On August 6, 2021 Immunic, Inc. (Nasdaq: IMUX), a clinical-stage biopharmaceutical company developing a pipeline of selective oral immunology therapies focused on treating chronic inflammatory and autoimmune diseases, reported financial results for the second quarter ended June 30, 2021 and highlighted recent activity (Press release, Immunic, AUG 6, 2021, View Source [SID1234586027]).

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"So far this year, we have made outstanding progress with both our selective oral DHODH inhibitor, IMU-838, as well as IMU-935, a highly potent and selective inverse agonist of the transcription factor RORγt, enabling what we believe will be an eventful and potentially transformative first half of 2022. In particular, we anticipate five data read-outs from clinical trials within the next twelve months, and expect to begin our first phase 3 program very soon. I want to congratulate our entire team for this remarkable momentum," stated Daniel Vitt, Ph.D., Chief Executive Officer and President of Immunic. "In June, we received U.S. Food and Drug Administration (FDA) clearance for our Investigational New Drug (IND) application for the phase 3 ENSURE program of IMU-838 in patients with relapsing-remitting multiple sclerosis (RRMS), and the supportive phase 2 CALLIPER trial in patients with progressive multiple sclerosis (PMS). Initiation of these trials in the second half of this year will mark a major milestone for our lead program. Additionally, we look forward to completing recruitment of our ongoing phase 2 CALDOSE-1 trial of IMU-838 in patients with ulcerative colitis (UC) during the second half of 2021, and reporting top-line data for this potential second key indication for IMU-838 in the first half of 2022."

"At our virtual R&D Day just last month, we presented very encouraging in vitro data showing that IMU-935 may inhibit both the generation of Th17 cells and the production of IL-17 cytokines that are responsible for the development of autoimmune diseases, without impairing thymocyte development, thereby avoiding a potential risk for lymphoma that has complicated third-party programs in this space. We also detailed highly encouraging new preclinical data which suggests that IMU-935 can affect castration-resistant prostate cancer (CRPC) both directly by reducing androgen receptor (AR) expression via RORγ and inhibiting tumor growth, and indirectly by inhibiting tumorigenesis-promoting Th17 and IL-17. Based on the strength of this data, we are preparing a phase 1 trial in metastatic CRPC (mCRPC) patients with Johann Sebastian de Bono, M.D., Ph.D., Regius Professor of Cancer Research and Professor in Experimental Cancer Medicine, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, acting as the Principal Investigator. We expect this trial to commence during the fourth quarter of this year and also anticipate availability of initial human data from moderate-to-severe psoriasis patients from our phase 1 trial of IMU-935 during the second quarter of 2022."

Dr. Vitt added, "As previously announced, at the end of the first quarter of 2021, we settled our remaining royalty obligation to 4SC AG for both IMU-838 and IMU-935, for $17.3 million, which was paid 50% in cash and 50% in shares of Immunic’s common stock during the second quarter. This strategic decision provides us with 100% of the future sales potential of our two lead programs and should drive significant value for our shareholders. Last month, we were able to offset this payment by bolstering our balance sheet with a $45.0 million financing, providing us with anticipated runway through multiple value inflection points into 2023."

Second Quarter 2021 and Subsequent Highlights

July 2021: Completed a $45.0 million underwritten public offering of common stock.
July 2021: Hosted a virtual R&D Day to provide an update on the preclinical and clinical development of IMU-935, including:
Based on preclinical studies performed by Immunic, as well as third-party research, the company believes that IMU-935’s observed selectivity may enable it to inhibit the generation of Th17 cells and the production of IL-17 cytokines without impairing RORγt function required for normal thymocyte development and may, therefore, avoid the risk of T cell malfunction and potential lymphoma formation seen in third-party RORγt programs.
In preclinical studies, IMU-935 was observed to suppress the expression of mutated AR-V7 in prostate cancer cell lines, thus potentially inhibiting tumor growth in CRPC patients who are insensitive to androgen-targeted therapies. By suppressing the expression of pro-tumorigenic IL-17, IMU-935 may also inhibit tumorigenesis in an indirect fashion. Based on these results, the company is currently preparing an open-label phase 1 dose escalation trial designed to establish a recommended phase 2 dose and to assess safety, tolerability, anti-tumor activity, biomarkers and pharmacokinetics (PK) of IMU-935 in patients with progressive mCRPC.
The full PK and blinded safety data from the completed single ascending dose (SAD) part of the phase 1 trial of IMU-935 was made available. The data set revealed dose-linear PK and a blood half-life that may be appropriate for once or twice daily dosing. Although the trial is still blinded, no significant safety findings have been detected in the SAD cohorts, to date.
June 2021: Announced FDA clearance of the company’s IND application to begin the phase 3 ENSURE program, comprised of two multicenter, randomized, double-blind trials designed to evaluate the efficacy, safety, and tolerability of IMU-838 versus placebo in RRMS patients. Additionally, announced FDA clearance of a separate IND application to initiate the supportive, multicenter, randomized, double-blind, placebo-controlled phase 2 CALLIPER trial of IMU-838 in patients with PMS, which will run concurrently with the phase 3 program in RRMS and which is designed to corroborate IMU-838’s neuroprotective potential.
June 2021: Announced the appointment of Inderpal Singh as General Counsel. Mr. Singh is responsible for legal and compliance matters and has become part of the management team of the company.
April 2021: Announced interim data from the 10 mg Cohort 2 of the EMPhASIS trial of IMU-838 in RRMS confirming, along with previously published data from Cohort 1, that the 30 mg once daily dosing of IMU-838 is the most appropriate dose for the company’s phase 3 program in RRMS. The experimental part of double-blind treatment in Cohort 2 has meanwhile been completed.
Anticipated Clinical Milestones

