Revive Therapeutics Ltd (RVVTF)

 

Revive Therapeutics updates on potential COVID-19 treatment, and its oral form of Psilosybin 

 

Revive Therapeutics Engages Novotech as Asia-Pacific CRO for Bucillamine in the Treatment of Infectious Diseases.

https://www.globenewswire.com/news-release/2020/04/08/2013654/0/en/Revive-Therapeutics-Engages-Novotech-as-Asia-Pacific-CRO-for-Bucillamine-in-the-Treatment-of-Infectious-Diseases.html



Revive Therapeutics Announces Filing of a Pre-CTA Meeting Request with Health Canada and Update on U.S. FDA IND Filing and Phase 3 Clinical Trial Design for Bucillamine in the Treatment of COVID-19
 

FDA’s support in advising Revive to move directly into a Phase 3 confirmatory trial provides an acknowledgment for the potential of Bucillamine in the treatment of COVID-19,” said Michael Frank, Chief Executive Officer of Revive. "Entering into a Phase 3 study is a major milestone for the Company, and we are excited to unlock the full potential of Bucillamine not only for this virus but also for other infectious diseases that we will investigate in the future.”

In addition to its recommendation, the FDA provided valuable guidance on study design and outcome measures for the Phase 3 study.  Importantly, the FDA agreed that Revive could rely on its data included in its previous IND with Bucillamine for gout to support the COVID-19 Phase 3 study and, therefore, the Company did not have to perform any Phase 1 or Phase 2 clinical studies.  The Company, along with its Contract Research Organization, Pharm-Olam, LLC, and its clinical development team led by Dr. Kelly McKee, Jr., MD, MPH, Chief Scientific Officer consultant and Dr. Onesmo Mpanju, PhD, Regulatory Affairs consultant, are actively incorporating the pre-IND meeting guidance and preparing the package for submission to the FDA.  The Company expects to file the final IND within the next 60 days and will plan to initiate the Phase 3 study thereafter.

Scientific Rationale of Bucillamine

Preclinical and clinical studies have demonstrated that reactive oxygen species contribute to the destruction and programmed cell death of pulmonary epithelial cells.¹ N-acetyl-cysteine (NAC) has been shown to significantly attenuate clinical symptoms in respiratory viral infections in animals and humans, primarily via donation of thiols to restore antioxidant and to reduce the activity of cellular glutathione ^2,3,4,5. Bucillamine (N-(mercapto-2-methylpropionyl)-l-cysteine) has a well-known safety profile and is prescribed in the treatment of rheumatoid arthritis in Japan and South Korea for over 30 years. Bucillamine, a cysteine derivative with two thiol groups, has been shown to be 16 times more potent as a thiol donor in vivo than NAC ⁶. The drug is non-toxic with high cellular permeability. The basis of the clinical study will analyze if Bucillamine has the potential, via restoration of glutathione activity and other anti-inflammatory activity, to lessen the negative consequences of SARS-CoV2 infection in the lungs and to help treat COVID-19 manifestations.

Bucillamine-induced Pneumonitis in a Patient With Rheumatoid Arthritis-associated Interstitial Pneumonia: A Case Report and Review of the Literature
An 81-year-old woman with rheumatoid arthritis (RA) who had been treated with bucillamine presented with dyspnea. Computed tomography of the chest showed ground-glass opacities and consolidations in both lungs and honeycombing in both basal lung areas. An elevation of the serum Krebs von den Lungen-6 level and hypoxemia were seen. Lymphocytosis with a decreased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. A transbronchial lung biopsy specimen showed organizing pneumonia. Based on a diagnosis of bucillamine-induced pneumonitis (BIP) with RA-associated pre-existing interstitial pneumonia, she was successfully treated with the cessation of bucillamine and systemic corticosteroid therapy. The risk factors and prognosis of BIP are discussed.

https://pubmed.ncbi.nlm.nih.gov/30918198/

 

CEO Interview: May 2020
https://www.youtube.com/watch?v=mOoawz-iK-M






May 2020 Revive Therapuetics Company Presentation https://www.revivethera.com/uploads/1/0/1/0/101019330/rvv_deck_-_may2020v3.pdf

 Advancing clinical development of Bucillamine for infectious diseases, including COVID-19 (Phase 3.)
 Developing novel Psilocybin and Cannabidiol therapeutics for various CNS and inflammatory disorders. 
 Robust patent portfolio covering methods and compositions of drugs. 
 Significantly undervalued compared to its peers.





