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Replimune Group, Inc. (REPL)

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  • J
    James
    Q1

    RP3 initial single agent data in all comers.
    RP1 plus Opdivo anti-PD1 failed CSCC initial data.
    RP1 single agent initial data in CSCC organ transplant patients.
    Detail on RP2/3 development strategy.
  • J
    James
    The updated interim data shows:

    In the nine-patient monotherapy cohort with RP2, two of the initial three patients who achieved response remain in response, these being a patient with esophageal (partial response; previously anti-PD-L1 failed) at 22 months from entering the trial and a patient with mucoepidermoid carcinoma (complete response) at 19 months from entering the trial. As previously reported, the third responding patient with uveal melanoma with a partial response (Yervoy/Opdivo failed) progressed at 15 months from entering the trial.

    Updated data from the 30-patient cohort of RP2 in combination with Opdivo shows durable responses ongoing at out to >425 days.

    To date, seven of the 30 patient (23.3%) cohort of RP2 in combination with Opdivo have achieved partial responses, with additional patients still on study with the opportunity to achieve a response. Six of the seven responses are ongoing with depth of response having been maintained or deepened over time.

    The responding patients are four of nine patients with cutaneous melanoma (all anti-PD1 or anti-PD1 and anti-CTLA-4 failed), two of eight patients with uveal melanoma (anti-PD1 or anti-PD1 and anti-CTLA-4 failed) and one of three patients with squamous cell carcinoma of the head and neck (anti-PD1 failed).

    Biomarker data continues to demonstrate substantial increases CD8 T cells and PD-L1 expression, with T cell receptor sequencing and Nanostring expression analysis further indicating potent and broad activation of an anti-tumour immune response.

    No correlation has been observed between the degree of anti-tumour response and the baseline levels of PD-L1 expression, in line with the intended mechanism of action for RP2 of turning immunologically ‘cold’ tumours ‘hot’.

    Overall the data, including the durability of the responses, continues to support that oncolytic immunotherapy-mediated expression of anti-CTLA-4 from RP2 provides potent & systemic anti-tumor effects, without substantial additional toxicity as compared to the oncolytic backbone (RP1), including without evidence of the side effects associated with systemic ipilimumab.

    Based on the observation of durable clinical responses in patients with liver metastases following treatment with both RP1 and RP2, the Company has amended the clinical trial protocol to enrol an additional 24 patients with liver metastases from lung cancer, gastrointestinal cancers, breast cancer and uveal melanoma.
  • A
    AC
    What could be the reason for the sell-off when the rest of biotechs are in green! Any thoughts?
  • A
    Anonymous
    single agent activity of RP2, to be presented at SITC:
    —-
    Initial results of a phase 1 trial of RP2, a first in class, enhanced potency, anti-CTLA-4 antibody expressing, oncolytic HSV as single agent and combined with nivolumab in patients with solid tumors

    Francesca Aroldi, MD, University of Oxford, Joseph Sacco, MSc, MBChB, MRCP, Ph, Kevin Harrington, PhD, FRCP, FRCR, Anna C. Olsson-Brown, MD, Pablo Nanclares, MD, Lavita Menezes, Praveen K. Bommareddy, MS, PhD, Suzanne Thomas, PhD, Howard L. Kaufman, MD, Selda Samakoglu, MD, PhD, Robert S. Coffin, PhD, Mark R. Middleton, MD, PhD

    Background
    RP2 is an enhanced potency oncolytic HSV-1 expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), a fusogenic protein (GALV-GP R-), and an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule which is being tested in an open-label, multicenter, phase 1 study alone and combined with PD-1 blockade (NCT04336241).

