RP2

Cutaneous squamous cell carcinoma that does not respond to treatment with an immunotherapy called a checkpoint inhibitor has no FDA-approved therapeutic alternatives. Replimune’s lead program, an oncolytic virus, has fallen short in a study hoped to give patients one. The company is still pressing forward with its engineered virus in other types of skin cancer, but not without a pipeline shakeup that means the end for other programs. Replimune’s lead therapeutic candidate, RP1, is based on based on a strain of the herpes simplex virus engineered to increase its anti-tumor activity. Injected into a solid tumor, replication of the virus kills cancer cells. This oncolytic virus is also intended to prompt an additional immune response against the cancer. The results announced Tuesday are from a Phase 2 clinical trial that the Woburn, Massachusetts-based company hoped would be a registrational study. A total of 211 patients with cutaneous squamous cell carcinoma were randomly assigned to receive RP1 plus the Regeneron Pharmaceuticals checkpoint inhibitor Libtayo, or Libtayo alone. The two main study goals were assessing the complete response rate and the overall response rate. Replimune said the study drug arm achieved a complete response rate of 38.1% versus 25% in the control arm—just short of achieving statistical significance. The overall response rate results were closer: 52.5% in the study drug arm versus 51.4% in the Libtayo-alone group. One possible explanation for the disappointing results is an imbalance in tumor burden at baseline across the treatment groups, which Replimune said “may have impacted the number of responses seen.” In particular, Replimune said a significantly greater number of patients with a high tumor burden (larger than 10 cm in diameter) at baseline were treated in the study drug group compared to the group given Libtayo alone. In patients with a lower total tumor burden, the complete response rate in patients treated with RP1 and Libtayo showed much clearer separation compared to those given Libtayo alone. Replimune said this clinical trial will continue in order to assess the duration of response, progression-free survival, and overall survival. In a note sent to investors Tuesday, Leerink Partners analyst Jonathan Chang wrote that the complete response rate results suggest the trial outcome would have been positive with a more robust study design. He said the results are a major setback for RP1, though the future readout of additional data offers the opportunity to salvage this program in cutaneous squamous cell carcinoma. Chang also said RP1 has an opportunity in melanoma, where the data look better so far. The Phase 2 test is evaluating RP1 in patients whose disease has failed to respond to treatment with a checkpoint inhibitor. This study evaluated the pairing of RP1 with the Bristol Myers Squibb immunotherapy Opdivo. Replimune said that in the full 140-patient cohort of patients whose cancer failed to respond to a checkpoint inhibitor, about 1 in 3 patients treated with the RP1/Opdivo combination achieved a durable response. The company believes this result will support a regulatory submission, which it plans to file in the second half of 2024. According to Replimune’s telling of a recent meeting with the FDA, the agency acknowledged that patients whose melanoma has failed to respond to treatment with an anti-PD1 checkpoint inhibitor represents an unmet need. Agreement was reached on the design of a confirmatory study, which the FDA wants Replimune to start by the time it files an application seeking accelerated approval. The Replimune pipeline also includes RP2 and RP3, oncolytic viruses engineered to enhance anti-tumor responses and address more tumor types. The company is planning a randomized controlled clinical test of RP2 as a second-line treatment in uveal melanoma. To maintain focus on this clinical trial and the others deemed priority studies, Replimune said it will discontinue development of RP2 and RP3 in squamous cell carcinoma of the head and neck and colorectal cancer. A second-line hepatocellular carcinoma clinical trial will continue with RP2 only. Development of RP3 will be discontinued. Replimune reported a cash position totaling $496.8 million as of the end of September. With the pipeline reprioritization, the company expects it will have enough cash to last into early 2026. Public domain image by Julio C. Valencia via the National Cancer Institute

