TOP10 failed clinical studies in September 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 September 2021 "Clinical Research Monthly" has screened out 10 clinical studies that have not reached the primary endpoints that are worthy of attention for your reference

1.

Margetuximab is an Fc-engineered monoclonal antibody targeting HER2

However, things backfired

The overall data analysis showed that in the ITT population, the median OS of the Margetuximab combined chemotherapy group and the trastuzumab combined chemotherapy group were 21.

In 2020, based on the PFS data of the SOPHIA study (median PFS: 5.

Comment: For HER2, which has been discovered for more than 30 years, the development of small molecule drugs is not satisfactory

2.

Schematic diagram of ABI-H2158 mechanism of action (Source: Assembly)

ABI-H2158 disrupts the formation of HBV capsid through allosteric binding and interference with core protein dimerization.

The Phase II clinical study of ABI-H2158 is a multicenter, randomized, placebo-controlled trial to evaluate the efficacy of ABI-H21588 in HBeAg-positive or HBeAg-negative patients with chronic hepatitis B who have no cirrhosis

In July 2020, Assembly Biosciences and Baiji Divine Assembly on R & D pipeline in paragraph 3 core clinical stage inhibitor (ABI-H0731, ABI-H2158 and ABI-H3733) for the treatment of chronic hepatitis B reached a cooperation

Source: AssemblyBio official website

Previously, on November 5, 2020, Assembly Bio announced that the Phase II clinical trial (study 211) of ABI-H0731 had failed

3.

X-linked myotube myopathy (XLMTM) is a rare, life-threatening, single-gene neuromuscular disease caused by mutations in the MTM1 gene.
Approximately 1 case occurs in every 40,000-50,000 newborn boys, and death is estimated to be within 18 months The rate is 50%.
There is currently no available treatment, and there are a large number of unmet clinical needs
.
AT132 is a gene therapy that Astellas acquired when it acquired Audientes Therapeutics in 2019
.

So far, a total of 24 subjects have been treated with AT132: 7 people have received a dose of 1.
3x1014 vg/kg, and 17 people have received a dose of 3.
5x1014 vg/kg
.
In August 2020, Astellas announced that MTM1 gene therapy AT132 led to the death of the third patient.
All three patients who died received 3.
5x1014 vg/kg dose treatment, and all had a history of hepatobiliary disease, with progressive cholestasis.
Hepatitis and death from sepsis (2 cases) or gastrointestinal bleeding (1 case), all of which are the consequences of liver failure
.

4.
Phase IIb study of Johnson & Johnson HIV vaccine to prevent HIV infection

On September 1, Pharmashots reported that Johnson & Johnson will terminate the Phase IIb clinical trial of Imbokodo (HVTN705/HPX2008) in sub-Saharan Africa.
The report from Johnson & Johnson pointed out that this experimental human immunodeficiency virus (HIV) The vaccine failed to provide substantial protection against the disease
.

The Phase IIb proof-of-concept Imbokodo trial recruited nearly 2,600 young women at high risk of HIV infection at 23 trial sites in five sub-Saharan African countries (ie, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe)
.
Subjects were vaccinated four times within a year, and a preliminary analysis was performed 24 months after the first dose of vaccine injection
.
The primary endpoint was defined as the difference in the number of new HIV infections between the vaccination group and the placebo group from the 7th to the 24th month
.

The test results showed that at the 24th month of follow-up, 63 out of 1109 subjects in the placebo group were infected with AIDS, while 51 out of 1079 subjects in the vaccination group were infected.
The effectiveness of the vaccine is estimated to be only 25.
2%, the confidence interval is lower than 0%
.

5.
Phase III study of Pevonedistat in the treatment of multiple diseases

On September 1, Takeda announced that pevonedistat combined with azacitidine will treat high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and low myeloblastic acute myeloid leukemia (AML) as the first-line treatment The PANTHER study (Pevonedistat-3001) did not meet the pre-set primary endpoint of event-free survival (EFS)
.

Pevonedistat mechanism of action

Pevonedistat is a first-in-class NEDD8 activating enzyme (NAE) small molecule inhibitor.
By inhibiting NAE, it inhibits the normal activation of the key ligase CRL during the ubiquitination process, and interferes with the degradation of cellular targets by the proteasome, thereby affecting Cell cycle, apoptosis and DNA replication lead to the death of cancer cells
.

Previously, the Phase II clinical trial data of Pevonedistat code-named Pevonedistat-2001 was approved by the FDA as a breakthrough therapy for the treatment of high-risk myelodysplastic syndrome (HR-MDS)
.

