Innovation Pharmaceuticals Reports Additional Findings Based on Review of Brilacidin Phase 2 COVID-19 Trial Results and Compassionate Use Cases
Brilacidin, Corporate
WAKEFIELD, MA / March 7, 2022 / ACCESSWIRE Innovation Pharmaceuticals (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, today reported findings from data review of the Company’s Brilacidin Phase 2 COVID-19 study and compassionate use of Brilacidin in critically-ill COVID-19 patients.
“Based on analyses of our Phase 2 trial results, Brilacidin showed promising treatment effects in NEWS2 clinical improvement scores and among patients with the most elevated biomarker levels,” said Leo Ehrlich, Chief Executive Officer at Innovation Pharmaceuticals. “These results, along with observations on the compassionate use of Brilacidin in COVID-19 related to dosing, as well as data being generated from ongoing scientific collaborations, are informing paths forward for our Brilacidin antiviral program. We believe Brilacidin has merit to help address COVID-19 and can play a role in preparing for future pandemics, given Brilacidin’s unique immunomodulatory and antiviral properties. Progress in the Brilacidin antiviral program largely will be dependent upon obtaining government funding for additional clinical development and leveraging external research relationships. Going forward, our business focus will be to advance Brilacidin in other disease areas and to pursue new business opportunities through joint ventures and other investments.”
Summary of Brilacidin COVID-19 Trial Design and Results
The Phase 2 trial (see NCT04784897) was a randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of Brilacidin treatment in addition to current standard-of-care (SoC) compared to SoC alone, in 120 hospitalized patients with moderate-to-severe COVID-19.
Study treatment, Brilacidin IV or saline IV (placebo), was administered as 3 doses or 5 doses. For efficacy analyses, the main comparison was between the Brilacidin 5-dose group and the pooled placebo group.
Even with randomization—stratified by age (<= 65 yrs, >65 yrs) and severity (moderate, severe)—patients allocated to the Brilacidin treatment groups exhibited a greater degree of disease burden at baseline, as reflected by higher, on average, elevated biomarker levels (e.g., CRP, viral load), in contrast to the pooled placebo group.
As previously released, Brilacidin did not show a difference compared to placebo in reducing Time to Sustained Recovery Through Day 29, the study's primary endpoint based on clinical status. There was also no difference in mortality between active and placebo, with both groups experiencing low mortality rates (7 percent) compared to other studies that evaluated patients with moderate-to-severe COVID-19. Beneficial Brilacidin treatment effects, however, were observed in NEWS2 secondary endpoints, as well as on the primary endpoint in patient subgroups, as summarized below.
Pharmacokinetic (PK) analysis (from measured plasma sample concentrations) provided comparable estimations to those seen previously in the Brilacidin IV program, although exposure was generally greater than observed prior (when comparing patients on similar treatment regimens for the indication of acute bacterial skin and skin structure infections [ABSSSI]). These new PK data will help inform any future Brilacidin IV dosing strategies.
Brilacidin was generally well-tolerated by patients, with an overall safety profile in COVID-19 patients consistent with previous clinical studies. The incidence of patients with at least one treatment-emergent adverse event (TEAE) was higher for Brilacidin treatment compared to placebo. However, the proportion of patients with TEAEs is similar across groups (72 percent on active, 65 percent on placebo) after excluding the Brilacidin-related adverse events of tingling (paresthesia) and hypoesthesia (numbness), which are known, transient, mostly mild, non-serious adverse events related to Brilacidin IV treatment. The incidence of serious adverse events was the same (12 percent on active, 12 percent on placebo), and no serious adverse events were reported as related to study treatment.
Secondary Endpoint Analysis
· NEWS2 Scores (Intent-to-Treat Population)
More patients in the Brilacidin 5-dose group achieved and maintained, for at least 24 hours, a National Early Warning Score 2 (NEWS2) of <=2. By 10 days (from randomization), 97 percent of the Brilacidin 5-dose group had achieved this NEWS2 endpoint compared to 84 percent of patients in the pooled placebo group. A NEWS2 score of 2 or less is clinically meaningful as an aggregate score of 4 or less translates to low clinical risk, per NEWS2 criteria.
