Replimune Group, Inc. operates as a clinical-stage biotechnology company.
The company engages in applying its leading expertise in the field of oncolytic immunotherapy to transform the lives of cancer patients through its novel oncolytic immunotherapies. The company’s proprietary oncolytic immunotherapy product candidates are designed and intended to maximally activate the immune system against cancer.
The company’s product candidates incorporate multiple mechanisms into a practical off-the-sh...
Replimune Group, Inc. operates as a clinical-stage biotechnology company.
The company engages in applying its leading expertise in the field of oncolytic immunotherapy to transform the lives of cancer patients through its novel oncolytic immunotherapies. The company’s proprietary oncolytic immunotherapy product candidates are designed and intended to maximally activate the immune system against cancer.
The company’s product candidates incorporate multiple mechanisms into a practical off-the-shelf approach that is intended to maximize the immune response against a patient’s cancer and to offer significant advantages over other approaches to inducing anti-tumor immunity, including personalized vaccine approaches.
The company’s proprietary RPx platform is based on a novel, engineered strain of herpes simplex virus 1, or HSV-1, backbone with payloads added to maximize immunogenic cell death and the induction of a systemic anti-tumor immune response. Its RPx platform is intended to have unique dual local and systemic activity 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. The company’s product candidates are expected to be synergistic with most established and experimental cancer treatment modalities, and, with an attractive safety profile its RPx platform is expected to have the versatility to be developed alone or combined with a variety of other treatment options. The company has three RPx product candidates in its portfolio, RP1 (vusolimogene oderparepvec), its lead product candidate, RP2 and RP3.
The company is conducting a number of clinical trials of RP1, both as a monotherapy and in combination with anti-PD-1 therapy, with a focus on establishing a major skin cancer franchise.
The company’s leading clinical trial of RP1 is its IGNYTE trial, a multi-cohort Phase 1/2 clinical trial being conducted in collaboration with Bristol Myers Squibb Company, or BMS, under which BMS has granted it a non-exclusive, royalty-free license to, and is supplying at no cost, its anti-PD-1 therapy, nivolumab, for use in combination with RP1. The leading tumor specific cohort in the IGNYTE trial is its registration directed Phase 2 expansion cohort enrolling patients with anti-PD-1 failed cutaneous melanoma who are being treated with RP1 in combination with nivolumab. In December 2023, the company reported the full data set of 156 patients (140 patients from the registration-directed expansion cohort and 16 anti-PD1 failed cutaneous melanoma patients from the prior phase 2 cohort), by investigator assessment, with an overall response rate, or ORR, of 31.4% and a complete response rate, or CR, of 12%. RP1 combined with nivolumab continues to be well-tolerated, with mainly Grade 1-2 on target side effects, observed. Following a Type C meeting with the U.S. Food and Drug Administration, or FDA, a Phase 3 study design was agreed. This confirmatory study, the company’s IGNYTE-3 trial, is a randomized, controlled, multicenter, open-label Phase 3 clinical study comparing RP1 in combination with nivolumab versus physician's choice treatment for patients with unresectable Stage IIIb-IV cutaneous melanoma whose disease progressed on an anti PD-1 and an anti-CTLA-4 containing regimen (administered either as a combination regimen or in sequence) or who are not candidates for treatment with an anti-CTLA-4 therapy. The FDA requested that the IGNYTE-3 trial be underway at the time of a BLA submission under the accelerated approval pathway and it plans to enroll patients into this trial in the second half of 2024. The FDA also indicated that all responding patients in the IGNYTE anti-PD-1 failed cohort of melanoma patients should be followed for at least 6 months with assessments completed through independent central review using RECIST v1.1, in addition to modified RECIST used in the study. Topline primary data from RP1 in combination with nivolumab in anti-PD-1 failed melanoma patients is expected in the second quarter of 2024 and it plans to submit a BLA for this cohort in the second half of 2024.
