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Wednesday, April 29, 2020

Trovagene (TROV)

Lead Drug Shows Potential as KRAS inhibitor in Colorectal Cancer

Trovagene, Inc. is a clinical stage biotechnology company focused on the development of new therapeutics for hematology and oncology. The company’s clinical programs of Onvansertib (PLK1 inhibitor) include Phase 1b/2 study in AML, Phase 1b/2 study in mCRPC and Phase 1b/2 trial in KRAS-mutant colorectal cancer.

Cosme Ordonez, MD, Ph.D., Senior Life Sciences Analyst, Noble Capital Markets, Inc.

Refer to the full report for the price target, fundamental analysis, and rating.

Trovagene’s lead drug effective in 88% of mCRC patients. The company yesterday released interim results from a Phase Ib/II clinical trial on the use of onvansertib for the treatment of metastatic colorectal cancer (mCRC) patients carrying KRAS mutations. Onvansertib is a first-in-class, third generation highly selective inhibitor of PLK1. In the trial, 7 out of eight patients (88%) responded to a drug treatment combination.

Data was presented at AACR 2020 Annual Meeting. The results were presented by Dr. Afsaneh Barzi at the American Association for Cancer Research (AACR) conference. Dr. Barzi was the principal investigator of the study. She is an associate professor of clinical medicine at Keck School of Medicine of USC and medical oncologist at…









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Companies Developing Coronavirus Treatments – Clinical/Preclinical

(Note: companies that
could be impacted by the content of this article are listed at the base of the
story [desktop version]. This article uses third-party references to provide a
bullish, bearish, and balanced point of view; sources are listed after the
Balanced section.)

The War Against Coronavirus

The outbreak of the novel coronavirus disease COVID-19 rapidly spreads around the globe. The various biotechnology firms, scientists, and physicians have been racing to understand this new virus and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. Selected treatment options are highlighted below.

The current treatment options

1. Antivirals

Antiviral drugs destroy the virus by targeting and inhibiting the viral replication. Various drugs and approaches -including generic antimalarial drugs, novel drugs, and repurposed drugs that were intended to treat similar viral diseases- are being investigated to find an effective treatment for COVID-19The World Health Organization (WHO) recently started the solidarity program to test four existing therapies. The program is an international clinical trial to help find an effective treatment for COVID-19. The trial will compare four treatment options against the standard of care, to assess their relative effectiveness against COVID-19. The trial is evaluating

 

• Chloroquine and hydroxychloroquine
• Remdesivir
• Combination of lopinavir and ritonavir
• The above two HIV drugs plus the anti-inflammatory small protein interferon beta

 

These drugs are also being investigated in separate clinical trials worldwide. Among all the antiviral agents that are under investigation, Gilead’s remdesivir is the most advanced in the clinic. In a study published by NEJM, Gilead reports that in the compassionate study with 53 patients the drug resulted in the clinical improvement of 68% of these patients. However, the study result included small number of patients, and there was no randomized control group to compare against. On April 16^th, The University of Chicago Medicine reported that it had recruited 125 people with COVID-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir with nearly all patients discharged in less than a week and there were only two deaths. Placebo controlled Chinese trial data suggested no significant improvements in fatality of patients. Among 158 patients (79 in the control arm), 13.9% of the remdesivir patients had died compared to 12.8% of patients in the control arm after 1 month of treatment. Reports suggest that Gilead will present additional data from the first 400 patients in the trial with severe symptoms in May.

2. Antibodies

These drugs are engineered to trigger the immune system to attack the virus. A plethora of companies are pursuing this approach.

3. Immune
   system inhibitors

This group of treatment is charged with controlling the increased immune response known as the cytokine storm. Clinical evidence suggests that a frenzied immune response in COVID-19 patients make people severely ill or cause death. Several strategies are under investigation including cell therapies and small molecules.

4. Convalescent Plasma

This treatment method involves infusing COVID-19 patients with plasma from people who have recovered from the illness. The plasma is rich in antibodies that can fight Covid-19. Clinical studies are underway to evaluate this approach. A caveat of plasma therapy is that there isn’t enough plasma from recovered patients to treat a large patient pool.

Exhibit 1. Companies Developing Coronavirus Treatment
(Clinical/preclinical and alphabetical order)

Several
companies are pursuing programs to combat coronavirus as shown in Exhibit 1
including:

Antiviral

Cocrystal Pharma

Cocrystal Pharma is developing a protease inhibitor in collaboration with Kansas State University Research Foundation. Based on this collaboration Cocrystal Pharma will develop certain proprietary broad-spectrum antiviral compounds for humans to treat coronavirus infections. The company hopes to initiate preclinical studies in H2 2020.

