TOP10 failed clinical studies in October 2021

Article source: Med

Author: Leaf

Based on the industry news section of the Medical Rubik's Cube website, NextPharma database and public information, the October 2021 "Clinical Research Monthly" has screened out 10 clinical studies worthy of attention that did not reach the primary endpoint for your reference
.

1.
Phase III study of Canakinumab in the treatment of non-small cell lung cancer

1.
Phase III study of Canakinumab in the treatment of non-small cell lung cancer

Novartis announced on October 25 that the IL-1β inhibitor Canakinumab (canakinumab, ACZ885) combined with pembrolizumab plus platinum dual-drug chemotherapy for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) The phase III clinical study (CANOPY-1) failed to achieve the primary endpoints of improving overall survival (OS) and progression-free survival (PFS)
.

Canakinumab Mechanism of Action (Source: Novartis)

Kananuzumab is a human monoclonal antibody that binds to human interleukin-1β (IL-1β) with high affinity and selectively, and neutralizes the activity of IL-1β by blocking its interaction with the receptor
.

Preliminary evidence shows that by neutralizing IL-1β, cananumumab can transform tumor-promoting inflammation into: 1) enhancing anti-tumor immune response; 2) reducing tumor cell proliferation, survival and invasiveness; 3) impairing angiogenesis

Comment: The failure of the CANOPY-1 study marks another setback for Novartis' hopes of converting cananumumab into a lung cancer drug
.

On March 9 this year, the phase III clinical trial (CANOPY-2) of cananumumab combined with docetaxel for adult NSCLC patients who have previously received PD1/PDL1 inhibitors and platinum-based chemotherapy did not reach the primary endpoint of improving OS

However, the results of a subgroup analysis based on the definition of the baseline inflammation biomarker hs-CRP and other biomarkers showed that in the pre-specified patient subgroups, both PFS and OS have potentially clinically meaningful improvements
.

These data will further support the evaluation of Canakunimab's role in lung cancer, and detailed data will be announced at a subsequent medical conference

2.
Phase III study of Eryaspase in the treatment of pancreatic cancer

2.
Phase III study of Eryaspase in the treatment of pancreatic cancer

On October 25, Erytech Pharma announced that the top-line results of the Phase III study (TRYbeCA-1) of Eryaspase second-line treatment of patients with metastatic pancreatic cancer.
Compared with chemotherapy alone, the experimental group did not reach its primary end point of overall survival (OS).

.

Affected by this news, ERYTECH dropped by 40% (-39.

Introduction to Eryaspase (Source: ASH)

L-Asparaginase (ASNase) can hydrolyze asparagine (ASN) to aspartic acid (ASP), reducing the plasma ASN level required for protein synthesis, usually derived from the bacteria Escherichia coli
.

Eryaspase is Erytech's use of its proprietary ERYCAPS® platform to encapsulate L-asparaginase in donor-derived red blood cells to alter the metabolism of asparagine and glutamine against cancer cells

A total of 512 patients were included in the TRYbeCA-1 study.
Compared with chemotherapy alone, the OS of the eryaspase treatment group was improved, and the hazard ratio (HR) was 0.
92 (95%CI, 0.
76-1.
11); however, in the intention-to-treat population, The difference was not statistically significant (p=0.
375)
.

The median OS with eryaspase plus chemotherapy was 7.

However, although patients receiving gemcitabine and albumin paclitaxel did not benefit from combined eryaspase, patients treated with irinotecan-based chemotherapy regimens showed a certain survival benefit, with an HR of 0.
77 (95% CI, 5.
7-1.
05), the median OS of the pre-specified subgroup of eryaspase treatment was 8.
0 months, while in the control group this data was 5.
7 months
.