IMU-838 in RRMS: The twin, multicenter, randomized, double-blind, phase 3 ENSURE-1 and ENSURE-2 trials of 30 mg daily IMU-838 or placebo will run concurrently. Dosing of the first patient is expected in the second half of 2021.
IMU-838 in PMS: The multicenter, randomized, double-blind, phase 2 CALLIPER trial of 45 mg daily IMU-838 or placebo is intended to run concurrently with and to complement the phase 3 program in RRMS. Dosing of the first patient is expected in the third quarter of 2021.
IMU-838 in UC: Recruitment of the phase 2 CALDOSE-1 trial of IMU-838 in patients with UC is expected to be completed in the second half of 2021 and top-line data of the induction phase is expected to be available in the first half of 2022, as previously announced.
IMU-935 phase 1 program in healthy volunteers and psoriasis patients: The multiple ascending dose (MAD) part of the phase 1 trial of IMU-935 is ongoing and progressing. Unblinded safety, pharmacodynamic and PK data from the SAD and MAD parts in healthy volunteers is expected to be available in the second half of 2021. Initiation of the third portion of the phase 1 trial in patients with moderate-to-severe psoriasis is expected in the third quarter of 2021 and initial human data from this patient population is expected to be available in the second quarter of 2022.
IMU-935 phase 1 trial in CRPC patients: An open-label phase 1 dose escalation trial designed to establish a potential recommended phase 2 dose and to assess safety, tolerability, anti-tumor activity, biomarkers and PK of IMU-935 in patients with progressive mCRPC, is expected to commence in the fourth quarter of 2021.
IMU-856 phase 1 program: The SAD part of the ongoing phase 1 trial of IMU-856 has been completed. Based on the favorable data available so far, the company expects to receive clearance from the Ethics Committee in Australia to proceed to the MAD part in healthy volunteers, in the near future. Unblinded safety data from the SAD and MAD parts in healthy volunteers is expected to be available in the first quarter of 2022. Initiation of the third portion of the phase 1 trial in patients with several diseases involving bowel barrier dysfunction is expected in the first half of 2022.
Financial and Operating Results

Research and Development (R&D) Expenses were $15.7 million for the three months ended June 30, 2021, as compared to $10.0 million for the same period ended June 30, 2020. The $5.7 million increase was primarily due to (i) a $2.6 million increase in preparation costs related to the phase 3 program of IMU-838 in multiple sclerosis, (ii) a $1.8 million increase in external development costs related to the phase 2 clinical trial of IMU-838 in patients with UC, (iii) a $1.7 million increase in preparation costs related to the phase 2 trial of IMU-838 in PMS, (v) a $0.6 million increase in external development costs related to the phase 1 clinical trial of IMU-935, (vi) a $0.5 million increase in external development costs related to the phase 1 clinical trial of IMU-856, (vii) a $0.7 million increase in personnel expenses in research and development and (viii) $0.1 million related to increased costs across numerous categories. The increases were partially offset by a decrease of $2.3 million related to drug supply costs for IMU-838, IMU-935 and IMU-856.

For the six months ended June 30, 2021, R&D expenses were $27.3 million, as compared to $16.4 million for the same period ended June 30, 2020. The $10.9 million increase was primarily attributable to (i) a $2.9 million increase in preparation costs related to the phase 3 program of IMU-838 in multiple sclerosis, (ii) a $2.4 million increase in preparation costs related to the phase 2 trial of IMU-838 in PMS, (iii) a $2.2 million increase in external development costs related to the phase 2 clinical trial of IMU-838 in patients with UC, (iv) a $1.4 million increase in external development costs related to the phase 2 clinical trial in patients with COVID-19 as trials did not start until the second quarter of 2020, (v) a $0.8 million increase in external development costs related to the phase 1 clinical trial of IMU-856, (vi) a $0.7 million increase in external development costs related to the phase 1 clinical trial of IMU-935, (vii) a $1.0 million increase in personnel expenses in research and development and (viii) $1.0 million related to increased costs across numerous categories. The increases were partially offset by a decrease of $1.5 million in drug supply costs for IMU-856.
General and Administrative (G&A) Expenses were $3.4 million for the three months ended June 30, 2021, as compared to $2.2 million for the same period ended June 30, 2020. The $1.2 million increase was primarily due to (i) a $0.7 million increase related to non-cash stock compensation expense, (ii) a $0.3 million increase of legal and consultancy costs and (iii) a $0.2 million increase across numerous categories.

For the six months ended June 30, 2021, G&A expenses were $7.1 million, as compared to $4.8 million for the same period ended June 30, 2020. The $2.3 million increase was primarily due to (i) a $1.7 million increase related to non-cash stock compensation expense and (ii) a $0.6 million increase across numerous categories, primarily for legal and consultancy services.
4SC Royalty Settlement: On March 31, 2021, Immunic AG and 4SC AG entered into a Settlement Agreement, pursuant to which Immunic AG settled its remaining obligation of a 4.4% royalty on net sales of IMU-838, for $17.25 million. The payment was made 50% in cash and 50% in shares of Immunic’s common stock. No further payment obligations remain between Immunic and 4SC AG.
Other Income was $1.2 million for the three months ended June 30, 2021, as compared to $0.8 million for the same period ended June 30, 2020. The $0.4 million increase was primarily attributable to (i) a $0.6 million foreign exchange gain on a $52.0 million intercompany loan between Immunic, Inc. and Immunic AG (the "Intercompany Loan") and (ii) a $0.3 million increase in research and development tax incentives for clinical trials in Australia as a result of increased spending on clinical trials in Australia. The increase was partially offset by a $0.5 million decrease in recognized deferred income attributable to reimbursements of research and development expenses in connection with the option agreement with Daiichi Sankyo Co., Ltd. realized in the second quarter of 2020.

