−Removed: We are a clinical-stage biopharmaceutical company pioneering a transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient.
−Removed: TIL therapy is an autologous, polyclonal cell therapy platform technology that was originally developed by the National Cancer Institute, or NCI, which conducted initial clinical trials of this therapy in diseases such as metastatic melanoma and cervical cancer.
−Removed: Our mission is to be the global leader in innovating, developing and delivering TIL therapies for patients with cancer.
−Removed: We have developed a new, shorter TIL manufacturing process known as Gen 2, which yields a cryopreserved TIL product.
−Removed: This centralized, proprietary, and scalable manufacturing method is being investigated in multiple indications.
−Removed: Our lead product candidates include lifileucel for metastatic melanoma and metastatic cervical cancer, as well as LN-145 for metastatic non-small cell lung cancer, or NSCLC.
−Removed: In addition, we are investigating the effectiveness and safety of combinations of TIL therapy with immune checkpoint inhibitors, or ICIs, in metastatic melanoma, cervical cancer, NSCLC, and head and neck squamous cell carcinoma, or HNSCC.
−Removed: We are investigating peripheral blood lymphocyte, or PBL, therapy for patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL, through our sponsored trials.
−Removed: We are developing first-in-class genetically edited TIL products based on the inactivation of genes that encode immune checkpoint proteins and other proteins, as well as the insertion of genes that encode immunomodulatory proteins.
−Removed: We are also developing an alternative interleukin-2, or IL-2, co-therapy for use with TIL therapies.
−Removed: Finally, we are investigating the potential for TIL therapy in other oncology indications and treatment settings through academic collaborations with leading cancer research centers.
−Removed: Our current product candidate pipeline is summarized in the figure below:
−Removed: TIL Monotherapy in Metastatic Solid Tumor Cancers
−Removed: We have investigated TIL monotherapy in metastatic melanoma, cervical cancer, NSCLC and HNSCC.
−Removed: We are conducting a Phase 2 clinical trial, C-144-01, of our lead TIL product candidate, lifileucel, for the treatment of metastatic melanoma.
−Removed: This multicenter pivotal trial enrolled melanoma patients with disease progression following treatment with at least one systemic therapy, including a PD-1 inhibitor and, if BRAF mutated, a BRAF inhibitor, or a combination of BRAF and MEK inhibitors.
−Removed: Cohort 4 of the C-144-01 clinical trial is a single-arm cohort intended to support the submission of a Biologics License Application, or BLA, to the FDA for lifileucel.
−Removed: Cohorts 2 and 4 of the C-144-01 trial use our Gen 2 manufacturing process.
−Removed: We completed and closed enrollment of patients into Cohort 2 of the C-144-01 trial in 2018.
−Removed: Results from Cohort 2 of the C-144-01 clinical trial were initially reported at the American Society of Clinical Oncology annual meeting, or ASCO, in June 2019 and most recently updated at ASCO in June 2021.
−Removed: As of the data extract in April 2021, in 66 patients with metastatic melanoma in Cohort 2, treatment with lifileucel resulted in an objective response rate, or ORR, of 36%, as assessed by investigator, with 3 complete responses and 21 partial responses.
−Removed: The disease control rate, or DCR, was 80.3%.
−Removed: Median duration of response, or DOR, in Cohort 2 had not been reached after 33.1 months of median study follow up.
−Removed: Results from Cohort 2 presented at ASCO in June 2021 also suggest that early intervention with lifileucel at the time of initial progression on anti-PD-1 therapy may maximize benefit.
−Removed: Patients in Cohort 2 were heavily pretreated and had a mean of 3.3 prior therapies.
−Removed: We have previously reported durable responses across a wide age range of metastatic melanoma patients, among those who have received prior anti-CTLA-4 and BRAF targeted treatments, regardless of BRAF mutation status, and in patients with PD-L1 high and low status.
−Removed: The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.
−Removed: In addition, detailed Cohort 2 data was published in the Journal of Clinical Oncology in May 2021.
−Removed: Pivotal Cohort 4 of the C-144-01 trial was enrolled to evaluate ORR as read out by an Independent Review Committee, or IRC, as the primary endpoint based on our interpretation of discussions with the FDA as part of an End of Phase 2, or EOP2, meeting held with the FDA in the third quarter of 2018.
−Removed: In October 2018, based on the data provided to the FDA during the EOP2 meeting, we announced that lifileucel had received a Regenerative Medicines Advanced Therapy, or RMAT, designation from the FDA.
−Removed: Enrollment in Cohort 4 of the C-144-01 trial commenced in March 2019 and patient dosing was completed in January 2020.
−Removed: A total of 87 patients were dosed with Gen 2 product released for Cohort 4.
−Removed: In May 2020, we disclosed initial results from Cohort 4 for 68 patients with two radiological assessments, as determined by investigator.
−Removed: Previously, we reported the submission of additional potency assay data to the FDA, and at the same time, we also announced that we had reached agreement with the FDA on the minimum duration of follow up for Cohort 4 to support our BLA submission for lifileucel in the treatment of metastatic melanoma.
−Removed: In May 2021, we announced that we had received regulatory feedback from the FDA regarding our potency assays for lifileucel.
−Removed: Following FDA feedback, we have continued our ongoing work developing and validating our potency assays and have engaged in discussions with the FDA during the second half of 2021.
−Removed: Our BLA submission for lifileucel in metastatic melanoma is expected to occur during the first half of 2022.
−Removed: In connection with this BLA submission, the IRC is expected to independently assess responses for Cohort 4 patients through the data cut date, which must be completed prior to BLA submission or disclosure of IRC-read data.
−Removed: We are also conducting a Phase 2 clinical trial, C-145-04, which is a multicenter pivotal trial to assess the safety and efficacy of our lead product candidate lifileucel for the treatment of patients with recurrent, metastatic, or persistent cervical cancer.
−Removed: In February 2019, lifileucel received Fast Track designation from the FDA for development in the treatment of cervical cancer with disease progression on or after chemotherapy.
−Removed: In March 2019, the protocol for this trial was amended to modify the primary endpoint of ORR to be determined by IRC.
−Removed: In May 2019, lifileucel received Breakthrough Therapy Designation, or BTD, from the FDA for development in the treatment of cervical cancer.
−Removed: Results from the C-145-04 clinical trial were reported at ASCO in June 2019.
−Removed: In 27 patients with metastatic cervical cancer, treatment with lifileucel resulted in an ORR of 44%.
−Removed: At the time of the study data cut, there were 3 complete responses and 9 partial responses.
−Removed: The DCR was 85%.
−Removed: Patients were heavily pretreated and had a mean of 2.4 prior therapies.
−Removed: The median DOR had not been reached.
−Removed: The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.
