Todos Medical and NLC Pharma Announce Primary and Secondary Endpoints Met in NLC-V-01 Phase 2 Clinical Trial of Oral Antiviral 3CL Protease Inhibitor Tollovir™ in the Treatment of Hospitalized COVID-19 Patients
2) moderate to severe adult COVID-19 in the outpatient setting,
3) moderate to severe pediatric COVID-19 in the outpatient setting,
4) the treatment of Long COVID in adults and
5) the treatment of Long COVID in the pediatric setting.”
Study design:
Primary Objective
To evaluate the safety and efficacy of Tollovir in addition to Standard of Care (SOC) in adult patients hospitalized due to infection with a confirmed diagnosis of SARS-CoV-2
Endpoints
Number of Patients
31 participants (adult patients with a confirmed diagnosis of SARS-CoV-2 infection, who are hospitalized due to the infection) were enrolled in the Tollovir Phase 2 clinical trial. The study was executed in two cohorts (parts) as follows:
Table 1 and Table 2 below displays the topline results for Part 2 and Part 1 (respectively) of the NLC-V-01 trial.
Table 1: Top line Clinical Trial Results (Part 2)
Part 2 Conclusion:
The data from part 2 indicates that patients exposed to Tollovir (TLVR2) + SOC showed better overall clinical improvement (as measured by the endpoints described in Table 1 above) as compared to patients who were treated with placebo + SOC.
Table 2: Top line Clinical Trial Results (Part 1)
Part 1 Conclusion:
Based on the data available in Part 1, there is not enough evidence to assume possible differences in terms of efficacy between Tollovir (TLVR1) + SOC vs. Placebo + SOC.
About Dr. Dorit Arad
About Tollovir®
About Todos Medical Ltd.
Todos is also distributing certain (COVID-19) testing materials and supplies to CLIA-certified labs in the United States. The products cover multiple suppliers of PCR testing kits, extraction kits, automation materials and supplies, as well as COVID-19 antibody and antigen testing kits.
Phase 2 Study NLC-V-01 closed early after interim data analysis due to positive clinical efficacy
Primary endpoint of time to clinical improvement reached with average reduction of 2.7 days in the Tollovir group vs. the placebo group
0% COVID-related deaths in Tollovir™ group vs. 22% COVID-related deaths in placebo group
Lead clinical site Shaare Zedek Medical Center now permits the use of Tollovir™ in hospitalized COVID-19 patients on a compassionate use basis
Company preparing Phase 2/3 clinical trial to support Emergency Use Authorizations
Company to host conference call today at 9:00am ET to discuss the positive Phase 2 trial results
Company to make a corporate presentation for Emerging Growth Conference today at 3pm ET
New York, NEW YORK, and Tel Aviv, ISRAEL – January 27, 2021 - Todos Medical, Ltd. (OTCQB:TOMDF), a comprehensive medical diagnostics and related solutions company, together with its 3CL protease theranostic joint venture partner NLC Pharma Ltd., today announced positive interim data for its Tollovir™ oral antiviral 3CL protease inhibitor Phase 2 clinical trial for the treatment of hospitalized (severe and critical) COVID-19 patients. Tollovir met its primary endpoint of reducing time to clinical improvement as measured by the National Emergency Warning System 2 (NEWS2) and met several key secondary clinical endpoints, including complete reduction in COVID-19 deaths. The Company has now formally closed the Phase 2 clinical trial due to positive interim efficacy data. Lead clinical site Shaare Zedek Medical Center now permits the use of Tollovir™ in hospitalized COVID-19 patients on a compassionate use basis.
“It is extremely exciting to see the validation of Tollovir in a placebo-controlled trial which now allows us to continue on the clinical and regulatory path towards Emergency Use Authorization for the treatment of COVID-19 patients” said Dr. Dorit Arad, Founder & CTO of NLC Pharma, Todos Medical’s 3CL science-based joint venture partner. “The data produced in this study closely mirrors data we generated in an Observational Clinical study conducted in 2020. The recent emergence of the Omicron variant has been pushing healthcare systems to the brink of collapse. Tollovir could be an incredibly powerful tool to reduce death and stabilize patients faster, thereby reducing their recovery time from this debilitating disease. Tollovir will help flatten the curve by freeing up hospital capacity to see more patients and perform other more routine non-COVID related hospital treatments.”