6.
Phase II study of FB-401 in the treatment of atopic dermatitis

On September 2, Forte Biosciences announced the top-line data of the Phase II clinical trial of FB-401 for the treatment of atopic dermatitis.
The results showed that the study failed to reach the statistical significance of the primary endpoint of EASI-50.
The primary endpoint was defined as the basis Assessed by the Eczema Area and Severity Index (EASI), the proportion of patients with at least 50% improvement in the severity of atopic dermatitis
.

On September 3 (Friday), affected by the news, Forte's stock fell from Thursday's closing price of $28.
59 to $5.
06, a drop of more than 82%
.
However, Forte Biosciences previously reported that as of June 30, 2021, its cash and cash equivalents were US$50.
8 million, which is enough to provide financial security for the next year
.

FB-401 is composed of three symbiotic gram-negative bacterium Rhodomonas mucosa.
Extensive preclinical and mechanism of action data have proved that FB-401 is expected to promote tissue repair, anti-inflammatory and inhibit Staphylococcus aureus And other potentially harmful bacteria, thereby improving atopic dermatitis disease
.

7.
Phase II study of Iscalimab for kidney transplant rejection

On September 3, Novartis announced the termination of a CIRRUS-1 study of CFZ533 (iscalimab) to prevent organ transplant rejection in kidney transplant patients
.
This decision was made after the interim analysis of the study
.

The interim analysis showed that for patients undergoing kidney transplantation, in addition to other immunosuppressive agents (induction therapy, mycophenolate mofetil and corticosteroids), the combined use of CFZ533 is not as effective as tacrolimus in preventing organ transplant rejection
.
Novartis is currently still further evaluating the experimental data of the CIRRUS-1 study, and will communicate with the scientific committee in detail after completion
.

CFZ533 (iscalimab) is modified from lucatumumab.
The N297A mutation is introduced in the Fc region, thereby losing the ability to bind to FcγR and no Fc-mediated effects
.
Iscalimab does not clear B cells, but it can inhibit the activation of the CD40 signaling pathway
.

Currently, clinical trials of CFZ533 for liver transplant patients, hidradenitis suppurativa, Sjogren’s syndrome and other indications are still in progress
.

8.
Phase III study of Rilzabrutinib in the treatment of pemphigus

On September 9, Sanofi updated the latest results of the Phase III study (PEGASUS) of Rilzabrutinib in the treatment of pemphigus (a rare autoimmune skin disease), showing that it did not meet its primary or key secondary endpoint
.

PEGASUS is a randomized, parallel, double-blind, placebo-controlled phase III clinical trial.
It is also the first and fastest-growing placebo-controlled trial of BTK inhibitors in the treatment of pemphigus
.
131 newly diagnosed or relapsed patients with moderate to severe pemphigus were recruited in 19 countries or regions around the world
.
The primary endpoint was the complete response rate of patients with the smallest dose (≤10 mg/day) corticosteroids (CS) from week 29 to week 37
.

Rilzabrutinib is one of the three BTK inhibitors that Sanofi acquired after purchasing PrincipiaBiopharma for US$3.
68 billion last year.
It is mainly developed for the treatment of pemphigus, immune thrombocytopenia and atopic dermatitis
.
Previously, Rilzabrutinib had obtained the orphan drug designation for pemphigus vulgaris and the fast-track designation granted by the FDA for pemphigus vulgaris and immune thrombocytopenia
.

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 common and deciduous forms), and systemic corticosteroid therapy is still the standard treatment
.

BTK enzymes play an important role in a variety of immune processes, including B cell expansion, immunoglobulin production, and the activation of innate immune system cells (such as mast cells, eosinophils, and basophils)
.
Therefore, this class of drugs has the potential to be applied to a variety of autoimmune diseases, including rheumatoid arthritis, chronic spontaneous urticaria, and multiple sclerosis
.
In addition to Rilzabrutinib, another BTK inhibitor Tolebrutinib obtained by Sanofi was developed for the treatment of multiple sclerosis, and completed the first proof-of-concept clinical study in the world
.

9.
Phase III study of Pegcetacoplan in the treatment of geographic atrophy (GA)

On September 9, Apellis Pharmaceuticals announced the top-line results of pegcetacoplan, which targets the complement C3 protein, in two phase III clinical trials, DERBY and OAKS
.

A total of 1,258 adult patients with geographic atrophy (GA) with age-related macular degeneration (AMD) were included in the two studies.
The OAKS study reached the primary endpoint, and the increase in GA lesions in the pegcetacoplan monthly or bi-monthly treatment group was significantly reduced by 22%, respectively (P=0.
0003) and 16% (p=0.
0052)
.
However, the DERBY study did not reach the primary endpoint of GA lesion growth (12% vs 11%)
.
According to the research results, the company plans to submit a new drug application (NDA) in the first half of 2022
.
Despite this, Apellis shares fell 31.
67% after the market
.