In the company’s non-melanoma skin cancer, or NMSC, cohort of the IGNYTE clinical trial, it provided a data update in December 2023 from the first 30 patients with at least 6 months of follow up, including patients with cutaneous squamous cell carcinoma, or CSCC, Merkel cell carcinoma, or MCC, basal cell carcinoma, and angiosarcoma in this cohort. The data showed that treatment with RP1 in combination with nivolumab led to an ORR of 30% which is consistent with data from the anti-PD-1 failed melanoma cohort with approximately one-third of patients responding and 60% demonstrating clinical benefit. The combination of RP1 and nivolumab was well tolerated in this patient population with a safety profile consistent with the overall experience seen with this treatment regimen to date. Enrollment remains open in this cohort.
Furthering development of the company’s RP1 clinical candidate, it has open for enrollment a Phase 1b/2 clinical trial of single agent RP1 in solid organ transplant recipients with skin cancers, including CSCC, which is referred to herein as ARTACUS or the ARTACUS trial. The company is enrolling up to 65 patients in the ARTACUS trial to assess the safety and efficacy of RP1 in liver, kidney, heart, lung, and hematopoietic cell transplant patients with skin cancers. In November 2023 it 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, or SITC, 38th Annual Meeting. RP1 monotherapy was well tolerated in these patients and the safety profile was similar to that observed in its other RP1 clinical trials in patients who are not immune suppressed. No immune-mediated adverse events or evidence of allograft rejection were observed. This data was also presented during oral presentation at the American Association of Cancer Research, or AACR, 2024 Annual Meeting in April 2024. The company continues to enroll patients into this trial.
In December, the company’s randomized, controlled Phase-2 clinical trial of RP1 with CSCC, referred to as CERPASS or the CERPASS trial, under agreement with its partner Regeneron did not meet either of the two primary endpoints. RP1 in combination with cemiplimab increased the CRR versus cemiplimab alone (38.1% vs. 25%, p=0.040), which was just short of the required threshold for statistical significance in this study. The ORR was comparable between the two study groups (52.5% for RP1 plus cemiplimab vs. 51.4% for cemiplimab alone, p=0.692).
The company is also developing or has been developing additional product candidates, RP2 and RP3, that have been further engineered to enhance anti-tumor immune responses and are intended to address additional tumor types, including traditionally less immune responsive tumor types. In addition to the expression of GALV-GP R (-) and human GM-CSF as in RP1, RP2 has been engineered to express an antibody-like molecule intended to block the activity of CTLA-4, a protein that inhibits the full activation of an immune response, including to tumors. RP3 has been engineered with the intent to further stimulate an anti-tumor immune response through activation of immune co-stimulatory pathways through the additional expression of the ligands for CD40 and 4-1BBL, as well as anti-CTLA-4 and GALV-GP R (-), but without the expression of GM-CSF.
The company continues the development of its clinical candidate RP2 with a focus on establishing a rare cancer franchise.
From the company’s Phase-1 clinical trial of RP2 alone and in combination with nivolumab, it has seen durable responses from a monotherapy cohort in a variety of difficult to treat tumors, as well as in combination with anti-PD1 and in particular in patients with uveal melanoma, among other tumor types. In November 2023, it presented updated data from a cohort of metastatic uveal melanoma patients during a Plenary Session at the 20th Annual International Society for Melanoma Research Congress. The updated data showed RP2 led to an 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. 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, or TRAEs, overall, in both cohorts were pyrexia, chills, fatigue, hypotension, and pruritis. Six patients had grade 3 TRAEs, including two cases of hypotension and no patients had grade 4 or 5 TRAEs. Based on the data in this population, the company is near final in the development of a registrational clinical trial protocol with RP2 combined with nivolumab in advanced uveal melanoma following input from the FDA.
The company’s development program in hepatocellular carcinoma, or HCC, that it is collaborating on with Roche for the supply of its approved drugs, atezolizumab and bevacizumab, has been limited to the 2L setting and will use RP2 rather than RP3. The Phase 2 clinical trial with RP2 in anti-PD1/PD-L1 progressed HCC with RP2 combined with atezolizumab and bevacizumab is expected to initiate in the second half of 2024. Although the company’s RP2/3 development in squamous cell carcinoma of the head and neck and colorectal cancer, or CRC, has been discontinued, as previously announced, it is continuing to treat patients who were already in screening or enrolled in these trials before the trials were discontinued. RP1, RP2, and RP3 are administered by direct injection into solid tumors, guided either visually or by ultrasound, computerized tomography or other imaging methods.
