Severe Influenza Treatment | POLB 001

Phase 2 Ready Orally Administered p38 MAP Kinase inhibitor

Severe influenza is typically characterised by a disproportionate systemic immune response, which can cause significant local damage in the lungs and can affect other organs in the body. The uncontrolled immune response commonly results in a need for hospitalization.

POLB 001 selectively inhibits overwhelming inflammation in severe influenza, while leaving the necessary immune functions intact to fight the infection. This contrasts with other immunomodulatory approaches, such as steroids, which affect both beneficial and damaging immune responses.

Compelling Data

Phase 2 ready oral small molecule, excellent bioavailability
Strong pre-clinical data package
Proven safety profile & well tolerated in Phase I clinical trial
Efficacy demonstrated in Phase 1b human challenge trial supports partnering

Strong Patent Portfolio

Granted patents for severe influenza out to 2038
Oncology patent applications filed in 2023, potential for protection out to 2043
Learn more about POLB 001 for cancer immunotherapy-induced CRS here

Major Market Opportunity

1 Billion estimated cases of influenza each year, 5-10 million hospitalisations, 500,000 annual influenza related deaths
Current treatments are effective within the first 48 hours of symptom onset but are less effective at more advanced stages of the disease
POLB 001 is strain agnostic and shelf stable making it ideal for stockpiling

Evidence for benefit of POLB 001 in the therapy of LPS-induced inflammation

Supplementing the applicability of POLB 001 to severe influenza on the one hand and immunotherapy-induced CRS on the other, POLB 001 has been investigated in a human lipopolysaccharide (LPS) challenge trial.

Randomised, double-blind, placebo-controlled, multiple dose, inflammatory challenge trial in healthy volunteers

Trial design

Endpoints

Intravenous LPS challenge

Bloods (cytokines, vascular markers, CRP)
Ex-vivo LPS response
Safety & tolerability (inc. vital signs, AE’s, ECG, Haematology)
Local inflammatory responses were also measured

Results Demonstrate POLB 001 can Potently Inhibit Inflammation

POLB 001 was widely distributed, reduced the inflammatory response and inhibited p38 MAPK activation and signaling following LPS challenge.

Excellent safety profile across two clinical studies
Potent target inhibition confirmed
Major reduction of key inflammatory markers
Clear dose response relationship observed

Potent and Selective Inhibition of p38 MAPK Signaling

Effective target engagement demonstrated

Levels of phosphorylated p38 MAPK in circulating monocytes

POLB 001 was widely distributed
POLB 001 inhibited p38 MAPK activation, direct measurement of activation
POLB 001 inhibited in vivo and ex vivo responses to LPS-induced TNF-α, indirect measurement p38 activity

Blood samples were taken before and after administration of intravenous LPS. Peripheral blood samples were analyzed by flow cytometry. Monocytes were gated by FSC, SSC and CD14+. Data is presented as mean MFI values of phospho-p38 +/- SEM

Reduced Key Inflammatory Cytokines Following LPS Challenge

Dose dependent reductions of inflammation

TNF-α

TNF-α reduction of 73.5% and 56.2% seen for 70 mg and 150 mg doses respectively (p = 0.0003†)

IL-6

IL-6 reduction of 57.4% and 63.5% seen for 70 mg and 150 mg doses respectively (p = 0.0002†)

IL-8

IL-8 reduction of 80.7% and 76.7% seen for 70 mg and 150 mg doses respectively (p < 0.0001†)

TNF-α, IL-6 and IL-8 levels decreased between 56-81% in subjects treated with 70 mg or 150 mg POLB 001 twice daily

†The exploratory analysis suggested statistically significant improvement in treatment (p<0.05) for the endpoints examined.

Reduced Key Indicators of LPS-Induced Systemic Inflammation

The reduction of systemic cytokines aligns with improvement in clinically meaningful endpoints

Mean Body Temperature

No significant effect on body temperature with a trend towards reduction compared to placebo.

Heart Rate Rise (bpm)

Suppressed increase in heart rate following IV LPS administration

C-Reactive Protein (CRP)

CRP level reductionof 33.1% and 33.3% seen for 70mg and 150mg doses respectively

POLB 001 Effectively Reduced Inflammation in Tissue

POLB 001 150 mg significantly reduced IL-1β† and TNF-α† responses in blister exudate compared to placebo

TNF-α in blister exudate

IL-1β in blister exudate

†The exploratory analysis suggested statistically significant improvement in treatment (p<0.05) for the endpoints examined.

