On March 10, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported the expansion of a randomized, controlled study with TG4001 in combination with avelumab versus avelumab monotherapy in patients with HPV16-positive anogenital tumors (NCT: 03260023) (Press release, Transgene, MAR 10, 2021, View Source [SID1234576419]).

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Transgene has amended the initial Phase Ib/II trial protocol to enable a more rapid start of this important Phase II study based on encouraging Phase Ib/II trial data. This randomized Phase II trial will be supported by a continuing collaboration with the alliance of Merck KGaA, Darmstadt, Germany, and Pfizer, which is supplying avelumab. Transgene retains all rights to TG4001.

PHASE II TRIAL AIMS TO SHOW THE SUPERIORITY OF TG4001 + AVELUMAB OVER AVELUMAB MONOTHERAPY

The initial Phase Ib/II trial conducted in Europe (France and Spain) has been amended to include a randomized comparison of the combination of TG4001 with avelumab versus avelumab monotherapy in anogenital cancers. The submission of the amended protocol has been initiated in Europe. In addition, Transgene received US FDA clearance of the protocol under TG4001 IND. Patient enrollment is expected to start in Q2 2021.

The trial will focus on patients with recurrent or metastatic HPV16-positive anogenital cancer without liver metastases, including cervical, vulvar, vaginal, penile, and anal cancer. This population was shown in the Phase Ib/II study to derive improved clinical benefit from the combination regimen [1, 2].

Patients will be randomized to either receive the combination regimen of the therapeutic vaccine TG4001 and avelumab or avelumab alone.

The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and a series of immunological parameters.

The Phase II trial will be supported by the extension of the collaboration with the alliance of Merck KGaA, Darmstadt, Germany, and Pfizer, which is supplying avelumab for this trial. Transgene retains all rights to TG4001.

An interim analysis will be performed after the enrollment of nearly 50 patients. Transgene expects to communicate the interim analysis data around the end of 2022. This timeline is based on patient enrollment starting in Q2 2021 and there being no major impact on recruitment from the Covid-19 pandemic.

Commenting on this novel investigational immunotherapy regimen, Prof. Christophe Le Tourneau, MD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute and Principal Investigator of the trial, added: "I am very pleased that we are now moving ahead with a new part of this Phase II study. The promising data that we generated in the Phase Ib/II part of this study, in patients without liver metastases, gives me confidence that the amended study can generate the additional data needed to confirm the treatment benefits of the combination of TG4001 and avelumab in this patient population with very limited therapeutic options."

RECURRENT AND METASTATIC HPV16-POSITIVE ANOGENITAL CANCERS NEED BETTER TREATMENT OPTIONS

The Phase II trial focuses on indications where standard therapeutic options and immune checkpoint inhibitors have limited efficacy. These indications represent areas of important medical need; they include cervical, vulvar, vaginal, penile, and anal cancer. The trial will enroll patients who have received a maximum of one line of chemotherapy for the treatment of their recurrent or metastatic disease or who are not eligible for chemotherapy.

Transgene estimates the number of people diagnosed annually with these cancers to be around 25,000 patients per year (US, Europe 27, UK) [3-9]. In spite of recent progress, patients with these severe and heterogeneous malignancies need better treatment options, particularly after the recurrence of the disease: median overall survival is less than 11 months [10-13] and median progression-free survival is around 2 months [10-13].

Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene, concludes about this study: "I am pleased we have been able to use a methodologically sound trial design to move ahead with this randomized Phase II study quickly. The results from the initial Phase Ib/II study demonstrated the potential of the combination of TG4001 with an immune checkpoint inhibitor in this advanced disease setting. We observed encouraging clinical outcomes with a response rate reaching 34.8% and median progression-free survival of 5.6 months in patients without liver metastases. The observed median progression-free survival shows that this combination can induce a sustained and durable benefit, which may be based on the induction of a specific immune response. This study is expected to provide us with the data required to discuss the registration path of TG4001."

About the trial
The multi-center, open label, randomized Phase II trial (NCT03260023) is designed to compare the efficacy of the combination of TG4001 and avelumab versus avelumab alone in patients with advanced, recurrent and/or metastatic HPV16-positive anogenital cancers who have disease progression after a maximum of one line of systemic treatment, or who are not eligible for first-line chemotherapy.

Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, is the Principal Investigator of the study. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE), which are providing avelumab for the trial. Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc. Transgene will continue to be the sponsor of the trial and conduct the trial.

