2020 inventory: Top 10 clinical trial failure cases! Roche is the most, AstraZeneca, Sanofi, GSK

It is a highly subjective task to list the most failed clinical trials in 2020, and the trials on the list need to have a significant impact on pharmaceutical companies and patients targeted by drugs. Large companies are more receptive to trial failure, but wasted investment and missed business opportunities can still cause huge losses; for small companies, failure can mean endangering the future of the business.

On the other hand, for patients, the treatment methods in the ten trials concerned could have taken a clinically significant step forward.

In the field of experiments, infectious diseases will be the leading role in 2020. Although people gradually feel that the covid-19 can be defeated, or at least relegated to a flu like state. But the news that the leading HIV vaccine failed after more than 30 years of research reminds us that infectious diseases are susceptible and difficult to overcome.

Drug candidates for a wide range of chronic diseases, such as cardiovascular disease, Alzheimer's disease and cancer, have also failed in trials, including a drug candidate for nonalcoholic steatohepatitis (NASH), which affects millions of people around the world, but there is still no effective treatment.

We need to have a thorough analysis. In the list of failed trials, Roche appeared the most frequently, and at least three clinical trials failed. This is due to the multinational pharmaceutical company's small sample size and opportunities. Of course, the three failed trials may also represent the company's willingness to take risks in developing high-risk projects. Well, here are the top ten clinical failure projects that deserve the most attention in 2020:

1) ALVAC-HIV/AIDSVAX B/E

Indication: HIV vaccine

Sponsors: GSK and Sanofi

In February, researchers in South Africa abandoned a large-scale study to test the combination of GSK and Sanofi vaccine components, because the research vaccine alvac-hiv / AIDSVAX B / E had no additional protection against HIV compared with placebo.

It is reported that this is a vaccine combination. One part is alvac-hiv vaccine developed by Sanofi Pasteur with Canary pox as carrier, and the other part is a two-component vaccine composed of gp120 protein subunit vaccine and adjuvant developed by GSK. The vaccine was tested in a phase 2B / 3 clinical trial called HVTN 702, which recruited 5400 sexually active men and women aged 18-35. The data showed 129 infections in the vaccine group and 123 in the placebo group. The annual infection rate was 4% in both groups.

The vaccine gap for HIV is particularly serious, because the vaccine program is the only program that shows a protective effect on HIV. In a clinical trial conducted in Thailand more than a decade ago, RV144 produced 31% of the efficacy, moderate but encouraging.

Follow up studies began with a new adjuvant designed to improve the efficacy. At that time, Anthony Fauci, director of the Institute of allergy and infectious diseases at the National Institutes of health, said: "if the vaccine is successful, combining it with existing antiretroviral drugs could be the last nail in the coffin of HIV."

Unfortunately, the data of GSK and Sanofi force people to realize the harsh state of HIV. Alvac-hiv / AIDSVAX B / E was the main candidate combination of AIDS vaccine in the world, but it didn't work at all.

Now, the baton has been passed to J & J and its academic partners, who are conducting clinical trials of J & J's "mosaic" vaccine ad26. The vaccine combines fragments from a variety of HIV strains in an attempt to stimulate a broad immune response.

A phase 2B study, imbokodo, recruited 2600 young women between the ages of 18 and 35 in sub Saharan Africa, with preliminary results expected in 2021. Meanwhile, three trials of mosaico are being conducted on 3800 men who have sex with men and transgender people in North America, Latin America and Europe, and the results will be published in 2023 or 2024.

It has been proved that compared with sars-cov-2, HIV is an organism that is more difficult to be used as a vaccine target, but the basic technology of some new covid-19 vaccines may provide another option. At present, the Pfizer / bio ntech and Moderna covid-19 vaccines have been approved by the US regulatory agencies based on mRNA, which is the recognition of immune methods.

Earlier this year, Moderna reported that an experimental HIV vaccine based on mRNA was proved to produce neutralizing antibodies against HIV like virus in monkeys, which raised hopes for the feasibility of a human vaccine.

2) Sars-cov-2 vaccine

Indication: covid-19

Sponsors: Sanofi and GSK

A small trial of Sanofi and GSK adjuvant recombinant protein covid-19 vaccine is the latest item on the list.