The mean change from baseline in NEWS2 was greater for the Brilacidin treatment groups than for the pooled placebo group, at all assessment timepoints (Study Days 3, 5, 8, 11, 15, and 29).
NEWS2 is an ordinal scale developed by the U.K.’s Royal College of Physicians to identify patients at risk for rapid clinical deterioration requiring critical care intervention and is considered a valuable tool for management of COVID-19. NEWS2 is based on certain physiological parameters—respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse, level of consciousness, and temperature. NEWS2 has been used as an endpoint for several COVID-19 clinical trials.
Post-Hoc Analysis
· Inflammatory Biomarkers: Patient Subgroup with Highest Quartile Baseline Values (Per Protocol Population)
For those patients with baseline values for C-Reactive Protein (CRP) in the highest quartile (4th quartile), all patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29, compared to 77 percent of patients in the pooled placebo subgroup. Time to sustained recovery was on average shorter in the Brilacidin 5-dose subgroup compared to placebo.
Additionally, for those patients with baseline values for Interleukin-6 (IL-6) in the highest quartile, more patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29 (89 percent compared to 67 percent on placebo). Time to sustained recovery also was on average shorter in the Brilacidin 5-dose subgroup compared to placebo for this quartile of patients.
Both CRP and IL-6 levels, when elevated at baseline, have been shown to predict worse outcomes in COVID-19 patients and our data was consistent with this. These two biomarkers have been used by other pharmaceutical companies as enrollment criteria to target COVID-19 patient populations most likely to benefit from treatment. The NIH-sponsored clinical evaluation of Humanigen’s drug, lenzilumab (ACTIV-5/BET-
, was updated to include, as the trial’s primary endpoint, survival without ventilation by 28 days in patients with baseline CRP levels under 150mg/l.
· Viral Load Biomarker: Patient Subgroup with Highest Quartile Baseline Values (Per Protocol Population)
For those patients with baseline values for viral load in the highest quartile, more patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29 (92 percent compared to 82 percent on placebo). Time to sustained recovery was also on average shorter in the Brilacidin 5-dose subgroup compared to placebo for this quartile of patients. This is notable given median time from symptom onset to treatment randomization averaged 9.53 days in the Brilacidin COVID-19 trial, and thus likely occurred after peak viral load in most patients.
· Time from Onset of Symptoms to Randomization (Per Protocol Population)
If a patient started study treatment within fewer than 7 days of onset of COVID-19 symptoms, patients in the Brilacidin 5-dose group achieved sustained recovery more quickly compared to the pooled placebo group (p=0.03). For this patient population, early treatment with Brilacidin from onset of symptoms appeared to have a potential positive impact on time to sustained recovery (the study’s primary endpoint), suggesting cases that can be treated close to initial onset of disease may be an attractive population to target for Brilacidin treatment.
Multiple monoclonal antibodies targeting COVID-19, as well as the oral COVID-19 antiviral molnupiravir (Lagevrio™), failed in hospitalized patients but later achieved success in treating earlier-stage disease. The antiviral remdesivir (Veklury™) also recently exhibited substantial benefit in non-hospitalized COVID-19 patients, including an 87 percent lower risk of hospitalization or death than placebo after a 3-day intravenous course of the drug.
· Standard-of-Care (SoC)
Review of Brilacidin Phase 2 COVID-19 trial data showed most patients (>87 percent) received treatment with systemic corticosteroids (generally at high doses, and for long durations), and treatment with mucolytics (>82 percent), antivirals (>68 percent), analgesics (>56 percent), immunosuppressants (>45 percent), anti-thrombotic agents (>97 percent), and other supportive medications as SoC for COVID-19.