RP2 as monotherapy and in combination with nivolumab showed a favorable safety profile and durable responses in nearly 30 percent of patients, all with previously treated diseaseWOBURN, Mass., Nov. 08, 2023 (GLOBE NEWSWIRE) -- Replimune Group, Inc. (NASDAQ: REPL), a clinical stage biotechnology company pioneering the development of a novel portfolio of oncolytic immunotherapies, today announced updated data from a cohort of metastatic uveal melanoma patients enrolled in the open-label, multicenter, Phase 1 study of RP2 as a single agent and in combination with nivolumab. The data were presented by Dr. Joseph Sacco during a Plenary Session at the 20th International Congress of the Society for Melanoma Research in Philadelphia. Treatment with RP2 led to an overall response rate (ORR) of 29.4 percent (5 of 17 patients; one of the responding patients was treated with RP2 monotherapy and four of the responding patients were treated with RP2 combined with nivolumab), including responses in patients with liver, lung, and bone metastases. The median duration of response (DOR) at the data cutoff was 11.47 months (range of 2.78 to 21.22 with responses ongoing). Nearly all patients (15 of 17, 88.2%) in the study had progressed on or after immunotherapy with 12 of 17 patients (70.6%) having received both prior anti-PD1 and anti-CTLA-4 therapy, including four of the responding patients. The slides are available on our website under presentations. RP2 was generally well tolerated both as monotherapy and in combination with nivolumab with no additive adverse events observed. The most common grade 1 or 2 treatment related adverse events (TRAEs) overall in both cohorts were pyrexia, chills, fatigue, hypotension and pruritis. Six patients had grade 3 TRAEs, including two cases of hypotension. There were no grade 4 or 5 TRAEs. “Metastatic uveal melanoma is an immunologically cold tumor type with few effective treatment options,” said Joseph Sacco, MBChB, PhD, FRCP, University of Liverpool and Clatterbridge Cancer Centre, UK. “In fact, single-agent and combination immune checkpoint inhibitor therapies, including ipilimumab combined with nivolumab, exhibit low response rates in patients with this disease, with combination therapies associated with significant toxicity. The data from this study are compelling given the rate of durable responses seen combined with a favorable safety profile, including in patients who had both liver and extra-hepatic metastases, further supporting the potential of RP2 in this patient population.” Uveal melanoma is the most common form of intraocular primary malignancy and accounts for approximately 90 percent of all cases of ocular melanoma and up to 5 percent of all melanomas. Approximately 50 percent of patients will develop distant metastases, with about 90 percent of such patients manifesting liver metastases. Once the disease metastasizes, median overall survival is less than one year. “These data from the trial cohort evaluating RP2 as monotherapy and in combination with nivolumab in metastatic uveal melanoma are highly promising,” said Robert Coffin, President and Chief Research & Development Officer at Replimune. “We are currently assessing the potential registrational path forward for RP2 in advanced uveal melanoma now that the Phase 1 development of RP2 in this disease is nearly complete. Metastatic uveal melanoma is a disease with significant unmet medical need where treatments remain limited, and no current standard of care options provide the potential for long term survival, other than in a minority of patients.” About RP2RP2 is a derivative of RP1, Replimune’s lead product candidate that is based on a proprietary new strain of herpes simplex virus engineered and genetically armed with a fusogenic protein (GALV-GP R-) and GM-CSF to maximize tumor killing potency, the immunogenicity of tumor cell death and the activation of a systemic anti-tumor immune response. RP2 additionally expresses an anti-CTLA-4 antibody-like molecule, as well as GALV-GP-R- and GM-CSF. RP2 is intended to provide targeted and potent delivery of these proteins 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. About Replimune Replimune Group, Inc., headquartered in Woburn, MA, was founded in 2015 with the mission to transform cancer treatment by pioneering the development of a novel portfolio of oncolytic immunotherapies. Replimune’s proprietary RPx platform is based on a potent HSV-1 backbone intended to maximize immunogenic cell death and the induction of a systemic anti-tumor immune response. The RPx platform is designed to have a unique dual local and systemic mechanism of action (MOA) consisting of direct selective virus-mediated killing of the tumor resulting in the release of tumor derived antigens and altering of the tumor microenvironment to ignite a strong and durable systemic response. This MOA is expected to be synergistic with most established and experimental cancer treatment modalities, leading to the versatility to be developed alone or combined with a variety of other treatment options. For more information, please visit www.replimune.com. Forward Looking Statements This press release contains forward looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements regarding our expectations about our cash runway, the design and advancement of our clinical trials, the timing and sufficiency of our clinical trial outcomes to support potential approval of any of our product candidates, our goals to develop and commercialize our product candidates, patient enrollments in our existing and planned clinical trials and the timing thereof, and other statements identified by words such as “could,” “expects,” “intends,” “may,” “plans,” “potential,” “should,” “will,” “would,” or similar expressions and the negatives of those terms. Forward-looking statements are not promises or guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in such forward-looking statements. These factors include risks related to our limited operating history, our ability