BIOPHYTIS BIO101 IN SARCOPENIA: UPDATE ON THE SARA PROGRAM: FROM SARA-INT TOWARDS THE PHASE 3 STUDY

Sarcopenia is a progressive muscle disorder increasing with age that may lead to mobility disability. SARA program strives to develop a viable option to treat community dwelling older adults suffering from sarcopenia. SARA-INT is a randomized three-arm interventional study (BIO101 175 mg bid / BIO101 350 mg bid / placebo) with treatment duration of 6 months. Eligibility criteria for sarcopenia were meeting FNIH criteria and Short Physical Performance Battery (SPPB) score ≤ 8/12 in men and women aged ≥ 65 years;primary endpoint was the 400-meter walking test (400MWT). 233 participants aged 65 years and older were randomized, 232 and 156 participants were included in the Full Analysis Set (FAS) and Per-Protocol (PP) populations, respectively. Due to COVID-19 pandemic, most end-of-treatment efficacy assessments are missing for 55% of the participants, reducing the studies' power. BIO101 350 mg bid treatment led to an improvement in the primary endpoint, the gait speed from the 400MWT of 0.07 m/s in the FAS population (not statistically significant) and of 0.09 m/s in the PP population (nominally statistically significant, p=0.008) after 6 months;this is close to MCID in sarcopenia (0.1 m/s). BIO101 350mg bid treatment effect on the 400MWT is confirmed in PP sub-populations at high risk of mobility disability. Trends were observed with other endpoints. BIO101 showed a very good safety profile at both doses. Biophytis will initiate the phase 3 program by end 2022, targeting a severe sarcopenic population. Outcomes of the interactions with regulatory agencies on study design will be presented.

BIOPHYTIS BIO101 IN SARCOPENIA: RESULTS OF THE PHASE 2 SARA-INT STUDY

Backgrounds: Sarcopenia is a geriatric condition characterized by a progressive loss of muscle mass and function, having high personal, social and economic burdens when untreated. Sarcopenia increases risk of falls and fractures;impairs ability to perform activities of daily living;is associated with cardiac and respiratory disease and cognitive impairment;leads to mobility disorders;and contributes to lowered quality of life, loss of independence or need for long-term care placement, and death. It is recognized as one of the five pillars of frailty. As of today, to our knowledge, only exercise and nutrition interventions seem somewhat effective interventions. Objectives: SARA-INT study is a Phase 2 study to develop a viable option to treat community-dwelling seniors suffering from age-related sarcopenia, including sarcopenic obesity. Methods: SARA-INT is a randomized double-blind three-arm study (BIO101 175 mg bid / BIO101 350 mg bid / placebo) with planned treatment duration of 6 Months;due to COVID-related measures, 49 patients continued up to 9 months of treatment. Main eligibility criteria for sarcopenia were meeting FNIH criteria and Short Physical Performance Battery (SPPB) score ≤ 8/12 in men and women aged ≥ 65 years. Primary analysis was the gait speed from the 400-meter walking test (400MWT) at month 6/9 in the FAS with secondary analyses at other timepoints, secondary endpoints were other physical activity assessments, muscle strength, muscle mass and Patient Reported Outcomes (PROs). Results: 233 participants were randomized in the study, 232 and 156 participants were included in the Full Analysis Set (FAS) and Per-Protocol (PP) populations, respectively. Due to COVID-19 pandemic, end-of-treatment assessments are missing for approximately half of the participants, impacting the treatment effect detection. In the primary analysis (at month 6/9 in the FAS population) of the primary parameter, the improvement in 400MWT compared to placebo was not statistically significant (0.0363 (0.03098) m/s and 0.0385 (0.02985) m/s in the BIO101 175 mg and 350 mg groups, p=0.2437 and p=0.2000, respectively). BIO101 350 mg bid treatment after 6 months showed a clinically relevant improvement in the 400MWT of 0.07 m/s in the FAS population (not significant) and of 0.09 m/s in the PP population (nominally statistically significant, p=0.008);this is close to the Minimal Clinically Important Difference (MCID) in sarcopenia (0.1 m/s). BIO101 350mg bid treatment effect on the 400MWT is confirmed in pre-defined sub-populations at higher risk of mobility disability such as slow walkers, obese and those with chair stand sub-score ≤2 from SPPB;trends were observed with other independent endpoints. BIO101 showed no difference in adverse events or safety laboratory parameters versus placebo (), and no severe adverse event associated with BIO101 treatment. Conclusions: After 6 to 9 months of treatment, BIO101 at 350 mg bid showed promising results with a clinically relevant improvement in the 400MWT gait speed, the primary endpoint of the study, confirmed in sub-populations at higher risk of mobility disability. BIO101 showed a very good safety profile at the doses of 175 and 350 mg bid. Biophytis is preparing to start a phase 3 program with BIO101 at 350 mg bid in 2022, targeting a similar patient population. Conflicts of interests: CT, WD, CM, RL, PD, RvM and SV are employees of Biophytis SA, AZ, and SA are employees of Biophytis Inc., JM is president of the Scientific Advisory Board of Biophytis, SDS is employee of BlueCompanion Ltd.