The company’s product candidates are designed to induce a robust immune response against a patient’s cancer. Its product candidates are intended to act at several key points in the pathways involved in the initiation of an immune response. Following direct injection into tumors, the company’s viruses replicate in cancer cells and then lyse, or break them open, releasing tumor antigens, including neo-antigens specific to the patient, which could otherwise be hidden from the immune system.
Oncolytic Immunotherapy platform and product candidates
The foundation of the company’s oncolytic immunotherapy product candidates consists of a proprietary strain of HSV-1 that it has engineered to replicate selectively in tumors and to express a fusogenic glycoprotein, a protein that triggers the fusion of the membranes between cells. HSV-1 is both highly cell lytic and inflammatory, and has a large carrying capacity, which makes it possible to incorporate multiple genes encoding therapeutic proteins. RP1 serves as its lead product candidate, with additional product candidates, RP2 and RP3, designed to express additional therapeutic proteins.
Lead product candidate: RP1
The company’s lead product candidate, RP1, is a selectively replicating version of HSV-1 that expresses GALV-GP R (-) and human GM-CSF. RP1 has the following properties:
The company has deleted the ICP34.5-encoding gene, which enables tumor-selective virus replication;
The company has deleted the ICP47-encoding gene, which is intended to prevent the inhibition of the antigen presentation pathway otherwise caused by ICP47 binding to the transporter associated with antigen presentation. ICP47 deletion is also intended to result in the increased and earlier expression of the HSV-1 US11 gene by placing the HSV-1 US11 gene under the control of ICP47 promoter which it believes will increase virus replication in tumors without reducing tumor-selectivity; and
The company has inserted the sequences for GALV-GP R (-) and human GM-CSF, resulting in the expression of these therapeutic proteins with the intention of increasing both the direct tumor cell killing and the potency of the anti-tumor immune response that is induced. It has developed RP1 as a monotherapy and for use in combination with immune checkpoint blockade therapy, particularly therapies targeting PD-1 or PD-(L)-1.
Pipeline product candidates: RP2 and RP3
The company has designed its RP2 product candidate to express an anti-CTLA-4 antibody-like protein intended to block the inhibition of the immune response otherwise caused by CTLA-4. RP2 may offer advantages compared with CTLA-4 approaches, including ipilimumab. By expressing anti-CTLA-4 only locally in the tumor and draining lymph nodes that activity will be retained, but that toxicity will be reduced. The company expects that its RP2 product candidate will be used as monotherapy and/or in combination with other treatment approaches, including anti-PD-1 therapy, which, when used in combination, which will result in both synergy with the oncolytic immunotherapy and the expression of anti-CTLA-4 in the tumor.
The company has designed its RP3 product candidate to express further immune-activating proteins that stimulate T cells, in addition to anti-CTLA-4 and GALV-GP R (-). These immune activating proteins are the ligands for two immune co-stimulatory pathways responsible for T cell proliferation and/or activation, the CD40L and 4-1BBL pathways.
Intellectual property
For the core technology in the company’s RPx platform and each of its product candidates, it initially filed six patent applications under the Patent Cooperation Treaty, or PCT. All six of these PCT applications have entered the national phase and are in different stages of pending and/or issued in a range of countries. Patent examination has started and continues in these national phase applications. Six U.S. patents have been granted by the applicable authorities in the U.S. Four patents have been granted by the applicable authorities in each of the European Union and Japan. Three patents have been granted by the applicable authorities in Hong Kong, two patents have been granted by the applicable authorities in each of China and Israel and one patent has been granted by the applicable authorities in each of Singapore, India, Mexico, and Australia. The granted U.S. patents include US patent numbers 10,570,377; 10,612,005; 10,626,377; 10,947,513; 11,427,810; and 11,473,063 and include description and claims directed to oncolytic virus compositions of matter, pharmaceutical compositions encompassing an oncolytic virus and methods of use in treating cancer with oncolytic virus compositions. The company has successfully defended all oppositions that have been brought by third parties against its issued patents to-date and have maintained its proprietary position. The company continues to vigorously pursue advancement and defense of its patents and patent applications through the respective patent offices in which they are granted or pending throughout the world.