“We are extremely pleased with the results from this clinical study in the hospital setting of our dual mechanism antiviral & anti-cytokine oral drug candidate Tollovir,” said Gerald E. Commissiong, President & CEO of Todos Medical. “We have already begun preparing manufacturing for commercial quantities of Tollovir so that we will be able to deliver shipments in jurisdictions where we expect to be granted accelerated Emergency Use Authorization (EUA), and are in the process of fine tuning our proposed Phase 2/3 clinical study protocol for hospitalized COVID-19 patients. The new protocol is the key document that will enable our regulatory team to engage with regulatory bodies worldwide, including US FDA. Our goal is to immediately target EUA in jurisdictions that will require limited additional clinical data. We are also preparing for the development of Tollovir for the treatment of:
Study NLC-V-01 was a double blinded randomized placebo controlled study designed to evaluate the safety and efficacy of NLC-V (Tollovir™) in adult patients with a confirmed diagnosis of SARS-CoV-2 infection, who are hospitalized due to the infection. Approximately 78 patients were set to be randomized using a 1:1 ratio (approximately 39 per arm) and stratified by weight group (<70 kg, 70-100kg, and >100kg) to receive Tollovir or placebo, in addition to standard of care. Patients who need mechanical ventilation received the randomized treatment using Liquid Syrup. The Company paused enrollment of the NLC-V-01 clinical trial after enrollment of 31 patients to perform an interim-analysis to evaluate the safety and efficacy profile of Tollovir.
Time to clinical improvement, defined as a National Early Warning Score 2 (NEWS2) of ≤ 2 maintained for 24 hours, in the treatment group (Tollovir) compared to the control group
Time elapsed from hospitalization (1st day) until hospital discharge in patients receiving Tollovir treatment
COVID-19 - related death(s) in the treatment group (Tollovir) compared to the control group
Incidence of deterioration and need for mechanical ventilation in both treatment group (Tollovir) and control group
Incidence and duration of time on supplemental oxygen in both treatment group (Tollovir) and control group
Part 1: Tollovir Clinical Trial Part 1 (TCTP1) (N=11): Tollovir formulation 1 (TLVR1) + SOC (N=6) vs. Placebo + SOC (N=5). This part of the study enrolled patients from December 2020 through February 2021 primarily during the Third COVID Wave (Alpha and Beta variants).
Part 2: Tollovir Clinical Trial Part 2 (TCTP2) (N=20): Tollovir formulation 2 (TLVR2) + SOC (N=11) vs. Placebo + SOC (N=9). This part of the study enrolled patients from May 2021 through November 2021 primarily during the Fourth COVID Wave (Delta variant).
All study design features were identical in Part 1 and Part 2, including enrollment criteria and statistical analysis plan. The only difference between Part 1 and Part 2 cohorts was a change in formulation of the Tollovir botanical drug formula: in TCTP1 the active drug was TLVR1 and in TCTP2 the active drug was TLVR2. TLVR1 primarily consisted of the botanical extract we identify as NLC-EXT-2, discovered by Dr. Dorit Arad in 2004 as a 3CL protease inhibitor with potent anti-cytokine activity. TLVR2 consists of a formulation that includes NLC-EXT-2 and NLC-EXT-1, a newly isolated compound first identified in January 2021 as part of raw material qualification experiments that was confirmed in April 2021 to have significantly more potent 3CL protease inhibitor than NLC-EXT-2. NLC-EXT-2 has a 3CL protease ICD50 binding affinity of 20mM vs. NLC-EXT-1 that has a 3CL protease ICD50 binding affinity of 0.8mM. Going forward for the next phase of clinical trials and commercialization, Tollovir will consist exclusively of the TLVR2 formulation that contains both NLC-EXT-1 and NLC-EXT-2 in the proprietary ratio used in Part 2 of the study (TCTP2). The data was analyzed by independent biostatistical service contractor InCSD using SAS 9.4, and the data tables below were prepared by InCSD’s President Dr. Luis Rojas. Dr. Jules Mitchel, a key clinical advisor to the Company, oversaw the analysis.