−Removed: In November 2019, we amended the C-145-04 trial to collect additional data on early-line patients as well as late-line patients by adding additional cohorts, in anticipation of a changing landscape in this indication, including Cohort 2 for patients that had previously received chemotherapy and anti-PD-1/anti-PD-L1 therapy.
−Removed: In January 2021, we announced that Cohort 2 of the C-145-04 trial had completed enrollment and that data from this cohort may be supportive of registration because of the expected changing landscape of care for cervical cancer patients.
−Removed: For example, because of recent regulatory approvals for pembrolizumab, there may be a potential shift from chemotherapy in front-line cervical cancer followed by pembrolizumab in second-line cervical cancer to the use of pembrolizumab in combination with chemotherapy in first-line cervical cancer.
−Removed: We intend to execute our registrational strategy based on dialog and feedback from the FDA on these cohorts and continue to plan for a potential BLA submission for lifileucel in cervical cancer.
−Removed: In November 2020, we announced that we had finalized the protocol for our potential registrational clinical trial in NSCLC, IOV-LUN-202, to investigate LN-145 in patients with metastatic NSCLC, without driver mutations, who previously received a single line of approved systemic therapy of combined checkpoint inhibitor and chemotherapy.
−Removed: The IOV-LUN-202 clinical trial includes three cohorts.
−Removed: Cohorts 1 and 3 of the IOV-LUN-202 clinical trial are enrolling patients with a PD-L1 TPS of less than one percent at the time they started front-line therapy, and Cohort 2 will enroll patients with a PD-L1 TPS of greater than or equal to one percent at the time they started front-line therapy.
−Removed: Cohort 3 will also explore manufacturing TIL extracted from core biopsies using our third-generation, or Gen 3, manufacturing process.
−Removed: In June 2021, we reported that the first patient was dosed in the IOV-LUN-202 clinical trial.
−Removed: We intend to continue to enroll patients in the IOV-LUN-202 clinical trial throughout 2022.
−Removed: We are engaged in regulatory discussions with the FDA on IOV-LUN-202 and intend to incorporate FDA feedback to optimize this clinical trial to support further registration in NSCLC.
−Removed: In June 2021, we reported initial data for LN-145 in Cohort 3B of our IOV-COM-202 clinical trial in metastatic NSCLC.
−Removed: IOV-COM-202 is a Phase 2, multicenter trial that is composed of seven cohorts.
−Removed: Cohort 3B of IOV-COM-202 enrolled patients with metastatic NSCLC that had progressed on prior ICI therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor therapy.
−Removed: Patients were treated with LN-145 monotherapy.
−Removed: We reported results from Cohort 3B of the IOV-COM-202 trial in June 2021.
−Removed: The ORR was 21.4% for the 28 patients in the analysis population, including one complete response and five partial responses, and the DCR was 64.3%, including two responders with PD-L1 negative tumors, and 3 responders who had primary refractory disease to checkpoint inhibitors.
−Removed: The treatment emergent adverse event, or TEAE, profile was consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and IL-2.
−Removed: All patients treated in Cohort 3B of the IOV-COM-202 trial received prior anti-PD-1/L1 therapy and all six responding patients also received prior chemotherapy.
−Removed: Historically, ORRs of approximately 20% were reported with ICIs as second-line therapy in ICI-naïve patients who progressed on front-line chemotherapy.
−Removed: We also provided an update on Cohort 3B at the Society for Immunotherapy in Cancer Annual Meeting, or SITC, in November 2021.
−Removed: As of the data extract in August 2021, following one-time treatment with LN-145 monotherapy, the ORR remained at 21.4% for the 28 patients in the analysis population, and was 25% in the efficacy-evaluable set of 24 patients, including one complete response and five partial responses.
−Removed: One complete response and one partial response were ongoing at 20.7 months and 3.0 months, respectively, at a median study follow up of 9.8 months.
−Removed: C-145-03 is our Phase 2, multicenter trial to assess the safety and efficacy of our product candidate LN-145 for the treatment of patients with metastatic HNSCC.
−Removed: In October 2018, we reported that preliminary data for 13 patients in the C-145-03 clinical trial yielded an ORR of 31% with a DOR ranging from 2.8 to 7.6 months.
−Removed: The adverse event profile remained consistent with previous reports.
−Removed: We redesigned our C-145-03 trial to include multiple cohorts, in order to allow for dosing of TIL therapies produced by multiple manufacturing methods, including our Gen 2 manufacturing process, our Gen 3 manufacturing process, and our PD-1 selected TIL manufacturing process.
−Removed: Our PD-1 selected TIL manufacturing process results in a product that we refer to as LN-145-S1.
−Removed: In January 2021, we announced that we will close the C-145-03 clinical trial after the trial reached its pre-specified enrollment target.
−Removed: TIL Combinations in Earlier Treatment Settings for Solid Tumors
−Removed: We are investigating the potential of our TIL therapies in earlier lines of treatment in combination with pembrolizumab or other ICIs in cancer patients who are naïve to anti-PD-1 therapy.
−Removed: ICIs are a class of immunotherapy drugs that seek to overcome one of cancer’s main escape mechanisms against an immune system attack.
−Removed: PD-1 is a checkpoint protein found on immune cells called T cells that normally acts as a type of “off switch” which helps prevent T cells from attacking other cells in the body.
−Removed: It is activated by binding to PD-L1, a protein found on both normal and cancerous cells, which thereby may shut down an attack by a T cell.
−Removed: Some cancer cells have large amounts of PD-L1 expressed on their surfaces, which helps them evade T cell attack.
−Removed: We are investigating the potential for our TIL therapy mechanism, together with checkpoint inhibition provided by ICIs, to improve response rates compared to ICIs alone in several sold tumor types, including in four cohorts in our IOV-COM-202 study in solid tumors as well as in one cohort in our C-145-04 clinical study in cervical cancer.
−Removed: In addition to its ongoing enrollment in the U.S., the IOV-COM-202 trial has also received regulatory approval in Canada and in certain European countries.
−Removed: In Cohort 1A of the IOV-COM-202 trial, we are enrolling advanced unresectable or metastatic melanoma patients who are naïve to anti-PD-1 therapy.
−Removed: We reported results from ongoing Cohort 1A of the IOV-COM-202 trial at ASCO in June 2021, as follows, from the initial seven patients.
−Removed: Seven patients received lifileucel in combination with pembrolizumab.
−Removed: Six of the seven patients had a confirmed objective response, with an ORR of 86%, including two complete responses, one unconfirmed complete response who had not yet reached the confirmatory complete response assessment, and three partial responses, with one best response of stable disease.
−Removed: The complete response rate, including the unconfirmed complete response, was 43%.
−Removed: The median follow up was 8.2 months.
−Removed: The Cohort 1A results also demonstrated that lifileucel can be safely combined with pembrolizumab.