    Methods
    The objectives were to assess initial safety and efficacy and determine the recommended phase 2 dose (RP2D) of RP2 alone and combined with nivolumab. Patients were to be treated using a 3+3 dose escalation at two dose levels of up to 10mL of RP2 Q2W up to 5 times (dose level 1: 105 PFU/mL then 4 doses of 106 PFU/mL; dose level 2: 106 PFU/mL then 4 doses of 107 PFU/mL). Following determination of the RP2D, additional HSV-1 seronegative patients were to be enrolled such that ≥3 had been dosed with RP2 at the RP2D, and a combination cohort of up to 30 patients dosed up to 8 times with RP2 at the RP2D combined with nivolumab (240mg Q2W for 4 months from the second RP2 dose, then 480 mg Q4W for 20 months) opened. Lesions were injected directly or under imaging guidance used for visceral lesions. Tumor biopsies were obtained for biomarker analysis. Viral shedding and anti-HSV antibody titers were also monitored.

    Results
    Six HSV seropositive patients were enrolled in the dose-escalation phase with primarily Grade 1-2 adverse events, including febrile and other constitutional symptoms, local inflammation, and erythema observed. There were no DLTs requiring dose level expansion. The RP2D was selected as up to 10mL of 106 PFU/mL followed Q2W by multiple doses of 107 PFU/mL. Of the six patients treated with single agent RP2, three (50%) have ongoing partial responses. Objective responses (including in uninjected tumors) were observed in patients with uveal melanoma (prior ipilumumab/nivolumab; extensive liver metastases), mucoepidermoid carcinoma (prior carboplatin/paclitaxel, bicalutamide, ceralasertib), and esophageal cancer (prior durvalumab, M6620, capecitabine, oxaliplatin, cisplatin, chemoradiation; liver and abdominal node metastases). Enrollment is underway in HSV seronegative patients and in combination with nivolumab. Updated data including biomarker and biodistribution data will be presented.

    Conclusions
    The Phase 1 clinical data supports the safety and efficacy of single agent RP2, including demonstration of uninjected tumor response in patients with difficult to treat advanced cancers. This data supports the hypothesis that anti-CTLA-4 delivered intra-tumorally through oncolytic virus replication, with accompanying antigen release and presentation, can provide potent anti-tumor effects.
  • M
    Mike
    Where can I discuss REPL infos, since this message board is closed?
    Dearly missing the old Message Board site.
  • J
    James
    “Based on the depth and durability of responses and the manageable safety profile we have seen in patients with non-melanoma skin cancers treated with RP1 in combination with Opdivo to date, we are amending the clinical trial protocol for our Phase 2 CERPASS clinical trial to include complete response (CR) rate as a primary endpoint in addition to overall response rate (ORR), and to reduce target enrollment to 180 patients,” said Robert Coffin, Ph.D. “Incorporating CR as an independent additional primary endpoint should ensure a robust assessment of the clinical meaningfulness of adding RP1 to Libtayo in the primary data analysis upon which a BLA submission and FDA’s assessment for approval will be based.”

    Under the modified clinical trial protocol for CERPASS, they plan to add CR rate as an additional independent primary endpoint, in addition to ORR, and to reduce target enrollment from 240 patients to 180 patients. Secondary endpoints will continue to include DOR, PFS, and OS. They maintain guidance and expect initial data next year. The company plans to submit the amended clinical trial protocol to the FDA in the first half of the year.
  • A
    Anonymous
    From the latest public offering-related SEC filing (June 8, 2020):

    "Based on the data generated to date, we have decided to amend the protocol to allow for an expansion of the second part of this clinical trial (of RP2 combined with nivolumab) from 12 to 30 patients."

    So they have seen some activity - would be interesting to learn which tumor types. Data to be released in H2/2020 - maybe July 1!?!
  • T
    Tartiaboy
    Just listened to the JP Morgan presentation: RP-1 CSCC data is phenomenal; likely three pivotal trials will be running by later this year.

    I don't think most people really understand what REPL means when they say that their technology is targeted to be a new corner stone of IO. I consider this my safest onco-biotech play, because the approach is already proven to work.

    Be First, be right (be patient).
  • J
    James
    The company will host an investor event to present updated data from its PhII skin cancer cohorts combining RP1 with Opdivo and data from its PhI trial of RP2 alone and in combination with Opdivo. The event will include presentations by Philip Astley-Sparke, Chief Executive Officer, Robert Coffin, Ph.D., President and Chief Research & Development Officer, and Professor Mark Middleton.