The DERBY study did not meet the primary endpoint (Source: Apellis)

GA is an advanced disease of age-related macular degeneration (AMD) and one of the main causes of blindness
.
Excessive complement activation drives irreversible pathological growth in GA, and C3 is a pathway target that precisely controls the overactivation of complement
.
Pegcetacoplan, as a C3 targeted therapy under development, is composed of 15 amino acid fragment cyclic peptides connected by two PEG molecules.
It is designed to regulate the excessive activation of the complement cascade and control the occurrence and progression of diseases
.

Pegcetacoplan drug introduction (Source: Apellis)

In May of this year, pegcetacoplan was used to treat adult patients with paroxysmal nocturnal hemoglobinuria (PNH), as well as PNH patients who switched from C5 inhibitor therapy to pegcetacoplan therapy
.
This is also the first targeted C3 therapy approved for the treatment of PNH
.
This approval is based on the head-to-head Phase 3 PEGASUS study (NCT03500549).
In terms of changes in hemoglobin levels from baseline to week 16, pegcetacoplan is superior to eculizumab
.

10.
Phase III study of Verdiperstat in the treatment of multiple system atrophy

On September 27, Biohaven announced the analysis results of a Phase III study of Verdiperstat in the treatment of multiple system atrophy (MSA)
.
Verdiperstat did not achieve statistically significant differences from placebo on either the pre-specified primary efficacy index or the key secondary efficacy index
.
The preliminary analysis of the safety data is consistent with the previous overall situation
.

Indications for Verdiperstat under development (Source: Biohaven)

Multiple system atrophy (MSA) is a disease in which parts of the brain (controlling muscle movement and language) and the autonomic nervous system (controlling involuntary movements) progressively degenerate.
It usually manifests as urinary and sexual dysfunction, and hypotension (orthogonal hypotension).
) Caused by dizziness and fainting, as well as movement disorders such as tremor, stiffness, unsteady gait, and difficulty speaking and swallowing.
The most common causes of death are infection and cardiopulmonary complications
.

Currently, there is no available treatment for MSA, usually only symptomatic and palliative treatment
.
Due to a large number of unmet clinical needs, Verdiperstat has previously obtained Fast Track and Orphan Drug designation from the FDA and the European Medicines Agency
.

Verdiperstat is a first-in-class potent, selective brain permeability and irreversible myeloperoxidase (MPO) inhibitor, developed by Biohaven for the treatment of neurodegenerative diseases
.
Verdiperstat may help protect neurons by inhibiting MPO-induced pathological oxidative stress and inflammation that leads to cell damage in neurodegenerative diseases
.
Although the mechanism of action of verdiperstat has proven to be ineffective against MSA, Biohaven is cooperating with the Sean M.
Healey & AMGALS Center of Massachusetts General Hospital to carry out a clinical trial of verdiperstat in the treatment of amyotrophic lateral sclerosis (ALS), which is expected to be in 2021 Recruitment was completed in the fourth quarter of the year
.

Verdiperstat was first developed by AstraZeneca and has completed seven clinical studies, including four Phase I studies for healthy subjects, two Phase IIa studies for Parkinson’s disease subjects, and one for MSA subjects Phase IIb study
.
Biohaven obtained global rights to the drug in 2018, paying more than $7 million in cash and stock
.

In addition to the above 10 clinical failures, RedHill Biopharma's Opaganib in the treatment of severe COVID-19 phase II/III study, Aerie Pharmaceuticals' AR-15512 in the treatment of dry eye phase IIb clinical trial, Theravance Biopharma's Ampreloxetine in the treatment of symptomatic neurogenic orthosis The phase III study of hypotension (nOH) and the two phase III clinical trials of Servier and Neurochlore's bumetanide in the treatment of autism spectrum disorder (ASD), etc.
, in the results announced this month, both Did not meet the primary endpoint of the study or show treatment efficacy
.

Reference materials:

1.
http://ir.
macrogenics.
com/news-releases/news-release-details/macrogenics-announces-final-overall-survival-results-sophia

2.
https://mp.
weixin.
qq.
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https://investor.
assemblybio.
com/news-releases/news-release-details/assembly-bio-announces-decision-discontinue-clinical-development

3.
https:// Meet-Statistical-Significance/default.
aspx

7.
https://mp.
weixin.
qq.
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8.
https://