Patients will receive TG4001 at the dose of 5×107 pfu, SC, weekly for 6 weeks, every 2 weeks up to six months, and every 12 weeks thereafter, in combination with avelumab or avelumab alone at 800 mg, IV every two weeks, until disease progression. The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and other immunological parameters. The trial could enroll up to 136 patients until the final analysis.

Patients with liver metastases will be followed in an ancillary arm and will be randomized to receive one of the treatment regimens; these patients will not be included in endpoint analyses.

About the data presented at SITC (Free SITC Whitepaper) 2020 and ESMO (Free ESMO Whitepaper) IO 2020 [1,2]
The results from the Phase Ib/II parts of the trial combining TG4001 with avelumab in HPV16-positive recurrent and/or metastatic malignancies were presented at SITC (Free SITC Whitepaper) 2020 [1] and ESMO (Free ESMO Whitepaper) IO 2020[2].

The combination of TG4001 and avelumab demonstrated anti-tumor activity (23.5% ORR) in patients with previously treated recurrent and/or metastatic HPV-related cancers (including patients with oropharyngeal cancers and anogenital cancers). Presence of liver metastases had a profound impact on the outcome in terms of ORR and PFS. In patients without liver metastases, an ORR of 34.8% and a median PFS of 5.6 months were achieved. The treatment induced HPV-specific T-cell responses and was associated with increased levels of immune cell infiltration in the tumors and expression of genes associated with activation of the immune system.

About TG4001
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated Vaccinia vector (MVA), which is engineered to express HPV16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to cells presenting the HPV16 E6 and E7 antigens, that can be found in HPV16-related tumors, and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety and promising efficacy results [1, 2, 14, 15]. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.

About HPV-Positive Cancers
HPV-positive cancers comprise a variety of malignancies, including anogenital cancers [3]. HPV-positive cancers include cervical [4], vaginal [5], vulvar [6], anal [7] and penile [8] cancers, i.e., approximately 25,000 cancers at metastatic stage eligible for a first-line treatment and in second line for a locoregional disease [9] (USA, EU 27, UK).

Current treatments mostly include chemoradiotherapy. However, better options are needed for advanced and metastatic HPV-positive cancers. It is thought that a therapeutic vaccine combined with other immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) could provide a promising potential treatment option that would address this strong medical need [16,17]. With immune checkpoint inhibitors, median overall survival remains less than 11 months [10-13] and median progression-free survival is between 2 and 4 months [10-13].

On March 10, 2021 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a late-stage targeted oncology company, reported it will present initial preclinical data on the Company’s synthetic lethal PRMT5 inhibitor during a late-breaking minisymposium at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting taking place April 10-15, 2021 (Press release, Mirati, MAR 10, 2021, View Source [SID1234576437]).

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"At Mirati, we are applying leading-edge drug discovery strategies, such as synthetic lethality, to translate this exciting research approach into meaningful, targeted therapeutic options for patients with cancer," said James Christensen, Ph.D., executive vice president and chief scientific officer, Mirati Therapeutics, Inc. "We look forward to presenting early preclinical data at AACR (Free AACR Whitepaper) from our internally-discovered, potentially first-in-class, synthetic lethal PRMT5 inhibitor, as an example of how Mirati is progressing the science of novel targets."

Mirati is developing a novel synthetic lethal PRMT5 inhibitor targeting the methylthioadenosine phosphorylase (MTAP)-deleted patient population. Deletions of the MTAP gene locus are commonly observed in pancreatic, lung, and bladder cancers, among others, and are linked to poor patient outcomes. PRMT5 is an enzyme critical to the survival of normal and tumor cells and is partially inhibited by methylthioadenosine (MTA) which accumulates in MTAP-deleted cancers. Mirati’s differentiated approach selectively targets the PRMT5/MTA complex in MTAP-deleted cancer cells while sparing normal cells and represents a precision medicine strategy.

Presentation Details

Title: Fragment based discovery of MRTX9768, a synthetic lethal-based inhibitor designed to bind the PRMT5/MTA complex and selectively target MTAP/CDKN2A-deleted tumors
Author: Matthew Marx, Ph.D., senior vice president, drug discovery, Mirati Therapeutics, Inc.
Abstract #: LB003
Late-Breaking Minisymposium 1
Saturday, April 10, 2021, 1:30 p.m. – 3:30 p.m.