    The event will begin at 8:00 a.m. Eastern Time on Thursday, June 3. The webcast and slides will be accessible live under “Events & Presentations” on the Investors page of the company's website.
  • J
    James
    ASCO-GI: A phase I/II study combining a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus and nab-paclitaxel/gemcitabine chemotherapy in advanced pancreatic cancer: An interim report.

    Background: Pancreatic ductal adenocarcinoma (PDAC) has been highly resistant to immunotherapeutics to date. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies.

    Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC are treated with LOAd703 intratumoral injections and standard nab-paclitaxel/gemcitabine (nab-P/G) chemotherapy. Starting on cycle 1 day 15 of nab-P/G, LOAd703 is injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects are eligible to receive 6 more injections. Three dose levels of LOAd703 are being investigated using a BOIN dose escalation design. Primary endpoints are safety and feasibility. Secondary endpoints include response rate and overall survival.
  • T
    Tartiaboy
    The key to valuing REPL is not in the efficacy of any one product, it's in understanding the break-though in viral oncology. This is a new platform that has already been proven with Tvec. RP1, RP2 and RP3 are new enhanced iterations. REPL is not limited to these three products.

    Knowledge is power. Do your DD.
  • J
    James
    Members from the company's management team will present and host one-on-one meetings at the following three virtual investor conferences.

    H.C. Wainwright Global Life Sciences Conference
    Date: March 9-10, 2021
    Pre-Recorded Formal Presentation will be made live: Tuesday, March 9, at 7:00 am ET

    Barclays Global Healthcare Conference
    Date: Thursday, March 11
    Fireside Chat Presentation Time: 9:10 am ET

    33rd Annual Roth Conference
    Date: Wednesday, March 17
    Presentation Time: 1:30 pm ET

    A simultaneous webcast of the fireside chat presentation at the Barclays Global Healthcare Conference will be available in the Investors section of website. A replay will be available for approximately 90 days following the conference.
  • J
    James
    RP1 SITC abstract results: ''As of 24th June 2020, 36 melanoma and 16 NMSC patients had been enrolled with follow up of <1-17 months. Of the melanoma patients, 16 previously antiPD1 treated cutaneous (8 also prior anti-CTLA-4), 8 anti-PD1 naïve cutaneous, 6 mucosal, and 6 uveal. Of the NMSC patients, 10 had squamous cell (CSCC), 3 had a basal cell, 1 had Merkel cell carcinomas, and 2 had angiosarcoma. Treatment emergent adverse events (TEAEs) remain consistent with phase 1, with RP1 side effects generally of Grade 1/2 constitutional-type symptoms, with no exacerbation of the side effects expected for nivolumab. At the data cut-off, 5 previously anti-PD1 treated (4 also anti-CTLA-4) cutaneous melanoma patients, 4 anti-PD1 naïve cutaneous melanoma patients, two mucosal melanoma patients (one anti-PD1 refractory) and one uveal melanoma patient (ipi/nivo refractory) have achieved response (WHO criteria for uveal). For NMSC, for the 13 patients with >8 weeks follow up, one of two angiosarcoma patients and seven of eight CSCC patients (5 CR) have achieved response (CSCC ORR 87.5%; CR rate 62.5%, including of uninjected visceral disease). Tumor biopsies in patients continue to routinely show immune activation, including robust recruitment of CD8+ T cells, reversal of T cell exclusion, and increased PD-L1 expression. Treatment remains ongoing, and current data will be presented.''
  • J
    James
    The company have announced that Robert Coffin, Ph.D., CEO and Director, will present at the 38th Annual J.P.Morgan Healthcare Conference on Tuesday, January 14, at 5:00 PM PT at the Westin St. Francis Hotel in San Francisco, CA.
  • A
    Anonymous
    Looks fantastic:

    Authors:
    Mark R. Middleton, Francesca Aroldi, Joseph Sacco, Mohammed M. Milhem, Brendan D. Curti, Ari M. Vanderwalde, Scott Baum, Adel Samson, Anna C. Pavlick, Jason Alan Chesney, Jiaxin Niu, Terence Duane Rhodes, Tawnya Lynn Bowles, Anna Olsson-Brown, Douglas Earl Laux, Praveen Bommareddy, Alex Deterding, Joseph Elassal, Robert S. Coffin, Kevin Harrington; Churchill Hospital, Oxford, United Kingdom;...View More
    Abstract Disclosures
    Research Funding:
    Replimune
    Background:
    RP1 is an oncolytic HSV that encodes a fusogenic GALV-GP R- protein and GM-CSF. RP1 demonstrated tolerable safety and tumor regression alone and with nivolumab (nivo) in ph 1 in patients (pts) with a number of tumor types. To further define the efficacy of the combination, ph2 cohorts of 30 pts with 4 tumor types were then opened. Initial data from the melanoma (mel) and the non-mel skin cancer (NMSC) cohorts will be presented.
    Methods:
    Unresectable stage IIIb-IV mel pts for whom anti-PD-1 was indicated or who were refractory to 1 prior standard therapy including anti-PD-1 or ipi/nivo were enrolled. NMSC pts were anti-PD1 naïve. Pts received up to 8 doses of RP1 (<=10 mL/visit based on tumor diameter) Q2W (first dose 106 PFU/mL then 107 PFU/mL). From the second RP1 dose pts also received nivo (240 mg IV Q2W for 4 mos then 480 mg IV Q4W up to 2 yrs in the absence toxicity or confirmed progressive disease (PD)). Imaging was done every 8 wks and response assessed by RECISTv1.1 (with confirmation required for PD).
    Results:
    As of Jan 22nd 2020, 30 mel pts and 9 NMSC pts had been enrolled with follow up between <1 and 7mo. Of the mel pts 21 were cutaneous, 5 were mucosal and 4 were ocular. Of the NMSC pts, 6 had squamous cell, 1 had basal cell, 1 had Merkel cell carcinomas and 1 had angiosarcoma. Recruitment of the mel cohort is complete, with recruitment into the NMSC cohort ongoing. Based on initial data in melanoma, a further cohort of 125 pts with anti-PD1 refractory cutaneous mel has been opened. Adverse events (AEs) in the ph2 cohorts have been consistent with those in ph1, with RP1 side effects of in general Grade 1/2 constitutional and related symptoms, self-limiting within 72hrs of RP1 injections, with no exacerbation of the side effects expected for nivo. With currently short follow up, multiple objective responses have been observed in treatment naïve mel, anti-PD1 refractory mel (including ipi/nivo refractory and mucosal), and NMSC. Of note 3 of the first 4 anti-PD1 refractory mel pts treated are responding to treatment, as are 5 of the first 6 CSCC pts, including 3 CR. Tumor biopsies routinely showed immune activation, including robust recruitment of CD8+ T cells and increased PD-L1 expression. Treatment remains ongoing in the majority of patients, and current data will be presented.
    Conclusions:
    RP1 and nivo has continued to be well tolerated, with promising signs of efficacy in patients with skin cancers, including with anti-PD1 refractory disease. These data support the further development of RP1 combined with anti-PD1 blockade. Clinical trial information: NCT03767348.
  • A
    AC
    It should close much higher than it's trading at now because the offering price is $23 per share. Am I reading correctly?
  • A
    Anonymous
    SITC Poster abstract (bodes well):

    ID: P433
    Initial results of the phase 1 portion of an ongoing phase 1/2 study of RP1 as a single agent and in combination with nivolumab in patients with solid tumors

    M R. Middleton, MD PhD, University of Oxford, Medicine, Joseph Sacco, Jaime Merchan, Amber Thomassen, Brendan D. Curti, MD, Ari M. VanderWalde, MD, MPH, MBioeth, Anna C. Olsson-Brown, MBChB (Hons), BSc (Hons), Francesca Aroldi, Nicos Fotiadis, Scott Baum, Howard L. Kaufman, MD, FACS, Kevin Harrington, MD

    Background
    Background: RP1 is an enhanced-potency oncolytic HSV-1 expressing a fusogenic glycoprotein (GALV-GP R-) and GM-CSF which is being tested in a Phase 1/2 clinical trial in ~150 patients with a range of solid tumors (NCT03767348).

