Common use of Strategy Clause in Contracts

Strategy. The strategy is to complete a minimal additional amount of preclinical safety in parallel with the clinical development program. [**]. The filing will be based on a [**]. We note that the current phase 2 study has no control group, and can give only general information about safety and tolerability, and no real information on efficacy in humans. For this reason the [**] will be designed with a ‘vanguard’ cohort of approximately [**] patients. Once the vanguard has completed 6 months of follow up, and interim analysis will be performed, assessing the study for 1) safety, 2) efficacy or futility and 3) performance of the endpoint. Specific, detailed and comprehensive criteria will be established to allow for stopping or continuation, or adjustments in sample size or inclusion criteria. The rules for the interim analysis will be agreed with regulatory authorities in advance of any unblinding, and appropriate adjustments will be made for type 1 error. Following the interim analysis the number of participating centers will be increased to speed enrollment, and the study will continue to completion. We will define [**] and then power the study to show at least a [**] with BL-1040 compared to placebo. This difference is clinically meaningful. To give maximum power we want to define an endpoint that has a [**] after treatment, which would be reduced to [**]. We will design a [**] that ensures an event rate that is [**] in the control arm. Failure could include [**] Any one of these events and the patient is [**]; none of these events and the patient is considered [**]. It is possible that other clinically relevant events may be added to the composite. Next we will estimate how often each of these events will happen. [**]. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Although not required under device approval regulations, approximately [**] patients would be desirable for a safety database. If we assume that the placebo event rate will be approximately [**], we would estimate the sample size of the pivotal study to be approximately [**] patients, including the [**] patients in the vanguard cohort. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] TOTAL [**] [**] [**] [**] [**] [**] [**] [**] [**] Budget will assume [**] of [**] patients, with a primary endpoint at [**] major adverse cardiac outcomes at [**], and a safety follow up annually for [**]. Monitoring: [**] Per Patient total: [**] [**] Pre Clinical [**] [**] Total [**] Given that 15-20% of the total clinical costs are committed before the first patient is enrolled, we estimate that cost to decision point is approximately [**]. It may be possible to reduce cost to the decision point by [**], trading off for time-to-launch. This alternative scenario has not been modeled. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Study Budget will assume a [**] (including ethnicity) of [**] patients. Study will start in [**] and end [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Total Enrollment [**] [**] Active Sites [**] [**] Enrollment/Site/Month (on average) [**] [**] Monthly Study Enrollment [**] [**] Time to Enroll Patient per Part (months) [**] [**] TOTAL ENROLLMENT TIME (months) [**] Initiate Project [**] FPI [**] [**] [**] LPI [**] DB Lock [**] CSR [**] Submit PMA [**] Based on the available preclinical data it is not possible to come to a firm estimate of POS at this time. However, there is evidence of efficacy in preclinical models, and a consensus among experts that the mechanism is plausible. Given the existing data on the prior use of this class of compounds in humans, the likelihood of adequate safety and tolerability seems higher than would otherwise be possible at this stage, and given the device designation, the probability of clinical and regulatory success is likewise higher than it might otherwise be. Assuming the likelihood of adequate safety at [**] and the likelihood of adequate efficacy at [**], the overall POS to filing is in the range of [**].

