALZ 4 showed that all primary and secondary endpoints
were met.

After 6 months of treatment, 37.
9% of donanemab subjects achieved complete clearance of amyloid plaques (defined as amyloid levels < 24.
1 CL) compared to 1.
6% of Aduhelm® participants

After 6 months of treatment, participants treated with donanemab had a 65.
2% reduction in brain amyloid plaque levels compared to baseline, compared with a 17.
0%
reduction in Aduhelm?.

Roche and Eli Lilly have different
fates.

Indications: Melanoma; Renal cell carcinoma and bladder cancer

On March 14, 2022, BMS and Nektar Therapeutics jointly announced the first data from the previous Phase 3 clinical study (PIVOT IO-001) of NKTR-214 plus Opdivo compared to Opdivo monotherapy, which showed that the study did not meet the primary endpoints of PFS and ORR, and the results of the interim analysis of OS were not statistically significant
.

Affected by the news, Nektar shares fell more than 60%
on the day.
At the time, however, the two companies decided to advance clinical research
in renal cell carcinoma and bladder cancer.
One month later, after an advance analysis of the Phase III clinical study of NKTR-214 combined with Opdivo in the treatment of kidney cancer and the Phase II clinical study for bladder cancer, the two companies announced the termination of all clinical studies
of NKTR-214 combined with Opdivo.

Since then, the NKTR-214, which was in the limelight that year, has come to an end
.

NKTR-214 is a CD122-biased agonist that acts on CD+8 effector T cells to stimulate the proliferation of tumor killer T cells and increase PD-1 expression
on these immune cells.

In 2018, BMS invested $1.
85 billion in down payments ($1 billion in cash and $850 million in equity investments), plus milestone payments, which will exceed $3.
6 billion in transactions to bet on the IL2 agonist track
.

In the early phase 1 study, NKTR-214 combined with Opdivo had amazing data on skin cancer, kidney cancer and bladder cancer, but these studies did not set up a control group, not to mention that combination immunotherapy was still a new thing, and the interaction mechanism of immunotherapy in the tumor microenvironment effector stage in immunotherapy was not studied enough, etc.
, which may lead to clinical failure
.

Of course, the failure of clinical research can not be one-sided from one or two factors, the road to the research and development of innovative drugs is "corpses everywhere", companions have no time to grieve, can only continue to move forward, just like the TIGIT target, Roche's clinical failure Other pharmaceutical companies did not give up, NKTR-214 ended in failure, and the road forward of IL2 research and development did not stop
.

Indications: breast cancer

Amcenstrant is an oral selective estrogen receptor degrader (SERD) that induces degradation based on the ubiquitination mechanism by binding to estrogen receptors (ER) on the surface of breast cancer cells to reduce ER levels and inhibit cancer cell growth
.

In order to seek performance growth points, Sanofi previously listed amcenestrant as a priority "potentially transformative" therapeutic drug, and conducted a number of clinical studies around amcenestrant, including: as a single agent for the second-line or multi-line treatment of ER+/HER2-metastatic breast cancer (AMEERA-3 study); Combined with the CDK4/6 inhibitor Ibrance (piperaciclib) for the first-line treatment of ER+/HER2-metastatic breast cancer (AMEERA-5 study) and adjuvant therapy for early-stage breast cancer (AMEERA-6 study).

On March 14, 2022, Sanofi announced the latest AMEERA-3 study of amcenestrant, which showed that the primary endpoint of improving PFS was not met, and Sanofi said that it will continue to evaluate the data from the AMEERA-3 trial, and the AMEERA-5 and AMEERA-6 trial projects will continue
as planned.

But in August, the phase 3 AMEERA-5 study of amcenestrant with piperaciclib failed to reach its endpoint, and Sanofi terminated all research on amcenestrant, including the adjuvant treatment for early-stage breast cancer (AMEERA-6 study).

Affected by successive bearish effects, Sanofi's share price fell by 17%
in August alone.
After the termination of the amcenestrant project, the only new project left in the "poor" Sanofi Phase 3 pipeline in the oncology field is tusamitamab ravtansine (an ADC drug used to treat non-small cell lung cancer), which is not expected to be submitted
until 2023.