−Removed: In November 2021, we provided updated results from 10 patients in an oral presentation at SITC in which there was a demonstrated ORR of 60%.
−Removed: Six out of the 10 patients had a confirmed objective response, including three complete responses and three partial responses.
−Removed: Historically, ORRs of 33% and a CR rate of 6% have been reported for pembrolizumab monotherapy in metastatic melanoma.
−Removed: Based on these results, we plan to expand enrollment in this cohort in early line melanoma in 2022.
−Removed: In Cohort 2A of the IOV-COM-202 trial, we are enrolling advanced, recurrent, or metastatic HNSCC patients who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy.
−Removed: The patients receive LN-145 in combination with pembrolizumab.
−Removed: We reported results from ongoing Cohort 2A of the IOV-COM-202 trial at the SITC meeting in November 2020, as follows.
−Removed: As of October 16, 2020, nine HNSCC patients have received LN-145 plus pembrolizumab with a median duration of follow up of 8.6 months.
−Removed: Four patients had a confirmed, objective response with an ORR of 44% including one complete response and three partial responses.
−Removed: Median DOR was not reached.
−Removed: The DCR at data cutoff was 89% in nine patients, and seven of the eight evaluable patients, or 87.5%, had a reduction in target lesions.
−Removed: The median number of prior therapies was 1.0 with 89% of the patients having received prior chemotherapy.
−Removed: Four patients were positive for Human Papilloma Virus, or HPV, three patients were HPV negative, and two patients had unknown HPV status.
−Removed: In November 2021, we provided updated results from 18 patients in an oral presentation at SITC in which there was a demonstrated ORR of 38.9%.
−Removed: Seven out of the 18 patients had an objective response, including one complete response, one unconfirmed complete response, four partial responses and one unconfirmed partial response.
−Removed: Historically, ORRs of 17% have been reported for pembrolizumab monotherapy in patients with HNSCC.
−Removed: Our oral presentation at SITC in November 2021 also included initial results from 14 patients treated with a combination of TIL therapy plus pembrolizumab in Cohort 3 of our C-145-04 cervical cancer study.
−Removed: The ORR was 57.1%, and eight out of 14 patients had an objective response, including one complete response, six partial responses and one unconfirmed partial response.
−Removed: Cervical cancer patients previously treated with standard of care systemic therapy achieve an ORR of 11%-14% with pembrolizumab monotherapy.
−Removed: The Cohort 1A and Cohort 2A results from the IOV-COM-202 study as well as Cohort 3 from the C-145-04 study demonstrated that lifileucel or LN-145 can be safely combined with pembrolizumab.
−Removed: The TEAE profile in all Cohorts was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion, and IL-2 regimens.
−Removed: Two additional cohorts, Cohort 3A and 3C in the IOV-COM-202 study, explore LN-145/ICI combination therapies in NSCLC patients.
−Removed: Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients with recurrent or metastatic NSCLC who have not received prior immunotherapy, including checkpoint inhibitors.
−Removed: Cohort 3C is investigating LN-145 therapy in combination with ipilimumab and nivolumab in patients with recurrent or metastatic NSCLC who have previously received one line of approved checkpoint inhibitor monotherapy as the only prior line of systemic therapy.
−Removed: In September 2021, we announced that our Iovance Cell Therapy Center, or the i CTC, had successfully manufactured and delivered its first clinical batch of LN-145 for the IOV-COM-202 trial, representing our first internally manufactured TIL product.
−Removed: We continue to supply the IOV-COM-202 trial, and other ongoing trials, with both internally manufactured and externally manufactured TIL products.
−Removed: Next-Generation and Genetically Modified Product Candidates
−Removed: Our clinical pipeline also includes next generation TIL product candidates and manufacturing processes, as well as a cytokine-engrafted protein.
−Removed: Our TIL candidate LN-145-S1, in which TIL are selected for PD-1 expression, is being investigated in post-anti-PD-1 melanoma in Cohort 1B of our IOV-COM-202 basket study as well as in post-anti-PD-1 HNSCC in Cohort 4 of our C-145-03 trial.
−Removed: We are using our Gen 3 manufacturing process in Cohort 1C of the IOV-COM-202 clinical trial in melanoma and in Cohort 3 of the IOV-LUN-202 clinical trial in NSCLC and have previously used it in the C-145-03 clinical trial in HNSCC.
−Removed: In November 2019, we announced that our Investigational New Drug, or IND, application for our PBL therapy, IOV-2001, was authorized by the FDA.
−Removed: Our sponsored clinical trial using this therapy, IOV-CLL-01, was cleared to proceed and patient dosing began in 2020.
−Removed: IOV-2001 is a non-genetically modified, polyclonal T cell product that is manufactured using a nine-day process starting from 50 mL of patient's blood.
−Removed: IOV-CLL-01 is a Phase 1/2 clinical trial evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory CLL or SLL.
−Removed: In January 2020, we announced a research collaboration and exclusive worldwide licensing agreement with Cellectis S.A., or Cellectis, a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic chimeric antigen receptor modified T cells.
−Removed: The worldwide exclusive license enables us to use certain TALEN® technology addressing multiple gene targets to develop TIL that have been genetically modified to create potentially more potent cancer therapies for use in several cancer indications.
−Removed: We are nearing completion of IND-enabling studies under this agreement and expect to initiate our first clinical study in 2022 of a genetically modified TIL product candidate, IOV-4001, in which the gene coding for the PD-1 protein is inactivated.
−Removed: Financial terms of the license include development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN-modified TIL products.
−Removed: In addition to IOV-4001, we are currently developing additional targets for genetic modification using the TALEN technology, including double-knock out programs in preclinical development.
−Removed: We continue to explore additional transient and permanent genetic modifications of TILs.
−Removed: For example, under the amended and restated patent license agreement we entered into in May 2021 with National Institutes of Health, or NIH, an agency of the U.S.
−Removed: Public Health Service within the Department of Health and Human Services, we license a patent family related to cytokine-tethered TILs, which are intended to potentially expand and activate TILs to achieve better efficacy while avoiding systemic side effects of cytokines.
−Removed: We are currently developing cytokine-tethered TIL products in preclinical studies.
−Removed: In addition, in January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.
−Removed: Under the agreement, we paid an upfront payment to Novartis and may pay milestones involved in initiation of patient dosing in various phases of clinical development for IOV-3001 and approval of a potential product in the U.S., EU, and Japan.
−Removed: We are currently conducting IND-enabling studies of this novel IL-2 analog.
−Removed: Novartis is also entitled to low-to-mid single digit percentage royalties from commercial sales of IOV-3001.
−Removed: Investigator-Sponsored Trials
−Removed: Through our academic collaborators, we are also exploring the potential for TIL therapies in additional indications.