Manufacturing and suppliers
Traditionally, the company’s third-party contract manufacturer in Europe had been responsible for the current good manufacturing practices (cGMP) manufacture and filling of its product candidates for use in its clinical trials.
Sales and Marketing
None of the company’s product candidates has been approved for sale. When its product candidates receive marketing approval, it intends to commercialize them on its own in the United States and potentially with pharmaceutical or biotechnology partners in other geographies. The company continues to build its in-house sales, marketing, and commercialization capabilities with the addition of sales, marketing, trade, and distribution, as well as other related expertise.
Collaborations
BMS
In February 2018, the company entered into a Clinical Trial Collaboration and Supply Agreement with BMS. Pursuant to the agreement, BMS is providing to it, at no cost, nivolumab, its anti-PD-1 therapy, for use in combination with RP1 in its ongoing Phase 1/2 clinical trial. Both parties will own the study data produced in the clinical trial, other than study data related solely to nivolumab, which will belong solely to BMS, or study data related solely to RP1, which will belong solely to it. In January 2020, this agreement was expanded to cover an additional cohort of 125 patients with anti-PD-1 failed melanoma.
In April 2019, the company entered into a separate agreement with BMS on terms similar to the terms set forth in the agreement described above, pursuant to which BMS will provide, at no cost to it, nivolumab for use in its Phase 1 clinical trial of RP2 in combination with nivolumab.
Regeneron
In May 2018, the company entered into a Master Clinical Trial Collaboration and Supply Agreement with Regeneron. Pursuant to the agreement it agreed to undertake one or more clinical trials with Regeneron for the administration of or product candidates in combination with cemiplimab, an anti-PD-1 therapy developed by Regeneron, across multiple solid tumor types. The first of which, agreed in June 2018, is its ongoing clinical trial testing RP1 in combination with cemiplimab versus cemiplimab alone in patients with CSCC.
Roche
In December 2022, the company entered into a Master Clinical Trial Collaboration and Supply Agreement with Roche in relation to its RP2 and RP3 programs in colorectal cancer, or CRC, and hepatocellular carcinoma, or HCC. Under the agreement, the companies intended to collaborate in 30 patient cohort signal finding studies in third-line, or 3L, CRC and in first- and second-line, or 1L and 2L, respectively, HCC. Following its re-prioritization of the company’s product development portfolio in December 2023, it has agreed with Roche to terminate the CRC collaboration and pursue the 2L cohort in HCC with RP2 only. Roche has expressed its intent to continue to supply its approved drugs, atezolizumab and bevacizumab for the 2L cohort in HCC but is unlikely to share costs following its re-prioritization.
Incyte
In July 2023, the company entered into a Clinical Trial Collaboration and Supply Agreement with Incyte Corporation, or Incyte. Under the agreement, the companies anticipate collaborating in a signal finding study in which Incyte will initiate and sponsor a clinical trial of INCB99280 (oral PD-L1 inhibitor) and RP1 in approximately 40 patients with unresectable, high risk CSCC in the neoadjuvant setting.
Regulatory matters
The company’s business activities must comply with numerous healthcare laws, including anti-kickback and false claims laws and regulations, as well as data privacy and security laws and regulations and, as well as state and federal consumer protection and unfair competition laws.
In addition, manufacturers and other entities involved in the manufacture and distribution of approved therapeutics are required to register their establishments with the FDA and certain state agencies, list their products, and are subject to periodic announced and unannounced inspections or remote regulatory assessment by the FDA and these state agencies for compliance with cGMP and other requirements, which impose certain procedural and documentation requirements upon sponsors and third-party manufacturers.
Research and Development Expenses
The company’s research and development expenses were $175.0 million for the year ended March 31, 2024.
History
Replimune Group, Inc. was founded in 2015. The company, a Delaware corporation, was incorporated in 2017.
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