Strategy. The strategy is to complete a minimal additional amount of preclinical safety in parallel with the clinical development program. [**]. *] The filing will be based on a [**]. We *] note that the current phase 2 study has no control group, and can give only general information about safety and tolerability, and no real information on efficacy in humans. For this reason the [***] will be designed with a ‘vanguard’ cohort of approximately [***] patients. Once the vanguard has completed 6 months of follow up, and interim analysis will be performed, assessing the study for 1) safety, 2) efficacy or futility and 3) performance of the endpoint. Specific, detailed and comprehensive criteria will be established to allow for stopping or continuation, or adjustments in sample size or inclusion criteria. The rules for the interim analysis will be agreed with regulatory authorities in advance of any unblinding, and appropriate adjustments will be made for type 1 error. Following the interim analysis the number of participating centers will be increased to speed enrollment, and the study will continue to completion. We will define [**] *], and then power the study to show at least a [***] with BL-1040 compared to placebo. This difference is clinically meaningful. To give maximum power we want to define an endpoint that has a [***] after treatment, which would be reduced to [***]. We will design a [***] that ensures an event rate that is [***] in the control arm. Failure could include [***] Any one of these events and the patient is [***]’; none of these events and the patient is considered [***]. It is possible that other clinically relevant events may be added to the composite. Next we will estimate how often each of these events will happen. [**]. *] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] Although not required under device approval regulations, approximately [***] patients would be desirable for a safety database. If we assume that the placebo event rate will be approximately [***], we would estimate the sample size of the pivotal study to be approximately [***] patients, including the [***] patients in the vanguard cohort. [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] [***] TOTAL [***] [***] [***] [***] [***] [***] [***] [***] [***] Budget will assume [***] of [***] patients, with a primary endpoint at [**] *], major adverse cardiac outcomes at [***], and a safety follow up annually for [**]. Monitoring: [**] Per Patient total: [**] [**] Pre Clinical [**] [**] Total [**] Given that 15-20% of the total clinical costs are committed before the first patient is enrolled, we estimate that cost to decision point is approximately [**]. It may be possible to reduce cost to the decision point by [**], trading off for time-to-launch. This alternative scenario has not been modeled. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Study Budget will assume a [**] (including ethnicity) of [**] patients. Study will start in [**] and end [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Total Enrollment [**] [**] Active Sites [**] [**] Enrollment/Site/Month (on average) [**] [**] Monthly Study Enrollment [**] [**] Time to Enroll Patient per Part (months) [**] [**] TOTAL ENROLLMENT TIME (months) [**] Initiate Project [**] FPI [**] [**] [**] LPI [**] DB Lock [**] CSR [**] Submit PMA [**] Based on the available preclinical data it is not possible to come to a firm estimate of POS at this time. However, there is evidence of efficacy in preclinical models, and a consensus among experts that the mechanism is plausible. Given the existing data on the prior use of this class of compounds in humans, the likelihood of adequate safety and tolerability seems higher than would otherwise be possible at this stage, and given the device designation, the probability of clinical and regulatory success is likewise higher than it might otherwise be. Assuming the likelihood of adequate safety at [**] and the likelihood of adequate efficacy at [**], the overall POS to filing is in the range of [**].

Strategy. The strategy is to complete a minimal additional amount of preclinical safety in parallel with the clinical development program. [**]. The filing will be based on a [**]. We note that the current phase 2 study has no control group, and can give only general information about safety and tolerability, and no real information on efficacy in humans. For this reason the [**] will be designed with a ‘vanguard’ cohort of approximately [**] patients. Once the vanguard has completed 6 months of follow up, and interim analysis will be performed, assessing the study for 1) safety, 2) efficacy or futility and 3) performance of the endpoint. Specific, detailed and comprehensive criteria will be established to allow for stopping or continuation, or adjustments in sample size or inclusion criteria. The rules for the interim analysis will be agreed with regulatory authorities in advance of any unblinding, and appropriate adjustments will be made for type 1 error. Following the interim analysis the number of participating centers will be increased to speed enrollment, and the study will continue to completion. We will define [**] and then power the study to show at least a [**] with BL-1040 compared to placebo. This difference is clinically meaningful. To give maximum power we want to define an endpoint that has a [**] after treatment, which would be reduced to [**]. We will design a [**] that ensures an event rate that is [**] in the control arm. Failure could include [**] Any one of these events and the patient is [**]; none of these events and the patient is considered [**]. It is possible that other clinically relevant events may be added to the composite. Next we will estimate how often each of these events will happen. [**]. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Although not required under device approval regulations, approximately [**] patients would be desirable for a safety database. If we assume that the placebo event rate will be approximately [**], we would estimate the sample size of the pivotal study to be approximately [**] patients, including the [**] patients in the vanguard cohort. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] TOTAL [**] [**] [**] [**] [**] [**] [**] [**] [**] Budget will assume [**] of [**] patients, with a primary endpoint at [**] major adverse cardiac outcomes at [**], and a safety follow up annually for [**]. Monitoring: [**] Per Patient total: [**] [**] Pre Clinical [**] [**] Total [**] Given that 15-20% of the total clinical costs are committed before the first patient is enrolled, we estimate that cost to decision point is approximately [**]. It may be possible to reduce cost to the decision point by [**], trading off for time-to-launch. This alternative scenario has not been modeled. [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Study Budget will assume a [**] (including ethnicity) of [**] patients. Study will start in [**] and end [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] [**] Total Enrollment [**] [**] Active Sites [**] [**] Enrollment/Site/Month (on average) [**] [**] Monthly Study Enrollment [**] [**] Time to Enroll Patient per Part (months) [**] [**] TOTAL ENROLLMENT TIME (months) [**] Initiate Project [**] FPI [**] [**] [**] LPI [**] DB Lock [**] CSR [**] Submit PMA [**] Based on the available preclinical data it is not possible to come to a firm estimate of POS at this time. However, there is evidence of efficacy in preclinical models, and a consensus among experts that the mechanism is plausible. Given the existing data on the prior use of this class of compounds in humans, the likelihood of adequate safety and tolerability seems higher than would otherwise be possible at this stage, and given the device designation, the probability of clinical and regulatory success is likewise higher than it might otherwise be. Assuming the likelihood of adequate safety at [**] and the likelihood of adequate efficacy at [**], the overall POS to filing is in the range of [**].