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PNB-001 / GPP- BALACOVIN is in the Phase 3 clinical trial for covid 19.

PNB-001 / GPP- BALACOVIN is one of the very few New Chemical Entity in the world to be tested in Covid 19.

12 Clinical Trials across India

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PNB 001 & COVID 19

Coronaviruses (CoV) are a large family of viruses that cause illnesses ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV). A novel coronavirus (nCoV) is a new strain that has not been previously identified in humans.

Ref 1: https://www.afro.who.int/news/coronavirus-disease-what-you-need-know

The outbreak of Novel coronavirus disease (COVID-19) was initially noticed in a seafood market in Wuhan city in Hubei Province of China in mid-December, 2019, has now spread to 214 countries/territories/areas worldwide. WHO (under International Health Regulations) has declared this outbreak as a “Public Health Emergency of International Concern” (PHEIC) on 30thJanuary 2020. WHO subsequently declared COVID-19 a pandemic on 11th March, 2020.

Current available evidence for COVID-19 suggests that the causative virus (SARS-CoV-2) has a zoonotic source closely related to bat-origin SARS-like coronavirus. It is an enveloped RNA beta coronavirus related to the Severe Acute Respiratory Syndrome (SARS) virus, and the virus has been shown to use the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry.

Ref2: https://www.mohfw.gov.in/pdf/UpdatedClinicalManagementProtocolforCOVID19dated03072020.pdf

The possible modes of transmission for SARS-CoV-2, including contact, droplet, airborne, fomite, fecal-oral, bloodborne, mother-to-child, and animal-to-human transmission. Infection with SARS-CoV-2 primarily causes respiratory illness ranging from mild disease to severe disease and death, and some people infected with the virus never develop symptoms.

Ref 3:  https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions

Most patients with COVID-19 predominantly have a respiratory tract infection associated with SARS-CoV-2 infection. However, in a small proportion of cases, they can progress to a more severe and systemic disease characterized by the Acute Respiratory Distress Syndrome (ARDS), sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury.

Ref2: https://www.mohfw.gov.in/pdf/UpdatedClinicalManagementProtocolforCOVID19dated03072020.pdf

1.     Medrxiv, a pre-print journal published by BMJ (British Medical Journal) and Yale University

 

Randomized, Comparative, Clinical Trial to Evaluate Efficacy and Safety of PNB001 in Moderate COVID-19 Patients

Authors:Eric Lattmann, Pradnya Bhalerao, BL ShashiBhushan, Neeta Nargundkar, Pornthip Lattmann, K Sadasivan Pillai, PN Balaram

Link  :  View / Download

Abstract:

Objective: To evaluate the efficacy and safety of PNB001 a CCK-A agonist and CCK-B antagonist, a new chemical entity with anti-inflammatory and immune stimulation properties, along with Standard of Care (SOC) in patients with moderate COVID-19 infection.

Design: Multi-center, randomized, parallel-group, comparative, open-label study.

Setting: Two tertiary-care hospitals in India.

Participants: Patients with laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) within 2 days of randomization, having pneumonia with no signs of severe disease (severe disease means SpO2≤94% on room air), and any two of the following signs or symptoms suggestive of COVID-19: fever, cough, dyspnea, or hypoxia.

Interventions: Patients were randomized 1:1 to receive PNB001 at an oral dose of 100 mg three times daily for 14 days with Standard of Care (PNB001+SOC) or only SOC.

Main outcome measures: The primary endpoints were mean change in the 8-point WHO Ordinal Scale score from baseline by Day 14 and mortality rate by Day 28. The key secondary endpoints were the percentage of patients showing the change in clinical status using the ordinal scale, improvement in inflammatory segments in X-ray chest, reduction of days of hospitalization, duration of supplemental oxygen use, days to negative PCR for COVID-19, and change in inflammation markers Interleukin-6 (IL6) and C-reactive protein (CRP) from baseline by Day 14.

Results: A total of 40 (20 in PNB 001+SOC arm and 20 in SOC arm) patients were randomized and received treatment. The primary endpoint showed significant clinical improvement from baseline to Day 14 with PNB001+SOC (0.22 Vs 1.12; P=0.0421). One patient in PNB001+SOC arm and two patients in SOC arm died (1 Vs 2; HR: 2.0 [95%CI=0.18, 22.05]; P=0.5637) by Day 28. At the end of the treatment by Day 14, more patients achieved zero ordinal scale in PNB001+SOC arm (17 Vs 12; P=0.0766). In the PNB001+SOC arm, change in mean chest X-ray score showed significant improvement (2.05 Vs 1.16; P=0.0321), and more patients quickly showed complete improvement (10 Vs 7; HR: 1.48 [95%CI=0.64, 3.44]; P=0.4309). In the PNB001+SOC arm, patients needed shorter duration of hospitalization in days (9.45 Vs 9.80) and more patients attained earlier discharge from the hospital (19 Vs 15; P=0.0486) with respect to days. The mean duration of supplemental oxygen requirement in days was shorter (5.45 Vs 7.10) and complete withdrawal from supplemental oxygen was more frequent with PNB001+SOC compared to SOC by Day 14 (17 Vs 13; P=0.1441). All patients in both the arms had negative PCR by the end of the study (18 Vs 17; P=0.6265) by similar time (7.6 Vs 7.0). Exploratory analysis done for IL-6, CRP, Neutrophil-Lymphocyte-Ratio (NLR), Platelet-Lymphocyte-Ratio (PLR) and Erythrocyte Sedimentation Rate (ESR) showed a statistically significant reduction by Day 14 demonstrating PNB001’s anti-inflammatory and immunomodulatory properties. Lymphocyte and neutrophil count also improved by Day 14. 11 adverse events (AE) in 8 patients were observed with PNB001+SOC compared to 13 AEs in 10 patients with SOC; none of the AEs in the PNB001+SOC arm were related to PNB001. The most common AE was tachycardia and acute respiratory distress syndrome; there were isolated cases of hepatic