In the field of SERD drugs, only one of AstraZeneca's fulvestrant injections has been approved for marketing in the world, and because it is intramuscular injection, patient compliance is poor
.
Although Sanofi withdrew from the SERD competition, the development of oral SERD drugs is still strong, and AstraZeneca, Eli Lilly and Roche are still involved
.

In April 2022, Roche announced its first-quarter financial results showing that a phase II acelERA study of its oral SERD Giredestrant (GDC-9545) for the treatment of ER+/HER2- locally advanced or metastatic breast cancer did not meet the primary endpoint
of PFS.

Giredestrant is still conducting multiple Phase III studies, including in combination with piperaciclib as a first-line treatment for
HR+/HER2- advanced breast cancer.

Indications: Leber congenital black montage

In November 2022, CRISPR legendary company Editas announced preliminary results from its phase I/II BRILLIANCE clinical trial (NCT03872479) of its in vivo gene-editing therapy EDIT-101 for the treatment of Leber's congenital black blindness, in which 3 of the 14 treated subjects met the responder threshold, and the improvement in optimal corrected visual acuity (BCVA) (LogMAR>0.
3) was
。

However, two of these were homozygous for IVS26 mutations, and there were only 300 such patients in the United States, showing clinical benefit but not showing therapeutic potential in the broader population, and unable to confirm baseline characteristics of pre-selected patients, Editas announced that it was discontinuing plans to develop EDIT-101 on its own, and planned to seek collaborators to continue development of EDIT-101
.

EDIT-101 is an investigational CRISPR/Cas9-based drug that treats Leber's congenital black haggy 10 (LCA10)
by deleting the IVS26 CEP290 mutant allele.
At present, EDIT-101 has been awarded the rare pediatric disease and orphan drug designation by the FDA, and the orphan drug designation granted by the EMA
.

CRISPR is a gene-editing technique that modifies, removes, and replaces DNA in a highly targeted way, and it can target DNA
in any cell or tissue.
The revolutionary discovery of CRISPR gene editing opens up wireless possibilities
for the entire biotechnology.

The 2020 Nobel Prize in Chemistry was awarded to Professor Emmanuelle Charpentier and Professor Jennifer Doudna, who made outstanding contributions to the field, for their invention of the genetic modification method CRISPR-Cas9
.

Editas is a gene-editing company
co-founded by Jennifer Doudna and Chinese scientist Zhang Feng.
The setback encountered by EDIT-101 in research and development has dealt a heavy blow to the "star therapy + star company", which shows that the research and development of innovative drugs based on CRISPR technology still has a long way to go
.

Indications: chronic spontaneous urticaria

The relationship between Regeneron and Sanofi is like Roche and Genentech, but Roche acquired Genentech, and now the former partners are gradually drifting apart, and a number of blockbuster drugs have been born in the process of cooperation between the two companies, the most important of which is Eylea and Dupixent, two tens of billions of dollars of super bombshells, in the process Sanofi missed Eylea but caught Dupixent
.

According to Sanofi's third quarter report, Dupixent's global sales of nearly 6 billion euros have exceeded last year's sales of 5.
249 billion euros, and Dupixent has become the main driver of
Sanofi's performance.

On February 18, 2022, Sanofi and its partner Regeneron updated the results of a phase III CUPID study B study B study B study with Dupixent in patients with omalizumab (omalizumab) refractory chronic spontaneous urticaria (CSU), and although positive numerical trends were observed for itching and urticaria reduction, the interim analysis showed no statistically significant
primary endpoint.

Dupilumab is a fully humanized monoclonal antibody that specifically inhibits overactivation signaling
of two key proteins, IL-4 and IL-13.
IL-4/IL-13 are two inflammatory factors that are thought to be key drivers of persistent intrinsic inflammation in specific dermatitis (AD
).