These seemingly aggressive SoC treatment strategies are likely attributable to the Delta variant of SARS-CoV-2, which became prevalent during trial enrollment and has been associated with significantly higher in-hospital mortality compared to earlier SARS-CoV-2 variants. Such implementation of a more aggressive COVID-19 SOC, as has been reported by other companies evaluating COVID-19 trial results, may have contributed to an overall lessening of observable Brilacidin treatment effects.
Brilacidin Compassionate Use in COVID-19—Observed Treatment Effects
Noticeable treatment effects attributed to the compassionate use of Brilacidin were reported by investigators. Patients receiving compassionate use of Brilacidin were at extremely advanced stages of disease and had exhausted other conventional treatment options. Compassionate use cases comprised Brilacidin being administered to critically-ill COVID‑19 patients over a longer duration (up to 10 days of treatment) than in the Phase 2 COVID-19 clinical trial (3 and 5 day dosing), with some patients also receiving higher and more frequent (twice daily) dosing. There appeared to be a potentially favorable treatment response based on increased Brilacidin dosing. For the Brilacidin compassionate use cases, in general, investigators observed more stable disease with initial improvements evident on chest x-rays and in COVID-19 disease biomarkers (e.g., CRP and ferritin). While nearly all of these critically-ill patients ultimately succumbed to severe hypoxic respiratory failure (secondary to COVID-19 viral pneumonia) and expired, survival time for these patients who initially were not expected to live beyond a few days was appreciably extended.
Brilacidin Antiviral Program—Planned Next Steps
Future progress in the broader Brilacidin antiviral program will largely be tied to obtaining government funding for additional clinical development while benefiting from ongoing collaborative research with NIH and other scientists. Brilacidin’s broad-spectrum antiviral activity is generating positive data. Publications and conference abstracts related to this research are being prepared.
Given the need for development of new small molecule antivirals and immunomodulators, the Company is planning to submit Brilacidin for possible inclusion in government-sponsored COVID-19 trial platforms, e.g., the NIH ACTIV program. Platform trials, which typically enroll hundreds of patients per treatment arm, can more accurately evaluate the treatment potential of COVID-19 drug candidates. Pursing a biomarker-driven approach, increasing Brilacidin dosing and treatment duration, targeting different patient populations, testing Brilacidin in combination with drugs exhibiting different mechanisms of action (e.g., remdesivir, given strong synergistic in vitro data)—all are possible elements of any future Brilacidin COVID-19 trial design. Compassionate use of Brilacidin also is anticipated to continue, which could further inform Brilacidin’s treatment effects in COVID-19. For more details on the Company’s Compassionate Use policy, please visit:
https://www.ipharminc.com/expanded-access-and...ionate-use
The Company also plans to seek additional clinical development support from the NIH Antiviral Program for Pandemics (APP). Brilacidin for prophylactic use, including assessing Brilacidin in pre-clinical animal models, is of particular interest due to Brilacidin’s blocking and neutralizing antiviral properties and industry investment in developing intranasal-targeted, direct-acting antivirals. Preliminary Brilacidin formulation work for inhaled delivery has been conducted, with the NIH APP a potential avenue to expand on this work, along with exploring the subcutaneous administration of Brilacidin, which has greater than 70 percent bioavailability via this route of administration.
Pipeline Advancement, Other Business Opportunities
Efforts to advance the Brilacidin Oral Mucositis (OM) program are a key focus. The Company is presently exploring timelines and scenario planning—including the option to seek a meeting with the U.S. Food and Drug Administration towards the initiation of a Phase 3 clinical trial evaluating oral rinse Brilacidin as a new treatment for the prevention of OM in head and neck cancer patients receiving chemoradiation. Brilacidin oral formulation development work for Ulcerative Colitis continues. The Company has also been notified by Alfasigma, its licensing partner, of their intent to initiate this year Phase 2 testing of Brilacidin in Ulcerative Proctitis/Proctosigmoiditis.
In other news, the Company is evaluating a number of potential pipeline additions and other unique business opportunities, including investments in medical-related technologies. In certain instances, management is in advanced discussions for products believed to be accretive to revenue by diversifying Innovation’s portfolio. The Company will provide updates on all such matters as appropriate.