to generate positive clinical trial results for our product candidates, the costs and timing of operating our in-house manufacturing facility, the timing and scope of regulatory approvals, the availability of combination therapies needed to conduct our clinical trials, changes in laws and regulations to which we are subject, competitive pressures, our ability to identify additional product candidates, political and global macro factors including the impact of the coronavirus as a global pandemic and related public health issues and the Russian-Ukrainian and Israel-Hamas political and military conflicts, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Our actual results could differ materially from the results described in or implied by such forward-looking statements. Forward-looking statements speak only as of the date hereof, and, except as required by law, we undertake no obligation to update or revise these forward-looking statements. Investor Inquiries Chris BrinzeyWestwicke, an ICR Company339.970.2843chris.brinzey@westwicke.com Media InquiriesArleen GoldenbergReplimune917.548.1582media@replimune.com

The Company plans to hold a conference call in early December to provide a comprehensive RP1 skin cancer program update including: Topline data from the CERPASS clinical trial of RP1 combined with Libtayo in cutaneous squamous cell carcinomaAn initial data snapshot for all 140 patients in the IGNYTE clinical trial cohort of RP1 in anti-PD1 failed melanomaInitial data from the IGNYTE cohort of RP1 in anti-PD1 failed non-melanoma skin cancersA recap of interim data from the ARTACUS clinical trial of RP1 monotherapy in solid organ transplant recipients with skin cancer recently presented at SITC 2023 WOBURN, Mass., Nov. 07, 2023 (GLOBE NEWSWIRE) -- Replimune Group, Inc. (NASDAQ: REPL), a clinical stage biotechnology company pioneering the development of a novel portfolio of oncolytic immunotherapies, today announced financial results for the fiscal second quarter ended September 30, 2023 and provided a business update. “We look forward to presenting the topline data from our registration-directed CERPASS clinical trial of RP1 in combination with Libtayo in cutaneous squamous cell carcinoma (CSCC) as well as sharing an initial snapshot from the full patient population in the IGNYTE clinical trial cohort of RP1 combined with Opdivo in anti-PD1 failed melanoma at an investor call in a few weeks time,” said Philip Astley-Sparke, CEO of Replimune. “We are also excited to present the design of a confirmatory study agreed with the FDA to support a potential approval of RP1 in anti-PD1 failed melanoma via the accelerated approval pathway. For RP2 and RP3, we are continuing to see anti-tumor activity in our Phase 1 program and look forward to providing a full update in early 2024.” Program Highlights & Milestones RP1 CERPASS clinical trial of RP1 combined with Libtayo® (cemiplimab-rwlc) in CSCC The trigger for the primary analysis from the registration-directed CERPASS clinical trial occurred in late June and data collection activities are now complete. The independent review process is expected to complete shortly, triggering a defined process timeline to disclosure in early December.Assuming positive data demonstrating overall clinical benefit, the Company plans to submit a Biologics License Application (BLA) for RP1 in Q2 2024. RP1 combined with Opdivo® (nivolumab) in anti-PD1 failed melanoma The Company will present initial snapshot data for all patients on its conference call in early December by which point all patients will have had at least 6 months follow up. The Company also plans to provide a regulatory update including the design of the intended confirmatory clinical trial to support a potential approval under the accelerated pathway. Planning for the confirmatory study is underway to ensure it has commenced ahead of any BLA submission. The per protocol primary analysis will take place 12 months post the last patient enrolled. Accordingly, the Company plans to submit the BLA in Q3 2024. RP1 combined with Opdivo in anti-PD1 failed non-melanoma skin cancers (NMSC) Recruitment remains ongoing into the cohort of patients with anti-PD1 failed NMSC, including CSCC. The Company plans to provide a data update of the first 30 patients with at least 6 months follow up on its conference call in early December. RP1 in solid organ transplant recipients with skin cancers Presented initial data from the ARTACUS clinical trial of RP1 monotherapy in solid organ transplant recipients with skin cancers at the Society for Immunotherapy of Cancer’s (SITC) 38th Annual Meeting in November 2023. The data included 23 evaluable patients with CSCC (n=20) and Merkel cell carcinoma (n=3).The data demonstrated an overall response rate (ORR) of 34.5% and a confirmed complete response (CR) rate of 21%.RP1 monotherapy was well tolerated, and the safety profile was similar to non-immunocompromised patients with advanced skin cancers (i.e. from the IGNYTE study). No immune-mediated adverse events or evidence of allograft rejection were observed. RP2 and RP3 RP2 and RP3 Phase 1 program Accrual in the Phase 1 program is now substantially complete. Any additional Phase 2 development programs not already