The LIBERTY-CUPID program, launched in 2020 using an accelerated direct entry phase 3 strategy, met the primary endpoint and all key secondary endpoints in previous trials in patients not yet treated with biologics, showing significant reductions in pruritus and urticaria
at week 24 compared with standard care antihistamines alone.

In March 2017, Dupixent was approved by the US Food and Drug Administration (FDA) to treat adult patients with moderate to severe AD who cannot adequately control the condition with topical prescription drugs alone or in combination with topical glucocorticoids (TCS) or who are not suitable for these drugs, becoming the first targeted biological drug
for the treatment of moderate to severe AD in adults.

On March 11, 2019 and May 6, 2020, the FDA approved Dupixent for the treatment of adolescents aged 12~17 and children aged 6~11
.

Although Dupixent's treatment of CUS has encountered setbacks, Sanofi has not given up on the project, and according to the third quarterly report, the project is still continuing
.

In addition to being approved by the FDA in September 2022 for the treatment of prurigo nodosum (PN), Dupixent has been approved to treat five diseases caused by type 2 inflammation: PN (≥ patients aged 18 years), eosinophilic esophagitis (EoE, ≥ patients aged 12 years), moderate to severe AD (patients ≥ 6 years old), moderate to severe asthma (patients ≥ 6 years old), and chronic rhinosinusitis with nasal polyps (CRSwNP, adult patients).

In addition to the approved indications, there are multiple indications with clinical trials underway
.

Indications: amyotrophic lateral sclerosis

In the summer of 2014, global social media suddenly set off a craze for ice bucket challenges, allowing the public to really understand a special group of people: frostbite patients
.

ALS, also known as amyotrophic lateral sclerosis (ALS), is a degenerative disease of voluntary motor neurons, and the survival time after diagnosis is generally only 2-4 years
.

At present, there are only two drugs approved by the FDA for the treatment of ALS in the world, namely riluzole (Riluzole) and edaravone (Edaravone), and there is still a huge unmet clinical need, but the development of new drugs for ALS in 2022 has been hindered
one after another.

One of the most talked about drugs in the ALS field is Amylyx's AMX0035, a patented oral fixed-dose drug combination consisting of two small molecules, sodium phenylbutyrate and ursodeoxycholic acid, the mechanism of action is unknown
.

On March 28, the FDA Advisory Committee voted 6-4 to reject the marketing application
for AMX0035.
The Phase 2 clinical data for AMX0035 was based on a single placebo as a control group, and most members of the panel questioned that the efficacy data for the drug were not convincing enough, arguing that Amylyx should provide more evidence that AMX0035 is effective in slowing ALS progression
.

The FDA review did not affect the approval of AMX0035 outside the United States, and on June 13, Health Canada approved AMX0035 for conditional marketing for the treatment of ALS
.

This is the first time the product has been approved globally and the first new ALS treatment
approved in Canada since 2018.

Interestingly, in September, the FDA voted 7:2 in favor of approving the drug
.
However, phase III clinical trials have failed to demonstrate that the benefits remain at risk of
withdrawal.

Also on March 28, Biogen announced the first-line results of the Phase 1 trial of BIIB078, showing that overall tolerability met the primary goal of the study, but compared with patients who received placebo, the BIIB078 group had a greater loss of motor function, did not meet any secondary goals, and did not show any clinical benefit, Biogen and Lonis decided to terminate the clinical trial and stop the loss
in time.

BIIB078 is an antisense oligonucleotide (ASO) drug candidate that has been developed for the treatment
of C9orf72-related ALS.

This is not the first time Biogen has failed in the ALS space, as Biogen's Phase 3 trial VALOR, a SOD1-targeted ASO drug, announced in October that it had not met its primary endpoint
.
However, Biogen has not given up on Tofersen
.

In July 2022, FDA accepted Tofersen's NDA marketing application, which has been prioritized for review, and the PDUFA date is set for January 25
, 2023.

Indications: treatment of metabolic acidosis and chronic kidney disease

What kind of bearish can make a company's stock price fall by more than 90% in a single day, for biotech, it may be a key clinical failure
.