In October, Erytech just announced that the eryaspase combined with FOLFIRINOX chemotherapy regimen will determine the follow-up recommended dosage regimen in the clinical study of the first-line treatment of pancreatic cancer (RESPECT IST, NCT04292743)

This time, ERYTECH announced that it will focus on the later development of eryaspase in ALL.
It has previously obtained the ALL fast-track qualification granted by the FDA and intends to submit a marketing application (BLA) for eryaspase for ALL treatment before the end of the year
.

3.
Phase II study of Difelikefalin in the treatment of atopic dermatitis and pruritus

3.
Phase II study of Difelikefalin in the treatment of atopic dermatitis and pruritus

On October 4, Cara Therapeutics announced the latest data of the Phase II study (KARE 2) of KORSUVA™ (difelikefalin) oral treatment of patients with mild to severe atopic dermatitis (AD) at the European Society of Dermatology and Venereology (EADV) in 2021.

.

The results showed that subjects who randomly received difelikefalin at a dose of 0.

Indications for Difelikefalin under investigation (Source: Cara)

Difelikefalin is a kappa opioid receptor agonist and the first and only FDA-approved treatment for chronic kidney disease-related pruritus
.
In August 2021, based on two key phase III randomized, multicenter, double-blind placebo-controlled results (KALM-1 and KALM-2), intravenous injection was approved for moderate to severe itching in kidney disease, and is suitable for receiving blood Adult patients on dialysis
.

The data set released this time contains 401 patients, although the primary endpoint was not reached; however, in the AD subgroup (BSA <10%) dominated by pruritus, significant improvement was observed in the 12th week in the combined difelikefalin dose group (p = 0.
039)
.
In addition, the proportion of subjects in the difelikefalin combined dose group that achieved an improvement of ≥4 points in I-NRS (the primary endpoint of supervision required for clinical phase III pruritus indications) at week 12 (32% vs 19%; p<0.
05 ) Is significantly higher than placebo
.

4.
Clinical study of two farnesoid X receptor agonist drugs in the treatment of non-alcoholic steatohepatitis

4.
Clinical study of two farnesoid X receptor agonist drugs in the treatment of non-alcoholic steatohepatitis

On October 4, Enanta Pharmaceuticals, dedicated to the development of small molecule drugs for viral infections and liver diseases, updated the latest developments in two clinical trials involving the clinically researched farnesoid X receptor (FXR) agonists EDP-305 and EDP -297, both of these drugs have been evaluated for the treatment of non-alcoholic steatohepatitis (NASH)
.
After reviewing the pre-planned interim analysis in the clinical phase IIb (ARGON-2) study of EDP-305 as a monotherapy and the data from the phase I clinical study of EDP-297, Enanta decided to adopt an external licensing strategy to further develop these two Project, and does not intend to continue further development internally
.

ARGON-2 is a randomized, double-blind, placebo-controlled Phase IIb multicenter study designed to evaluate the safety and effectiveness of 1.
5 mg and 2.
0 mg of EDP-305 in patients with NASH confirmed by liver biopsy
.
The results of the interim analysis of some patients at 12 weeks and the review of the clinical data of all tested doses of EDP-305 showed that the 1.
0 mg dose of EDP-305 provides the best balance of efficacy and tolerability
.
Although Enanta did not provide detailed data analysis results, the final decision of Enanta to terminate the ARGON-2 study evaluating EDP-305 as a monotherapy and seeking external authorization, no longer internal development, is enough to show that the data is not optimistic
.

EDP-297 is the second more selective and potent FXR agonist developed by Enanta
.
However, clinical results showed that although strong target activity was observed at lower doses of EDP-297, the overall balance of activity and tolerability was comparable to EDP-305
.
It is not difficult to guess that the highly active and selective EDP-297 is also not satisfactory
.

Comment: NASH is a serious non-alcoholic fatty liver disease (NAFLD), which is common in the United States and all over the world, and is closely related to diabetes and obesity
.
NASH is characterized by excessive accumulation of fat in the liver, leading to stress and liver cell damage, which can lead to inflammation and fibrosis, causing permanent damage, including cirrhosis and liver function damage, as well as cancer and eventually death
.
NASH is the main cause of liver transplantation in the United States and Europe, and the FDA has not yet approved any treatments
.