Antibodies

CytoDyn

The acute respiratory distress syndrome (ARDS) of COVID-19 results from the accumulation of neutrophils within the pulmonary circulation and alveolar spaces. Leronlimab (PRO 140) inhibits the migration of Tregs into areas of inflammation, which can inhibit the innate immune response against pathogens and, most importantly, the migration of macrophages and release of pro-inflammatory cytokines in lungs. The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation.

The company recently announced that it has treated the first patient with leronlimab, in a Phase 2b/3 study evaluating it in severe and critically ill COVID-19 patients. The study will evaluate the two-week administration of leronlimab in the patient population. The primary endpoint is the mortality rate at 28 days and secondary endpoint is the mortality rate at 14 days. The company plans to conduct an interim analysis of the data from 50 patients. The company will also evaluate leronlimab in a Phase 2b study in mild-to-moderate COVID-19 patients. CytoDyn has also administered leronlimab in about 30 patients, through hospitals and clinics, under Emergency Investigational New Drug (EIND) authorizations granted by the FDA. Data from patients under EIND has been promising. The first five patients with mild-to-moderate infection have been removed from oxygen. The data demonstrated that patients had encouraging immune restoration as well as a dramatic reduction in the critical cytokine storm after seven days of treatment. Particularly, restoration in the CD8 T-lymphocyte population, and a dramatic reduction in the critical cytokine storm cytokines IL-6, TNF-alpha. Patients are also benefiting from leronlimab treatment by being removed from external ventilation or extubated within seven days.

Humanigen

Humanigen is focused on preventing and treating cytokine storm with lenzilumab, the company’s proprietary Humaneered anti-human GM-CSF monoclonal antibody. Humanigen has announced that FDA has permitted to commence a Phase 3 study of lenzilumab in patients with COVID-19. Humanigen is developing a neutralizing, IgG1, monoclonal antibody against human GM-CSF, the upstream initiator of cytokine stress. Lenzilumab has demonstrated a sufficient safety and tolerability profile in other diseases, including severe asthma. Humanigen plans to enroll patients in a multicenter, randomized, placebo-controlled, double-blinded clinical trial with lenzilumab for the prevention of respiratory failure and/or death in hospitalized patients with pneumonia associated with COVID-19 in patients.

Nascent Biotech

Nascent Biotech’s lead product, pritumumab, is a fully natural human IgG antibody. Pritumumab is obtained by a proprietary technology from a B-cell isolation from a tumor-draining lymph node of a patient with cervical cancer. Pritumumab target is vimentin. Vimentin interacts directly with the coronavirus during its binding process to the non-infected cell and anti-vimentin antibodies can reduce the uptake of the coronavirus in pre-treated animals. Pritumumab is being studied to validate its inhibition of the virus to recognize, and therefore infect, the target cells.

Immune
Modulators

Can-fite

Can-Fite recently received approval to initiate a pilot clinical study of its drug candidate piclidenoson for the treatment of moderate-to-severe symptoms COVID-19 infected patients. It is also being evaluated in a multinational Phase 3 studies as a first-line treatment for rheumatoid arthritis, and as a treatment for moderate-to-severe psoriasis. Piclidenoson exerts its mechanism of action by modulation of key signaling proteins, such as PI3K, GSK-3?, PKA, PKB/Akt, IKK, and NF-kB, thereby de-regulating the Wnt and the NF-kB pathways. Consequently, this results in apoptosis of inflammatory cells.

The company is conducting a pilot trial that is a randomized, open-label, 2-arm study of Piclidenoson plus standard supportive care, compared to standard supportive care alone. Forty hospitalized COVID-19 infected patients with moderate-to-severe symptomatic disease will be randomized in a 1:1 ratio to one of the trial arms and will be treated for up to 4 weeks.

Capricor

Capricor reported earlier this month that two patients were treated in Los Angeles, California with infusions of CAP-1002. The company also reported that they plan to treat additional patients and submitted an expanded access Investigational New Drug (IND) application to investigate the use of CAP-1002 in certain COVID-19 patients. CAP-1002 consists of allogeneic cardiosphere-derived cells, or CDCs, a type of cardiac cell therapy that has been shown in pre-clinical and clinical studies to exert potent immunomodulatory activity and is being investigated for its potential to modify the immune system’s activity to promote cellular regeneration. The cells function by releasing exosomes that are taken up largely by macrophages and T-cells and begin a cycle of repair. CAP-1002 is also under clinical development for the treatment of Duchenne muscular dystrophy. In published pre-clinical data, the company reported that that CAP-1002 mitigates the release of anti-inflammatory cytokines as well as macrophage activation in several models of inflammatory diseases including sepsis and other autoimmune diseases. It is believed that COVID-19 induced ARDS pneumonia is a response to the cytokine storm and CAP-1002 could be a beneficial for the patients.