On March 10, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported that four abstracts featuring three of its drug candidates will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, which will convene virtually from April 10-14 (Press release, Turning Point Therapeutics, MAR 10, 2021, View Source [SID1234576523]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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For lead drug candidate, repotrectinib, two poster presentations will highlight new preclinical combination data with MEK and MEK/Raf inhibitors, as well as repotrectinib’s potency against wildtype and TRKC A/B/C as compared to approved TRK inhibitors. For MET/SRC/CSF1R inhibitor, TPX-0022, the company will present preclinical data demonstrating potential utility in combination with immune checkpoint inhibitors. For its newest drug candidate, ALK-inhibitor TPX-0131, Turning Point will present preclinical potency data against ALK resistance mutations and in-vivo data demonstrating brain tissue penetration.

The four posters to be presented are:

Title: Repotrectinib increases effectiveness of MEK inhibitors in KRAS mutant cancer models
Abstract Number: 1104

Title: Molecular characteristics of repotrectinib that enable potent inhibition of TRK fusion proteins and broad mutant selectivity
Abstract Number: 1119

Title: TPX-0022, a potent MET/SRC/CSF1R inhibitor that modulates the tumor immune microenvironment in preclinical models
Abstract Number: 1444

Title: TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations
Abstract Number: 1469

AACR plans to make poster presentations available via its website on Sat., April 10, the first day of the virtual Annual Meeting.

On March 10, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported the expansion of a randomized, controlled study with TG4001 in combination with avelumab versus avelumab monotherapy in patients with HPV16-positive anogenital tumors (NCT: 03260023) (Press release, Transgene, MAR 10, 2021, View Source [SID1234621820]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Transgene has amended the initial Phase Ib/II trial protocol to enable a more rapid start of this important Phase II study based on encouraging Phase Ib/II trial data. This randomized Phase II trial will be supported by a continuing collaboration with the alliance of Merck KGaA, Darmstadt, Germany, and Pfizer, which is supplying avelumab. Transgene retains all rights to TG4001.

PHASE II TRIAL AIMS TO SHOW THE SUPERIORITY OF TG4001 + AVELUMAB OVER AVELUMAB MONOTHERAPY

The initial Phase Ib/II trial conducted in Europe (France and Spain) has been amended to include a randomized comparison of the combination of TG4001 with avelumab versus avelumab monotherapy in anogenital cancers. The submission of the amended protocol has been initiated in Europe. In addition, Transgene received US FDA clearance of the protocol under TG4001 IND. Patient enrollment is expected to start in Q2 2021.

The trial will focus on patients with recurrent or metastatic HPV16-positive anogenital cancer without liver metastases, including cervical, vulvar, vaginal, penile, and anal cancer. This population was shown in the Phase Ib/II study to derive improved clinical benefit from the combination regimen [1, 2].

Patients will be randomized to either receive the combination regimen of the therapeutic vaccine TG4001 and avelumab or avelumab alone.

The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and a series of immunological parameters.

The Phase II trial will be supported by the extension of the collaboration with the alliance of Merck KGaA, Darmstadt, Germany, and Pfizer, which is supplying avelumab for this trial. Transgene retains all rights to TG4001.

An interim analysis will be performed after the enrollment of nearly 50 patients. Transgene expects to communicate the interim analysis data around the end of 2022. This timeline is based on patient enrollment starting in Q2 2021 and there being no major impact on recruitment from the Covid-19 pandemic.

Commenting on this novel investigational immunotherapy regimen, Prof. Christophe Le Tourneau, MD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute and Principal Investigator of the trial, added: "I am very pleased that we are now moving ahead with a new part of this Phase II study. The promising data that we generated in the Phase Ib/II part of this study, in patients without liver metastases, gives me confidence that the amended study can generate the additional data needed to confirm the treatment benefits of the combination of TG4001 and avelumab in this patient population with very limited therapeutic options."

RECURRENT AND METASTATIC HPV16-POSITIVE ANOGENITAL CANCERS NEED BETTER TREATMENT OPTIONS

The Phase II trial focuses on indications where standard therapeutic options and immune checkpoint inhibitors have limited efficacy. These indications represent areas of important medical need; they include cervical, vulvar, vaginal, penile, and anal cancer. The trial will enroll patients who have received a maximum of one line of chemotherapy for the treatment of their recurrent or metastatic disease or who are not eligible for chemotherapy.