Farnesoid X receptor is the main regulator of bile acid levels in the liver and small intestine.
It responds to bile acids by regulating gene transcription of key enzymes and transporters, many of which play important roles in lipid metabolism, insulin resistance, inflammation and fibrosis Role
.
The steroidal drug obeticholic acid is a representative drug of farnesoid X receptor agonists and has also received much attention; however, after modifying the clinical endpoint, the research data has not been affirmed by the FDA
.
EDP-305 and EDP-297 are a class of non-bile acid FXR agonists, which contain steroidal and non-steroidal ingredients
.
In China, many companies are also developing farnesol X receptor agonist drugs for the treatment of NASH
.

5.
Phase II study of TAK-994 in the treatment of narcolepsy

5.
Phase II study of TAK-994 in the treatment of narcolepsy

On October 5th, the investigational oral orexin agonist TAK-994 showed a safety signal in the phase II clinical study.
Takeda decided to suspend the administration of patients and stop the two phase II studies of narcolepsy in advance
.

In July 2021, Takeda just announced that the FDA granted TAK-994 a breakthrough therapy qualification for the treatment of narcolepsy type 1 patients with excessive daytime sleepiness
.
TAK-994 is the first oral selective orexin 2 receptor (OX2R) agonist to enter clinical development.
It is used to treat a rare neurological disease type 1 narcolepsy (NT1), which is characterized by excessive daytime sleepiness, Cataplexy (signs and symptoms of the disease), the cause is suspected to be the loss of orexin-producing neurons
.

Takeda is working to quickly evaluate all available data and has determined the benefit/risk profile of TAK-994 to provide information for further development
.
In addition, Takeda is advancing multiple orexin pipeline products, and currently includes an oral orexin agonist TAK-861 that is in phase I clinical research
.

6.
Phase II study of Deucravacitinib in the treatment of ulcerative colitis

6.
Phase II study of Deucravacitinib in the treatment of ulcerative colitis

On October 7, Bristol-Myers Squibb (BMS) announced the Phase II clinical study (LATTICE-UC2) of oral selective tyrosine kinase 2 (TYK2) inhibitor Deucavacitinib in moderate to severe ulcerative colitis (UC) As a result, the study did not reach the primary efficacy endpoint and secondary efficacy endpoint of clinical remission at week 12
.

Currently, BMS has not announced specific details
.
However, BMS stated that it will complete a comprehensive review of the LATTICE-UC study data, and still plans to seek the therapeutic potential of Deucravacitinib in ulcerative colitis.
It will continue to be evaluated in the second phase II IM011-127 trial.
Higher dose administration will be included
.

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 the adverse effects related to JAK1-3 inhibition (AE ) Occurs
.
In particular, in the recent final safety review conclusions, the FDA believes that similar products of JAK cannot avoid the safety signals shown by tofacitinib
.
Therefore, the TYK2 inhibitor Deucravacitinib is considered to have more safety advantages, and the current peak sales are still expected to reach US$4 billion
.

Deucravacitinib design mechanism (Source: BMS)

In 2019, when BMS announced the acquisition of Celgene Corporation for $74 billion, it faced a choice between Deucravacitinib and Otezla in order to win the approval of the US Federal Trade Commission, the antitrust regulator
.
In the end, BMS chose to sell Otezla for $13.
4 billion while retaining Deucravacitinib
.