Cellular Biomedicine group

The Cellular biomedicine group is conducting a Phase 1 single-arm design, open-label, combined interventional clinical trial, to explore the safety and efficiency of exosomes derived from allogeneic adipose mesenchymal stem cells (MSCs-Exo) treatment for severe patients hospitalized with novel coronavirus pneumonia (NCP).

MediciNova

MediciNova will initiate clinical studies to investigate its drug, ibudilast (MN-166), to ARDS associated with Covid-19. The study will be conducted in collaboration with Yale’s Advanced Therapies Group. Ibudilast’s exerts its mechanism of action by inhibiting macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE) -4 and -10. In doing so it also inhibits pro-inflammatory cytokines and promotes neurotrophic factors. Furthermore, in previous human studies ibudilast demonstrated a significant decrease in serum MIF levels. Ibudilast’s anti-neuroinflammatory and neuroprotective actions were shown in previous clinical studies.

Pluristem

Pluristem recently successfully treated one patient with PLX cells in the United States under the compassionate use program. Prior to this, the company reported 100% survival rate for all seven high-risk patients under treatment from their compassionate use program in Israel. Furthermore, of the 6 patients that completed one week follow up, 4 of the 6 (66%) patients demonstrated improvement in respiratory parameters and 3 of the 6 (50%) patients were in advanced stages of weaning from ventilators.

PLX cells are allogeneic mesenchymal-like cells that have immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages, and thus may prevent or reverse the dangerous overactivation of the immune system. Therefore, PLX cells may potentially reduce the incidence and or severity of COVID-19 pneumonia and pneumonitis. Pluristem’s main target is to initiate a multinational clinical trial as soon as possible for PLX cells in the treatment of patients suffering from complications associated with COVID-19.

 

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Vaccine Status — Which Companies are In What Stage

(Note: companies that
could be impacted by the content of this article are listed at the base of the
story [desktop version]. This article uses third-party references to provide a
bullish, bearish, and balanced point of view; sources are listed after the
Balanced section.)

Developing a vaccine against Covid19 is of obvious global importance. Vaccines stimulate immune systems to produce antibodies, similar to the subject being exposed to the disease. Production of antibodies and stimulation of immune systems help the human body to develop immunity against disease. This provides a preventative measure of protection. As it relates to the novel coronavirus, several approaches (Exhibit 1) are being investigated by scientists in the biotechnology and pharmaceutical industry, hospitals, and academic research institutes. Each approach holds different advantages and disadvantages. For example, the RNA and DNA-based vaccines are leading in their clinical advancement due to advantages in the speed of development. However, their safety profile is not well defined, and these vaccines could run into potential hurdles and face stricter regulatory approvals. Two US-based companies are currently in clinical trials, the first vaccine into the clinic was Moderna’s mRNA-1273 on March 16th, followed by Inovio’s DNA vaccine on April 6th.

Exhibit
1: Types of vaccines

Source:
Wall Street Journal

Upcoming
trials include

• Biontech/Pfizer – starting in April 2020
• Novavax Inc – Mid-May 2020
• Johnson & Johnson – September 2020
• Vaxart/Emergent Biosolutions – H2 2020

Exhibit 2.
Companies Developing Vaccine Against Coronavirus (Stage
and alphabetical order)

Selected
companies below are currently developing vaccines against coronavirus:

Currently
or soon in the clinic:

Inovio
Pharmaceutical

Inovio Pharmaceutical
in collaboration with Beijing Advaccine Biotechnology is investigating INO-4800 DNA vaccine in a Phase 1 clinical trial. The trial aims to enroll up to 40 healthy adult volunteers in Philadelphia, PA (at the Perelman School of Medicine at the University of Pennsylvania) and Kansas City, MO (at the Center for Pharmaceutical Research). Each participant will receive two doses of INO-4800 four weeks apart, and the initial immune responses and safety data from the study are expected by late summer.

Moderna

Moderna’s mRnA-1273 was developed in 42 days and it remains on schedule to complete Phase 1 trials. The trials are being conducted by The National Institute of Allergy and Infectious Diseases (NIAID). The trial has so far enrolled 45 subjects and the company announced on April 14^th that the trial had started recruiting for its highest dose. The trial has three arms that are administering doses of 25 mcg, 100 mcg, and 250 mcg. Data is expected in Q2-Q3 2020. On April 16^th, Moderna’s vaccine also received $483 million from the U.S. government to assist in the development and testing of the vaccine.