−Removed: As part of our collaboration program with The University of Texas M.D.
−Removed: Anderson Cancer Center, or MDACC, two Phase 2 trials were initiated in 2018.
−Removed: Both trials are sponsored by MDACC.
−Removed: The first trial, NCT03449108, investigates LN-145 manufactured by us, using our manufacturing processes, to treat patients with soft tissue sarcoma, osteosarcoma, platinum resistant ovarian cancer, and thyroid cancer.
−Removed: A second trial under the collaboration with MDACC, NCT03610490, was previously active.
−Removed: This trial treated patients with platinum resistant ovarian cancer, pancreatic and colorectal cancer with TIL manufactured by MDACC.
−Removed: The data obtained using this manufacturing process may not be representative of our data using our Gen 2 manufacturing process.
−Removed: We also collaborate with many other academic institutions using our TIL therapies.
−Removed: For example, a trial in collaboration with The Ohio State University, NCT05176470, is expected to start recruiting in 2022, and explores the use of lifileucel in high-risk melanoma in the neoadjuvant setting.
+Added: We are a clinical-stage biopharmaceutical company pioneering a transformational approach to treating cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells using therapies personalized for each patient.
+Added: We are preparing for potential U.S.
+Added: regulatory approval and commercialization of the first autologous T-cell therapy to address a solid tumor cancer.
+Added: Our mission is to be the global leader in innovating, developing and delivering tumor infiltrating lymphocyte, or TIL, therapies for patients with solid tumor cancers.
+Added: Our autologous TIL therapy platform uses a centralized, scalable and proprietary 22-day manufacturing process to grow polyclonal T-cells unique to each patient and yields a cryopreserved, individualized therapy.
+Added: We have applied multiple TIL therapy modalities in clinical trials in solid tumors, including TIL monotherapies for patients with later stage disease who have progressed on or after standard of care, as well as TIL combinations with standard of care therapies in patients who are earlier in their disease, to potentially improve outcomes compared to current standard(s) of care.
+Added: Our lead product candidate, lifileucel, is being developed in advanced, or metastatic or unresectable, melanoma as well as in other indications.
+Added: Lifileucel was investigated in two consecutive cohorts in a clinical trial of advanced melanoma patients post-anti-PD-1 therapy, including in a prospectively defined pivotal cohort.
+Added: These patients had progressed on or after standard of care therapy, which is immune checkpoint inhibitors, or ICIs, and, targeted BRAF/MEK inhibitor therapy where appropriate.
+Added: Based on the positive results of these cohorts, we initiated a rolling Biologics License Application, or BLA, submission to the U.S.
+Added: Food and Drug Administration, or FDA, for lifileucel in August 2022.
+Added: We expect to complete this rolling BLA submission in the first quarter of 2023.
+Added: Our Phase 3 clinical trial of lifileucel in combination with pembrolizumab, TILVANCE-301, is intended to be registrational in frontline advanced melanoma and serve as a confirmatory clinical trial to support full approval of lifileucel monotherapy in post-anti-PD-1 melanoma.
+Added: We are also pursuing registrational strategies for lifileucel in advanced cervical cancer and for our TIL therapy, LN-145, in metastatic non-small cell lung cancer, or NSCLC.
+Added: To continuously innovate and maintain our global leadership within the field, we are investigating next generation approaches to optimize TIL products, manufacturing processes and treatment regimens, including a first-in-human clinical trial of our lead genetically modified TIL therapy, IOV-4001.
+Added: We are also exploring a 16-day manufacturing
+Added: process, tumor tissue procurement via core biopsy, additional genetically modified TIL therapies including multiple immune checkpoint gene edits and cytokine-tethered TIL therapies, and a novel interleukin-2, or IL-2, analog, designated IOV-3001, as potential avenues to improve manufacturing timelines, sample collection and supportive treatments involved in the overall TIL therapy process and treatment regimen.
+Added: Highlights of our current development pipeline are presented in the figure below:
+Added: Platform Technologies and Manufacturing
+Added: Our T-cell-based immunotherapy technology platforms are potentially applicable to many solid tumor types and blood cancers.
+Added: Each platform is focused on leveraging patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.
+Added: Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, our polyclonal T-cells are personalized therapies designed to target a variety of neoantigens that are unique to the patient or tumor.
+Added: The majority of solid tumor immune targets are patient-specific, with fewer than 1% shared among patients.
+Added: TIL therapy is our lead T-cell-based immunotherapy platform in multiple advanced solid tumor cancers.
+Added: For blood cancers, our peripheral blood lymphocyte, or PBL, therapy platform is based on polyclonal T-cells that are collected from a patient’s blood sample, and then amplified and reinvigorated.
+Added: TIL Clinical Development in Advanced, Metastatic or Unresectable Solid Tumor Cancers
+Added: Building on the prior TIL therapy clinical trials conducted at single academic centers, including the National Cancer Institute, or NCI, we have investigated TIL therapy in global, multi-center Phase 2 clinical trials in advanced melanoma, cervical cancer, NSCLC, and head and neck squamous cell carcinoma, or HNSCC.
+Added: Additional information about our clinical trials is summarized below.
+Added: In post-anti-PD-1 advanced melanoma, we are investigating lifileucel in our C-144-01 clinical trial that supports our BLA submission and potential approval of lifileucel in advanced post-anti-PD-1 melanoma.
+Added: In frontline advanced melanoma patients who are naïve to anti-PD-1 therapy, we are investigating lifileucel in combination with pembrolizumab in the IOV-COM-202 clinical trial and the Phase 3 TILVANCE-301 clinical trial.
+Added: TILVANCE-301 is a randomized Phase 3 clinical trial intended to support registration in advanced frontline melanoma as well as to serve as a confirmatory trial for full approval in advanced post-anti-PD-1 melanoma.
+Added: We are also executing a registrational strategy for lifileucel in advanced cervical cancer.
+Added: C-145-04 is a multicenter Phase 2 clinical trial that is currently enrolling a pivotal cohort to support a BLA in cervical cancer following progression on or after chemotherapy and pembrolizumab.
+Added: In NSCLC, we are investigating our TIL therapy, LN-145, in two clinical trials in several NSCLC patient populations with significant unmet need.
+Added: IOV-LUN-202 is a clinical trial of LN-145 in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy.
+Added: IOV-COM-202 also includes cohorts of NSCLC patients treated with LN-145 monotherapy and combination therapy.
+Added: Our first genetically modified, PD-1 inactivated TIL therapy, IOV-4001, entered a first-in-human Phase 1/2 clinical trial, IOV-GM1-201, in 2022 in patients with previously treated advanced melanoma and NSCLC.