Challenges in the Development of Drugs for Sarcopenia and Frailty - Report from the International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force.

Sarcopenia and frailty represent two burdensome conditions, contributing to a broad spectrum of adverse outcomes. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met virtually in September 2021 to discuss the challenges in the development of drugs for sarcopenia and frailty. Lifestyle interventions are the current mainstay of treatment options in the prevention and management of both conditions. However, pharmacological agents are needed for people who do not respond to lifestyle modifications, for those who are unable to adhere, or for whom such interventions are inaccessible/unfeasible. Preliminary results of ongoing trials were presented and discussed. Several pharmacological candidates are currently under clinical evaluation with promising early results, but none have been approved for either frailty or sarcopenia. The COVID-19 pandemic has reshaped how clinical trials are conducted, in particular by enhancing the usefulness of remote technologies and assessments/interventions.

Cardiovascular admissions in intensive care units during COVID-19 pandemic

The COVID-19 pandemic has led to measures of social isolation, labor restrictions, a strong information campaign and the suspension of scheduled medical activities. The aim of this study was to describe the impact of these measures on the number of hospitalizations in Cardiovascular Intensive Care Units, with the hypothesis that the social behavior generated by this emergency promotes a decreased demand for medical care, even when severe cardiovascular disease is involved. We compared the number of admissions in March-April 2010-2019 versus March-April 2020, based on a prospective study including six institutions (three public and three private) that use Epi-CardioR as a multicenter registry of cardiovascular care unit discharge. Altogether, we included 6839 patients discharged during the 11-year study period (2010-2020). The average number of patient admissions on March-April 2010-19 was 595 (CI 95%: 507-683) and decreased to 348 in 2020 fall of 46.8%, p.

Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacydata, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Concerns and demands regarding COVID-19 Survey of health personnel

The COVID-19 pandemic affected the organization of health services and had consequences for health teams, according to the pre-existing safety and working conditions. During the first week of April 2020, a cross sectional study was carried out with a qualitative-quantitative approach. The aim was to explore the conditions determining the organizational climate: leadership, communication. institutional resources, cohesion/conflict management, and training;and how these were perceived by health personnel to deal with the pandemic. A total of 5670 healthcare workers participated in an online survey and 50 were interviewed, from all subsectors of the Argentinean health system (public, private and union-health insurance);72.9% were women, 51.4% were physicians, and the predominant age group was under 40 years. In the qualitative sample (interviews), 52% were men, 62% were physicians, and the average age was 44.8 years. The dimensions of the organizational climate were stratified and five independent predictors of perception of conditions were identified: age, gender, tasks performed, health system subsector, and jurisdiction. The condition most frequently perceived as inadequate were the inaccessibility of institutional resources and the access to personal protective equipment was a major concern. Claims included the need of institutional strategies to support healthcare workers and of a clear and uniform communication. In conclusion, at the time of the study, the health personnel perceived serious deficits in their organizations regarding the conditions necessary to confront COVID-19, with differences among subsectors of the health system.