announced which are driven by data from the full Phase 1 data and other opportunistic considerations are expected to be announced in early 2024.The Company will present updated data from a cohort of metastatic uveal melanoma patients enrolled in the open-label, multicenter Phase 1 study of RP2 as a single agent and in combination with nivolumab during a Plenary Session at the 20th Annual International Society for Melanoma Research Congress on November 8, 2023. RP2 and RP3 Phase 2 program RP2 and RP3 in combination with atezolizumab and bevacizumab in third-line colorectal cancer (CRC) Two signal finding cohorts of 30 patients each are being enrolled in collaboration with Roche. Patients in the first cohort will be treated with atezolizumab combined with bevacizumab and RP2 and the second cohort with atezolizumab and bevacizumab and RP3. This clinical trial is ongoing. RP2 and RP3 in combination with atezolizumab and bevacizumab in second-line (2L) hepatocellular carcinoma (HCC) Two signal finding cohorts of 15 patients each will be enrolled in collaboration with Roche. The first cohort will enroll 2L patients treated with standard of care atezolizumab combined with bevacizumab and RP3, and the second cohort will enroll 2L patients treated with atezolizumab combined with bevacizumab and RP2. This clinical trial has recently initiated. RP3 in combination with standard of care therapy in squamous cell carcinoma of the head and neck (SCCHN) Initiation has been delayed due to the global shortage of cisplatin and carboplatin. Corporate Update Announced the appointment of Emily Hill as Chief Financial Officer (CFO). Ms. Hill was most recently CFO of the commercial stage biotech company PTC Therapeutics and has more than 15 years of experience in the biotechnology and life sciences industry having held senior financial management and investor relations roles at several leading public biotechnology and pharmaceutical companies.Due to the timing of expected data, the company will commence a quiet period on November 13, 2023 that will remain in effect until the planned conference call in early December. Financial Highlights Cash Position: As of September 30, 2023, cash, cash equivalents and short-term investments were $496.8 million, as compared to $583.4 million as of March 31, 2023. The decrease was primarily related to cash utilized in operating activities in advancing the Company’s expended clinical development plans.Based on the current operating plan, the Company believes that existing cash, cash equivalents and short-term investments, as of September 30, 2023, will enable the Company to fund operations into the second half of calendar year 2025. R&D Expenses: Research and development expenses were $49.1 million for the second quarter ended September 30, 2023, as compared to $28.8 million for the second quarter ended September 30, 2022. 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 $4.4 million in stock-based compensation expenses for the second quarter ended September 30, 2023.S,G&A Expenses: Selling, general and administrative expenses were $14.7 million for the second quarter ended September 30, 2023, as compared to $12.7 million for the second quarter ended September 30, 2022. The increase was primarily driven by personnel related costs, including sales and marketing personnel associated with pre-launch planning and build of the Company’s commercial infrastructure. Selling, general and administrative expenses included $4.7 million in stock-based compensation expenses for the second quarter ended September 30, 2023.Net Loss: Net loss was $60.0 million for the second quarter ended September 30, 2023, as compared to a net loss of $43.1 million for the second quarter ended September 30, 2022. About CERPASS CERPASS is Replimune’s registration-directed randomized, global Phase 2 clinical trial to compare the effects of Libtayo® (cemiplimab-rwlc) alone versus a combination of Libtayo and Replimune’s investigational oncolytic immunotherapy RP1. The clinical trial enrolled 211 patients with locally advanced or metastatic cutaneous squamous cell carcinoma who are naïve to anti-PD-1 therapy. The clinical trial will evaluate complete response rate and overall response rate as its two independent primary efficacy endpoints as assessed by independent review, as well as secondary endpoints including duration of response, progression-free survival, and overall survival. The clinical trial is being conducted under a clinical trial collaboration agreement with Regeneron and full commercial rights retained by Replimune. Libtayo is a registered trademark of Regeneron. About IGNYTE IGNYTE is Replimune’s multi-cohort Phase 1/2 clinical trial of RP1 in combination with Opdivo® (nivolumab). There are 3 tumor specific cohorts in this clinical trial including a cohort in anti-PD1 failed melanoma with registrational intent that has completed enrollment with 140 patients enrolled. This cohort was initiated after completing enrollment in a prior Phase 2 cohort in the same clinical trial of approximately 30 patients with melanoma. The additional cohorts currently enrolling and are in non-melanoma skin cancers which includes both naïve and anti-PD1 failed CSCC, and in anti-PD1 failed microsatellite