tw0122
1 year ago
The highlights of the presentation are as follows:
Phase II clinical trial and immunohistochemistry study
The trial enrolled a total of 62 patients, including 36 newly diagnosed GBM (new GBM) patients and 26 recurrent GBM patients
Study participants’ mean age at screening was 58.9 years old for new GBM and 59.6 years old for recurrent GBM
39% of patients were female in both groups
94% of new GBM patients and 100% of recurrent GBM patients were Caucasian
All of the subjects received TMZ and MN-166 (ibudilast) treatment
Progression-Free Survival at 6 months (PFS6) was 44% for new GBM and 31% for recurrent GBM
Immunohistochemistry evaluation was performed for the patients whose pre-treatment tumor tissue samples were available from resected tumors at the initial surgery or biopsy to evaluate MIF (macrophage migration inhibitory factor), pERK, Ki67, CD3, CD11b, and CD74
CD3 expression was a good predictor for tumor progression at five months in recurrent glioblastoma subjects treated with MN-166 (ibudilast) and TMZ as subjects with progression had higher CD3 tumor infiltration than subjects with no progression (p
Raffis
4 years ago
Yale researchers will begin a clinical trial at Yale New Haven Hospital to test the effectiveness of a drug called ibudilast (MN-166) for treating acute respiratory distress syndrome (ARDS), a life-threatening lung condition developed by some of the most seriously ill COVID-19 patients. The researchers are part of Yale’s Advanced Therapies Group, which was formed in response to the pandemic and is identifying and advancing possible treatments for the disease.
The drug — which has been approved for years in Japan and Korea for the treatment of asthma — has shown promising results for reducing inflammation associated with ARDS in mouse models. The researchers have partnered with the California company MediciNova to launch the trial. MediciNova had been developing ibudilast as a treatment for multiple sclerosis and neuroinflammation before shifting its attention to COVID-19.
The trials will be controlled studies that test the safety and efficacy of ibudilast for use in patients with COVID-19.
The researchers anticipate FDA approval soon “to treat patients with COVID-19 pneumonia before they develop severe respiratory distress and require mechanical ventilation,” said Dr. Geoffrey Chupp, professor of medicine (pulmonary), director of the Yale Center for Asthma and Airways Disease, and principal investigator of the clinical trial.
The most severely ill COVID-19 patients develop ARDS, which causes hyper-inflammation and fluid buildup in the lungs and leads to a sharp drop in oxygen levels. These patients need ventilators to support their breathing, and their prognosis for survival has been poor. The researchers hope that the drug will reduce damaging inflammation and mitigate the progression of COVID-19-related ARDS, diminish lung injury, and allow patients to recover.
“COVID-19 causes an intense inflammation reaction known as a ‘cytokine storm,’” said Chupp. In patients, this presents as COVID-19-related pneumonia or ARDS.
“If you can modulate that,” he said, “you can dial back the severity of the illness.”
“We have designed a placebo-controlled trial to see if blocking the effects of macrophage inhibitory factor, or MIF, can protect patients with COVID-19 from developing ARDS,” said Dr. Maor Sauler, assistant professor of medicine (pulmonary) and co-investigator in the study, who researches the effects of MIF on inflammatory diseases in the lung.
Ibudilast is a type of drug known as a MIF inhibitor. MIF is a gene that regulates the immune response — a driver of inflammation and the so-called “cytokine storm.” Over-expression of the gene has been found to play a key role in a number of diseases, including ARDS, asthma, rheumatoid arthritis, lupus, and multiple sclerosis.
Dr. Richard Bucala, chief of rheumatology, allergy, and immunology at Yale School of Medicine and rheumatologist-in-chief at Yale New Haven Health, is a pioneer in the discovery of drugs that interfere with the MIF pathway to target disease. He was the first to clone MIF and its receptor, and he has developed small-molecule MIF inhibitors to treat autoimmune diseases and cancer. MN-166’s inhibition of MIF activity was discovered by Elias Lolis, professor of pharmacology. Bucala, who co-directs the Advanced Therapies Group with Dr. Naftali Kaminski, led the partnership with MediciNova. Kaminski is the Boehringer Ingelheim Pharmaceuticals, Inc. professor of medicine (pulmonary).
“We are excited for this partnership opportunity to initiate this study, given the high morbidity and mortality of COVID-19, and the present lack of any evidence-based therapies,” said Bucala. “We additionally hope that insights from this trial will help us to better understand how ARDS develops, irrespective of its underlying cause.”
COVID-19 patients who are on ventilators for ARDS currently have few treatment options.
“Once a patient is in respiratory failure on a ventilator, there is no specific treatment for reducing lung injury and minimizing ARDS,” Chupp said. “All approaches are just to support the patient until the lung heals.”