Previously, phase 1 / 2 trials among 440 participants showed that the vaccine stimulated an immune response similar to that of patients recovering from cowid-19 in adults aged 18-49, but apparently did not appear to be effective in the elderly due to "insufficient antigen concentration". This means that the vaccine must be reconstituted and a new phase 2B study carried out, and the two partners have been hoping to enter phase 3 by the end of 2020.

The use of recombinant proteins in vaccines has been considered to take longer than other technologies (such as mRNA), but it also has greater expansion potential to meet global demand. Sanofi and GSK have said they expect to produce 1 billion doses of vaccine in 2021, and global demand is expected to be in short supply for some time. But for now, approval of the vaccine is likely to be delayed until the end of this year.

In developed countries, this delay may not be a big deal. After all, large-scale use of mRNA based vaccines has begun. But for low-income countries, it is a huge setback. Since Sanofi / GSK will provide nearly a third of the vaccine dose that global vaccine procurement agencies rely on, the delay in the trial is a heavy blow for poor countries.

In general, with the introduction of Pfizer / biontech and Moderna vaccines, people are increasingly optimistic about the prevention of covid-19 by vaccines. However, the delay of Sanofi / GSK vaccine, the lingering problem of AstraZeneca adenovirus vaccine azd1222, and the recent news that Australian biotechnology company CSL gave up its phase 1 Research candidate vaccine uq-csl v451 are timely reminders that drug and vaccine development is a high-risk undertaking.

3) Balovaptan

Indication: Autism

Sponsor: Roche

For those areas where there is still no approved treatment, it is always disappointing when a candidate drug is eliminated. In 2020, Roche abandoned the development of balovaptan, which has been a leader in the potential treatment of autism spectrum disorder (ASD).

According to the Centers for Disease Control and Prevention (CDC), about one in 59 children is diagnosed with autism, accompanied by social and communication difficulties and other symptoms such as repetitive behavior.

At present, only antipsychotic drugs such as risperidal have indications for autism (ASD) in clinical guidelines. These drugs are specially used to reduce the irritability of autistic patients, but they can also cause serious side effects.

Roche had hoped that balovaptan (formerly known as rg7314) would be the first drug to address the underlying mechanism of ASD. This is a huge challenge for the pharmaceutical industry, mainly because ASD is a diverse and heterogeneous disease. Novartis and seaside therapeutics also failed in their autism treatment programs.

Balovaptan, a vasopressin 1A receptor antagonist, is a potential target for ASD drugs for the first time a few years ago. It can help neurons in the brain communicate with each other and seems to play a role in social connections.

Similar methods have been studied on oxytocin. Oxytocin appears to enhance social function in a small study of autistic children conducted in 2017, but other clinical trials failed.

Two years ago, the US FDA awarded balovaptan the title of breakthrough therapy, but Roche disclosed in its financial report update in the first quarter of 2020 that an interim analysis showed that the possibility of the drug showing curative effect was very small, and the company abandoned the plan of conducting phase 3 trials in adult ASD patients.

Since then, balovaptan no longer appears in Roche's pipeline of drug candidates. Although Roche is still committed to the treatment of autism, its attention has now shifted to g7816, a small molecule, highly selective positive allosteric regulator of GABAA α 5 receptor. According to Roche, GABAA α 5 receptors are expressed in key brain regions affected by ASD.

In addition, earlier this year, another potential treatment was found in a UK China Study: the study of bumetanide, a general blood pressure drug, in 83 children with ASD found that compared with placebo, the severity of symptoms in children was reduced and side effects were less. Bumetanide also plays a role in GABA pathway.

4) Semorinemab

Indication: Alzheimer's disease

Sponsor: Roche / AC immune

With the development of anti amyloid drugs in Alzheimer's disease (AD), targeting tau protein has become a new focus of dementia drug researchers. However, in September 2020, semolinemab, one of the leading candidates in the field of anti tau drugs, also encountered setbacks, indicating that this goal may be equally challenging.

The phase 2 trial of this anti tau antibody against 500 patients with early-stage (prodromal to mild) ad, tauriel, failed. The results showed that compared with placebo, semolinemab could not reach its primary efficacy end point, which was to reduce the total score of Clinical Dementia Rating Scale (CDR). At the same time, the drug missed two secondary endpoints, namely cognitive ability and activities of daily living. This result is a big blow for other pharmaceutical companies (including aberway, Borgen and Lilly) that are developing tau targeted drugs.