For the six months ended June 30, 2021, other income was $(1.0) million, as compared to $1.3 million for the same period ended June 30, 2020. The $2.3 million decrease was primarily attributable to (i) a $1.9 million foreign exchange loss on the Intercompany Loan and (ii) a $1.0 million decrease in recognized deferred income attributable to reimbursements of research and development expenses in connection with the Daiichi Sankyo Agreement realized in the first six months of 2020. The decrease was partially offset by a $0.6 million increase in research and development tax incentives for clinical trials in Australia as a result of increased spending on clinical trials in Australia.
Net Loss for the three months ended June 30, 2021, was approximately $17.9 million, or $0.82 per basic and diluted share, based on 21,749,439 weighted average common shares outstanding, compared to a net loss of approximately $11.5 million, or $0.90 per basic and diluted share, based on 12,695,989 weighted average common shares outstanding for the same period ended June 30, 2020.

Net loss for the six months ended June 30, 2021 was approximately $52.5 million, or $2.44 per basic and diluted share, based on 21,463,656 weighted average common shares outstanding, compared to a net loss of approximately $19.9 million, or $1.70 per basic and diluted share, based on 11,722,725 weighted average common shares outstanding for the same period ended June 30, 2020.
Cash and Cash Equivalents as of June 30, 2021, were $87.2 million, which does not include the approximately $42.2 million raised in the equity offering on July 19, 2021. Management expects its current cash and cash equivalents to be sufficient to fund operations into 2023.

On August 6, 2021 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) reported its financial results and development highlights for the quarter ended June 30, 2021 (Press release, Oncolytics Biotech, AUG 6, 2021, View Source [SID1234586026]). All dollar amounts are expressed in Canadian currency unless otherwise noted.

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"Our second quarter accomplishments have advanced our lead clinical breast cancer program down a clear path towards a registrational study and substantially de-risked our broader clinical pipeline," said Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech Inc. "Clinical AWARE-1 data show that pelareorep is an immunotherapeutic agent that synergistically combines with checkpoint inhibitors. These findings support the statistically significant overall survival benefit observed in our prior phase 2 breast cancer trial, achieving a key regulatory objective. They also suggest that pelareorep’s efficacy can be further enhanced by combining it with checkpoint inhibition. We are currently working to confirm this hypothesis in the BRACELET-1 breast cancer trial, which will support pelareorep’s advancement to a registrational study."

Dr. Coffey continued, "Beyond our lead program, we also presented clinical proof-of-concept data in pancreatic cancer that further demonstrate pelareorep’s immunologic mechanism of action and potential to address unmet needs across multiple indications. Together with AWARE-1 data, these results support our ongoing trials evaluating pelareorep-checkpoint inhibitor combinations and highlight pelareorep’s potential as an enabling technology for multiple classes of immunotherapeutic agents. Looking forward, our strong financial foundation leaves us well-positioned to build on this momentum and advance pelareorep’s clinical development. As we work towards this goal, we will remain primarily focused on breast cancer and our stated clinical milestones while pursuing a partnership strategy to further broaden pelareorep’s potential impact."

Second Quarter and Subsequent Highlights

Breast Cancer Program

Achieved primary endpoint in AWARE-1 study

Data from the twenty HR+/HER2- early-stage breast cancer patients included in AWARE-1’s first two cohorts were presented in an electronic poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (link to PR; link to poster). Results from these patients, who were treated with pelareorep and letrozole without (cohort 1) or with (cohort 2) the PD-L1 inhibitor atezolizumab (Tecentriq), showed that that pelareorep and letrozole treatment upregulated tumor PD-L1 expression, induced the generation and expansion of T cell clones, promoted tumor infiltration of CD8+ T cells, and increased CelTIL score, a measure of tumor cellularity and inflammation that is significantly correlated with event-free and overall survival. These desirable effects were further enhanced in patients receiving atezolizumab, demonstrating that pelareorep and atezolizumab synergistically combine to generate an anti-cancer immune response in the tumor and peripheral blood. Notably, cohort 2 met the pre-specified success criteria for the study’s primary endpoint, with six of ten patients achieving at least a 30% increase in CelTIL score following treatment. Together, these data support the results of a prior successful phase 2 trial (IND-213) that showed a statistically significant near doubling of overall survival with pelareorep treatment. This supports the clinical rationale behind the phase 2 BRACELET-1 trial: Evaluating the safety and efficacy of pelareorep and chemotherapy alone, and in combination with a PD-L1 inhibitor, in HR+/HER2- breast cancer patients.

Gastrointestinal Cancers Program

Phase 2 data demonstrating clinical proof-of-concept for pelareorep-checkpoint inhibitor combination therapy in pancreatic cancer

Data from a phase 2 trial evaluating pelareorep in combination with the PD-1 inhibitor pembrolizumab (KEYTRUDA) in pancreatic adenocarcinoma patients who progressed after first-line treatment were featured in an electronic poster presentation at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (link to PR; link to poster). Findings from the trial indicate that pelareorep and pembrolizumab synergize and show anti-cancer activity in these difficult-to-treat patients, with a 42% disease control rate achieved and durations of control ranging from approximately 2.5 months to approximately 7 months despite the absence of chemotherapy in the treatment regimen. Biomarker data showed that patients achieving disease control had increased activation of anti-cancer CD8+ T cells in the peripheral blood, and reduced levels of pro-tumor Treg cells in the peripheral blood and tumor compared to those with progressive disease. These results, which are consistent with what has been seen in clinical trials in other indications, such as breast cancer, highlight the broad applicability of pelareorep’s immunotherapeutic mechanism of action. They also bode well for a successful outcome in the phase 1/2 GOBLET trial, which includes a cohort evaluating pelareorep and the PD-L1 inhibitor atezolizumab in combination with chemotherapy as a first-line treatment in metastatic pancreatic cancer patients (link to PR).