Brilacidin, Corporate
WAKEFIELD, MA / March 7, 2022 / ACCESSWIRE Innovation Pharmaceuticals (OTCQB:IPIX) (“the Company”), a clinical stage biopharmaceutical company, today reported findings from data review of the Company’s Brilacidin Phase 2 COVID-19 study and compassionate use of Brilacidin in critically-ill COVID-19 patients.
“Based on analyses of our Phase 2 trial results, Brilacidin showed promising treatment effects in NEWS2 clinical improvement scores and among patients with the most elevated biomarker levels,” said Leo Ehrlich, Chief Executive Officer at Innovation Pharmaceuticals. “These results, along with observations on the compassionate use of Brilacidin in COVID-19 related to dosing, as well as data being generated from ongoing scientific collaborations, are informing paths forward for our Brilacidin antiviral program. We believe Brilacidin has merit to help address COVID-19 and can play a role in preparing for future pandemics, given Brilacidin’s unique immunomodulatory and antiviral properties. Progress in the Brilacidin antiviral program largely will be dependent upon obtaining government funding for additional clinical development and leveraging external research relationships. Going forward, our business focus will be to advance Brilacidin in other disease areas and to pursue new business opportunities through joint ventures and other investments.”
Summary of Brilacidin COVID-19 Trial Design and Results
The Phase 2 trial (see NCT04784897) was a randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of Brilacidin treatment in addition to current standard-of-care (SoC) compared to SoC alone, in 120 hospitalized patients with moderate-to-severe COVID-19.
Study treatment, Brilacidin IV or saline IV (placebo), was administered as 3 doses or 5 doses. For efficacy analyses, the main comparison was between the Brilacidin 5-dose group and the pooled placebo group.
Even with randomization—stratified by age (<= 65 yrs, >65 yrs) and severity (moderate, severe)—patients allocated to the Brilacidin treatment groups exhibited a greater degree of disease burden at baseline, as reflected by higher, on average, elevated biomarker levels (e.g., CRP, viral load), in contrast to the pooled placebo group.
As previously released, Brilacidin did not show a difference compared to placebo in reducing Time to Sustained Recovery Through Day 29, the study's primary endpoint based on clinical status. There was also no difference in mortality between active and placebo, with both groups experiencing low mortality rates (7 percent) compared to other studies that evaluated patients with moderate-to-severe COVID-19. Beneficial Brilacidin treatment effects, however, were observed in NEWS2 secondary endpoints, as well as on the primary endpoint in patient subgroups, as summarized below.
Pharmacokinetic (PK) analysis (from measured plasma sample concentrations) provided comparable estimations to those seen previously in the Brilacidin IV program, although exposure was generally greater than observed prior (when comparing patients on similar treatment regimens for the indication of acute bacterial skin and skin structure infections [ABSSSI]). These new PK data will help inform any future Brilacidin IV dosing strategies.
Brilacidin was generally well-tolerated by patients, with an overall safety profile in COVID-19 patients consistent with previous clinical studies. The incidence of patients with at least one treatment-emergent adverse event (TEAE) was higher for Brilacidin treatment compared to placebo. However, the proportion of patients with TEAEs is similar across groups (72 percent on active, 65 percent on placebo) after excluding the Brilacidin-related adverse events of tingling (paresthesia) and hypoesthesia (numbness), which are known, transient, mostly mild, non-serious adverse events related to Brilacidin IV treatment. The incidence of serious adverse events was the same (12 percent on active, 12 percent on placebo), and no serious adverse events were reported as related to study treatment.
Secondary Endpoint Analysis
· NEWS2 Scores (Intent-to-Treat Population)
More patients in the Brilacidin 5-dose group achieved and maintained, for at least 24 hours, a National Early Warning Score 2 (NEWS2) of <=2. By 10 days (from randomization), 97 percent of the Brilacidin 5-dose group had achieved this NEWS2 endpoint compared to 84 percent of patients in the pooled placebo group. A NEWS2 score of 2 or less is clinically meaningful as an aggregate score of 4 or less translates to low clinical risk, per NEWS2 criteria.