Tau is a protein existing in the cells of the central nervous system. It has become a drug target for Alzheimer's disease. Because it gathers together and forms a "tangle" in the brain of Alzheimer's patients, it leads to diseases related to cell damage and neuron death.

An early pioneer in this field, taurx, a tau aggregation inhibitor named lmtx, is in phase 2 / 3 trials, and the results are expected to be released in 2021; abbv's candidate abbv-8e12 and Bojian's biib092 are also in phase 2 trials; and Eli Lilly's aci-3024 is in the first phase of research.

Roche also conducted another study lauriet on patients with moderate AD, and the results will be published in 2022. This early study is believed to be an opportunity for semolinemab to demonstrate the best treatment for Alzheimer's disease.

In addition, Roche added another tau drug to its production line in July last year through a US $120 million upfront deal with Belgian pharmaceutical company ushimab, with a total transaction value of US $2 billion, which provides an alternative solution once semolinemab is proved invalid. Ucb0107, the target candidate for the deal, had not yet started testing ad when the agreement was reached, but a phase 1 study had been conducted in patients with the neurodegenerative disease progressive supranuclear palsy (PSP).

Worryingly, as the failure of targeted tau drugs increases, the pharmaceutical industry may eventually invest billions of dollars in R & D funds into projects that are as disappointing as those targeting amyloid. At present, there are still a large number of targeted amyloid drugs in research and development. Roche has two kinds of drugs, gantenerumab and crenezumab, but they are in the late testing stage. Bojian is also looking for its leading drug candidate, aducanumab, to be approved by March this year.

5) Tecentriq

Indication: triple negative breast cancer

Sponsor: Roche

In March 2019, Roche checkpoint inhibitor tecentriq (atezolizumab) was approved to be combined with Bristol Myers Squibb / new base chemotherapy drug Abraxane (albumin combined with paclitaxel) in the treatment of newly diagnosed triple negative breast cancer (TNBC) patients with positive PD-L1, becoming the first choice of immunooncology for highly invasive tumors and breast cancer. However, fast forward to August 2020, impassion131, a phase 3 trial targeting PD-L1 positive patients with metastatic TNBC, did not reach the end point.

In the previous phase 3 study of impassion130, the combination of tecentriq and Abraxane showed a statistically significant progression free survival benefit. Although there was no formal analysis, the improvement of overall survival in patients with metastatic TNBC and patients with tumor expression of PD-L1 (≥ 1%) also had clinical significance. Therefore, the combination of tecentriq and Abraxane in the treatment of unresectable locally advanced or metastatic TNBC and adult patients with PD-L1 expression (≥ 1%) has obtained accelerated approval from the US FDA.

However, in the impassion131 trial, Roche used a conventional, paclitaxel generic (unlike Abraxane, not bound to albumin) in combination with its PD-L1 inhibitor, tecentriq, in patients with the same metastatic, PD-L1 positive TNBC. The results showed that compared with paclitaxel combined with placebo, tecentreq combined with paclitaxel could not reduce the risk of disease progression or death, and the survival rate of immunotherapy group had a downward trend. According to the FDA, the application of tecentriq in TNBC patients depends on the therapeutic effect proved in other trials.

Roche had previously hinted that tecentriq's sales could reach $1 billion and would be approved for treatment of bladder and lung cancer. Due to the unstable effect of tecentriq in the treatment of TNBC, it is likely to affect the sales growth of the drug. But there is still good news in 2020. Roche found in impassion031 study that tecentriq can be effectively used as a preoperative (neoadjuvant) treatment for TNBC patients regardless of the status of PD-L1.

6) Edasalonexent

Indication: Duchenne muscular dystrophy

Sponsor: catabasis

In 2020, among the companies developing DMD drugs, more than one company in the late stage of research and development will be disappointed, but the failure of edasalonexent, a catabasis company, is the most impressive.

Since its development in 2011, the drug has been considered as a potential therapy for patients with DMD, regardless of the potential mutation in patients with DMD. At present, approved DMD drugs, such as exondys 51 (eteplirsen) from Sarepta and viltepso (viltolarsen) from ns Pharma, all target the specific mutation of DMD. In addition, edasalonexent is also considered as a three in one therapy for DMD, which can slow down muscle atrophy, protect heart function and reduce fractures.