Comment: Based on the failure of this research, BMS envisions Deucavacitinib as the next-generation follow-up product of Otezla
.
Despite the fact that Deucravacitinib, announced in April, has obtained positive results in two key phase III clinical studies of head-to-head apremilast for the treatment of moderate to severe plaque psoriasis, and may become the basis for the first application in the next few months
.
However, the competition in the field of psoriasis is already very fierce.
It not only includes a variety of blockbuster drugs, but also will face the impact of generic drugs/biosimilar drugs.
It is no wonder that Eli Lilly does not plan after the positive results of IL-23p19 monoclonal antibody mirikizumab Declaring the indication for the market, but turning to ulcerative colitis and Crohn's disease
.
If Deucravacitinib still fails to obtain a positive result in ulcerative colitis, it will have a certain impact on its growth into a blockbuster drug and its peak sales of $4 billion; after all, BMS has listed it as one of the four blockbuster drug plans.
One
.

7.
Lucerastat in the treatment of Fabry disease phase III study

7.
Lucerastat in the treatment of Fabry disease phase III study

On October 11, Itorsia announced that the Phase III study (MODIFY) of Lucerastat for the treatment of Fabry disease did not meet the primary endpoint
.
However, Itorsia did not release the data, indicating that it is still analyzing the data; at the same time, most patients choose to continue the open-label extended study, and future data may provide a basis for lucerastat's research decision
.

Lucerastat is a small molecule glucosylceramide synthase inhibitor
.
Preclinical studies have shown that lucerastat is a soluble, bioavailable inhibitor of glucosylceramide synthase, which can reduce the presence of α-galactosidase A substrates in tissues affected by Fabry disease (including kidney, liver and Dorsal root ganglia)
.
Fabry disease, as a rare hereditary lysosomal storage disease, is mainly due to the dysfunction or lack of alpha-galactosidase A (alpha-GalA), which breaks down glycosphingolipid Gb3 (Globotriaosylceramide) fat products
.
Over time, Gb3 deposits accumulate throughout the body, leading to the pathophysiology of the nervous system, such as neuropathic pain (mainly pain in the hands and feet)
.

Biochemical mechanism of Fabry disease (Source: idorsia)

MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel group study to determine the effectiveness and safety of lucerastat as an oral monotherapy for adult patients with Fabry disease
.
MODIFY determined the effect of the study treatment on neuropathic pain during the 6-month treatment period, measured using Idorsia's proven Fabry disease pain instrument
.
118 patients were randomly assigned to the lucerastat or placebo group at a ratio of 2:1
.
At the end of the double-blind period, 107 patients entered an ongoing open-label extension study (NCT03737214), which was designed to evaluate the long-term safety of adult patients treated with lucerastat orally for up to 48 months And tolerability, and further evaluate its clinical efficacy on renal and cardiac function
.

8.
Tofersen's Phase III Study on the Treatment of Amyotrophic Lateral Sclerosis

8.
Tofersen's Phase III Study on the Treatment of Amyotrophic Lateral Sclerosis

On October 17, Biogen announced the antisense drug Tofersen (BIIB067) for the treatment of superoxide dismutase 1 (SOD1) gene mutations in the 2021 virtual meeting of the American Association of Neurology (ANA) Key Phase III VALOR study results for patients with sclerosis (ALS)
.
The results showed that the study did not reach the primary endpoint, and there was no significant statistical difference in the changes in the revised Amyotrophic Lateral Sclerosis Function Rating Scale (ALSFRS-R) score from baseline to week 28 in the faster progressing population (1.
2; p =0.
97)
.
However, in multiple secondary and exploratory measurements of biological activity and clinical function, trends in favor of Tofersen have been observed
.

28-week test results (Source: Bojian)

ALS is a progressive neurodegenerative disease with an average death time of three to five years.
The most common cause of death is respiratory failure
.
SOD1-ALS is a rare hereditary form of ALS, accounting for only 2% of approximately 168,000 ALS cases worldwide
.
Currently, no gene-targeted therapy for ALS has been approved
.
The clear pathogenesis of ALS has not yet been fully established.
90% of ALS are sporadic and only 10% are familial
.
SOD1 gene mutation is the first identified genetic cause of ALS.
SOD1 mutation accounts for 10-20% of familial ALS and 1-2% of occasional ALS
.
ALS is a very serious disease, with a survival period of only 2-5 years after diagnosis
.