On October 24, 2022, Tricida announced key results from veverimer's Phase III clinical VALOR-CKD trial, which aims to evaluate veverimer's ability to
slow the progression of CKD in patients with metabolic acidosis and chronic kidney disease (CKD).
The results showed that the VALOR-CKD study did not meet the primary endpoint, with 149 subjects in the veverimer group and 148 subjects in the placebo group having no clinical advantage
over the median duration of treatment of 26.
7 months.

Metabolic acidosis is a serious condition usually caused by CKD that is thought to accelerate kidney deterioration
.
It is estimated that there are about 4.
3 million people with CKD in
the United States.

Veverimer is a novel non-absorbent polymer that, after oral administration as a suspension, binds to hydrochloric acid in the stomach and intestines, excreting it through feces
.
Veverimer does not deliver sodium or other counterion ions and can be used to treat CKD and common comorbidities such as high blood pressure, cardiovascular disease, heart failure, or edema
.

Veverimer is Tricida's only product pipeline, in May 2022, Tricida announced the early cessation of the VALOR-CKD study for administrative reasons, so that it can continue to operate for 6 months after reporting the top line results, and now it has not reached the primary endpoint, and there is no need for statistical testing of the secondary endpoint.

We don't know what Tritida's fate will be, and Triida's share price has been below $1 since October, and it is likely to be delisted
.

This may be the end of most "lonely braves" in the development of innovative drugs, there are many such biotech companies, and such stories cannot be told at all
.

Behind every clinical trial are thousands of patients who need treatment, and clinical failure is a loss of funds and missed business opportunities for the company, and it may be a dashing
hope for treatment for patients.

Whether it is MNC with strong funds and rich pipelines such as Roche and BMS, or Amylyx and Tricid as the lone brave of innovative drug research and development, or Editas as a pioneer in advanced biotechnology, pay tribute to these great enterprises and pay tribute to the researchers who have quietly contributed to the
research and development of innovative drugs.

Each failed clinical trial is more like a monument in the field of medicine, commemorating the unremitting efforts
of mankind to eliminate various diseases.

Resources

1.
Inventory of failed clinical projects of global large pharmaceutical companies in recent years (China Association for the Promotion of Pharmaceutical Innovation).

2.
Roche's two consecutive defeats reveal the cruel truth of new drug research and development (Tiger Sniff).

       3.
ASCO GU 2022:First-Line Pembrolizumab with or Without Lenvatinib in Patients with Advanced Urothelial Carcinoma(LEAP-011):A Phase 3,Randomized,Double-Blind Study（UroToday-GU oncology Today）.

       4.
Detailed data From The Phase II Crenezumab Alzheimer’s Prevention Initiative Study In Autosomal Dominant Alzheimer’s Disease PresentedataAIC.
（AC Immune SA）

5.
Treat early Alzheimer (AD)! Roche anti-amyloid antibody drug gantenerumab 2 global phase 3 study failed! (Biovalley)

6.
Two phase III studies of NKTR-214 combined with Opdivo in the treatment of melanoma failed (PIVOT IO-001).

(MsedSci Mace)

       7.
Bristol Myers Squibb and Nektar Announce updat on Phase 3 PIVOT IO-001 Trial evaluating Bempegaldesleukin(BEMPEG)in Combination with Opdivo(nivolumab)in Previously Untreated Unresectable or metastatic Melanoma.
（BMS）

8.
New drugs for breast cancer! Sanofi estrogen receptor degrader amcenestrant for the treatment of ER+/HER2-breast cancer Phase 2 study failed! (Biovalley)

9.
Sanofi/Regeneron Dupixent is approved by the FDA as a targeted biological therapy (Biovalley)
for the treatment of moderate to severe atopic dermatitis (AD).

10.
Amylyx Pharmaceuticals Announces FDA Approval of RELYVRIO?for the Treatment of ALS.
(Amylyx)

       11.
Tricidas shares plunge as phase 3 fail seals fate of FDA-rejected kidney disease drug.
（Fierce Biotech）

12
.
Various public materials on the Internet such as Guosen Securities and the official websites of each company.