The mean change from baseline in NEWS2 was greater for the Brilacidin treatment groups than for the pooled placebo group, at all assessment timepoints (Study Days 3, 5, 8, 11, 15, and 29).
NEWS2 is an ordinal scale developed by the U.K.’s Royal College of Physicians to identify patients at risk for rapid clinical deterioration requiring critical care intervention and is considered a valuable tool for management of COVID-19. NEWS2 is based on certain physiological parameters—respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse, level of consciousness, and temperature. NEWS2 has been used as an endpoint for several COVID-19 clinical trials.
Post-Hoc Analysis
· Inflammatory Biomarkers: Patient Subgroup with Highest Quartile Baseline Values (Per Protocol Population)
For those patients with baseline values for C-Reactive Protein (CRP) in the highest quartile (4th quartile), all patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29, compared to 77 percent of patients in the pooled placebo subgroup. Time to sustained recovery was on average shorter in the Brilacidin 5-dose subgroup compared to placebo.
Additionally, for those patients with baseline values for Interleukin-6 (IL-6) in the highest quartile, more patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29 (89 percent compared to 67 percent on placebo). Time to sustained recovery also was on average shorter in the Brilacidin 5-dose subgroup compared to placebo for this quartile of patients.
Both CRP and IL-6 levels, when elevated at baseline, have been shown to predict worse outcomes in COVID-19 patients and our data was consistent with this. These two biomarkers have been used by other pharmaceutical companies as enrollment criteria to target COVID-19 patient populations most likely to benefit from treatment. The NIH-sponsored clinical evaluation of Humanigen’s drug, lenzilumab (ACTIV-5/BET-
, was updated to include, as the trial’s primary endpoint, survival without ventilation by 28 days in patients with baseline CRP levels under 150mg/l. · Viral Load Biomarker: Patient Subgroup with Highest Quartile Baseline Values (Per Protocol Population)
For those patients with baseline values for viral load in the highest quartile, more patients in the Brilacidin 5-dose subgroup achieved sustained recovery through Day 29 (92 percent compared to 82 percent on placebo). Time to sustained recovery was also on average shorter in the Brilacidin 5-dose subgroup compared to placebo for this quartile of patients. This is notable given median time from symptom onset to treatment randomization averaged 9.53 days in the Brilacidin COVID-19 trial, and thus likely occurred after peak viral load in most patients.
· Time from Onset of Symptoms to Randomization (Per Protocol Population)
If a patient started study treatment within fewer than 7 days of onset of COVID-19 symptoms, patients in the Brilacidin 5-dose group achieved sustained recovery more quickly compared to the pooled placebo group (p=0.03). For this patient population, early treatment with Brilacidin from onset of symptoms appeared to have a potential positive impact on time to sustained recovery (the study’s primary endpoint), suggesting cases that can be treated close to initial onset of disease may be an attractive population to target for Brilacidin treatment.
Multiple monoclonal antibodies targeting COVID-19, as well as the oral COVID-19 antiviral molnupiravir (Lagevrio™), failed in hospitalized patients but later achieved success in treating earlier-stage disease. The antiviral remdesivir (Veklury™) also recently exhibited substantial benefit in non-hospitalized COVID-19 patients, including an 87 percent lower risk of hospitalization or death than placebo after a 3-day intravenous course of the drug.
· Standard-of-Care (SoC)
Review of Brilacidin Phase 2 COVID-19 trial data showed most patients (>87 percent) received treatment with systemic corticosteroids (generally at high doses, and for long durations), and treatment with mucolytics (>82 percent), antivirals (>68 percent), analgesics (>56 percent), immunosuppressants (>45 percent), anti-thrombotic agents (>97 percent), and other supportive medications as SoC for COVID-19.