Additional Immunotherapeutic Combinations and Opportunities

Preclinical data highlighting pelareorep’s ability to synergize with multiple classes of anti-cancer agents

Data presented in two electronic poster presentations at the AACR (Free AACR Whitepaper) Annual Meeting 2021 showed that pelareorep enhanced the anti-tumor efficacy of the poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor talazoparib and the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib, which are both FDA approved for the treatment of breast cancer. The observed synergistic effects were notably mediated through immunologic mechanisms rather than through the molecular pathways typically associated with PARP-1 and CDK4/6 inhibition (link to PR; link to CDK4/6 poster; link to PARP-1 poster). Together, these results suggest that pelareorep may enhance the therapeutic potential of PARP-1 and CDK4/6 inhibitors by expanding the mechanisms by which they exert anti-tumor effects.

Changes to the Board of Directors

William G. Rice, Ph.D. has stepped down from Oncolytics Biotech’s Board of Directors to avoid any potential conflicts that might arise from the development of pelareorep with molecules being developed by Aptose Biosciences Inc., the company for which Dr. Rice serves as Chairman of the Board, President & Chief Executive Officer. "I’m a staunch supporter of Oncolytics and wish to express my sincere gratitude for the time serving the Board and working with a wonderful group of directors and officers," stated Dr. Rice. Oncolytics would like to thank Dr. Rice for his guidance during his tenure as a member of the Board.

Financial Highlights

As of June 30, 2021, the Company reported $50.8 million in cash and cash equivalents. The Company raised $8.1 million during the second quarter through issuing of common stock through its ATM facility.
Operating expense for the second quarter of 2021 was $3.5 million, compared to $3.0 million in the second quarter of 2020.
R&D expense for the second quarter of 2021 was $3.2 million, compared to $2.5 million in the second quarter of 2020.
Net cash used in operating activities for the second quarter of 2021 was $6.8 million, compared to $6.3 million for the second quarter of 2020.
The net loss for the second quarter of 2021 was $7.2 million, compared to a net loss of $6.8 million in the second quarter of 2020. The basic and diluted loss per share was $0.13 in the second quarter of 2021, compared to a basic and diluted loss per share of $0.17 in the second quarter of 2020.
Anticipated Milestones and Catalysts

Dosing of the first patient in phase 1/2 GOBLET study in gastrointestinal cancer: H2 2021
Final biomarker data for AWARE-1 breast cancer study in the intended target population for a registrational study: H2 2021
Completion of enrollment in phase 2 BRACELET-1 metastatic breast cancer study: Q4 2021
Interim safety update from phase 2 IRENE study in triple-negative breast cancer: Q4 2021*
Interim safety data from phase 1 WINSHIP 4398-18 multiple myeloma study: Q4 2021*
*Guidance provided by clinical investigators

Oncolytics expects to provide updates on the timing of the following milestones:

Interim safety update from BRACELET-1 metastatic breast cancer study
Phase 2 BRACELET-1 metastatic breast cancer study: final data
Webcast and Conference Call

Management will host a conference call for analysts and institutional investors at 8:00 a.m. ET today, August 6, 2021. To access the call, please dial (888) 664-6383 (North America) or (416) 764-8650 (International) and, if needed, provide confirmation number 5114-8191. A live webcast of the call will also be available by clicking here or on the Investor Relations page of Oncolytics’ website (LINK) and will be archived for three months. A dial-in replay will be available for one week and can be accessed by dialing (888) 390-0541 (North America) or (416) 764-8677 (International) and using reference code: 148-191#.

About AWARE-1

AWARE-1 is an open label window-of-opportunity study in early-stage breast cancer enrolling 38 patients into five cohorts:

Cohort 1 (n=10), HR+ / HER2- (pelareorep + letrozole)
Cohort 2 (n=10), HR+ / HER2- (pelareorep + letrozole + atezolizumab)
Cohort 3 (n=6), TNBC (pelareorep + atezolizumab)
Cohort 4 (n=6), HR+ / HER2+ (pelareorep + trastuzumab + atezolizumab)
Cohort 5 (n=6), HR- / HER2+ (pelareorep + trastuzumab + atezolizumab)
The study combines pelareorep, without or with atezolizumab, and the standard of care therapy according to breast cancer subtype. Tumor tissue is collected from patients as part of their initial breast cancer diagnosis, again on day three following initial treatment, and finally at three weeks following treatment, on the day of their mastectomy. Data generated from this study are intended to confirm that pelareorep is acting as a novel immunotherapy, to evaluate potential synergy between pelareorep and checkpoint blockade, and to provide comprehensive biomarker data by breast cancer subtype. The primary endpoint of the study is overall CelTIL score (a measurement of cellularity and tumor-infiltrating lymphocytes). Secondary endpoints for the study include CelTIL by breast cancer subtype, safety, and tumor and blood-based biomarkers.

For more information about the AWARE-1 study, refer to View Source

Tecentriq (atezolizumab) is a registered trademark of Genentech, a member of the Roche Group.