Endpoint/Statistics
Tollovir™(TLVR2)
N = 11
Placebo
N = 9
Difference
(Tollovir vs. Placebo)
Time (days) to clinical improvement as measured by NEWS 2
n
11
9
Mean
8.3
11.0
-2.7
Median
8.0
15.0
-7
Time (days) in the hospital
n
11
9
Mean
10.6
17.8
-7.2
Median
8.0
8.0
0
Time (days) to discharge from the hospital
n
10
6
Mean
9.7
8.3
1.4
Median
8
8
0
No. of Patients Deterioration to Mechanical Ventilation, n(%)
1 (0.09)
3 (0.33)
-24%
No. of Deaths related to COVID-19 while on Treatment, n(%)
0 (0.00)
2 (0.22)
-22%
Total Deaths, n(%)
1* (0.09)
3 (0.33)
-24%
Need for supplemental oxygen, n(%)
8(0.73)
8 (0.89)
-16%
Time on supplemental oxygen
n
8
8
Mean
3.8
5.8
-2
Median
3.0
7.0
-4
C-Reactive Protein at Day 10
n
7
3
Mean
3.44
14.79
-11.35
Median
1.16
9.98
-8.82
Interleukin-6 (IL-6) at Day 10
n
4
3
Mean
24.6
36.23
-11.63
Median
10.95
13.8
-2.85
D-Dimer at Day 10
n
5
2
Mean
2,55.8
29,554.0
-29,298.2
Median
779.0
29,554.0
-28,775.2
* A patient had a stroke prior receiving study treatment. The patient received the study treatment for the 10 days via feeding tube and achieved COVID-19 clinical improvement as measured by NEWS2, 9 days after stopping the study treatment (on day 19) the patient expired.
Endpoint/Statistics
Tollovir™(TLVR1)
N = 6
Placebo
N = 5
Difference
(Tollovir vs. Placebo)
Time to clinical improvement as measured by NEWS 2
n
0
0
Mean
N/A
N/A
N/A
Median
N/A
N/A
N/A
Time (duration) in the hospital
n
5
5
Mean
7.2
6.2
1
Median
9.0
6.0
3
Time to discharge from the hospital
n
3
4
Mean
6.0
5.5
1
Median
4.0
5.5
-1.5
Deterioration to Mechanical Ventilation, n(%)
0
0
0%
Deaths related to COVID-19 while on Treatment, n(%)
0
0
0%
Total Deaths, n(%)
0
0
0%
Need for supplemental oxygen, n(%)
4 (0.67)
4(0.8)
13%
Time on supplemental oxygen
n
4
Mean
2.5
3.8
-1.3
Median
1.5
4.0
-2.5
C-Reactive Protein at Day 10
n
1
0
Mean
6.2
N/A
N/A
Median
6.2
N/A
N/A
Interleukin-6 (IL-6) at Day 10
n
0
0
Mean
N/A
N/A
N/A
Median
N/A
N/A
N/A
D-Dimer at Day 10
n
1
0
Mean
3.84
N/A
N/A
Median
3.84
N/A
N/A
For more information, please visit www.todosmedical.com. For more information on the Company’s CLIA/CAP certified lab Provista Diagnostics, Inc. please visit www.provistadx.com.
Dr. Dorit Arad is a D.C. in physical organic chemistry from the Technion who has more than 25 years of experience in the life science industry as an international researcher, executive and entrepreneur. Dr. Arad is a pioneer in the discovery and development 3CL protease biology related products and product candidates. Dr. Dorit Arad is an interdisciplinary scientist with expertise in Computer assisted Drug Design, Biotechnology, mechanism-based drug design, Diagnostics, infectious disease and cancer.