In a mid-term trial published in 2017, edasalonexent failed to reach the clinical end point, making the drug a high-risk project. However, catabasis continued the phase 3 study Polaris DMD, and the drug missed the primary and secondary endpoints.

Catabasis had no choice but to give up the oral NF KB inhibitor. The move left the company with only one preclinical treatment for cystic fibrosis and more than $52 million in cash reserves. And edasalonexent is catabasis's second biggest R & D failure. Four years ago, the company abandoned its lead drug, cat-20154, after a phase 2 trial of a treatment for high cholesterol failed.

Of course, in addition to catabasis, idebenone of santhera, a Swiss biotech company, has also encountered the same situation. In order to save costs, the company has been forced to lay off 50 people and turn to vamorolone, a DMD candidate for phase 2B. The data is expected to be released in the second quarter of 2021.

However, three potential gene therapy methods are making progress in clinical development. Pfizer pf-06939926, Sarepta / Roche candidate srp-9001 and solid Biosciences sgt-001 all have preliminary data of human trials, and the first two should enter the later trials this year. Solid's project was shelved because of clinical shelving, but now it has been allowed to restart the research.

Meanwhile, Eli Lilly recently joined the competition through a partnership with precision Biosciences, while ultragenyx has developed another product candidate with solid bio. Estelle plans to start clinical trials of its treatment asp-0367 by the end of 2020.

7) Elafibranor

Indication: nonalcoholic steatohepatitis

Sponsor: genfit

The year 2020 proves once again how difficult the challenge of nonalcoholic steatohepatitis (NASH) to drug researchers is. In a phase 3 study, resolve-it, published in July, genfit's elafibranor showed that it could not improve the prognosis of patients.

Compared with placebo, elafibranor did not reach the primary endpoint of Nash resolution without aggravating fibrosis scars, nor did it reach the secondary goal of the trial, which proved to be the overall failure of the drug. The French biotech company said the data are unlikely to support the PPAR α / δ agonist's approval as a treatment for fatty liver in the United States and Europe, so the investment needed to continue the trial is unreasonable. To save cash, genfit cut its staff by 40%.

Although genfit abandoned the study, it did not give up the drug completely. It is still promoting the treatment of primary cholangitis (PBC). PBC is a chronic autoimmune disease. The intrahepatic bile duct is gradually destroyed, leading to cirrhosis. A phase 3 trial called elative is in progress.

In recent years, biopharmaceutical companies have flocked into the field of Nash treatment. They are attracted by the aura of the first batch of drugs approved to treat diseases that affect millions of people around the world and are increasingly common. They believe that they will get high returns. As a result, elafabranor also added to the list of failed drugs whose key trials failed to affect Nash. In 2019, the two heavyweight Nash trial drugs are selonsertib, Gilead's ASK1 inhibitor, and emricasan, Novartis / conatus's Pan cysteine protease inhibitor. The recent failure cases include seladelpar, PPAR δ agonist of cymabay therapeutics.

At present, the leader in this field is intercept's optical acid (OCA), which has submitted an application to the US FDA, but was rejected in June last year because its benefits are "uncertain". OCA has been approved to treat PBC, so elafibranor also hopes to win the expected indication.

In addition, genfit continues to develop a blood based diagnostic method for NASH, which was originally designed to support the elafibranor project. As an alternative to liver biopsy, it may be a valuable commercial product in itself.

8) Epanova

Indication: mixed dyslipidemia

Sponsor: AstraZeneca

AstraZeneca's fish oil derivative epanova tries to emulate amarin's blockbuster best-selling drug vascepa, and hopes to show that it can reduce the heart risk of patients with hyperlipidemia, replacing the statins Crestor dominated in this field before losing patent protection.

But hope was dashed in January 2020, when AstraZeneca announced its decision to abandon the phase 3 clinical study strong, which used epanova (omega-3 carboxylic acid) as an additional drug to statins to reduce cardiovascular risk in patients with mixed dyslipidemia, a disease characterized by elevated triglyceride levels.

In 2013, AstraZeneca acquired omthera pharmaceuticals, which is headquartered in the United States, and incorporated epanova into its production line to establish its cardiovascular drug business. Since 2014, epanova has been approved for a small range of indications for the treatment of severe hypertriglyceridemia, but it has never been on the market, and AstraZeneca has turned to support its use in a wider patient population, hoping to commercialize it through the strength trial.