PATENT PORTFOLIO Title USPTO No. Status Use of Bucillamine in the Treatment of Infectious Diseases, including COVID-19 62/991,996 Provisional patent filed Use of Bucillamine in the Treatment of Gout US9662305 Issued on May 30, 2017 Drug Delivery System US 8642088 US 9545423 US 10104888 Issued on February 4, 2014 Issued on January 17, 2017 Issued on October 23, 2018 Psilocybin effervescent and psilocybin tablet - Solid Oral Pharmaceutical Compositions 62/985,052 Provisional patent filed Psilocybin hard-shell capsules - Pharmaceutical Capsule Compositions 62/985,070 Provisional patent filed Psilocybin gum drops - Pharmaceutical Gumdrop Compositions 62/985,084 Provisional patent filed Psilocybin oral strips and transmucosal - Thin-Film Pharmaceutical Delivery System and Formulations 62/985,098 Provisional patent filed Psilocybin - Pharmaceutical Formulations and Methods for Sublingual and Buccal Administration 62/984,590 Provisional patent filed Methods for the Extraction and Crystallization of Psilocybin 62/985,360 Provisional patent filed Use of Cannabidiol in the Treatment of Autoimmune Hepatitis US 8242178 Issued on August 14, 2012

Focus on Infectious Diseases, including COVID-19, and Rare Disorders:

1. Bucillamine Infectious Diseases (COVID-19) Filing IND IND for Phase 3 Market size =TBD 
2. Psilocybin Undisclosed Pre-clinical Target FDA Orphan Status + $500M
3. Psilocybin Undisclosed Multiple Indications Pre-clinical Target FDA Orphan Status Market size =TBD
4. CBD Liver Diseases (Autoimmune Hepatitis) Filing IND Received FDA Orphan Status IND for Phase 2 Psilocybin Undisclosed Pre-clinical Target FDA Orphan Status + $500M Psilocybin Undisclosed Multiple Indications Pre-clinical Target FDA Orphan Status TBD + $100M 50k US Population

Infectious Disease Opportunity:

Focus on Bucillamine in the treatment of infectious diseases § Well-known safety profile and prescribed for arthritis in Japan and South Korea for over 30 years §
Revive’s clinical history with Bucillamine § Obtained 2 FDA INDs with Bucillamine and FDA orphan drug status § FDA Phase 2 clinical study for acute gout flares and cystinuria § Bucillamine (BUC) scientific rationale as an intervention for COVID-19 (see Appendix) § BUC is 16x more potent than particularly N-acetylcysteine (NAC); NAC has shown to prevent acute lung injury caused by influenza virus                                                                                                                   BUC shown superior function in restoring glutathione and therefore greater potential to prevent acute lung injury during influenza infection
 BUC also shown to prevent oxidative and reperfusion injury in heart and liver tissues §
 BUC proven safety and MOA similar to NAC, but with much higher potency §
Advancing towards FDA Phase 3 clinical study for COVID-19

Pschedelic Opportunity 

§ Acquired Psilocin Pharma Corp. § Derrick Welch, Founder with 14 years of HC experience; 5 years in Cannabis § Worked with Xanthic Bio Pharma and Green Growth Brands
§ Developed water Soluble THC and CBD products (Beverages, effervescent tablets)
§ Novel Psilocybin formulations, extraction and purification methods
§ Suited for pharmaceutical development and recreational markets where legal
§ Patent pending Psilocybin formulations (natural synthetic derived)
§ Capsules, Sublingual Spray, Gel Cap, Effervescent Tablets, and Oral Strips
§ Targeting rare diseases, mental health and addiction