Tollovir® is a 3CL protease inhibitor and anti-cytokine therapeutic candidate for the treatment of the nidovirus subcategory of coronaviruses that includes SARS-CoV-2, COVID-19, SARS-CoV-1, MERS and 229E. Tollovir is made from ingredients that are qualified to ensure strong inhibition of the 3CL protease in vitro, as well as strong anti-cytokine activity. Tollovir has successfully completed a Phase 2 clinical trial in Israel for the treatment of patients hospitalized with COVID-19. Tollovir will be developed for the treatment of hospitalized COVID-19 (severe and critical), moderate COVID-19, long-haul COVID and potentially pediatric COVID-19. Todos has licensed rights for Tollovir to T-Cell Protect Hellas S.A. for the Greek market.
Founded in Rehovot, Israel with offices in New York City, Todos Medical Ltd. (OTCQB:TOMDF) engineers life-saving diagnostic solutions for the early detection of a variety of cancers. In 2021, Todos completed the acquisition of U.S.-based medical diagnostics company Provista Diagnostics, Inc. to gain rights to its Alpharetta, Georgia-based CLIA/CAP certified lab currently performing PCR COVID testing and Provista's proprietary commercial-stage Videssa® breast cancer blood test. The Company's state-of-the-art and patented Todos Biochemical Infrared Analyses (TBIA) is a proprietary cancer-screening technology using peripheral blood analysis that deploys deep examination into cancer's influence on the immune system, looking for biochemical changes in blood mononuclear cells and plasma. Todos' two internally-developed cancer-screening tests, TMB-1 and TMB-2, have received a CE mark in Europe. Todos is focused on the commercialization of Videssa and will bring the TBIA tests to market thereafter.
Todos has entered into a joint venture with NLC Pharma targeting diagnostic and testing solutions to address the COVID-19 pandemic. The Joint-Venture is pursuing the development of diagnostic tests targeting the 3CL protease, as well as 3CL protease inhibitors that target a fundamental reproductive mechanism of coronaviruses. The Company’s proprietary therapeutic candidate Tollovir™ is currently in a Phase 2 clinical trial to treat hospitalized COVID-19 patients in Israel, and is preparing to initiate Phase 2/3 clinical trials for both hospitalized and non-hospitalized patients in Israel.
Todos is also developing blood tests for the early detection of neurodegenerative disorders, such as Alzheimer's disease. The Lymphocyte Proliferation Test (LymPro Test™) is a diagnostic blood test that determines the ability of peripheral blood lymphocytes (PBLs) and monocytes to withstand an exogenous mitogenic stimulation that induces them to enter the cell cycle. It is believed that certain diseases, most notably Alzheimer's disease, are the result of compromised cellular machinery that leads to aberrant cell cycle re-entry by neurons, which then leads to apoptosis. LymPro is unique in the use of peripheral blood lymphocytes as a surrogate for neuronal cell function, suggesting a common relationship between PBLs and neurons in the brain.
Certain statements contained in this press release may constitute forward-looking statements. For example, forward-looking statements are used when discussing our expected clinical development programs and clinical trials. These forward-looking statements are based only on current expectations of management, and are subject to significant risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements, including the risks and uncertainties related to the progress, timing, cost, and results of clinical trials and product development programs; difficulties or delays in obtaining regulatory approval or patent protection for product candidates; competition from other biotechnology companies; and our ability to obtain additional funding required to conduct our research, development and commercialization activities. In addition, the following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; delays or obstacles in launching our clinical trials; changes in legislation; inability to timely develop and introduce new technologies, products and applications; lack of validation of our technology as we progress further and lack of acceptance of our methods by the scientific community; inability to retain or attract key employees whose knowledge is essential to the development of our products; unforeseen scientific difficulties that may develop with our process; greater cost of final product than anticipated; loss of market share and pressure on pricing resulting from competition; and laboratory results that do not translate to equally good results in real settings, all of which could cause the actual results or performance to differ materially from those contemplated in such forward-looking statements. Except as otherwise required by law, Todos Medical does not undertake any obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. For a more detailed description of the risks and uncertainties affecting Todos Medical, please refer to its reports filed from time to time with the U.S. Securities and Exchange Commission.