The effort is one of many by Yale’s Advanced Therapies Group to find new treatments, diagnostics, and targets for combatting COVID-19. Recently, the group helped to lay the groundwork for clinical trials of the novel drug sobetirome to treat patients with ARDS, also at Yale New Haven Hospital.
https://news.yale.edu/2020/04/23/yale-launches-clinical-trial-drug-treat-severe-covid-19-patients
Raffis
4 years ago
About MN-001 Positive Phase 2 Results
“MN-001 (tipelukast) is a novel, orally bioavailable small molecule compound which exerts its effects through several mechanisms to produce its anti-fibrotic and anti-inflammatory activity in preclinical models, including leukotriene (LT) receptor antagonism, inhibition of phosphodiesterases (PDE) (mainly 3 and 4), and inhibition of 5-lipoxygenase (5-LO). The 5-LO/LT pathway has been postulated as a pathogenic factor in fibrosis development and MN-001’s inhibitory effect on 5-LO and the 5-LO/LT pathway is considered to be a novel approach to treat fibrosis. MN-001 has been shown to down-regulate expression of genes that promote fibrosis including LOXL2, Collagen Type 1 and TIMP-1. MN-001 has also been shown to down-regulate expression of genes that promote inflammation including CCR2 and MCP-1. In addition, histopathological data shows that MN-001 reduces fibrosis in multiple animal models.
Previously, MediciNova evaluated MN-001 for its potential clinical efficacy in asthma and had positive Phase 2 results. MN-001 has been exposed to more than 600 subjects and considered generally safe and well-tolerated.”
https://medicinova.com/clinical-development/core/mn-001-nash/
Development Plans
Recent preclinical results provide compelling evidence that MN-001 warrants further evaluation for the treatment of NASH in humans. MediciNova has an open IND at FDA. Due to safety data from previous clinical studies of MN-001, FDA has approved the protocol for a Phase 2 study as the first clinical trial of MN-001 in NASH.
https://medicinova.com/clinical-development/core/mn-001-nash/liver-fibrosis/
Raffis
4 years ago
Phase II Study – MN-221-CL-004
This clinical trial achieved statistical significance in its primary endpoint of mean change in forced expiratory volume in one second, or FEV1, from baseline to measurement at 15 minutes (the end of the infusion) at doses of 10, 16, 30 and 60 micrograms per minute of MN-221 (p-value less than or equal to 0.0006) compared to placebo.
There were no clinically significant cardiovascular, electrocardiogram, or ECG, or vital sign changes observed at any dose tested. In addition, no serious adverse effects were observed in this clinical trial.
Raffis
4 years ago
To see whether mice develop an illness similar to the one in people, the researchers infected mice with the modified adenovirus, and then five days later gave them the COVID-19 virus through the nose. The virus quickly spread along the respiratory tract and especially to the lungs, where it replicated to high numbers and caused pneumonia with marked inflammation, much as it does in people. The researchers also found lower levels of virus in the heart, spleen and brain—all organs that can be targets of the virus in people. The mice lost 10% to 25% of their body weight during their illnesses but ultimately recovered.
"The mice develop a similar lung disease to what we see in humans," said Diamond, who is also a professor of molecular microbiology, and of pathology and immunology. "They get quite sick for a while but eventually recover, like the vast majority of people who get COVID-19. You can use this technique with almost any strain of laboratory mouse to make them susceptible to SARS-CoV-2 and then do whatever kind of study you want: test vaccines or drugs, study the immune response, and many other things related to how the virus causes disease."
https://medicalxpress.com/news/2020-06-covid-mouse-drugs-vaccines.html
A mouse model study was conducted to assess systemic IgG and mucosal IgA antibody production against S1 Ag after intranasal vaccination with MediciNova’s BC-PIV SARS-CoV-2 vaccine prototype. We confirmed a high IgA antibody titer against S1 Ag in the nasal lavage fluid from mice given intranasal BC-PIV SARS-CoV-2 vaccine. We also confirmed that a high IgG antibody titer against S1 Ag was induced in mice serum.
Yuichi Iwaki, M.D., Ph.D., President and Chief Executive Officer of MediciNova, Inc., commented, "We are very encouraged that our intranasal BC-PIV SARS-CoV-2 vaccine induced high titers of systemic serum IgG and mucosal IgA neutralizing antibodies in a mouse model study. These successful results support the scientific and technical rationale of our intranasal vaccine in addition to similar success with BioComo’s BC-PIV RSV vaccine prototype. We look forward to reporting additional progress on our intranasal COVID-19 vaccine in the near future.”
https://finance.yahoo.com/news/medicinova-announces-intranasal-covid-19-103000673.html
Raffis
4 years ago
Medicinova’s resources are jointly helping BioComo to produce a COVID-19 vaccine - - President Masayuki Fukumura, Mie prefecture, Japan; http://www.biocomo.jp/).