LIVER DISEASE OPPORTUNITY
§ Focus on Autoimmune Hepatitis (AIH) § AIH - rare disease (~ 76k patients in US) causing liver inflammation • Drawbacks of current therapies (steroids): Severe side effects in 13%, relapse after drug withdrawal in 50%-86%*
§ Obtained FDA orphan drug status for CBD in the treatment of AIH
§ Seeking to file FDA IND to conduct Phase 2 clinical study in patient affected by AIH § Big Pharma interest in liver diseases § Allergan acquisition of Tobira for $1.7 billion
§ Novartis license of Conatus drug for $650 million
§ Gilead acquisition of Nimbus for $1.2 billion


STRATEGIC PARTNERS:
A. Pharm Olam
B.Psilocin Corp (Aquired) 
C.Wisconsin University
D.South Carolina University 
E.WARF Wisconsin Alumni Research Foundation 
F.Sanyal Biotechnology 

Value Driving Milestones for 2020
Q2 Submit FDA IND for Phase 3 clinical study of Bucillamine in the treatment of COVID-19
Q2 Initiate Phase 3 clinical study of Bucillamine in the treatment of COVID-19 in the U.S.
Q2 Submit IND for Phase 2 clinical study of CBD in the treatment of Autoimmune Hepatitis
Q2/3 Pre-IND meeting with FDA for Bucillamine in various infectious diseases (undisclosed)
Q3 Initiate Phase 2 clinical study of CBD in the treatment of Autoimmune Hepatitis
Q3 Pre-IND meeting with FDA for Psilocybin (undisclosed indications)
Q3/4 Results from Phase 3 clinical study of Bucillamine in the treatment of COVID-19
Q4 Results from Phase 2 clinical study of CBD in the treatment of Autoimmune Hepatitis
Q4 Submit FDA IND for Phase 2 clinical study of Bucillamine (undisclosed indication)

Team:

Management § Michael Frank Chairman and CEO § Carmelo Marrelli Chief Financial Officer § Derrick Welsh Founder, Psilocin Pharma Corp. Clinical § Dr. Kelly McKee, Jr., MD, MPH Chief Scientific Officer, Consultant § Dr. David Boulware, MD, MPH, CTropMed, FIDSA Clinical and Scientific Advisor § Dr. Onesmo Mpanju, PhD FDA Regulatory Affairs, Consultant. Board of Directors § Michael Frank Chairman and CEO § William Jackson Director § Joshua Herman Director § Christian Scovenna Director § Andrew Lindzon Director.


Appendix – Bucillamine Scientific Rationale for COVID-19

Current antiviral interventions for influenza have exhibited modest efficacy, especially in improving mortality in at-risk populations, such as the elderly.1,2 Novel antivirals have been plagued by poor oral bioavailability and lack of efficacy when not delivered early.1 This is because these drugs mostly act to prevent the early processes of virus binding to cells or viral replication.2 Thiols, particularly N-acetylcysteine (NAC), with antioxidant and reducing activity have been investigated as effective therapies that abrogate the potential for influenza to cause severe disease.3,4,5 Restoration of glutathione, the major intracellular thiol antioxidant, is a critical functional activity of NAC.6 Reactive oxygen species (ROS) generation during influenza virus infection aggravate destructive inflammation and programmed death of epithelial cells.7 Studies in human cells and animal models have shown that NAC works to prevent acute lung injury caused by influenza virus infection through inhibition of these ROS-mediated mechanisms.4,7 NAC has been investigated clinically and found to significantly attenuate clinical symptoms associated with influenza infection, especially in elderly at-risk patients.5 While NAC is easily taken up by cells and has low toxicity, clinical efficacy has required long-term and high-dose administration because of modest relative potency, limiting its clinical applicability. Bucillamine (N-(mercapto-2-methylpropionyl)-l-cysteine), which has a well-known safety profile and is prescribed in the treatment of rheumatoid arthritis in Japan and South Korea for over 30 years, is a cysteine derivative with 2 thiol groups that is 16-fold more potent than NAC as a thiol donor in vivo, giving it vastly superior function in restoring glutathione and therefore greater potential to prevent acute lung injury during influenza infection.8 Bucillamine has also been shown to prevent oxidative and reperfusion injury in heart and liver tissues8 and is highly cell permeable for efficient delivery into cells.8,9 Bucillamine has unrealized potential for the treatment of influenza with both proven safety and proven mechanism of action similar to that of NAC, but with much higher potency, mitigating the previous obstacles to using thiols therapeutically. It is also reasonable to hypothesize that similar processes related to ROS are involved in acute lung injury during nCov-19 infection, possibly justifying the investigation of Bucillamine as an intervention for COVID-19.