instability high, or MSI-H/dMMR tumors. This trial is being conducted under a collaboration and supply agreement with Bristol-Myers Squibb. Opdivo is a registered trademark of Bristol-Myers Squibb. About RP1 RP1 is Replimune’s lead product candidate and is based on a proprietary new strain of herpes simplex virus engineered and genetically armed with a fusogenic protein (GALV-GP R-) and GM-CSF intended 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 immune-activating 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, but does not express GM-CSF. RP2 and RP3 are intended to provide targeted and potent delivery of these proteins 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. About Replimune Replimune Group, Inc., headquartered in Woburn, MA, was founded in 2015 with the mission to transform cancer treatment by pioneering the development of a novel portfolio of oncolytic immunotherapies. Replimune’s proprietary RPx platform is based on a potent HSV-1 backbone intended to maximize immunogenic cell death and the induction of a systemic anti-tumor immune response. The RPx platform is designed to have a unique dual local and systemic mechanism of action (MOA) consisting of direct selective virus-mediated killing of the tumor resulting in the release of tumor derived antigens and altering of the tumor microenvironment to ignite a strong and durable systemic response. This MOA is expected to be synergistic with most established and experimental cancer treatment modalities, leading to the versatility to be developed alone or combined with a variety of other treatment options. For more information, please visit www.replimune.com. Forward Looking Statements This press release contains forward looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements regarding our expectations about our cash runway, the design and advancement of our clinical trials, the timing and sufficiency of our clinical trial outcomes to support potential approval of any of our product candidates, our goals to develop and commercialize our product candidates, patient enrollments in our existing and planned clinical trials and the timing thereof, and other statements identified by words such as “could,” “expects,” “intends,” “may,” “plans,” “potential,” “should,” “will,” “would,” or similar expressions and the negatives of those terms. Forward-looking statements are not promises or guarantees of future performance, and are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in such forward-looking statements. These factors include risks related to our limited operating history, our ability to generate positive clinical trial results for our product candidates, the costs and timing of operating our in-house manufacturing facility, the timing and scope of regulatory approvals, the availability of combination therapies needed to conduct our clinical trials, changes in laws and regulations to which we are subject, competitive pressures, our ability to identify additional product candidates, political and global macro factors including the impact of the coronavirus as a global pandemic and related public health issues and the Russian-Ukrainian and Israel-Hamas political and military conflicts, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Our actual results could differ materially from the results described in or implied by such forward-looking statements. Forward-looking statements speak only as of the date hereof, and, except as required by law, we undertake no obligation to update or revise these forward-looking statements. Investor Inquiries Chris Brinzey ICR Westwicke 339.970.2843 chris.brinzey@westwicke.com Media Inquiries Arleen Goldenberg Replimune 917.548.1582 media@replimune.com Replimune Group, Inc. Condensed Consolidated Statements of Operations (Amounts in thousands, except share and per share amounts) (Unaudited) Three Months Ended September 30, Six Months Ended September 30, 2023 2022 2023 2022 Operating expenses: Research and development $49,101 $28,834 $89,538 $58,312 Selling, general and administrative 14,730 12,745 29,941 24,143 Total operating expenses 63,831 41,579 119,479 82,455 Loss from operations (63,831) (41,579) (119,479) (82,455)Other income (expense): Research and development incentives 443 574 836 1,425 Investment income 6,049 1,112 12,235 1,455 Interest expense on finance lease liability (542) (550) (1,086) (1,102) Interest expense on debt obligations (955) - (2,070) - Other (expense) income (1,409) (2,659) (35) (4,678) Total other income (expense), net 3,586 (1,523) 9,880 (2,900)Loss before income taxes $(60,245) $(43,102) $(109,599) $(85,355) Income tax (benefit) (201) - - - Net loss $(60,044) $(43,102) $(109,599) $(85,355)Net loss per common share, basic and diluted $(0.90) $(0.79) $(1.65) $(1.57)Weighted average common shares outstanding, basic and diluted 66,582,280 54,770,291 66,475,577 54,492,395 Replimune Group, Inc. Condensed Consolidated Balance Sheets (Amounts In thousands, except share and per share amounts) (Unaudited) September 30, March 31, 2023 2023 Consolidated Balance Sheet Data: Cash, cash equivalents and short-term investments $496,761 $583,386 Working capital 468,343 558,778 Total assets 562,398 646,591 Total stockholders' equity 465,172 555,292