Transgene estimates the number of people diagnosed annually with these cancers to be around 25,000 patients per year (US, Europe 27, UK) [3-9]. In spite of recent progress, patients with these severe and heterogeneous malignancies need better treatment options, particularly after the recurrence of the disease: median overall survival is less than 11 months [10-13] and median progression-free survival is around 2 months [10-13].

Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene, concludes about this study: "I am pleased we have been able to use a methodologically sound trial design to move ahead with this randomized Phase II study quickly. The results from the initial Phase Ib/II study demonstrated the potential of the combination of TG4001 with an immune checkpoint inhibitor in this advanced disease setting. We observed encouraging clinical outcomes with a response rate reaching 34.8% and median progression-free survival of 5.6 months in patients without liver metastases. The observed median progression-free survival shows that this combination can induce a sustained and durable benefit, which may be based on the induction of a specific immune response. This study is expected to provide us with the data required to discuss the registration path of TG4001."

About the trial
The multi-center, open label, randomized Phase II trial (NCT03260023) is designed to compare the efficacy of the combination of TG4001 and avelumab versus avelumab alone in patients with advanced, recurrent and/or metastatic HPV16-positive anogenital cancers who have disease progression after a maximum of one line of systemic treatment, or who are not eligible for first-line chemotherapy.

Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, is the Principal Investigator of the study. The trial is being conducted in collaboration with Merck KGaA, Darmstadt, Germany, and Pfizer Inc. (NYSE: PFE), which are providing avelumab for the trial. Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc. Transgene will continue to be the sponsor of the trial and conduct the trial.

Patients will receive TG4001 at the dose of 5×107 pfu, SC, weekly for 6 weeks, every 2 weeks up to six months, and every 12 weeks thereafter, in combination with avelumab or avelumab alone at 800 mg, IV every two weeks, until disease progression. The primary endpoint of the trial is progression-free survival (PFS) according to RECIST 1.1. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and other immunological parameters. The trial could enroll up to 136 patients until the final analysis.

Patients with liver metastases will be followed in an ancillary arm and will be randomized to receive one of the treatment regimens; these patients will not be included in endpoint analyses.

About the data presented at SITC (Free SITC Whitepaper) 2020 and ESMO (Free ESMO Whitepaper) IO 2020 [1,2]
The results from the Phase Ib/II parts of the trial combining TG4001 with avelumab in HPV16-positive recurrent and/or metastatic malignancies were presented at SITC (Free SITC Whitepaper) 2020 [1] and ESMO (Free ESMO Whitepaper) IO 2020[2].

The combination of TG4001 and avelumab demonstrated anti-tumor activity (23.5% ORR) in patients with previously treated recurrent and/or metastatic HPV-related cancers (including patients with oropharyngeal cancers and anogenital cancers). Presence of liver metastases had a profound impact on the outcome in terms of ORR and PFS. In patients without liver metastases, an ORR of 34.8% and a median PFS of 5.6 months were achieved. The treatment induced HPV-specific T-cell responses and was associated with increased levels of immune cell infiltration in the tumors and expression of genes associated with activation of the immune system.

About TG4001
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated Vaccinia vector (MVA), which is engineered to express HPV16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to cells presenting the HPV16 E6 and E7 antigens, that can be found in HPV16-related tumors, and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety and promising efficacy results [1, 2, 14, 15]. Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.

About HPV-Positive Cancers
HPV-positive cancers comprise a variety of malignancies, including anogenital cancers [3]. HPV-positive cancers include cervical [4], vaginal [5], vulvar [6], anal [7] and penile [8] cancers, i.e., approximately 25,000 cancers at metastatic stage eligible for a first-line treatment and in second line for a locoregional disease [9] (USA, EU 27, UK).

Current treatments mostly include chemoradiotherapy. However, better options are needed for advanced and metastatic HPV-positive cancers. It is thought that a therapeutic vaccine combined with other immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) could provide a promising potential treatment option that would address this strong medical need [16,17]. With immune checkpoint inhibitors, median overall survival remains less than 11 months [10-13] and median progression-free survival is between 2 and 4 months [10-13].

On March 10, 2021 DiaMedica Therapeutics Inc. (Nasdaq: DMAC), a clinical-stage biopharmaceutical company focused on developing novel treatments for neurological disorders and kidney diseases, reported a business update and financial results for the year ended December 31, 2020 (Press release, DiaMedica, MAR 10, 2021, View Source [SID1234576388]). DiaMedica will host a conference call Thursday, March 11, 2021, at 7:00 a.m. Central Time to discuss its business update and full year financial results.