OncoSec

OncoSec is awaiting FDA approval for an IND application filed by Providence Cancer Institute to pursue a first-in-human Phase 1 clinical trial of OncoSec’s novel DNA?encodable, investigational vaccine CORVax12. CORVax1 consists of OncoSec’s existing product candidate, TAVO (interleukin-12 or IL-12 plasmid), in combination with an immunogenic component of the SARS-CoV-2 virus recently developed by researchers at NIAID and licensed to OncoSec on a non-exclusive basis.

Preclinical or discovery stage:

Dyadic

Dyadic is collaborating with The Israel Institute for Biological Research (IIBR) to develop therapeutics against Covid-19. As per the collaboration, IIBR will develop potential candidates and Dyadic will use their C1 technology to manufacture vaccines and monoclonal antibodies. C1 expression system is at the discovery stage to manufacture large volumes of low-cost biologic products such as enzymes and proteins.

Generex Biotechnology

Generex Biotechnology (GNBT) has signed a contract with EpiVax to use their computational tools to predict epitopes that can be used to generate peptide vaccines against the Covid-19 using the patented NuGenerex Immuno-Oncology (NGIO – Formerly Antigen Express) Ii-Key technology. The patented NuGenerex Immuno-Oncology (Formerly Antigen Express) Ii-Key technology uses synthetic peptides that mimic essential protein regions from a virus that is chemically linked to the 4-amino acid Ii-Key to robustly activate immune system. In particular, the Ii-Key ensures potent activation of CD4+ T cells, which in turn facilitates antibody production to ward off infection. This Ii-Key modification can be applied to any protein fragment of any pathogen to increase the potency of immune stimulation.

EpiVax has identified many “hotspots” in the amino acid sequences of the nCOV-2019 coronavirus proteins. Using the epitopes predicted by EpiVax, Generex will manufacture a series of synthetic amino acid peptides that mimic the epitopes of the virus and send them to China for testing

Heat
Biologics

Heat Biologics (HTBX) is developing therapeutic vaccines in collaboration with the University of Miami to support the development of a vaccine leveraging Heat’s proprietary gp96 platform designed to target the SARS-CoV-2 coronavirus that causes COVID-19.

iBIO

iBio is developing IBIO-200 a virus-like particle (VLP) based vaccine for the COVID-19 disease in collaboration with Texas A&M University. VLP based vaccines have a unique mechanism of action by which they interact with immune cells differently than soluble antigens and can stimulate both humoral and cellular responses. iBIO-200 has been designed to display enhanced vaccine uptake by antigen-presenting cells to increase the overall immune response.

IMV
Inc.

IMV Inc. plans to develop of a DPX-based vaccine for COVID-19. DPX is the Company’s proprietary lipid-based delivery platform with no aqueous components in the final formulation. The DPX platform can be formulated with peptide antigens. The Company is using sequences of the virus and immunoinformatics to predict antigens to generate neutralizing antibodies against SARS-CoV-2. IMV began manufacturing the peptide candidates targeting these epitopes. The company plans to conduct preclinical studies in collaboration with the University Laval in Quebec City. Simultaneously, in collaboration with the Canadian Center for Vaccinology and the Canadian Immunization Research Network the design of a Phase 1 clinical study in 48 healthy subjects has been completed. The clinical sites are identified in both Nova Scotia and Quebec.

Tonix

Tonix Pharmaceuticals announced a collaboration with Southern Research to develop a vaccine TNX-1800 against Covid-19. The company is using its proprietary horsepox virus vector platform for the development of TNX-1800. Tonix has previously reported that horsepox has efficacy as a vaccine and good tolerability in mice and cynomolgus macaques. 

Vaxart

Vaxart uses a specific virus called adenovirus type 5 (Ad5) as part of its novel technology platform to help train the immune system to recognize and defeat dangerous invading pathogens. The Ad5 virus serves as a vector to deliver the antigen and booster molecules to stimulate immune responses. The antigen is the pathogen protein designed to trigger the targeted immune response and the booster molecule is an adjuvant that stimulates and adds to the immune response. Vaxart can use the same vector with different antigens to provide an effective standardized and scalable approach for vaccine development. Vaxart’s approach to develop a vaccine for Covid-19 involves generating potential vaccine candidates based on the published genome of the 2019 Novel Coronavirus (2019-nCoV). Recently, Vaxart announced that it had produced five COVID-19 vaccine candidates for testing in its preclinical models. The company expects to advance the best performing vaccine to manufacturing for clinical trials.

 

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