Previously, consensus analysts predicted that epanova's top sales would be between $1 billion and $2 billion, which would greatly help consolidate AstraZeneca's franchise in the cardiovascular, renal and metabolic (cvrm) field. However, after epanova was abandoned, AstraZeneca immediately reduced the book value of the project by US $100 million. At present, the project has withdrawn from the listing channel.

At the same time, amarin has its own problems. In April 2020, the US District Court declared five patents of vascepa invalid, clearing the way for potential generic competition such as hikma pharmaceutical company and Dr Reddy laboratory. At present, amarin is preparing to sell vascepa in Europe without a "big money" marketing partner, hoping that the patent protection will last until 2039.

9) Hydroxychloroquine

Indication: covid-19

Sponsor: several pharmaceutical companies

In 2020, there will be a series of failed trials in the field of covid-19 treatment, but the most famous one is hydroxychloroquine. It stood out because then US President Donald Trump strongly promoted the drug, describing it as a "game changer" and saying that he had been taking it prophylactically to prevent infection, as did other public figures such as Brazilian president jair bolsonaro. And the publicity came before clinical results showed that hydroxychloroquine had no effect on cowid-19.

Hydroxychloroquine and related drug chloroquine were touted as possible drugs for the prevention or treatment of covid-19 in the early stage of the pandemic. Based on in vitro data, they can inhibit sars-cov-2 virus. Based on preliminary data only, hydroxychloroquine was granted an emergency use authorization (EUA) in June 2020, allowing it to be used in hospitals to combat the pandemic of cowid-19. But with a number of studies found that, whether as a post exposure prevention or as a treatment of cowid-19, this low-cost drug has no benefits, so the price of this drug has plummeted.

In the Oxford University large-scale rehabilitation trial, the 28 day mortality of 1542 patients receiving hydroxychloroquine was similar to that of 3132 patients receiving standard treatment. The drug also did not improve hospital stay or other clinical outcomes. Studies have also shown that in these patients, inefficient corticosteroid dexamethasone can effectively reduce mortality and succeed in the case of hydroxychloroquine failure.

Since then, who has stopped the hydroxychloroquine group of its clinical trials, and Novartis, a generic manufacturer of hydroxychloroquine, and the National Institutes of Health (NIH) of the United States have also quickly ended the study of hospitalized patients with cowid-19. In the face of more and more clinical evidence that the drug is ineffective, the U.S. FDA warned not to use it in patients with cowid-19, and withdrew the EUA. On the other hand, the failure of hydroxychloroquine in the treatment of hospitalized patients with cowid-19 has become a catalyst for researchers to turn their attention to more promising drug candidates.

Currently, the copcov trial funded by the bill and Melinda Gates Foundation and other organizations is analyzing whether hydroxychloroquine has any benefits for the prevention of covid-19. This possibility seems to be contrary to the drug, but the researchers insist that the dosage used is safe, and it may take several months for the vaccine to be widely spread, so this is a study worthy of further study.

10) IW-3718

Indication: gastroesophageal reflux disease (GERD)

Sponsor: Ironwood

Ironwood once claimed that iw-3718, its main candidate, could be a product with annual sales of US $2 billion. However, in September 2020, the drug failed in the phase 3 trial of refractory gastroesophageal reflux disease (GERD) and was "snowballed", which failed.

The study found that up to 40% of GERD patients can not get the desired remission from the current drugs, and in western countries, about one in five people have GERD, which represents a huge potential market. But in the trial, iw-3718 did not significantly improve the severity of heartburn in patients who could not control GERD symptoms with standard drugs, compared with placebo.

Iw-3718 is a gastric maintenance preparation of colesevelam, a lipid-lowering drug. It can combine bile acids in the stomach to prevent bile acids from reaching and stimulating the esophagus. The data show that iw-3718 did not reach the main end point in phase 2 test, and there may be problems in R & D after that, but Ironwood insisted on regardless. In the end, it cost more than $10 million to cancel the entire project and cut about a third of its staff, trying to cut about $95 million from costs by the first quarter of 2021.

Fortunately, Ironwood also has an approved drug to maintain cash flow, namely linzess (linaclotide), a treatment drug for irritable bowel syndrome (IBS) developed in collaboration with aberway. Its sales in the third quarter of 2020 were $221 million, of which $100 million was owned by Ironwood. This also made the company profitable for the sixth consecutive quarter.