April 12, 2024

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Top 10 most regrettable innovative drugs in 2021

Top 10 most regrettable innovative drugs in 2021


Top 10 most regrettable innovative drugs in 2021


The milestone clinical research of new medicines that revolutionized medical treatments is indeed encouraging, but the negative clinical results that failed to challenge the problem of unmet clinical needs are also worthy of reflection and reference.


The Med team selected 10 regrettable innovative drugs in 2021 from the perspectives of disease treatment, clinical medication, research progress, and corporate impact, for your reference.

NO.1 Bintrafusp alfa(M7824)

Company: Merck
Drug mechanism: TGFBR2/PDL1 antibody fusion protein
Impact of failure: One of the most clinically failed drugs in 2021, with a $3 billion transaction terminated

Bintrafusp alfa (M7824) is a bifunctional fusion protein. One end is an antibody structure that can recognize PD-L1 (Y), and the other end is a fusion protein (Trap) that can bind to TGF-β receptor type II. It is designed to simultaneously Blocking the two signal pathways of PD-L1 and TGF-β, relieves the immune system’s suppression state, and improves the immune system’s killing effect on cancer cells. The drug was discovered by Merck, Germany, and GlaxoSmithKline paid a large sum of money to Merck to jointly develop Bintrafusp alfa.


Top 10 most regrettable innovative drugs in 2021
Bintrafusp alfa (M7824) structure



However, in 2021, Bintrafusp alfa clinical studies have failed successively, including the head-to-head phase III study with Merck’s PD-1 antibody Keytruda in NSCLC (INTR@PID Lung 037), first-line and second-line biliary tract cancer studies, etc. The indications for clinical studies have also been reduced from 5 to 1, leaving only clinical studies on the second-line treatment of cervical cancer.

Due to the failure to reach a milestone event, GlaxoSmithKline and Merck jointly decided to terminate their agreement on bintrafusp alfa, effective September 30, 2021. According to data generated during the agreement, GlaxoSmithKline does not need to pay milestone payments, nor does it have future milestone obligations.


Top 10 most regrettable innovative drugs in 2021

The PD-1/L1 and TGF-β signaling pathways belong to the hot specific dual-antibody targeting pathways, respectively.

The failure of the head-to-head study with PD-1 antibody Keytruda is regrettable, but the failure of combination chemotherapy to show efficacy is thought-provoking.


In any case, the research results of Bintrafusp alfa will provide new insights into the biological understanding of TGF-β. Fortunately, some bispecific antibodies will also usher in positive data in 2021.

However, based on the combination of drugs or the two confirmed targets, whether a simple new combination innovation in drug form can bring satisfactory results, Bintrafusp alfa may be a warning.


NO.2 Canakinumab (Canakinumab, ACZ885)

Company: Novartis
Drug mechanism: anti-IL-1β monoclonal antibody
The impact of failure: the concept of tumor immunity in situ casts a shadow

Canakinumab (ACZ885) is a human monoclonal antibody that selectively binds to human interleukin-1β (IL-1β) with high affinity, and neutralizes it by blocking its interaction with the receptor Activity of IL-1β. Preliminary evidence shows that by neutralizing IL-1β, Canakinumab can turn pro-tumor inflammation into: 1) enhancing anti-tumor immune response; 2) reducing tumor cell proliferation, survival and invasiveness; 3) impairing angiogenesis. Pro-tumor inflammation promotes tumor development by driving the carcinogenic process and inhibiting anti-tumor immune response. Canakinumab is a first-in-class IL-1β inhibitor targeting pro-tumor inflammation in NSCLC.


Top 10 most regrettable innovative drugs in 2021
Canakinumab Mechanism of Action (Source: Novartis)


In a post-mortem analysis of the Phase III CANTOS trial for cardiovascular disease, cananumumab found that lung cancer mortality was significantly reduced with the increase in the dose of Canakinumab. Based on this, Novartis initiated the concept of Canakinumab to promote tumor inflammatory transition (PTI). verify.


Unfortunately, Novartis announced in March and October this year that two NSCLC phase III clinical studies (CANOPY-1/2) did not meet the primary endpoint of improving OS.