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Clinical Developments

DM199 for the Treatment of Acute Ischemic Stroke

Productive Type B Meeting with the FDA

Initiation of Phase 2/3 Trial in AIS

The U.S. Food and Drug Administration (FDA) accepted DiaMedica’s request for a Type B Pre-IND meeting request related to its development plan for its product candidate, DM199, in the treatment of acute ischemic stroke (AIS). In written responses to the questions submitted by DiaMedica, the FDA agreed with DiaMedica’s proposals regarding key elements of a Phase 2/3 trial for DM199 in patients with AIS. These plans include an adaptive trial design with a primary endpoint based upon the modified Rankin Scale (mRS) at day 90.

The FDA also acknowledged that, provided the study results qualify, a single trial may support a Biologics License Application (BLA) submission. Additionally, based upon the clinical and preclinical testing performed to date and currently in process, the FDA did not require any additional studies in preparation for an investigational new drug (IND) submission and initiation of the Company’s planned Phase 2/3 trial.

DiaMedica believes that the feedback received from the FDA provided a well-defined regulatory pathway and is proceeding with the preparation of an IND submission to initiate a Phase 2/3 adaptive trial design which will include an interim analysis to allow for an increase in the sample size, if necessary, to improve powering.

DiaMedica plans to submit the IND later this month for its proposed Phase 2/3 AIS trial and initiate it this summer. DiaMedica expects the trial will be a double blinded, placebo controlled, randomized study of approximately 350 participants, based on a 90% powering for statistical significance on the primary endpoint of mRS at day 90. Secondary endpoints will include stroke recurrence, mRS shift, NIHSS and Barthel Index, deaths, safety and tolerability measures, and biomarkers relating to KLK1. The Company also plans to discuss with the FDA the addition of a sub-study for proof of efficacy in reducing stroke recurrence based upon the statistically significant reduction in severe recurrent strokes observed in its ReMEDy Phase 2 AIS trial.

The results of the Company’s ReMEDy Phase 2 trial in AIS will be the subject of oral and poster presentations at the upcoming International Stroke Conference 2021 being held virtually on March 17-19, 2021.

The Company will also be hosting a Stroke KOL webinar on the Treatment of Acute Ischemic Stroke on March 19th at noon Eastern Time. To register for the webinar, please click here.

"We are very pleased with the progress we’ve made in recent weeks advancing our DM199 program for AIS patients," said Rick Pauls, President and Chief Executive Officer of DiaMedica. "Our Phase 2/3 trial builds on statistically and clinically significant results from our ReMEDy trial, and we’re committed to designing and executing a study that meets the qualifications for and could provide evidence to support a BLA submission."

DM199 for the Treatment of Chronic Kidney Disease

Completion of Enrollment in CKD Caused by Type II Diabetes Cohort; Data Read-out in Q2 2021

Enrollment Continues in IgA Nephropathy and CKD in African Americans with Hypertension

DiaMedica’s Phase 2 REDUX (Latin for restore) trial is a multi-center, open-label, investigation to assess the safety and efficacy of multiple doses of DM199, administered over 90 days, in participants with chronic kidney disease (CKD) (Stage 2 or 3) targeting enrollment of approximately 90 participants in three equal Cohorts. Cohort 1 of the study is focused on non-diabetic, African Americans with hypertension, a group that is at greater risk for CKD than Caucasians. Additionally, the study is designed to identify African American participants with the APOL1 gene mutation as an exploratory biomarker as these individuals have an even higher risk of developing CKD. Cohort 2 of the study is focused on participants with IgA Nephropathy (IgAN) and Cohort 3 includes participants with diabetic kidney disease (DKD).

As of March 1, 2020, DiaMedica had enrolled a total of 68 subjects, including a fully enrolled DKD Cohort, and approximately 70% of the IgAN and 50% of the African American Cohorts. The Company has continued to experience slower than expected enrollment in the first two Cohorts of the REDUX trial due to the COVID-19 pandemic. However, with the significant declines in new COVID-19 cases and the anticipated availability and effectiveness of vaccines, the Company currently anticipates completion of Cohort 1 and Cohort 2 in the second half of 2021. Preliminary topline results from the DKD Cohort are expected to be available in the second quarter of 2021.