These seemingly aggressive SoC treatment strategies are likely attributable to the Delta variant of SARS-CoV-2, which became prevalent during trial enrollment and has been associated with significantly higher in-hospital mortality compared to earlier SARS-CoV-2 variants. Such implementation of a more aggressive COVID-19 SOC, as has been reported by other companies evaluating COVID-19 trial results, may have contributed to an overall lessening of observable Brilacidin treatment effects.
Brilacidin Compassionate Use in COVID-19—Observed Treatment Effects
Noticeable treatment effects attributed to the compassionate use of Brilacidin were reported by investigators. Patients receiving compassionate use of Brilacidin were at extremely advanced stages of disease and had exhausted other conventional treatment options. Compassionate use cases comprised Brilacidin being administered to critically-ill COVID‑19 patients over a longer duration (up to 10 days of treatment) than in the Phase 2 COVID-19 clinical trial (3 and 5 day dosing), with some patients also receiving higher and more frequent (twice daily) dosing. There appeared to be a potentially favorable treatment response based on increased Brilacidin dosing. For the Brilacidin compassionate use cases, in general, investigators observed more stable disease with initial improvements evident on chest x-rays and in COVID-19 disease biomarkers (e.g., CRP and ferritin). While nearly all of these critically-ill patients ultimately succumbed to severe hypoxic respiratory failure (secondary to COVID-19 viral pneumonia) and expired, survival time for these patients who initially were not expected to live beyond a few days was appreciably extended.
Brilacidin Antiviral Program—Planned Next Steps
Future progress in the broader Brilacidin antiviral program will largely be tied to obtaining government funding for additional clinical development while benefiting from ongoing collaborative research with NIH and other scientists. Brilacidin’s broad-spectrum antiviral activity is generating positive data. Publications and conference abstracts related to this research are being prepared.
Given the need for development of new small molecule antivirals and immunomodulators, the Company is planning to submit Brilacidin for possible inclusion in government-sponsored COVID-19 trial platforms, e.g., the NIH ACTIV program. Platform trials, which typically enroll hundreds of patients per treatment arm, can more accurately evaluate the treatment potential of COVID-19 drug candidates. Pursing a biomarker-driven approach, increasing Brilacidin dosing and treatment duration, targeting different patient populations, testing Brilacidin in combination with drugs exhibiting different mechanisms of action (e.g., remdesivir, given strong synergistic in vitro data)—all are possible elements of any future Brilacidin COVID-19 trial design. Compassionate use of Brilacidin also is anticipated to continue, which could further inform Brilacidin’s treatment effects in COVID-19. For more details on the Company’s Compassionate Use policy, please visit:
https://www.ipharminc.com/expanded-access-and...ionate-use
The Company also plans to seek additional clinical development support from the NIH Antiviral Program for Pandemics (APP). Brilacidin for prophylactic use, including assessing Brilacidin in pre-clinical animal models, is of particular interest due to Brilacidin’s blocking and neutralizing antiviral properties and industry investment in developing intranasal-targeted, direct-acting antivirals. Preliminary Brilacidin formulation work for inhaled delivery has been conducted, with the NIH APP a potential avenue to expand on this work, along with exploring the subcutaneous administration of Brilacidin, which has greater than 70 percent bioavailability via this route of administration.
Pipeline Advancement, Other Business Opportunities
Efforts to advance the Brilacidin Oral Mucositis (OM) program are a key focus. The Company is presently exploring timelines and scenario planning—including the option to seek a meeting with the U.S. Food and Drug Administration towards the initiation of a Phase 3 clinical trial evaluating oral rinse Brilacidin as a new treatment for the prevention of OM in head and neck cancer patients receiving chemoradiation. Brilacidin oral formulation development work for Ulcerative Colitis continues. The Company has also been notified by Alfasigma, its licensing partner, of their intent to initiate this year Phase 2 testing of Brilacidin in Ulcerative Proctitis/Proctosigmoiditis.
In other news, the Company is evaluating a number of potential pipeline additions and other unique business opportunities, including investments in medical-related technologies. In certain instances, management is in advanced discussions for products believed to be accretive to revenue by diversifying Innovation’s portfolio. The Company will provide updates on all such matters as appropriate.
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