About BRACELET-1

The BRACELET-1(BReast cAnCEr with the Oncolytic Reovirus PeLareorEp in CombinaTion with anti- PD-L1 and Paclitaxel) study is an open-label, phase 2, randomized study in patients with HR+/HER2-, endocrine-refractory metastatic breast cancer being conducted under a co-development agreement with Merck KGaA, Darmstadt, Germany and Pfizer. PrECOG LLC, a leading cancer research network, is managing the study. The study will take place at 20 trial sites and is expected to enroll 45 patients randomized into three cohorts. A three-patient safety run-in was conducted with patients receiving pelareorep, paclitaxel, and avelumab prior to randomization. The three cohorts being treated are as follows:

Cohort 1 (n=15): paclitaxel
Cohort 2 (n=15): paclitaxel + pelareorep
Cohort 3 (n=18): paclitaxel + pelareorep + avelumab (Bavencio)
Patients in cohort 1 will receive paclitaxel on days 1, 8, and 15 of a 28-day cycle. Patients in cohort 2 will receive the same paclitaxel regimen as cohort 1, plus pelareorep on days 1, 2, 8, 9, 15 and 16 of the 28-day cycle. Patients in cohort 3 will receive the same combination and dosing regimen as cohort 2, plus avelumab on days 3 and 17 of the 28-day cycle. The primary endpoint of the study is overall response rate. Exploratory endpoints include peripheral and tumor T cell clonality, inflammatory markers, and safety and tolerability assessments.

For more information about the BRACELET-1 study, refer to View Source

About GOBLET

The GOBLET (Gastrointestinal tumOrs exploring the treatment comBinations with the oncolytic reovirus peLarEorep and anTi-PD-L1) study is a phase 1/2 multiple indication biomarker, safety, and efficacy study in advanced or metastatic gastrointestinal tumors. The study will be conducted at 15 centers in Germany. The primary endpoint of the study is safety, with overall response rate and biomarker evaluation (T cell clonality and CEACAM6) as exploratory endpoints. Approximately 55 patients are planned to be enrolled in four independent cohorts:

Pelareorep in combination with atezolizumab, gemcitabine, and nab-paclitaxel in 1st line metastatic pancreatic cancer patients (n=12);
Pelareorep in combination with atezolizumab in 1st line MSI (microsatellite instability)-high metastatic colorectal cancer patients(n=19);
Pelareorep in combination with atezolizumab and TAS-102 in 3rd line metastatic colorectal cancer patients (n=14); and
Pelareorep in combination with atezolizumab in 2nd line advanced and unresectable anal cancer patients (n=10).

On August 6, 2021 Syntrix reported that A new study led by researchers at NYU Grossman School of Medicine and its Laura and Isaac Perlmutter Cancer Center revealed for the first time that activation of CXCR2 may be a general resistance-response to non-small cell lung cancer (NSCLC) treatments that inhibit the RAS/RAF/MEK/ERK signaling pathway, and may explain why many patients with lung cancer do not respond to such treatments (Press release, Syntrix, AUG 6, 2021, View Source [SID1234586025]).

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Published in Cancer Discovery, findings from the study show that inhibition of CXCR2 signaling with SX-682 increased sensitivity of lung cancer to both investigational and FDA-approved therapies targeting the RAS/RAF/MEK/ERK signaling pathway.

Lung cancer is the most common cause of cancer-related death worldwide, with over 1.8 million lung cancer deaths annually and approximately 236,000 new cases in the U.S. NSCLC accounts for approximately 84% of new lung cancer diagnoses each year.

"These findings have major clinical implications with many existing and new NSCLC treatments inhibiting the RAS/RAF/MEK/ERK signaling pathway, including targeted therapies such as osimertinib to mutant EGFR, and sotorasib and adagrasib (MRTX849) to mutant RAS," said John A. Zebala, MD, PhD, co-author of the study and President at Syntrix Pharmaceuticals.

Using cell culture and mouse models, the NYU team demonstrated how inhibition of SHP2 (SHP2 is required for KRAS activation), KRAS, EGFR or MEK caused activation of CXCR2 signaling that drew granulocytic myeloid-derived suppressor cells (gMDSCs) into tumors. The infiltrating gMDSCs impaired the anti-tumor actions of T cells. The researchers found the same effects on CXCR2 signaling and gMDSC influx in tumors from patients treated with the KRAS G12C-specific inhibitor, adagrasib.

The researchers found that combining SX-682 with SHP2 inhibition in an extremely aggressive mouse tumor model significantly depleted gMDSC infiltration and generated CD8+ effector T cells with strong anti-tumor activity. Compared with SHP2 inhibition alone, the combination completely suppressed tumor growth after two weeks of treatment, the time point at which untreated tumor-bearing mice started to die. The combination also prolonged survival (median: 38 days) compared to SHP2 inhibition alone (median: 27 days) or SX682 alone (median: 21.5 days), more than doubling overall survival compared with untreated (median: 18 days) mice. The team found no toxicity after five weeks of combination treatment. The study concludes that the results support testing of RAS/ERK pathway inhibitors with SX-682 in NSCLC patients.

ABOUT SX-682: SX-682 is an oral allosteric small-molecule inhibitor of CXCR1 and CXCR2 (CXCR1/2) being investigated in several Phase 1/2 clinical trials. CXCR1/2 are a combined "master switch" of the tumor microenvironment. Clinical studies have shown an inverse correlation between blood CXCR1/2 ligands and immune-checkpoint blockade (ICB) response and survival. SX-682 has been validated in major solid tumor models, where it exhibits mono-agent activity, blocks metastasis, depletes MDSCs, activates infiltration and killing by immune effector cells, reverses chemo-resistance, and enhances ICB.