Tofersen is similar to Bojian's other ALS antisense drug Noxinassen, and both require intrathecal administration
.
As an antisense therapy, Tofersen binds to SOD1 mRNA to be degraded by RNase-H, reducing the synthesis of SOD1 protein
.
VALOR is a 28-week phase III randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, pharmacodynamics and biomarker effects of tofersen 100 mg in the treatment of SOD1 mutant ALS adults
.
A total of 108 subjects were enrolled in the study (72 received tofersen 100 mg, 36 received placebo)
.
Among them, 60 subjects met the prognostic enrichment criteria for rapid disease progression defined by the research protocol, and constituted the main analysis population (rapidly progressing population)
.
Forty-eight subjects did not meet the prognostic enrichment criteria and belonged to the "slow progress" population
.

VALOR research design (Source: Bojian)

In the first key secondary endpoint, the total SOD1 protein (target-related marker) changes in the cerebrospinal fluid, the difference between the tofersen group and the placebo group in the faster and slower populations was 38% and 26%, respectively
.
In the second key secondary endpoint, plasma neurofilament light chain (NfL) (a potential marker of neuronal degeneration) changes, the difference between the tofersen group and the placebo group in the faster and slower progressing groups are respectively 67% and 48%
.

In addition, the collection of pre-specified data from the VALOR study and its ongoing Open Label Expansion Study (OLE) enhances these findings, showing that early activation of tofersen can improve SOD1-ALS patients' motor function, respiratory function, muscle strength, and quality of life.
There are fewer drops in many indicators
.

9.
Phase II study of AT-527 in the treatment of COVID-19 infection

9.
Phase II study of AT-527 in the treatment of COVID-19 infection

On October 19, Atea Pharmaceuticals updated the top-line results of the global phase II MOONSONG study for the subgroup of patients with mild to moderate COVID-19 out-of-hospital.
The AT-527 treatment group (550mg, bid) overall population on the 29th day of SARS- The change in CoV-2 viral load from baseline was not significantly lower than that in the placebo group.
About two-thirds of patients were still symptomatic and low-risk patients who failed to reach the primary endpoint of the study
.
Affected by this news, Atea's stock price fell more than 70% at one time, and finally closed at -65.
96%
.

AT-527 is an RNA polymerase inhibitor with a dual mechanism of action, which can inhibit virus replication and was developed as a direct oral antiviral drug
.
Atea reached an exclusive strategic cooperation agreement on AT-527 with Roche on October 22, 2020
.
Roche obtained the development and commercial rights of AT-527 outside the United States.
For this purpose, it paid Atea a down payment of US$350 million, followed by sales miles and royalties
.

Although the primary endpoint was not reached, in the analysis of high-risk subgroups with other potential health conditions, the AT-527 550mg group and 1100mg group observed a downward trend in viral load compared to the placebo group on day 7
.
Therefore, based on the top-line results of the MOONSONG study and the changes in the COVID-19 treatment situation, Atea and Roche will jointly evaluate the next steps of the global Phase III MORNINGSKY study, including the study endpoints and patient populations.
The results may not be until 2022.
Announced half a year
.

10.
Phase III study of Avasopasem in the treatment of severe oral mucositis

10.
Phase III study of Avasopasem in the treatment of severe oral mucositis

On October 19, Galera Therapeutics announced the results of the Phase III trial (ROMAN) of Avasopasem (GC4419) for the treatment of severe oral mucositis (SOM) in locally advanced head and neck cancer (HNC) patients receiving radiotherapy
.
The data showed that Avasopasem did not reach the primary endpoint of reducing the incidence of SOM
.
Affected by this news, Galera's stock price finally closed with a 69.
59% drop
.

