Medior

About

Medior is a biosciences company seeking to repurpose existing antiviral medications to treat SARS-CoV-2 (Covid-19). We are working on modifications in delivery format to use a known therapy to combat a novel virus.

Reasons to Invest

New drug development takes years and substantial capital investment;
Repurposing existing therapies is faster and a fraction of the cost;
Exciting opportunity to treat novel viruses means expanding markets and the potential for growth;
Extraordinary possibility for market development

Covid-19 Pandemic

Since the 4Q2019, a novel virus causing severe acute respiratory syndrome spread globally. For nearly a year now, we have been witnessing an uncontrolled spread of a pandemic, caused by the coronavirus known as SARS-CoV-2 (“Covid-19”).

Globally there are ~50mm infected and ~1.2mm dead

Death rate of over 2% from those infected
Potential of killing >100mm globally

Economically, Covid-19 has led to extreme results:

2020 global economic output is expected to shrink ~5.2%.
Increased unemployment throughout all developed economies
Millions of workers on government supported job retention schemes - 19% of total workforce furloughed in United Kingdom, 23% in Germany, 29% in Italy and 41% in France Continuing social unrest.
In the US, real GDP in 2Q2020 contracted 31.7%, expected to continue through 2020
Over 20mm jobs lost during
After initially lifting restrictions most have paused or reversed reopening plans

A successful vaccine against Covid-19 would be a great lifesaving advance. But vaccines alone won’t be enough to bring the crisis under control. We need to be realistic: A vaccine is not a silver bullet. People will continue to contract the virus because some won’t get vaccinated and because the vaccine may not be effective for everyone, particularly older populations at higher risk for illness and death. The annual flu vaccine, for example, reduces the risk for illness by only 40% to 60%, even in years when the vaccine is well matched to the circulating virus strain. It will take months for COVID-19 vaccines to reach a large enough percentage of the population to create “herd immunity” — and that’s assuming they win the public’s trust and the vaccination effort goes smoothly. There are also questions around how long immunity to COVID-19 may last. And vaccines may come up short in frail or older people, especially those with preexisting conditions. Worst of all, the virus may mutate around our vaccines and start re-infecting people. Effective treatments, that are accessible to everyone who needs them, have to be part of the solution to the coronavirus pandemic. Developing COVID-19 drugs could help people live longer and slow the spread of the virus. They could also be used as prophylactic treatment. There is not a single treatment for people who show early signs or mild symptoms of COVID-19. Developing COVID-19 drugs to treat people with mild cases is critical and may be more important than developing a vaccine, which will probably not protect everyone nor last long-term in an individual.

Vaccine

Goal is to develop a vaccine targeting a specific strain of the virus

Covid-19 fortunately has not as yet shown a strong tendency to mutate

Evidence suggests Covid-19 may be challenging to combat via vaccine owing to virus’s ability to effect immune memory

Clinical analysis shows unexplained neuro/motor effects associated with virus

Several vaccine trials were suspended due to unexplained illnesses in trial participants

Not all viruses are candidates for vaccine; for example, no HIV vaccine has ever been developed due to certain challenges

Drug

Goal is to target inhibit growth/multiplication of the virus at any stage of its development via specific chemical substances

Potential drugs include ‘high-molecular’ forms containing peptide or antibody units and so-called ‘small-molecule chemicals’, characterized by the ability to interact with any of the key enzymes implicated in the development  of this pathogen.

According to multiple studies, one promising route targets structural modifications of selected chemical compounds to obtain a product with the greatest potential for application against Covid-19.

This is referred to as “Repurposing”, which is further discussed in these materials.

A completely new drug would take very significant amount of time to develop.

Situation Overview

Development of Covid-19 Drugs

Globally, governments have pledged billions of dollars for Covid-19 vaccine and treatment options.

Many pharmaceutical firms are racing to develop and test potential drugs that could help nations get back to "normal“.

According to the IMF, "Until such medical interventions become available, no country is safe."

Hospitals and research labs are testing different therapies on coronavirus-positive patients in an effort to find a potential COVID-19 treatment.

Type of COVID-19 Treatment Being Studied

550+

Drug development programs in planning

350+

Trials reviewed by Food and Drug Administration

5

COVID-19 treatments currently authorized for Emergency Use

0

Treatments currently approved by FDA for use in COVID-19

How do you normally develop drugs?

Drug development is a long and involved process. It often takes in the region of 15 years for a drug to be approved and prescribed to patients.

1

Research & development

2

Precllinical studies

3

Clinical trials

4

Review and approval

Drug development is a long and involved process. It often takes in the region of 15 years for a drug to be approved and prescribed to patients.

1. This phase can include the early science done to understand a condition, and identify druggable targets. This is followed by identifying, or creating a compound to work on this target. Tens of thousands of compounds may be assessed, with their potential to be therapeutic.

2. This will include tests of your selected compound in chemical models, cell models, and eventually animal models of your disease. These tests will look for efficacy but also safety and toxicity of the drug.

3. This is the first stage at which a drug is tested in humans. Phase I trails are entirely geared towards tolerability and safety. As you move through Phase II there is a growing focus on efficacy, and a growing size of trial, with Phase III trials large and efficacy focused.

4. If trials are successful the drug then needs to be assessed by regulators before reaching patients.

Repurposing antiviral drugs is a key focus to address the Covid-19 threat.

No NEW drugs
Sceen for drugs based on known behaviour

Safety profile known
Human use approved

Early stage safety trials streamlined or skipped

Repurposing offers a quicker, cheaper, and collaborative route to the development of effective treatments.
It is an ideal route to rapidly address conditions with a high unmet need.
There are surprising commonalities between rare diseases and emerging infectious diseases that mean both can benefit from a repurposing approach to more rapidly deliver patient impact.
Repurposing projects have a real chance an delivering a meaningful intervention to patients in a timely manner.