On August 6, 2021 Replimune Group, Inc. (NASDAQ: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported financial results for the fiscal first quarter ended June 30, 2021 and provided a business update (Press release, Replimune, AUG 6, 2021, View Source [SID1234586024]).

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"The data we presented in June continues to demonstrate the depth and durability of responses observed with RP1 and RP2, which we believe indicates the potential to provide new treatment options for a range of difficult-to-treat cancers with clear unmet need, including for patients with anti-PD-1 failed disease," said Philip Astley-Sparke, CEO of Replimune. "Beyond our evolving skin cancer franchise where we expect to complete accrual in our registration directed CERPASS study in CSCC and in our registration directed cohort of patients with anti-PD-1 failed melanoma mid next year, we are designing a comprehensive development plan with the goal of establishing our product candidates as a cornerstone of cancer treatment regimens, including in patients with liver metastases. The detail behind these plans will be made available early next year."

Recent Events and Corporate Updates

Presented data at June Virtual Investor Event that continues to indicate the durable efficacy of RP1 and RP2. During the event, Replimune provided a data update from the Phase 2 cohorts of RP1 in combination with Opdivo in patients with melanoma and CSCC and other non-melanoma skin cancers and from the RP2 Phase 1 monotherapy cohort in patients with difficult-to-treat cancers. In addition to these updates, Replimune presented initial data with RP2 in combination with Opdivo. The RP1 data presented showed compelling depth and durability of response with RP1 that strongly supports the ongoing studies with registrational intent in CSCC and anti-PD-1 failed melanoma. The RP2 monotherapy and combination data presented also showed compelling activity in patients with immune insensitive tumors and with anti-PD-1 failed disease.
Announced intention to initiate a development program in patients with liver metastases from various cancer types. In June, the Company announced its intention to initiate a development program for patients with liver metastases from various cancer types based on preliminary data in which durable clinical responses have been observed following treatment with RP1 in combination with Opdivo and RP2 alone and in combination with Opdivo. The Company also intends to further evaluate whether RP2 and/or RP3 will be used in this program and present the detailed development plan in the first quarter of 2022.
First RP1 batches produced and filled at state-of-the-art manufacturing facility. Work to compare these batches to the contract manufactured material used in the Company’s clinical studies is ongoing. RP1 batches produced and filled at the Company’s 63,000-square-foot manufacturing facility in Framingham, MA, will be released once comparability work has been completed. Technology transfer and process development work for RP2 and RP3 are underway in readiness for bringing the facility on-line to support all of the Company’s clinical development activities.
Program Highlights*

CERPASS – Registration directed Phase 2 clinical trial in CSCC

RP1 in combination with Libtayo (cemiplimab) in CSCC: The Company continues to actively enroll patients in CERPASS, its registration directed, global, randomized Phase 2 study of RP1 in combination with Libtayo vs. Libtayo alone in patients with advanced CSCC. The Company recently submitted an amended protocol to the U.S. Food and Drug Administration (FDA) adding complete response (CR) rate as an independent primary endpoint, in addition to overall response rate (ORR), and with a reduction in sample size from 240 patients to 180 patients. The Company expects to complete enrollment in time for the primary data read-out to be triggered in late 2022.
IGNYTE – multi cohort Phase 2 clinical trial of RP1 combined with Opdivo

Anti-PD-1 failed melanoma cohort: The Company’s 125-patient cohort in the IGNYTE Phase 2 clinical trial of RP1 in combination with Opdivo continues to actively enroll patients. While the Company still expects to release data from this cohort in late 2022, in order to document sufficient durability of response, an important secondary endpoint of the study, the timing of the primary analysis upon which a filing is intended to be made is expected to be extended by approximately 6 months from year end 2022.
Non-melanoma skin cancer (NMSC) cohort: The Company has enrolled 29 of the 30-patient PD-1 naïve cohort of RP1 in combination with Opdivo in non-melanoma skin cancers and continues to enroll patients with anti-PD-1 failed NMSC. The Company expects to provide initial data from the anti-PD-1 failed patients in the first quarter of 2022.
Anti-PD(L)-1 failed non-small cell lung cancer (NSCLC) cohort: Dosing is underway in a 30-patient cohort of RP1 in combination with Opdivo in anti-PD(L)-1 failed NSCLC. A planned amendment to the IGNYTE protocol also includes modifications to the patient eligibility criteria which are expected to enhance enrollment into the trial. The Company now plans to provide initial data from this cohort in the first quarter of 2022.
MSI-H/dMMR tumor cohort: Due to development challenges in the anti-PD-1 naïve setting, the Company has decided to not pursue RP1 with Opdivo for the treatment of anti-PD-1 naïve patients with MSI-H/dMMR tumors, but instead amend the clinical trial protocol to enroll patients with anti-PD-1 failed disease. This complements other cohorts in the clinical trial where patients with anti-PD-1 failed disease of other tumor types are being enrolled.
ARTACUS – Phase 1b/2 clinical trial of RP1 as monotherapy in solid organ transplant recipients with skin cancers

The Company is currently enrolling its clinical trial assessing the safety and efficacy of RP1 in liver and kidney transplant recipients with CSCC. The protocol has recently been amended to now enroll up to 65 patients with potentially registrational intent. The Company now expects to present initial data from this clinical trial in the first quarter of 2022.
RP2 and RP3