Medicinova said: President and Chief Executive Officer of MediciNova, Inc., commented, "Given the current global pandemic of COVID-19, we appreciate this very important opportunity to jointly develop a vaccine against SARS-CoV-2 with BC-PIV in collaboration with BioComo and Mie University. Previously, BioComo has been successful in developing vaccines against Ebola virus and RS virus with their BC-PIV technology, which made us confident that their technology will be successful for SARS-CoV-2 vaccines.”
BioComo said: Masayuki Fukumura, President of BioComo, commented, “We are very pleased to proceed with the co-development of a SARS-CoV-2 vaccine with MediciNova which has a proven track record of international clinical development for unmet medical needs.”
MediciNova has been granted exclusive worldwide development rights to use BC-PIV for SARS-CoV-2 vaccine development from BioComo and Mie University.
Raffis
4 years ago
BC-PIV, an innovative non-transmissible viral vector co-developed by BioComo and Mie University, is derived from the recombinant human parainfluenza virus type 2 (hPIV2). BC-PIV is highly efficient to transfer multiple foreign proteins to recipients with a strong safety profile, without secondary protein infections. BC-PIV displays the gene and foreign protein inside and outside of the viral membrane. BC-PIV can carry large membrane proteins of viruses and signal transduction receptors/ligand proteins on the viral surface. BC-PIV can carry proteins that require a proper three-dimensional structure or multimeric structure while maintaining the structure. BC-PIV elicits good immunogenicity against antigen proteins without adjuvants. The SARS-CoV-2 vaccine prototype has been developed to include the specific SARS-CoV-2 antigen protein in order to express maximum antigenicity. To date, BioComo has succeeded in producing a recombinant Ebola virus vaccine (https://www.nature.com/articles/s41598-019-49579-y) and a Respiratory Syncytial virus prefusion F vaccine (unpublished data) using this BC-PIV platform technology.
Yuichi Iwaki, M.D., Ph.D., President and Chief Executive Officer of MediciNova, Inc., commented, "Given the current global pandemic of COVID-19, we appreciate this very important opportunity to jointly develop a vaccine against SARS-CoV-2 with BC-PIV in collaboration with BioComo and Mie University.
Previously, BioComo has also successfully developed vaccines against Ebola and RS viruses with BC-PIV technology and assured a successful vaccine for SARS-CoV-2.
We feel a great sense of mission to initiate this SARS-CoV-2 vaccine project in addition to our MN-166 project targeting ARDS, which is a very serious and potentially fatal disease that can be caused by COVID-19."
Masayuki Fukumura, President of BioComo, commented, “We are very pleased to proceed with the co-development of a SARS-CoV-2 vaccine with MediciNova which has a proven track record of international clinical development for unmet medical needs. We initiated the development of a novel BC-PIV SARS-CoV-2 vaccine with Dr. Tetsuya Nosaka in March of this year (http://www.biocomo.jp/20200319.pdf).
Multiple stabilized Spike protein mutants of SARS-CoV-2 were devised and the respective genes and proteins were loaded onto BC-PIV.
We already completed core characterization studies with mice models.
BC-PIV is characterized by its ability to load a large antigenic protein retaining the three-dimensional structure of the vector envelope and its high affinity for the nasal mucosa and upper respiratory tract mucosa and induces local mucosal immunity.
BC-PIV can be an intra-nasal vaccine in addition to an intra-muscular injection because of its high affinity to nasal and upper respiratory tract mucosa, which is the same route of the natural infection of SARS-CoV-2. An intra-nasal vaccine is expected to induce local mucosal immunity.
GMP manufacturing has been one of the barriers for us until now, but through our joint development with MediciNova, we will proceed with further non-clinical and clinical trial development as quickly as possible globally and not only in Japan.
We are thrilled with the challenge to develop a vaccine that has potential clinical application to limit the spread of SARS-CoV-2.”
Tetsuya Nosaka, Professor at Mie University Graduate School of Medicine, commented, “I am very excited about the outcome of the long-standing development of the vector and genetically modified vaccines with BioComo that can be applied to prevent COVID-19, a major global health threat. We believe BC-PIV is effective, safe, convenient, and cost efficient as a vaccine vector, and have been seeking an opportunity for the clinical application for long time.
However, the academic research environment has been less encouraging lately. Therefore, it is a great encouragement for us as member of the academic community to achieve this international joint development with MediciNova, which has an abundant track record of manufacturing and clinical development.
We are confident that the BC-PIV SARS-CoV-2 vaccine will be successful and hope that this vaccine will be available in a clinical setting as soon as possible and will be the “gospel” for the people in the world.”
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