Recently, at the annual lung cancer ceremony, Professor Wu Yilong believed that the failure of these two studies heralded the disillusionment of Canakinumab’s concept of tumor immunity in situ.


NO.3 osimertinib combined with bevacizumab

Company: AstraZeneca
Drug mechanism: EGFR mutation
Impact of failure: Osimertinib is not suitable for combination with bevacizumab for first-line/second-line EGFR-mutant NSCLC

Osimertinib is a third-generation EGFR inhibitor developed by AstraZeneca. It has been approved for the first-line and second-line (EGFR T790M) treatment of EGFR-mutant NSCLC in China. In May, the Annals of Oncology published the results of a Phase II study (ETOPBOOSTER) funded by AstraZeneca and Roche for the second-line treatment of osimertinib and bevacizumab in the treatment of EGFR/T790M mutant NSCLC.


The data showed that at a median follow-up of 34 months, the median PFS of the combination treatment group and the single-agent group were 15.4 months (95% CI9.2-18.0) and 12.3 months (6.2-17.2), respectively; the median OS was respectively At 24.0 months (17.8-32.1) and 24.3 months (16.9-37.0), no significant PFS difference was observed between the two groups (HR 0.96; 0.68-1.37; p=0.83).

Coincidentally, at the ESMO meeting held in September, the results of a randomized phase II study (WJOG9717L) of osimertinib combined with bevacizumab versus osimertinib in the first-line treatment of non-squamous NSCLC with EGFR mutations was announced. The treatment also did not obtain a significant difference. However, in both studies, subgroup analysis showed a trend of benefit for quitters.


Top 10 most regrettable innovative drugs in 2021
Key results of WJOG9717L study (Source: ESMO2021)


These two studies suggest that for NSCLC patients with EGFR mutations, osimertinib combined with bevacizumab cannot show a significant difference in benefit in clinical treatment, whether it is first-line or second-line treatment. In other words, osimertinib single-agent therapy can better protect patients’ cost-effectiveness and clinical efficacy.


NO.4 TLR ISAC drugs

Company: Silverback/Bolt
Drug mechanism: TLR agonist antibody coupling (ISAC)
The impact of failure: How to develop ISAC drugs more effectively, the thoughts after the enthusiasm

Toll-like receptor (TLR) agonists can activate antigen presenting cells (APC) and enhance the immunity of T cells to tumor neoantigens.

The anti-tumor activity of immune checkpoint inhibitors can be improved by using in combination with such innate immune agonists.

However, the systemic administration of TLR agonists often causes toxic reactions. Although intratumoral injection (oncolytic virus) can improve the tolerability of the drug, it is also limited by many factors in practice.

Antibody-conjugated drugs (ADC) specifically deliver toxins/immune agonists (TLRs, etc.) to cancer cells through targeted antibodies, providing an idea for solving systemic exposure.

SBT6050 is a Her2 immunostimulatory antibody conjugate (ISAC) drug developed by Silverback Therapeutics, which aims to guide the TLR8 agonist linker payload to activate myeloid cells in tumors that express high levels of HER2.

BDC-1001 is a HER2 targeting ISAC developed by Bolt Biotherapeutics for the delivery of TLR7/8 agonists.

TLR8 is expressed in bone marrow cell types that are ubiquitous in human tumors.

TLR8 agonism can activate a wide range of anti-tumor immune mechanisms, including pathways involved in innate and adaptive immune responses.

Strictly speaking, SBT6050 and BDC-1001 have not completely failed, and related research is still going on.

However, from the data disclosed by the two drugs this year, there is no encouraging data. Among the multiple early data disclosed by SBT6050, only 1 patient showed PR, and the same was true for BDC-1001 (of 40 patients with curative effect evaluation, 1 case was PR).

In December, after the release of BDC-1001 data, Bolt Biotherapeutics’ stock price suffered a cut (-56%). However, there are early signs of BDC-1001’s low efficacy.


ISAC drug research is very hot this year, and many domestic companies have deployed or introduced technology.

Experts in the industry have pointed out that all drugs have an open identity, that is, the mechanism of action, but we do not know how many hidden identities are in most cases.