RP2 alone and in combination with Opdivo in difficult-to-treat cancers: The Company has fully enrolled the initial 30-patient cohort evaluating RP2 combined with Opdivo in difficult-to-treat cancers. The Company remains on track to provide updated data from this program in the second half of 2021. The Company intends to expand this clinical trial to provide further signal confirmation for the treatment of patients with liver metastases from various tumor types. A protocol amendment to facilitate the expansion is expected to be made in the third quarter of 2021.
RP3 alone and in combination with anti-PD-1 therapy: The Phase 1 clinical trial evaluating RP3 alone in solid tumor patients is actively recruiting patients. Initial data from this cohort of the Phase 1 trial is now expected to be presented in the first quarter of 2022. In addition to this cohort, the Company expects to begin enrolling a cohort evaluating RP3 in combination with anti-PD-1 therapy in solid tumor patients by the end of 2021, with focus on patients with lung, breast and gastrointestinal cancers including colorectal cancer.
RP2 and/or RP3 in patients with liver metastases from a range of tumor types: Based on the observation of the clinical responses in patients with liver metastases from a range of difficult-to-treat tumor types following treatment with RP1 in combination with Opdivo and RP2 alone and in combination with Opdivo, the Company plans to initiate a clinical development program with RP2 and/or RP3 with particular focus on patients with liver metastases from a range of prevalent cancer types. The Company expects to initiate a multi-tumor type Phase 2 clinical program with RP2 and/or RP3 in these patients around mid-year 2022. The details of this development program, including tumor types and setting, are intended to be disclosed in first quarter of 2022.
*Program Highlight dates are on a calendar-year basis.

Financial Highlights

Cash Position: As of June 30, 2021, cash, cash equivalents and short-term investments were $458.3 million, as compared to $476.3 million as of March 31, 2021. This decrease was primarily related to cash utilized in operating activities in advancing our expanded clinical development plan.

Based on the current operating plan, Replimune believes that existing cash and cash equivalents and short-term investments will fund operating expenses and capital expenditure requirements into the second half of 2024, excluding any confirmatory trial required by the FDA or other regulatory body.
R&D Expenses: Research and development expenses were $18.6 million for the first quarter ended June 30, 2021, as compared to $12.2 million for the first quarter ended June 30, 2020. This increase was primarily due to increased clinical and manufacturing expenses driven by the Company’s lead programs and increased personnel expenses. Research and development expenses included $2.5 million in stock-based compensation expenses for the first quarter ended June 30, 2021.
G&A Expenses: General and administrative expenses were $8.8 million for the first quarter ended June 30, 2021, as compared to $5.7 million for the first quarter ended June 30, 2020. The increase was primarily driven by personnel-related costs, professional fees, and facility expansion. General and administrative expenses included $3.8 million in stock-based compensation expenses for the first quarter ended June 30, 2021.
Net Loss: Net loss was $27.3 million for the first quarter ended June 30, 2021, as compared to a net loss of $17.5 million for the first quarter ended June 30, 2020.
About CERPASS
CERPASS is Replimune’s registration-directed randomized, global Phase 2 clinical study to compare the effects of Libtayo alone versus a combination of Libtayo and Replimune’s investigational oncolytic immunotherapy RP1. The clinical trial will enroll 180 patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC) who are naïve to anti-PD-1 therapy. The trial will evaluate complete response (CR) rate and overall response rate (ORR) as its two primary efficacy endpoints as assessed by independent review, as well as duration of response, progression-free survival (PFS), and overall survival (OS) as its secondary endpoints. The study is being conducted under a clinical trial collaboration agreement with Regeneron in which the costs of the trial are shared and full commercial rights retained by Replimune. Libtayo is being jointly developed by Regeneron and Sanofi.
Libtayo is a registered trademark of Regeneron.

About IGNYTE
IGNYTE is Replimune’s multi-cohort Phase 1/2 trial of RP1 plus Opdivo. There are 4 tumor specific cohorts currently enrolling in this trial including a 125-patient extension cohort of RP1 combined with Opdivo in anti-PD-1 failed cutaneous melanoma. This cohort was initiated after completing enrollment in a prior Phase 2 cohort in the same trial of approximately 30 patients with melanoma. The additional cohorts are studying RP1 in combination with Opdivo in non-melanoma skin cancers which includes both naïve and anti-PD-1 failed CSCC, in microsatellite instability high, or MSI-H/dMMR tumors and anti-PD(L)-1 failed non-small cell lung cancer, or NSCLC. This trial is being conducted under a collaboration and supply agreement with Bristol-Myers Squibb Company.
Opdivo is a registered trademark of Bristol-Myers Squibb Company.

About RP1
RP1 is Replimune’s lead Immulytic product candidate and is based on a proprietary new strain of herpes simplex virus engineered to maximize tumor killing potency, the immunogenicity of tumor cell death and the activation of a systemic anti-tumor immune response.

About RP2 & RP3
RP2 and RP3 are derivatives of RP1 that express additional proteins. RP2 expresses an anti-CTLA-4 antibody-like molecule and RP3 additionally expresses the immune co-stimulatory pathway activating proteins CD40L and 4-1BBL. RP2 and RP3 are intended to provide targeted and potent delivery to the sites of immune response initiation in the tumor and draining lymph nodes, with the goal of focusing systemic immune-based efficacy on tumors and limiting off-target toxicity.

On August 6, 2021 Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, reported financial results and business highlights for the third quarter of fiscal 2021 ended June 30, 2021 (Press release, Twist Bioscience, AUG 6, 2021, View Source [SID1234586023]).

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"It is an exciting time to be at the forefront of synthetic biology," said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. "The opportunity continues to expand as our customers pursue new and innovative solutions to life’s grand challenges in the areas of healthcare, sustainable chemicals, food, agriculture and more. Together with the promise of future applications, we continue to deliver solid revenue growth and extend our proprietary silicon-based DNA synthesis platform to new markets ripe for disruption."