Tilorone as a Broad-Spectrum Antiviral Therapeutic

Indications and Usage

• Treatment of EBOV
• Post-exposure Prophylaxis of EBOV
• Treatment of acute infections from ZIKV, CHIK, SARS-CoV, MERS-CoV, and/or influenza.

Indications and Usage

Human Pharmacology: After oral administration, it is rapidly absorbed from the digestive tract. Bioavailability is 40-60%. Binding to plasma proteins is ~80%. It is not subject to biotransformation. T1/2 = 48 h, and is excreted unchanged in feces (70%) and urine (9%). It does not accumulate. According to Wacker et al. (1972) 16 h after intraperitoneal injection in mice high concentrations of 14C-Tilorone were found in liver, followed by spleen, kidney, and lung. Concentration in lungs was 16 times higher than in blood.
Not a PGP substrate.

Indications and Usage

No serious adverse effects. Acceptable therapeutic index to support treatment for life threatening.

Patient Populations

All age-groups and populations

Drug Interactions

Compatible with antibiotics and other drugs for the treatment of viral and bacterial diseases.

Tilorone – modes of antiviral action

Interferon induction

Tilorone is the first recognized synthetic, small molecular weight compound that is an orally active interferon inducer. Tilorone induces the formation of interferons (alpha, beta, gamma) by intestinal epithelial cells, hepatocytes, T-lymphocytes, and granulocytes. After ingestion, the maximum production of interferon is determined in the sequence of the intestine - liver - blood after 4-24 hours.

The Hypothesized Mechanism of Action for Tilorone is Activation of Innate Immunity Pathways such as the RIG-I-Like Receptor Pathway that Induces IFN and Activates a Cellular Antiviral Response.

However,
In vitro antiviral data in Vero 76 cells may underestimate antiviral activity due to lacking IFN pathways. (Ekins, Sean et al., 2020). (Vero cells are interferon-deficient; unlike normal mammalian cells, they do not secrete interferon alpha or beta when infected by viruses.)

Tilorone – modes of antiviral action. Direct antiviral effect

Lysomorphotropic mechanism of action

Lysosomotropic compounds can diffuse freely and rapidly across the membranes of acidic cytoplasmic organelles in their unprotonated form, then when they enter the acidic environment they become protonated.

Tilorone, is an amphiphilic cationic compound.
The lysosomotropic mechanism may also have an important role as Tilorone blocks viral entry. Cationic amphiphilic drugs have been proposed recently as a useful starting point for broad spectrum antivirals.

Tilorone highly accumulates in lysosomes/endosomes and their membranes, reaching about 100-fold higher intracellular than their extracellular concentration (Ulf Norinder et all, 2020)

Interaction of lysosomotropic cationic amphiphilic drugs (CADs) and coronavirus with membrane trafficking in the cell (Ulf Norinder et all, 2020)

Tilorone as Potential COVID-19 Drugy

Tilorone anti-Sars-Cov-2 in-vitro efficacy (Seungtaek Kim et all, 2020)

Dose- response anti-Sars-Cov-2 for Tilorone.

Blue squares represent inhibition of virus infection (%)
Red triangles represent cell viability (%)

Tilorone anti-Sars-Cov-2 in-vitro efficacy (own data)

In our own in vitro screening using visual detection of the cytopathic effect of infected Vero cells the direct ativiral effect has been determined with an EC50 of about 30 μM.

There are some preliminary signs that Tilorone, which was originally developed as an influenza treatment, may also work against other coronaviruses, including the ones that cause M E R S and S A R S . At least in vitro, it seems to have pan-coronavirus activity, it could be used against not just this coronavirus but others.

Some key events in COVID-19 pathogenesis could be targeted by Tilorone:

Cytokine storm. In severe SARS-CoV-2 infections, ARDS is the ultimate result of a cytokine storm. In this scenario, the release by immune effector cells of large amounts of pro-inflammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3, CCL5) precipitates and sustain s the aberrant systemic inflammatory response. The cytokine storm is readily followed by the immune system “attacking” the body, which in turn will cause ARDS and multiple organ failure, the final result being death, at least in the most severe cases of SARS-CoV-2 infection.
Interferone type I deficiency. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-b and low IFN-a production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor–kB and characterized by increased tumor necrosis factor–a and interleukin-6 production and signaling. Type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches. (Jérôme Hadjadj et all, 2020)
Auto-antibodies against type I IFNs. At least 10% of patients with life- threatening COVID-19 pneumonia have neutralizing auto- Abs against type I IFNs. The crucial role of type I IFNs in protective immunity against SARS-CoV-2 confirmed for patients with inborn errors of type I IFNs and life- threatening COVID-19 . These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2, which is a poor inducer of type I IFNs. The neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production, tip the balance in favor of the virus with insufficient innate and adaptive immune responses (Paul Bastard et all, 2020).

Some key events in COVID-19
pathogenesis could be targeted by Tilorone

Interferons deficiency as substantial difference between COVID-19 and Common respiratory viruses

In comparison to other respiratory viruses, SARS-CoV-2 infection drives a lower antiviral transcriptional response that is marked by low IFN-I and IFN-III levels and elevated chemokine expression, which could explain the pro- inflammatory disease state associated with COVID-19.

SARS-CoV-2 infection induces low IFN-I and -III levels with a moderate ISG response
Strong chemokine expression is consistent across in vitro, ex vivo, and in vivo models
Low innate antiviral defenses and high pro-inflammatory cues contribute to COVID-19
(Daniel Blanco-Melo et all, 2020)