+Added: IOV-4001 utilizes the gene-editing TALEN® technology, licensed from Cellectis S.A., or Cellectis, to inactivate the gene coding for the programmed cell death protein-1, or PD-1.
+Added: Beyond our Iovance-sponsored clinical trials, we have academic collaborations with leading cancer research centers to investigate TIL therapy, including next-generation processes and technologies, in other cancers and treatment settings.
+Added: Next-Generation Therapeutic and Manufacturing Approaches
+Added: Our current next-generation technology platforms are designed to optimize TIL therapy across four key initiatives:
+Added: genetic modification, potency, manufacturing process and treatment regimens.
+Added: More information on our next-generation approaches is included in the Next-Generation Product Candidates section of this Annual Report on Form 10-K.
+Added: Intellectual Property
+Added: We have established a leading intellectual property portfolio developed internally and licensed from third parties.
+Added: We currently own more than 60 U.S.
+Added: patents related to TIL therapy, including patents directed to compositions and methods of treatment and manufacturing in a broad range of cancers.
+Added: Pending patent applications and granted patents cover the fields of TIL therapy, marrow infiltrating lymphocytes, or MIL therapy, and PBL therapy.
+Added: We also license rights to a broad range of technologies related to our platforms.
+Added: More details on our intellectual property portfolio are included within this Annual Report on Form 10-K.
Corporate Strategy
−Removed: We aim to be the global leader in innovating, developing and delivering TIL therapy for patients with cancer.
−Removed: We are pioneering a transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient.
−Removed: We are committed to continuous innovation in developing TIL cell therapy, including gene-edited cell therapy, shorter manufacturing processes, and alternatives to IL-2 across a spectrum of tumor types including but not limited to melanoma, cervical cancer, NSCLC and HNSCC that may extend and improve life for patients with cancer.
−Removed: Key elements of our strategy include:
−Removed: Expedite clinical development, regulatory approval, and commercialization of our lead product candidate lifileucel for the treatment of metastatic melanoma as well as Iovance TIL and additional polyclonal cell therapies for cancer.
−Removed: Based on results of TIL therapy from our own clinical trials in metastatic melanoma as well as trials sponsored by the NCI, we are focused on expediting the development, regulatory approval and commercialization of our lead product candidate, lifileucel, for the treatment of patients with metastatic melanoma.
−Removed: We intend to file a BLA for lifileucel in metastatic melanoma in the first half of 2022.
−Removed: We are also investigating TIL monotherapy as a one-time treatment for advanced cervical cancer and NSCLC patients who have progressed following standard of care treatments, TIL in combination with ICIs for melanoma, cervical, NSCLC and HNSCC as treatment in earlier disease settings, and a PBL therapy intended to address hematologic malignancies.
−Removed: Continue to expand manufacturing capacity for TIL products.
−Removed: We continue to invest in improving the process and efficiency of manufacturing our product candidates in the U.S.
−Removed: and Europe for TIL manufacturing.
−Removed: We began construction of the i CTC, our own manufacturing facility, in 2019, in Philadelphia, Pennsylvania, in order to provide for better margins and rapid implementation of innovative changes for TIL therapies that we may develop or commercialize.
−Removed: We intend to carefully manage our cost structure, and reduce the long-term cost of manufacturing our products, although there can be no assurance that we will be able to reduce our manufacturing costs to commercially attractive levels.
−Removed: As of the end of 2021, we have completed commissioning activities and the i CTC had successfully manufactured and delivered first clinical batch of LN-145 for the IOV-COM-202 trial, representing our first internally manufactured TIL product.
−Removed: Currently we use the i CTC as well as several contract manufacturing organizations, or CMOs, to supply our TIL-based products for our clinical trials under various manufacturing services agreements, or MSAs.
−Removed: The use of CMOs is intended to supplement the manufacturing capacity at the i CTC.
−Removed: In 2016, we entered into a three-year MSA and related statements of work with WuXi Advanced Therapies, Inc., or WuXi, for two current Good Manufacturing Practices, or cGMP, manufacturing suites to be established and operated by WuXi for us in order to increase our TIL manufacturing capacity in facilities with both clinical and commercial capability for two suites.
−Removed: We have since extended our MSA with WuXi until February 2022 for the first suite and December 2022 for the second suite.
−Removed: In 2017, we entered into a three-year MSA and related statements of work with PharmaCell B.V., or PharmaCell, a contract manufacturing services company based in the Netherlands, to manufacture our autologous cell therapy products for use in our
−Removed: European clinical trials.
−Removed: PharmaCell was subsequently acquired by Lonza Group Ltd., or Lonza.
−Removed: Lonza continues to manufacture TIL products for our European clinical trials in its clinical and commercial facility in Geleen, the Netherlands.
−Removed: We have since extended our agreements with Lonza until April 2022.
−Removed: Also in 2017, we entered into a two-year MSA and related statements of work with Moffitt, to manufacture our autologous cell therapy products for use in clinical trials, which has since been extended until March 2025.
−Removed: Moffitt continues to manufacture TIL products for our clinical trials in the U.S.
−Removed: Continue to improve our TIL manufacturing processes and develop new TIL manufacturing technology to become the preferred provider of TIL therapy in the U.S.
−Removed: and the rest of the world.
−Removed: We are currently manufacturing TIL for our ongoing clinical studies at the i CTC and remain on track to provide commercial supply from this facility upon potential BLA approval.
+Added: Be the global leader in innovating, developing and delivering TIL therapy
+Added: Our mission is to be the global leader in innovating, developing and delivering TIL therapy for patients with cancer.
+Added: We are pioneering this transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient.
+Added: We are committed to continuous innovation in developing TIL cell therapy and optimizing the TIL treatment regimen that may extend and improve life for patients with cancer.
+Added: Obtain regulatory approval and successfully commercialize our lead product candidate lifileucel for the treatment of post-anti-PD-1 advanced melanoma
+Added: Our top priority is to expedite the regulatory approval and commercialization of our lead product candidate, lifileucel, for the treatment of patients with post-anti-PD-1 advanced melanoma.
+Added: We initiated a rolling BLA for lifileucel in post-anti-PD-1 advanced melanoma in August 2022 and plan to complete the BLA submission in the first quarter of 2023.
+Added: Our medical affairs team is in the field educating key opinion leaders, or KOLs, and presenting and publishing our clinical results.
+Added: commercial leadership team is preparing to launch lifileucel in 2023, if approved.
+Added: We have experienced marketing, payer access and distribution teams, and we are building a specialty oncology sales force for launch.
+Added: More than half the team has prior cell therapy experience.
+Added: The five primary areas of our pre-launch efforts include:
+Added: ● onboarding of authorized treatment centers, or ATCs, with the goal of 40 ATCs for commercial launch;
+Added: ● collaboration with healthcare professionals, or HCPs, who will be handling or administering our product;
+Added: ● operational excellence in launch execution, commercial manufacturing and delivery of therapy;
+Added: ● communication with payors about the value of lifileucel;
+Added: ● establishment of a cross-functional, patient-centric organization.