FISCAL 2021 THIRD QUARTER FINANCIAL RESULTS

Orders: Total orders received for the third quarter of fiscal 2021 were $39.1 million, compared to $24.7 million for the same period of fiscal 2020.
Revenue: Total revenues were $35.0 million for the third quarter of fiscal 2021 compared to $21.2 million for the same period of fiscal 2020.
Cost of Revenues: Cost of revenues for the third quarter of fiscal 2021 was $20.9 million compared to $16.5 million for the same period of fiscal 2020.
Research and Development Expenses: Research and development expenses for the third quarter of fiscal 2021 were $19.8 million compared to $10.4 million for the same period of fiscal 2020.
Selling, General and Administrative Expenses: Selling, general and administrative expenses for the third quarter of fiscal 2021 were $34.5 million compared to $22.5 million for the same period of fiscal 2020.
Net Loss: Net loss for the third quarter of fiscal 2021 was $40.0 million, or $0.82 per share, compared to $28.2 million, or $0.67 per share, for the third quarter of fiscal 2020.
Cash Position: As of June 30, 2021, the company had $519.4 million in cash, cash equivalents and short-term investments.
"Our gross margin was 40% for the quarter, reflecting the higher contribution margin and mix of NGS tools. We are raising our revenue guidance based on continued strength across our business," commented Jim Thorburn, CFO of Twist.

Fiscal Third Quarter 2021 and Recent Highlights

Shipped products to approximately 1,800 customers in the third quarter of fiscal 2021 versus approximately 1,400 in the same period of fiscal 2020.
Shipped 107,000 genes during the third quarter versus 83,000 in the same period of fiscal 2020.
Supported the Engineering Biology Research Consortium (EBRC) and its Statement of Ethics in Engineering Biology Research. A companion paper, titled "Guiding ethical principles in engineering biology research," to contextualize the purpose and principles behind the Statement has also now been published in ACS Synthetic Biology.
Acquired iGenomX, a company offering multiplex library preparation tools for next-generation sequencing (NGS) workflows. The acquisition is expected to enhance Twist’s capabilities to support multiplex sequencing preparations across multiple markets and to accelerate Twist’s conversion of customers from static microarray platforms to genotyping by sequencing workflows.
Launched the Twist Library Preparation Enzymatic Fragmentation Kit 2.0, a robust all-in-one solution designed to maximize accuracy and efficiency in library construction and amplification when conducting next-generation sequencing (NGS). The kit is optimized for challenging NGS applications including liquid biopsy, somatic variant testing and genome-wide association studies. In addition, the kit excels in preparing samples where the amount of sample input DNA is either very limited or heavily degraded, as in the case of many banked oncology samples.
Announced a collaboration with Regeneron Genetics Center LLC (RGC), a wholly-owned subsidiary of Regeneron, for the production of a custom next-generation sequencing (NGS) population genetics genotyping assay. Arising from a need to incorporate the genetic differences of global populations, this assay is designed to gain new insights into disease mechanisms, identify novel drug targets, and accelerate drug discovery and development. Twist markets the assay as the Twist Diversity SNP Panel, and makes the content available to researchers globally for their population genomics studies.
Began shipping synthetic RNA reference controls for the SARS-CoV-2 Delta (B.1.617.2), Kappa (B.1.617.1) and B.1.617.3 variants first identified in India and spreading rapidly worldwide.
The DNA Data Storage Alliance, of which we are a participating member, published its first white paper titled "Preserving our Digital Legacy: An Introduction to DNA Data Storage."
Inclusion in the State Street Global Advisors Gender Diversity Index (SHE).
Appointed Melissa Starovasnik, Ph.D., formerly vice president, protein sciences and head of large molecule drug discovery at Genentech, Inc., to the Board of Directors.
Updated Fiscal 2021 Financial Guidance

The following statements are based on Twist’s current expectations for fiscal 2021. The following statements are forward-looking, and actual results could differ materially depending on market conditions and the factors set forth under "Forward-Looking Statements" below. Twist does not plan to update, nor does it undertake any obligation to update, this outlook in the future.

For the full fiscal year 2021, Twist provided the following updated financial guidance:

Increasing revenue guidance, which is now expected to be in the range of $129 million to $132 million
Synbio revenue including Ginkgo Bioworks is expected to be in the range of $54 to $56 million
NGS revenue is estimated to be in the range of $69 to $70 million
Biopharma revenue is estimated to be approximately $6 million
Gross margin is expected to be 38% to 40% for fiscal 2021
Operating expenses including R&D and SG&A are expected to be $200 million for the year
Net loss is expected to be approximately $150 million, reflecting our increased investments in our commercial organization and research and development activities
R&D is expected to be approximately $70 million
Stock-based compensation is expected to be approximately $37 million
Depreciation is expected to be $10 million
Capital expenditures are expected to be $40 million, including expansion into "Factory of the Future"
Conference Call Information

The company plans to hold a conference call and live audio webcast for analysts and investors today at 8:00 a.m. Eastern Time to discuss its financial results and provide an update on the company’s business. The call can be accessed by dialing (866) 688-0947 (domestic) or (409) 217-8781 (international) and refer to the conference ID 3485949. A telephonic replay of the conference call will be available beginning approximately four hours after the call through August 13, 2021 and may be accessed by dialing (855) 859-2056 (domestic) or (404) 537-3406 (international). The replay conference ID is 3485949. The webcast replay will be available for two weeks.

Given the circumstances globally, it is recommended to dial-in at most 15 to 20 minutes prior to the call start to reduce waiting times. If a participant will be listen-only, they are encouraged to listen via the webcast on Twist’s investor page.