"We look forward to reporting upcoming topline results from our Phase 2 REDUX trial," commented Dr. Harry Alcorn, Jr., DiaMedica’s Chief Medical Officer. "While we intend to follow the data from all three Cohorts, we anticipate that for CKD, we will have the opportunity to initially position D199 in patients with IgA Nephropathy, an orphan drug indication, and in the longer term provide a treatment option to the overall CKD and DKD patient populations."

Strengthening the Balance Sheet

During 2020, the Company completed two underwritten public offerings of its common shares receiving gross proceeds of $31.5 million, and net proceeds of $28.8 million, after deducting the underwriting discount and estimated offering expenses. DiaMedica ended 2020 with $27.5 million in cash, cash equivalents and marketable securities which should provide sufficient capital to fund the Company’s operations through mid-2022 and which the Company believes will allow it to complete the REDUX trial and initiate its Phase 2/3 trial in AIS.

Financial Results

Research and development (R&D) expenses were $8.3 million for the year ended December 31, 2020 compared to $7.9 million for the year ended December 31, 2019, an increase of $0.4 million. The increase was primarily due to a combination of costs incurred for the REDUX Phase 2 CKD study initiated late in 2019, driven in particular by the addition of Cohort 3 targeting participants with DKD, which fully enrolled during the fourth quarter of 2020, and increased non-cash share-based compensation costs. These increases were partially offset by decreases in clinical study costs incurred for the ReMEDy stroke study, which wound down in the first half of 2020, and non-recurring costs of the Phase 1b CKD study which was started and completed in the prior year period. Additionally, there was a year over year net decrease in drug manufacturing and development costs.

General and administrative (G&A) expenses were $4.4 million and $3.7 million for the years ended December 31, 2020 and 2019, respectively. This $0.7 million increase was primarily due to increased non-cash share-based compensation costs, outside professional services and directors and officers’ liability insurance. The increase in 2020 was partially offset by reduced travel and meeting costs primarily due to the COVID-19 pandemic.

Total other income, net was $0.4 million for the year ended December 31, 2020 compared to $1.0 million for 2019. This decrease was driven primarily by reduced R&D incentives receivable from the Australian Government, paid for qualifying research work performed by DiaMedica’s Australian subsidiary during 2020, related to the decreased ReMEDy stroke study costs. This decrease was partially offset by increased foreign currency transaction gains recognized during 2020.

Balance Sheet and Cash Flow

The Company had cash, cash equivalents and marketable securities of $27.5 million, current liabilities of $2.0 million and working capital of $25.9 million as of December 31, 2020, compared to $7.9 million in cash, cash equivalents and marketable securities, $1.3 million in current liabilities and $7.5 million in working capital as of December 31, 2019. The increases in the Company’s combined cash, cash equivalents and marketable securities and in its working capital are due primarily to the Company’s February and August 2020 public offerings.

Net cash used in operating activities was $9.2 million for the year ended December 31, 2020, compared to $9.1 million for the year ended December 31, 2019. This slight increase relates primarily to the combination of the increase in the net loss, partially offset by an increase in non-cash share-based compensation.

Conference Call Information

DiaMedica Management will host a conference call to discuss its 2020 financial results and business update on Thursday, March 11 2021, at 7:00 a.m. Central Time:

Interested parties may access the conference call by dialing in or listening to the simultaneous webcast. Listeners should log on to the website or dial in 15 minutes prior to the call. The webcast will remain available for play back on DiaMedica’s website, under investor events and presentations, following the earnings call and for 12 months thereafter. A telephonic replay of the conference call will be available until March 18, 2021, by dialing (855) 859-2056 (US Toll Free), (404) 537-3406 (International), replay passcode 9297319.

About DM199

DM199 is a recombinant (synthetic) form of human tissue kallikrein-1 (KLK1). KLK1 is a serine protease (protein) that plays an important role in the regulation of diverse physiological processes including blood flow, inflammation, fibrosis, oxidative stress and neurogenesis via a molecular mechanism that increases production of nitric oxide and prostaglandin. KLK1 deficiency may play a role in multiple vascular and fibrotic diseases such as chronic kidney disease, retinopathy, stroke, vascular dementia, and resistant hypertension where current treatment options are limited or ineffective. DiaMedica is the first company to have developed a recombinant form of the KLK1 protein. The KLK1 protein, produced from porcine pancreas and human urine, has been used to treat patients in Japan, China and Korea for decades. DM199 is currently being studied in patients with chronic kidney disease and patients with acute ischemic stroke.