    Methods
    Methods: The objectives were to define the safety of RP1 alone and with nivolumab, determine the recommended phase 2 dose (RP2D), and in 30 patient phase 2 cohorts, assess efficacy in melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H tumors. Initial phase 1 results will be reported where patients were treated by intra-patient dose escalation of RP1 (up to 10mL of 104-108PFU/mL) by intratumoral injection into a single tumor Q2W up to 5 times followed by 12 patients dosed 8 times at the RP2D combined with nivolumab (240mg Q2W for 4 months from the second RP1 dose, then 480 mg Q4W for 20 months). Clinically accessible lesions were directly injected, with imaging guidance for deep/visceral lesions. Pre- and on-treatment tumor biopsies were obtained for biomarker analysis. Viral shedding and anti-HSV antibody titers were also monitored.

    Results
    Results: 22 heavily pretreated patients with advanced tumors were enrolled into the dose-rising phase with largely low-grade adverse events, including febrile and other constitutional symptoms, local inflammation and erythema. No clear differences were seen between superficial and visceral dosing. RP1 was detected at the injection site and in blood for up to 14 days (next injection), suggesting virus replication. All HSV seronegative patients seroconverted after three injections. Biological activity was demonstrated including tumor necrosis and shrinkage, with extended clinical benefit and delayed (post-treatment termination and initial PD) systemic reduction in multiple tumors in two patients (ipilimumab/nivolumab-refractory melanoma and chemotherapy-refractory cholangiocarcinoma) without intervening treatment. The RP2D was selected as up to 10mL of 106PFU/mL followed Q2W by multiple doses of 107PFU/mL. Twelve evaluable patients (6 direct injection, 6 image-guided) were then enrolled into the phase 1 expansion combined with nivolumab. This demonstrated tolerability and clinical activity, including complete and partial responses in patients with chemotherapy-refractory cutaneous squamous carcinoma, and ipilimumab/nivolumab-refractory melanoma. Treatment remains ongoing, and current data will be presented, including biomarker data (CD8, PD-L1 staining and Nanostring analysis from tumor biopsies).

    Conclusions
    Conclusions: The Phase 1 clinical data supports the safety and efficacy of RP1 alone and when combined with nivolumab, including demonstration of abscopal anti-tumor effects in patients refractory to prior checkpoint inhibitors. The Phase 2 portion of this clinical trial is open in the US and the UK.

    Trial Registration
    NCT03767348

    Ethics Approval
    The study was approved by applicable institutional review or ethics boards.

    Consent
    NA

    Category:

    Keywords:
    Clinical study;Tumor microenvironment
  • J
    James
    The company will host a conference call to provide updated data from patients with melanoma and non-melanoma skin cancers treated with RP1 combined with Opdivo in its ongoing PhI/II trial. The investor event will be held on June 3. They will not be presenting data at the ASCO Annual Meeting this year.
  • T
    Tartiaboy
    If you are just passing through ask yourself this question? Why does a new biotech with NO products, NO revenue and just starting clinical trials have a market cap of almost $500M? Is that justified? I say yes.

    Be First, be right (be patient).
  • A
    Anonymous
    Follow James link to the presentation, and you'll see:

    One of the Partial responses of RP2 monotherapy (in the abstract) converted into a complete response, confirmed by PET scan October 16.

    As non clinician I do not know how hard to treat a "Mucoepidermoid carcinoma of the parotid" is, but I like the single agent activity.

    they also cranked up the numbers:

    total patients treated: 9
    ongoing treatment: 4
    PR / CR: 3
    progressive disease, as assessed at 3 month, treatment not ongoing at 3 month: 5

    hopefully the 125m raise can be sustained at 40. we will see in a few hours.