+Added: Prepare for commercial manufacturing to meet forecasted demand
We believe that we are the only company in the U.S.
to have a centralized, demonstrated, and commercially viable TIL manufacturing process.
−Removed: In 2018, we first utilized our Gen 2 TIL manufacturing process, which reduced TIL manufacturing time from 5-6 weeks to 22 days, allowing for a commercially viable product candidate.
−Removed: The Gen 2 process also produces a cryopreserved TIL product for ease of administration and handling.
−Removed: The Gen 2 manufacturing process was utilized in Cohort 2 and Cohort 4 of our C-144-01 trial and has also been selected for use in most of our ongoing TIL clinical development program.
−Removed: We have included Gen 2 as the manufacturing process for registration for our discussions with the FDA and the anticipated BLA filing for lifileucel.
−Removed: Our strategy is to establish our Gen 2 process as a commercial manufacturing process for TIL therapies, including lifileucel.
−Removed: We also continue to develop and evaluate potential future TIL manufacturing processes, including our 16-day Gen 3 process and genetically modified TIL and other next generation TIL products and processes.
−Removed: Collaborate with governmental, academic and corporate partners to improve and develop TIL and PBL therapies for new indications or for use in combination with other therapies, and to evaluate new manufacturing methods.
−Removed: In addition to our own research and process development efforts, we seek to collaborate with government, academic research institutions, and corporate partners to improve TIL manufacturing and to develop and explore TIL therapies for new indications.
−Removed: For example, we have ongoing licensing agreements and collaborations with Moffitt, MDACC, Yale University, Cellectis, Novartis, Melanoma Institute Australia, or MIA, and Beth-Israel Deaconess Medical Center, or BIDMC, to evaluate several new solid tumor and hematologic indications for TIL and PBL therapy in clinical and preclinical studies as well as, in some cases, new TIL manufacturing approaches.
−Removed: In August 2021, we extended our Cooperative Research and Development Agreement, or CRADA, with the NCI for another 3-year term.
−Removed: This collaboration with the NCI is directed at research on unmodified TIL therapy and also addresses HPV-associated cancers (cervical and head and neck), lung, bladder, and breast cancers.
−Removed: This collaboration also focuses on Strategies to expand TIL with less differentiated and more stem-like attributes which may result in improved persistence, functionality, and better anti-tumor activity.
−Removed: For example, in December 2021 we presented data at ESMO Immuno-oncology 2021 that demonstrated temporally inhibiting AKT signaling during ex vivo TIL expansion enhances cytokine production and function while increasing the population of less differentiated (CD39/CD69) CD8+T-Cells.
−Removed: A description of certain of these collaborations and related agreements is provided in the following sections of this Annual Report on Form 10-K.
+Added: To date more than 600 patients have been treated with Iovance TIL therapy manufactured using our proprietary processes, by contract manufacturing organizations, or CMOs, and by us at our own manufacturing facility, the Iovance Cell Therapy Center, or i CTC.
+Added: The i CTC is currently manufacturing TIL for our ongoing clinical trials and preparing to provide commercial supply upon potential BLA approval.
+Added: We began construction of the i CTC in 2019, in Philadelphia, Pennsylvania, in order to control manufacturing capacity, product quality, manage logistics around supply and delivery, implement process improvement and realize potential cost efficiencies for TIL therapies that we may develop or commercialize.
+Added: We intend to carefully manage our cost structure, and reduce the long-term cost of manufacturing our products, although there can be no assurance that we will be able to reduce our manufacturing costs to commercially attractive levels.
+Added: We are building capacity to treat thousands of cancer patients annually, with flexibility to expand within existing shell space and an option to build on an adjacent lot to support future growth.
+Added: We expect i CTC to supply most of our commercial TIL therapies at launch, with CMOs to supplement our internal manufacturing capacity under various manufacturing services agreements, or MSAs.
+Added: Details of related agreements are provided in the Research, Development, Manufacturing and License agreements section of this Annual Report on Form 10-K.
+Added: Continue to improve our TIL manufacturing processes and technology
+Added: In 2018, we first utilized our TIL manufacturing process known as Gen 2, which reduced TIL manufacturing time from 5-6 weeks to 22 days while producing a cryopreserved TIL product for ease of administration and handling.
+Added: We intend to establish Gen 2 as a viable commercial manufacturing process for our initial TIL therapies.
+Added: Gen 2 was utilized in all patients in both Cohorts 2 and 4 of our C-144-01 clinical trial and is the manufacturing process for registration and the BLA submission for lifileucel.
+Added: Gen 2 is also being utilized in most of our ongoing TIL clinical development programs.
+Added: We also continue to develop and evaluate potential future TIL manufacturing processes, including our 16-day Gen 3 process, as well as processes for genetically modified and other next generation TIL products.
+Added: Advance and expand our pipeline of polyclonal T-cell therapies
+Added: We seek to collaborate with government, academic research institutions, and corporate partners to improve TIL manufacturing, and to develop and explore next generation approaches as well as TIL therapies for new indications.
+Added: We have a Cooperative Research and Development Agreement, or CRADA, with the National Institutes of Health, or NIH, and the National Cancer Institute, or NCI.
+Added: We also have ongoing licensing agreements and collaborations with H.
+Added: Lee Moffitt Cancer Center, or Moffitt, The University of Texas M.D.
+Added: Anderson Cancer Center, or MDACC, Yale University, The Ohio State University, Cellectis, Novartis Pharma AG, or Novartis, Melanoma Institute Australia, or MIA, and Beth-Israel Deaconess Medical Center, or BIDMC.
+Added: A description of some of these collaborations and related agreements is provided in the Collaborations for New Tumor Types and Treatment Settings section of this Annual Report on Form 10-K.
Iovance-Sponsored Clinical Trials
−Removed: We currently have six ongoing Phase 2 clinical studies.
−Removed: The ongoing studies include C-144-01, of our lead product candidate, lifileucel, for the treatment of metastatic melanoma;
−Removed: C-145-04, of our product candidate lifileucel for recurrent, metastatic or persistent cervical cancer;
−Removed: IOV-LUN-202, a potentially registration-supporting study of our product candidate LN-145 in NSCLC;
−Removed: IOV-COM-202, a basket trial that will treat three cohorts of checkpoint naïve patients with TIL therapy in combination with pembrolizumab for metastatic melanoma, HNSCC and NSCLC, a cohort that will treat relapsed and refractory NSCLC patients with TIL monotherapy, as well as a cohort for NSCLC for TIL therapy in combination with ipilimumab and nivolumab.