Whether every drug will work like the mechanism of action is even more uncertain, and rational drug design still has a long way to go.

Rational research is not a fanaticism. The development of new drugs requires the ability to interpret evidence from complex information and establish a chain of evidence.


NO.5 Pembrolizumab + Lenvatinib

Company: Merck
Drug mechanism: immune checkpoint
Impact of failure: Large-scale Phase III studies need to be cautious

Pembrolizumab combined with lenvatinib and pembrolizumab head-to-head phase III clinical trial (LAEP-007) is also a recent failed study named by Professor Wu Yilong at the annual lung cancer ceremony. Previously, pembrolizumab combined with lenvatinib has been approved for use in renal cell carcinoma, endometrial cancer and other tumors.

However, the phase III LAEP-007 study ended in failure.

The data shows that it is very unlikely that pembrolizumab combined with lenvatinib will achieve the expected effect in the treatment of mNSCLC with PD-L1 TPS ≥ 1%.

Even in the population with PD-L1 TPS≥50%, the combination therapy group showed no benefit in PFS and OS. Therefore, DMC recommends discontinuing the study and stopping the combination therapy.

Key Results of LAEP-007 Research


Professor Wu Yilong’s evaluation of the study believes that the first-line joint large-scale phase III clinical study must be cautious and more cautious.

Of course, there are uncertainties in the development of new drugs, and early clinical evidence may not completely translate into clinical benefits, and sometimes there is no alternative.

In 2021, Zai Lab’s early introduction of repetinib failed in the Phase III study of the treatment of gastrointestinal stromal tumors, and magituximab compared with trastuzumab (respectively combined with chemotherapy) did not show Better OS benefits.

However, unlike the evidence of definite early clinical benefit, there are many drugs that blindly carry out Phase III clinical studies without sufficient evidence, and ultimately inevitably “draw water in a bamboo basket.”


NO.6 Deucravacitinib

Company: Bristol-Myers Squibb
Drug mechanism: TYK2 inhibitor
Loss effect: TYK2 is not easy to completely replace Jak inhibitor

In October, Bristol-Myers Squibb (BMS) announced the results of the phase II study (LATTICE-UC2) of the oral selective tyrosine kinase 2 (TYK2) inhibitor Deucravacitinib in moderate to severe ulcerative colitis (UC). The primary and secondary efficacy endpoints of clinical remission at week 12 were reached.

TYK2 is a member of the JAK family and plays an important role in mediating the signal transduction of pro-inflammatory cytokines (including IL-12, IL-23 and type I interferons).

Deucravacitinib selectively binds to the regulatory domain of the TYK2 protein to make TYK2 in an inactive conformation, thereby inhibiting the activity of TYK2.

Since the regulatory domain of TYK2 is different from the regulatory domains of Janus kinase (JAK) 1, 2 and 3, Deucravacitinib at therapeutic doses will not inhibit JAK1, JAK2 or JAK3, thereby avoiding JAK1-3 inhibition-related adverse reactions (AE )happened.

The FDA’s final safety review of JAK inhibitors concluded that similar products cannot avoid the safety signals shown by tofacitinib, and Pfizer and AbbVie have revised the safety labels of related products.

Deucravacitinib design mechanism (Source: BMS)


Based on the safety advantages of TYK2 inhibitor Deucravacitinib, the peak sales are currently expected to reach US$4 billion.

However, ulcerative colitis is also an important battlefield for TYK2 inhibitors. After all, the competition in the field of psoriasis is already fierce. It not only includes a variety of blockbuster drugs, but also will face the impact of generic drugs/biosimilar drugs.

Eli Lilly does not intend to declare this after the positive results of IL-23p19 monoclonal antibody mirikizumab Indications.

Therefore, if ulcerative colitis is missed, it will inevitably have an impact on its growth into a blockbuster drug and its peak sales of $4 billion.


NO.7 Tominersen

Company: Ionis/Roche
Drug mechanism: antisense therapy
Loss impact: Huntington gene therapy hopes are dashed

Tominersen (IONIS-HTTRx, RG6042) is a kind of antisense nucleic acid drugs (ASOs).