Galera pipeline and indication development

The ROMAN trial is a randomized, double-blind, placebo-controlled trial designed to evaluate avasopasem's reduction in the incidence and severity of radiation-induced SOM in 455 locally advanced head and neck cancer patients who received seven weeks of radiotherapy plus cisplatin
.
Patients were randomly assigned to two treatment groups (3:2) and received 90 mg avasopasem or placebo by infusion on the day of radiation therapy
.
The results showed that compared with the placebo group, the incidence of SOM in the avasopasem treatment group was relatively reduced by 16% (54% vs 64%, p=0.
113), and the primary endpoint of the study was not reached
.
In terms of secondary endpoints, compared with the placebo group, the number of SOM days in the avasopasem treatment group was relatively reduced by 56% (8 vs 18 days, p=0.
011), and the severity of SOM (grade 4 incidence) was relatively reduced by 27% (24% vs.
33%, p=0.
167).

Oral mucositis is one of the main side effects of radiotherapy and is characterized by severe pain, inflammation, ulcers and oral bleeding
.
Severe oral mucositis (SOM) occurs in about 70% of patients with head and neck cancer who receive radiation therapy, which is defined as the inability to eat solid food (level 3) or drink liquids (level 4)
.
Avasopasem (GC4419) is a selective small molecule dismutase mimic, which is under development to reduce radiation-induced severe oral mucositis (SOM) in patients with locally advanced head and neck cancer (HNC) and reduce the esophagus in patients with radiation-induced lung cancer Inflammation
.
The FDA has awarded avasopasem fast track and breakthrough therapy designations for reducing SOM induced by radiotherapy
.

In addition to the above 10 clinical failures, Ocular Therapeutix's micro-innovative drug OTX-CSI (cyclosporine) for the treatment of dry eye disease (DED) in Phase II clinical trials did not achieve significant advantages
.
Servier’s LONSURF® (Trifluridine/Tipiracil) combined with Bevacizumab has not been shown to be superior to capecitabine combined with Bevac for patients with unresectable metastatic colorectal cancer (mCRC) who are not eligible for intensive treatment.
The superiority of monoclonal antibodies, the phase III SOLSTICE trial did not reach the primary endpoint
.
In addition, Cortexyme's atuzaginstat (COR388) phase II/III clinical trial for the treatment of Alzheimer's disease did not meet the dual primary endpoints, causing the company's share price to fall by 70%
.
The Phase III trial of ANG-3777 developed by Angion Biomedica and Vifor Pharma for use in donor kidney transplant patients who are potentially at risk of delayed graft function (DGF) failed to reach its primary endpoint, and the stock price fell 55% after the market
.
CPI-613 (devimitat) developed by Rafael Holdings in the clinical phase III study of the treatment of pancreatic metastatic adenocarcinoma also failed to reach its primary end point, causing its stock price to fall by more than 70% that day
.

In addition to clinical failures, the termination of development of some drugs is worthy of attention
.
In particular, Daiichi Sankyo’s antibody-conjugated drug DS-6157 against the GPR20 target did not show a definite clinical response in a phase I clinical study conducted in patients with gastrointestinal stromal tumors, and decided to terminate the development
.
With the same Linker and payload technology, Daiichi Sankyo has gradually revealed its kingly demeanor in the field of ADC drugs.
Enhertu also won the first global head-to-head research victory among Her2 ADC drugs
.
DS-6157 has the same Linker, payload and DAR as Enhertu, but failed to replicate the success of Her2 ADC, which shows the importance of new mechanism research in the development of innovative drugs
.

Reference materials:

1.
https:// in-Patients-with-Second-line-Advanced-Pancreatic-Cancer.
html

3.
https://ir.
caratherapeutics.
com/news-releases/news-release-details/cara-therapeutics-presents-late-breaking-results-kare-phase-2

4.
https:// to-Severe-Ulcerative-Colitis/default.
aspx

7.
https:// C2%AE-trifluridinetipiracil-bevacizumab-in-a-1st-line-setting-for-patients-with-unresectable-mCRC-non-eligible-for-intensive-therapy

13.
https://