−Removed: Additional melanoma cohorts are offered in this trial as well to investigate Gen 3 manufacturing and PD-1 selected TIL.
−Removed: In 2021, we completed enrollment in an additional study, C-145-03, of LN-145, for recurrent and/or metastatic HNSCC.
−Removed: We are also investigating polyclonal T cell therapy in blood cancers.
−Removed: Our Phase 1/2 clinical trial, IOV-CLL-01, is enrolling patients with CLL/SLL to receive our PBL therapy, IOV-2001.
−Removed: Additional information about our clinical trials is presented as follows:
−Removed: Lifileucel for Metastatic Melanoma
−Removed: We are developing lifileucel to treat metastatic melanoma.
−Removed: Melanoma is a common type of skin cancer, accounting for approximately 106,110 patients diagnosed and 7,180 deaths each year in the U.S.
−Removed: according to the NCI’s Surveillance, Epidemiology and End Results program, or SEER, program.
−Removed: Our Phase 2 trial, C-144-01, is a prospective, registrational, four-cohort interventional study evaluating lifileucel in metastatic melanoma patients who have progressed after prior anti-PD-1 therapy and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy.
−Removed: Patients enrolled in this trial to date have failed several prior treatment regimens.
−Removed: Lifileucel has received a RMAT designation from the FDA in metastatic melanoma.
−Removed: Patients with metastatic melanoma who have failed at least one treatment under the current standards of care have an unfavorable prognosis with very few curative treatment options.
−Removed: The National Comprehensive Cancer Network, or NCCN, makes recommendations for the treatment of patients with unresectable or metastatic melanoma.
−Removed: Initial therapy can include checkpoint inhibitors either alone or in combination (ipilimumab, nivolumab, pembrolizumab), targeted therapies for patients with BRAF mutations (dabrafenib/trametinib, vemurafenib/cobimetinib, or other combinations).
−Removed: For patients not responding or progressing and who have an adequate clinical status, agents selected from the previous list or of a different therapeutic class can be used as well as high dose IL-2.
−Removed: NCCN experts also recommend participating in a clinical trial at any stage of disease.
−Removed: Patients who do not respond to the current second-line therapies have very few treatment options and typically have a very poor prognosis, with limited median survival measured in months.
−Removed: According to estimates from the SEER program, there were approximately 7,180 deaths due to melanoma.
−Removed: If approved, we believe lifileucel may be able to treat a portion of the patients that have received all other approved treatment options.
−Removed: C-144-01 is investigating lifileucel in advanced melanoma patients who have been treated with at least one systemic therapy including an anti-PD-1 antibody, and if BRAF mutation positive, a BRAF inhibitor or BRAF inhibitor with MEK inhibitor.
−Removed: We are using our Gen 2 manufacturing process for most of our ongoing Phase 2 trials, and as a result, Cohort 1 of C-144-01, using our Generation 1, or Gen 1, manufacturing process, was closed to enrollment in 2017 and subsequent patients were enrolled in Cohorts 2-4, both of which use our Gen 2 process.
−Removed: The planned enrollment in C-144-01 was reached in late 2018 and Cohort 2 is closed to enrollment.
−Removed: Cohort 3 is a retreatment cohort.
−Removed: Cohort 4, a pivotal cohort, was added in 2019 and completed dosing in January 2020.
−Removed: Clinical results from Cohort 2 in the C-144-01 clinical study have been presented at several medical meetings.
−Removed: Initial results from Cohort 2 were initially reported at ASCO in June 2019 and most recently updated at ASCO in June 2021.
−Removed: In 66 patients with metastatic melanoma, treatment with lifileucel resulted in an ORR of 36%, with 2 complete responses and 22 partial responses.
−Removed: The DCR was 80%.
−Removed: Patients were heavily pretreated and had a mean of 3.3 prior therapies.
−Removed: In June 2021, we announced that median DOR in Cohort 2 had still not been reached after 33.1 months of median study follow up, as assessed by investigator.
−Removed: The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.
−Removed: Pivotal Cohort 4 of the C-144-01 trial was enrolled to evaluate ORR as read out by an Independent Review Committee, or IRC, as the primary endpoint based on our interpretation of discussions with the U.S.
−Removed: Food and Drug Administration, or the FDA, as part of an End of Phase 2, or EOP2, meeting held with the FDA in the third quarter of 2018.
−Removed: In October 2018, based on the data provided to the FDA during the EOP2 meeting, we announced that lifileucel had received a Regenerative Medicines Advanced Therapy, or RMAT, designation from the FDA.
−Removed: Enrollment in Cohort 4 of the C-144-01 trial commenced in March 2019 and patient dosing was completed in January 2020.
−Removed: A total of 87 patients were dosed with Gen 2 product released for Cohort 4.
−Removed: In May 2020, we disclosed initial results from Cohort 4 for 68 patients with two radiological assessments, as determined by investigator.
−Removed: Previously, we reported the submission of additional potency assay data to the FDA, and at the same time, we also announced that we had reached agreement with the FDA on the minimum duration of follow up for Cohort 4 to support our BLA submission for lifileucel in the treatment of metastatic melanoma.
−Removed: In May 2021, we announced that we had received regulatory feedback from the FDA regarding our potency assays for lifileucel.
−Removed: Following FDA feedback, we have continued our ongoing work developing and validating our potency assays and have engaged in discussions with the FDA during the second half of 2021.
−Removed: Our BLA submission for lifileucel in metastatic melanoma is expected to occur during the first half of 2022.
−Removed: In connection with this BLA submission, the IRC is expected to independently assess responses for Cohort 4 patients through the data cut date, which must be completed prior to BLA submission or disclosure of IRC-read data.
+Added: TIL Therapy in Advanced Solid Tumor Cancers
+Added: Lifileucel for Advanced Melanoma
+Added: Melanoma is a common type of skin cancer, accounting for an estimated 99,780 patients diagnosed and 7,650 deaths in 2022 in the U.S.
+Added: according to the Surveillance, Epidemiology and End Results program, or SEER, program.
+Added: We are developing lifileucel to treat advanced melanoma.
+Added: Our Phase 2 clinical trial, C-144-01, is a prospective, clinical trial evaluating lifileucel in advanced melanoma patients who have progressed on or after prior anti-PD-1 therapy and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy.
+Added: There are no FDA approved therapies in this treatment setting for advanced melanoma after anti-PD-1 therapy.
+Added: Based on the unmet need in post-anti-PD-1 advanced melanoma, as well as initial clinical data, lifileucel received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA in 2018.
+Added: In the C-144-01 trial, our Generation 1, or Gen 1, manufacturing process with non-cryopreserved product was used in Cohort 1, which was closed to enrollment in 2017.