After binding to Huntingtin mRNA, it degrades pathogenic mRNA through the RNA degradation system. It aims to reduce all forms of Huntingtin protein (HTT) (including its mutant mHTT). ).

In March, Roche announced that it would discontinue Tominersen’s Phase III clinical study (GENERATION HD1) for the treatment of Huntington’s disease (HD).

The decision was based on the results of a pre-planned review, and the Independent Data Monitoring Committee (iDMC) made this recommendation based on the subject’s potential benefit/risk profile.

Huntington’s disease (HD) is a rare inherited and progressive disease that can cause nerve cells in the brain to collapse, causing problems in thinking, movement, and functional ability, and thus disability.

HD has a devastating effect on people with the disease, and the genetic nature of HD means that it can have a profound impact on future generations or entire families.

Currently, only two drugs have been approved specifically for the treatment of Huntington’s disease in the United States.

In 2008, the FDA approved tetrabenazine for the treatment of chorea, and deuterated tetrabenazine was approved in 2017. However, these two drugs only improve disease symptoms.

Tominersen’s key trial was stopped, and hopes for a new treatment for Huntington’s disease patients were once again dashed. This triggered a lot of thinking and discussion.

Nature also published a review article for this.

First of all, in terms of biodistribution, there are speculations and doubts whether intrathecal administration is sufficient to penetrate the deep brain tissue involved in Huntington’s disease, so that it may not reach a sufficient level, that is, the deepest part of the brain where neuron loss occurs first.

Secondly, tominersen “destroyed” both wild-type and mutant huntingtin proteins, and wild-type huntingtin proteins have neuroprotective effects.

Third, ASO may cause inflammation. There are dose-related white blood cells in the cerebrospinal fluid. The test results also show that more frequent dosing (8-week vs. 16-week regimen) leads to worse results.

However, only a week later, Wave Life Sciences also announced the clinical Ib/IIa (PRECISION-HD2 and PRECISION-HD1) research results of two antisense nucleic acid drugs for the treatment of HD.

The data shows that all the evaluated doses of WVE-120102 and WVE-120101 did not show statistically significant evidence of clinical efficacy, and Wave will terminate the relevant drug research.

Wave ASO retained the integrity of the healthy huntingtin protein, but it still ended in failure. Two pieces of news caused Wave’s stock price to fall 46%.

To make matters worse, there are not many post-clinical products for Huntington’s disease, which means that Huntington’s disease patients will have to wait longer for the emergence of treatments.



NO.8 Ultomiris (ravulizumab)

Company: Alexion (AstraZeneca)
Drug mechanism: anti-C5 monoclonal antibody
Impact of failure: No new drug has been launched for ALS for 20 years

In August, AstraZeneca announced that its rare disease company Alexion had decided to terminate the global phase III clinical study (CHAMPION-ALS) of Ultomiris (ravulizumab) in adult amyotrophic lateral sclerosis (ALS).

This decision is based on the independent data monitoring committee (IDMC) after reviewing the pre-set interim analysis data, and found that there is a lack of efficacy, and recommended that the trial be terminated.

In 2021, AstraZeneca completed the acquisition of Alexion in the form of US$39 billion in cash and stock, obtained a variety of rare disease product pipelines including Ultramiris, and officially entered the rare disease field.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or LouGehrig’s disease, is a progressive neurodegenerative disease characterized by nerve cells (motor nerves) in the brain and spinal cord that control muscles throughout the body.

When nerve cells die, the brain can no longer activate and control muscle movement, resulting in severe disability, paralysis and eventually death.

Ultomiris (ravulizumab) is the first and only long-acting C5 complement inhibitor that works by inhibiting the C5 protein in the complement cascade.

In 2018, Ultomiris was approved for marketing for the first time, and has been approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS) in adults and children.

Ultomiris is not the only drug that failed in the field of ALS this year. Bojian’s antisense drug Tofersen (BIIB067) is a key phase III VALOR study and CNM for patients with superoxide dismutase 1 (SOD1) gene mutations in amyotrophic lateral sclerosis (ALS). -Au8’s phase II study (RESCUE-ALS) and Arimoclomol’s key clinical phase III study (ORARIALS-01) both disclosed negative results in 2021.