enzyme elevation and hyperglycemia. Overall, the safety profile was similar between PNB001+SOC and SOC arms.

Conclusions: PNB001 with standard of care showed significant clinical improvement in moderate COVID-19 patients when compared to standard of care and was well tolerated by moderate COVID-19 patients.

2.     Medwin Publishers:

A Randomized, Comparative Clinical Trial to Evaluate Efficacy and Safety of PNB-001 as Immune Modulator in Moderate COVID-19 Patients

 Authors:Eric Lattmann, Pradnya Bhalerao, BL ShashiBhushan, Neeta Nargundkar, Pornthip Lattmann,  PN Balaram

Link: View / Downlaod

Abstract:

Introduction: Several therapeutic agents are being evaluated for the treatment of coronavirus disease 2019 (COVID-19). PNB-001 is a potent anti-inflammatory agent with immune stimulation properties. It is a first in class CCK A agonists and CCKB antagonist, being responsible for its unique action. Methods: We conducted a multi-centre, randomized, parallel group, comparative, open label study to assess efficacy and safety of PNB-001 in patients with moderate COVID-19 infection. Patients were randomly assigned to receive PNB-001 100 mg orally with Best Care BC (PNB 001 + BC) or only Best Care (BC). A total of 40 patients (20 in Adjunct and 20 in BC arm) were randomised and received treatment. Results: The primary endpoint, change in the 8-point WHO Ordinal Scale score for COVID-19 showed significant Clinical Improvement from baseline to day 15 with PNB 001 + BC (P=0.042). Death rate, one patient on PNB 001+BC and two patients in BC arm died (1 Vs 2; HR: 2.0 [95%CI=0.18, 22.05]; P=0.56) by Day 28. Mean Chest X-ray score showed significant improvement (2.05 Vs 1.16; P=0.032) as well as more patients quickly showed complete improvement. Patients needed shorter duration of hospitalization and on day 15, 1 patient was hospitalised on adjunct compared to 5 on BC (P=0.048), thus giving 80% of reduction on the hospitalisation parameter. Mean duration of supplemental oxygen requirement was shorter. 50% of patients were off oxygen on day 6 on adjunct compared to day 8 on BC. Exploratory analysis done for ESR, CRP, IL-6, and N/L ratio and immune parameters showed a statistically significant reduction by Day 15. Lymphocytes were increased into the reference range (P=0.032) and neutrophils were reduced (P=0.013). The role of PNB-001 as immune modulator was clearly established. NLR was reduced significantly for adjunct compared to BC. A total of 24 (11 Vs 13) adverse events were reported in 18 (8 Vs 10) patients and none of the 11, were related to PNB-001. Overall safety profile was found better in test than control arm. Conclusion: PNB-001 when combined with BC improved the clinical status of patients with moderate COVID-19 infection compared to BC alone. Hospitalisation and dead rate was further reduced by 80% and 50%, respectively. PNB-001 was well tolerated by patients with moderate COVID-19 and acted by stimulation of the immune system. Key Findings: Anti-inflammatory activity was improved further for test agent PNB-001 even in presence of potent steroids. The immune stimulating properties of PNB-001, analysed in form of NLR, are key to fight COVID-19 infection. NLR was found highly useful as predictive and clinical biomarker and it was significantly reduced by PNB-001.

3.     ResearchGate:

A Randomized, Comparative, Clinical trial to Evaluate Efficacy and Safety of PNB-001 as IMMUNE MODULATOR in Moderate COVID-19 patients

Authors:Eric LattmannPradnya BhaleraoBL ShashiBhushanNeeta NargundkarPornthip LattmannK Sadasivan PillaiPN Balaram

Link: View / Download

Abstract:

PNB-001, Baladol®, was tested now in 74 healthy subjects in clinical phase 1. Following a SAD study with 42 subjects, Baladol® was tested in MAD, (multiple ascending doses) at low, medium and high doses over a period of 14 days in 32 healthy subjects. Overall, Baladol® was tested safe and with an efficient therapeutic window. From 32 subjects 30 completed the MAD trial and only 2 adverse reactions were observed. 1 AE was vomiting in a female subject and at a high dose, a >2.5-fold increase of ALT was identified. In pre-clinical models, PNB-001 is highly efficient in inflammation and the inflammation data were completed by results from Dengue fever studies, in which PNB-001 was tested highly efficient. A pilot trial is launched in Covid-19 patients and a clearly defined cohort will be enlarged until NDA (new drug application) is obtained within months.