We are open to partnering, contact our team at

Partnering@PoolbegPharma.com

A small molecule immunomodulator – ideally placed to address the significant unmet need in severe influenza

LPS human challenge trial completed in December 2022, positive results from the successful trial were published in March 2023
POLB 001 treatment resulted in a highly significant reduction in p38 MAP kinase driven cytokines
POLB 001 exhibited a marked reduction in multiple markers of systemic and local inflammation compared with placebo
Trial results demonstrate expected utility in severe influenza and other acute inflammatory conditions
Selectively inhibits overwhelming inflammation in viral infections, such as influenza, while leaving the necessary immune functions intact to fight the infection. This contrasts with other immunomodulatory approaches, such as steroids, which affect both beneficial and damaging immune responses
Strain agnostic and unaffected by seasonal variants which is a significant advantage over treatments available on the market
Shelf stable oral drug making it an ideal stock piling candidate for both seasonal and pandemic outbreaks

Influenza

1 BILLION

Estimated Global Cases

1 in 8

Annual Global Infection Rate

5 – 10 MILLION

Global Influenza In Numbers Graphic 3 01

Hospitalisations

~500,000

Global Influenza In Numbers Graphic 4 01

Annual Influenza Related Deaths

Severe influenza can cause life changing injuries

Severe influenza is typically characterised by disproportionate systemic immune responses known as hypercytokinaemia or ‘cytokine storm’. This is a whole-body immune response to the virus which can cause significant local damage in the lungs which can affect other organs in the body. Due to tissue damage in the lung, patients often develop bacterial or fungal infections and potentially life-threatening respiratory failure.

What separates POLB 001 from other influenza treatments?

By targeting the host immune response rather than the virus itself, POLB 001 is unaffected by viral strain or variants.

Current treatments are most effective when given within the first 48 hours of symptom onset as they block viral replication but are less effective at more advanced stages of the disease. Despite limited evidence of their effectiveness, current treatment guidelines for patients presenting with advanced disease is to receive antiviral treatment as there are no other approved treatment options available. There is a major unmet need for effective treatments to improve outcomes in severe influenza.

POLB 001 selectively inhibits overwhelming inflammation in viral infections while leaving the necessary immune functions intact to fight the infection. This contrasts with other immunomodulatory approaches, such as steroids, which affect both beneficial and damaging immune responses.

By inhibiting p38 MAP kinase, POLB 001 can reduce the expression of tissue-damaging cytokines such as IL-6 and TNFα. POLB 001 has been shown to be safe and well-tolerated and has demonstrated the ability to block cytokine expression in circulating immune cells in treated subjects.

LPS Human Challenge Trial

A randomised, double-blind, placebo-controlled, multiple dose, LPS human challenge study in 36 healthy volunteers to assess the potential efficacy of POLB 001 in treating the hyperinflammatory responses associated with severe influenza. As part of the trial, researchers stimulated the immune systems of healthy volunteers with LPS across three cohorts. LPS triggers a robust immune response and acts as a surrogate for the hyperinflammatory effects associated with severe influenza infection, as well as other acute inflammatory conditions. Each cohort received escalating doses of POLB 001 to evaluate its effectiveness in suppressing the body’s harmful inflammatory response to both intradermal (a shallow injection) and intravenous (an injection in a vein) administered LPS, which will produce a broad-ranging dataset.

Key highlights from the study

POLB 001 resulted in a highly significant reduction in p38 MAP kinase driven cytokine levels (TNF-α, IL-6, and IL-8) decreased between 56-81% across all cytokines in subjects treated with 70 mg or 150 mg POLB 001 (all highly significant P values ≤0.0003).

POLB 001 treatment exhibited a marked reduction in multiple markers of systemic and local inflammation compared with placebo
A clear dose-response relationship was demonstrated

Well tolerated across all doses and no serious adverse events or volunteer withdrawals were reported
Learn more here

Positive Results from POLB 001 LPS Human Challenge Trial, March 2023

Jeremy Skillington, CEO
David English, VP Business Development
Derek Gilroy, Professor of Immunology at University College London

We are open to partnering, contact our team at

Partnering@PoolbegPharma.com

Trial Design

A randomized, double-blind, placebo-controlled, multiple dose, LPS challenge study in healthy volunteers

Three cohorts with escalating dose, 12 volunteers per cohort (9 POLB 001 versus 3 placebo, double blind, randomised)

POLB 001 or placebo doses orally, twice daily for 7 consecutive days

POLB 001 – severe influenza

Compelling Data

Strong Patent Portfolio

Major Market Opportunity

Evidence for benefit of POLB 001 in the therapy of LPS-induced inflammation

Trial design

Endpoints

Results Demonstrate POLB 001 can Potently Inhibit Inflammation

Potent and Selective Inhibition of p38 MAPK Signaling

Levels of phosphorylated p38 MAPK in circulating monocytes

Reduced Key Inflammatory Cytokines Following LPS Challenge

TNF-α

IL-6

IL-8

Reduced Key Indicators of LPS-Induced Systemic Inflammation

Mean Body Temperature

Heart Rate Rise (bpm)

C-Reactive Protein (CRP)

POLB 001 Effectively Reduced Inflammation in Tissue

TNF-α in blister exudate

IL-1β in blister exudate

Influenza

1 BILLION

1 in 8

5 – 10 MILLION

~500,000

LPS Human Challenge Trial

Key highlights from the study

Trial Design