The most recently marketed drug by ALS is Exservan, which was approved in 2019. However, Exservan is a modified preparation of riluzole (sublingual film) that was launched in 1995 and cannot be classified as an innovative drug in a complete sense.

Therefore, the most recent ALS drugs will go back to 2001. Fortunately, AMX0035 (phenylbutyric acid + tauroursodeoxycholic acid) submitted a listing application this year, or it will provide a new option.


NO.9 Rilzabrutinib

Company: PrincipiaBiopharma (Sanofi)
Drug mechanism: BTK inhibitor
The impact of failure: the era of small molecule targeted therapy for pemphigus is delayed

In September, Sanofi updated the latest results of the Phase III study (PEGASUS) of Rilzabrutinib in the treatment of pemphigus, showing that it did not meet its primary or key secondary endpoints.

Pemphigus is a potentially life-threatening autoimmune disease. Its clinical features are mainly blisters and ulcers affecting the skin and mucous membranes.

There are currently limited options for the treatment of pemphigus (including vulgaris and deciduous forms), and systemic corticosteroid therapy is still the standard treatment; in addition, only rituximab is approved for the treatment of pemphigus.

Rilzabrutinib is one of the three BTK inhibitors that Sanofi acquired after purchasing Principia Biopharma for USD 3.68 billion in 2020.

It is mainly developed for the treatment of pemphigus, immune thrombocytopenia and atopic dermatitis.

The failure of the Phase III clinical study of Rilzabrutinib has left no small molecule targeted drugs in the late-stage clinical pipeline of pemphigus.

Similar to pemphigus, palmoplantar pustulosis is also a rare chronic skin disease characterized by repeated episodes of palm and plantar pustules.

Common clinical symptoms include scaly, erythema, itching, burning and pain, etc., which may last for many years and are life-threatening. In March, the Phase II clinical trial of Imsidolimab for the treatment of moderate to severe palmoplantar pustulosis (POPLAR) failed to meet its primary endpoint.

Affected by this news, AnaptysBio’s stock price fell more than 30%. In the same month, the Phase II clinical study of Sparsolizumab in the treatment of palmoplantar pustulosis did not meet the primary endpoint.



NO.10 LentiGlobin

Company: Bluebird
Medication: Gene therapy
The impact of failure: gene therapy is unfavorable and ill-fated

In February, Bluebird Bio announced that it had suspended LentiGlobin gene therapy for phase I/II (HGB-206) and III (HGB-206) and III of sickle cell disease (SCD) due to suspected unanticipated serious adverse reactions acute myeloid leukemia (AML). Phase (HGB-210) clinical research.

2021 is a ill-fated year for gene therapy, and LentiGlobin is only the beginning of clinical frustration.

Gene therapy SRP9001 clinical phase II study (Study 102) failed, gene therapy cotoretigene toliparvovec (BIIB112) phase II/III clinical study (XIRIUS) and Timrepigeneemparvovec (BIIB111) phase III study (STAR) did not reach primary or secondary clinical trials end.

Gene therapy and oncolytic viruses are relatively hot fields in recent years, and many pharmaceutical giants have related layouts.

However, more companies currently choose to use adeno-associated virus (AAV).

Although the probability of integrating into human genetic material is smaller than that of lentiviral vectors, there are similar concerns.

The clinical shelving of LentiGlobin was cancelled in June, but was partially shelved on December 20.

In addition, other gene therapies have been urgently suspended or partially suspended by the FDA due to safety and other factors, including BioMarin’s AAV gene therapy BMN307, Pfizer PF-06939926 (AAV9) and PF-07055480 (AAV6).

On the other hand, gene therapy is frustrated, but gene editing therapy is developing rapidly.

The gene editing therapies developed by Intellia Therapeutics, CRISPR Therapeutics and Vertex Pharmaceuticals are progressing rapidly, and they have begun to disclose early positive data, and they will even submit gene editing therapy in 2022. Listing application.

Of course, the field of gene therapy is not all frustrated. It is also Bluebird.

The European Commission approved the listing of Skysona in July, and the FDA also accepted Skysona’s listing application and granted priority review.


Top 10 most regrettable innovative drugs in 2021

(source:internet, reference only)

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