ying the investigation of Bucillamine as an intervention for COVID-19. Appendix – Bucillamine Scientific Rationale for COVID-19

s 1. Muthuri SG, Venkatesan S, Myles PR et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data Lancet Respir Med. 2014 May;2(5):395-404. doi: 10.1016/S2213-2600(14)70041-4. 2. Duwe S. Influenza viruses – antiviral therapy and resistance. GMS Infect Dis. 2017; 5: Doc04. 3. Zhang RH, Li CH, Wang CL et al. N-acetyl-l-cystine (NAC) protects against H9N2 swine influenza virus-induced acute lung injury. Int Immunopharmacol. 2014 Sep;22(1):1-8. doi: 10.1016/j.intimp.2014.06.013. 4. Ungheri D, Pisani C, Sanson G et al. Protective effect of n-acetylcysteine in a model of influenza infection in mice. Int J Immunopathol Pharmacol. 2000 SepDec;13(3):123-128. 5. De Flora S, Grassi C, and Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997; 10: 1535–1541 DOI: 10.1183/09031936.97.10071535 6. Poole LB. The Basics of Thiols and Cysteines in Redox Biology and Chemistry. Free Radic Biol Med. 2015 Mar; 0: 148–157. doi: 10.1016/j.freeradbiomed.2014.11.013. 7. Mata M, Morcillo E, Gimeno C, Cortijo J. N-acetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV). Biochem Pharmacol. 2011 Sep 1;82(5):548-55. doi: 10.1016/j.bcp.2011.05.014. 8. Horowitz LD. Bucillamine: a potent thiol donor with multiple clinical applications. Cardiovasc Drug Rev. 2003 Summer;21(2):77-90. 9. Sagawa A, Fujisaku A, Ohnishi K et al. A multicentre trial of bucillamine in the treatment of early rheumatoid arthritis (SNOW study). Mod Rheumatol. 2011 Jun;21(3):251-7. doi: 10.1007/s10165-010-0385-4

https://www.globenewswire.com/news-release/2020/04/23/2020948/0/en/Revive-Therapeutics-Announces-U-S-FDA-Recommendation-to-Proceed-Directly-Into-A-Phase-3-Confirmatory-Clinical-Trial.html

https://www.globenewswire.com/news-release/2020/03/25/2006595/0/en/Revive-Therapeutics-Engages-Pharma-Olam-and-Strengthens-Infectious-Diseases-Clinical-Development-Team-to-Advance-U-S-FDA-Clinical-Study-for-COVID-19.html

https://www.thecannabisinvestor.ca/3-psychedelic-stocks-investors-should-have-on-their-radar-in-2020/

https://www.globenewswire.com/news-release/2020/04/29/2024191/0/en/Revive-Therapeutics-Provides-an-Update-on-its-Psilocybin-Based-Pharmaceutical-Program.html

https://www.globenewswire.com/news-release/2020/03/05/1996118/0/en/Revive-Announces-Closing-of-the-Acquisition-of-Psilocin-Pharma-Corp.html

Website: https://www.revivethera.com