+Added: Our Gen 2 process with cryopreserved product was used in subsequent patients enrolled in both Cohorts 2 and 4.
+Added: Cohort 2 was closed to enrollment in late 2018.
+Added: Cohort 3 is an optional retreatment cohort.
+Added: Cohort 4, a pivotal cohort, was added in 2019, following an end of Phase 2, or EOP2, meeting held with the FDA in the third quarter of 2018 and completed dosing in January 2020.
+Added: Cohort 4 built on the Cohort 2 results in the same patient population and used the same eligibility criteria, treatment and manufacturing process.
+Added: Cohort 4 was designed to evaluate objective response rate, or ORR, read by an independent review committee, or IRC, using RECIST v1.1 as the prospectively defined primary endpoint.
+Added: The results from Cohort 2, including ORR as assessed by investigator, were presented at several medical meetings since 2018 and published in the Journal of Clinical Oncology in May 2021.
+Added: We reported durable responses across a wide age range of metastatic melanoma patients, among those who have received prior anti-CTLA-4 and BRAF targeted treatments, regardless of BRAF mutation status, and in patients with PD-L1 high and low status.
+Added: In May 2022, we announced topline IRC read data from the C-144-01 clinical trial from Cohort 4, which met the primary endpoint, ORR, of the clinical trial.
+Added: In addition, we reported updated data from Cohort 2 and pooled Cohorts 2 and 4.
+Added: We presented additional data from C-144-01 Cohorts 2 and 4 at the Society for Immunotherapy of Cancer, or SITC, Annual Meeting in November 2022.
+Added: The SITC 2022 presentation included pooled efficacy data read by IRC and safety data from 153 patients with advanced melanoma, including 66 patients enrolled in Cohort 2 and 87 patients enrolled in Cohort 4, with a median study follow up of 36.5 months and a data cutoff date of July 15, 2022.
+Added: Across both cohorts, patients had received a median of 3 lines of prior therapy, including anti-PD-1 therapy in 100% of patients and anti-CTLA-4 therapy in 81.7% of patients, with prior combination anti-PD-1 and anti-CTLA-4 therapy received in 53.6% of patients.
+Added: Baseline disease characteristics were generally similar between Cohorts 2 and 4.
+Added: However, Cohort 4 patients showed both a higher disease burden and a higher proportion of patients with elevated lactate dehydrogenase, or LDH, a well-known negative prognostic factor in melanoma.
+Added: The ORR assessed by an IRC using RECIST v1.1 was 31.4%, with 9 complete responses and 39 partial responses.
+Added: The median time from lifileucel infusion to best response was 1.5 months, and responses deepened over time.
+Added: Median duration of response, or mDOR, was not reached as estimated by Kaplan-Meier, or KM, method.
+Added: Responses lasted for 24 months or greater in 41.7% of responders, including 47.8% of responders in Cohort 2 and 36.0% of responders in Cohort 4.
+Added: Median overall survival, or mOS, had not been reached in patients who achieved a response at first assessment at 6 weeks, and mOS in all patients was 13.9 months.
+Added: The treatment-related adverse event, or TEAE, profile was generally consistent with the underlying advanced disease and the safety profile of the lymphodepletion and IL-2 regimens.
+Added: In December 2022, we published additional detail from C-144-01 in the Journal for Immuno Therapy of Cancer, or JITC.
+Added: Based on results from the C-144-01 clinical trial, we held a pre-BLA meeting with the FDA in July 2022 and initiated a rolling BLA for lifileucel in metastatic melanoma in August 2022.
+Added: The BLA submission includes C-144-01 data from pivotal Cohort 4 and supportive Cohort 2.
+Added: We plan to complete the rolling BLA submission in the first quarter of 2023.
+Added: We are also pursuing a registrational path for lifileucel in combination with pembrolizumab in frontline advanced melanoma.
+Added: Our strategy is based on clinical results from Cohort 1A of the IOV-COM-202 clinical trial that support the combination, as well as prior published NCI data for TIL monotherapy in anti-PD-1 naïve melanoma patients.
+Added: We reported initial results and updates from ongoing Cohort 1A of the IOV-COM-202 clinical trial at the American Society of Clinical Oncology, or ASCO, annual meeting in June 2021, SITC in November 2021.
+Added: The Cohort 1A results to date have demonstrated that lifileucel can be safely combined with pembrolizumab.
+Added: At our most recent medical meeting oral presentation at SITC, in November 2021, updated results from 10 patients demonstrated ORR of 60%.
+Added: Six out of the 10 patients had a confirmed objective response, including three complete responses and three partial responses.
+Added: The TEAE profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion, and IL-2 regimens.
+Added: In an April 2022 corporate announcement, we provided updated data that demonstrated a 67% ORR in 12 patients in Cohort 1A.
+Added: Eight patients had a confirmed objective response per RECIST v1.1, including three complete responses and five partial responses.
+Added: Six of the eight responders had ongoing response at the time of the last data cut, and five responders had a duration of response of more than one year.
+Added: In a January 2023 corporate press release, we disclosed that updated efficacy and safety results from nearly 20 patients treated in Cohort 1A remain consistent with previously reported Cohort 1A data and continue to support our strategy in frontline advanced melanoma.
+Added: During the fourth quarter of 2022, we reached agreement with the FDA and began start up activities for a Phase 3 multicenter, open-label, randomized, parallel group, treatment clinical trial, TILVANCE-301, in frontline advanced melanoma.
+Added: The TILVANCE-301 trial, or NCT05727904, will randomize 670 patients to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm.
+Added: The clinical trial will enroll participants with unresectable or metastatic melanoma who have had no prior therapy for metastatic disease.
+Added: Previous adjuvant/neoadjuvant therapy with a single line of BRAF-targeted therapy, PD-1 inhibitor, or CTLA-4 inhibitor is allowed, if completed at least 6 months before progression to metastatic disease.
+Added: In the experimental arm, a tumor sample is resected from each patient for lifileucel manufacturing.
+Added: Patients receive pembrolizumab prior to and after the lifileucel regimen, every 6 weeks until disease progression.
+Added: In the control arm, pembrolizumab monotherapy is given every 6 weeks until disease progression, with an optional crossover period to lifileucel monotherapy upon confirmed progressive disease verified by a blinded independent review committee, or BIRC, and if patients meet eligibility criteria.
+Added: The FDA agreed to dual primary endpoints of ORR to support accelerated approval and progression free survival, or PFS, to support full approval of lifileucel in frontline advanced melanoma.
+Added: TILVANCE-301 is also designed to serve as a confirmatory clinical trial to support full approval of lifileucel in post-anti-PD-1 advanced melanoma.
+Added: The dual primary endpoints will be verified by BIRC using RECIST v1.1.
Lifileucel for Cervical Cancer
−Removed: We are also developing lifileucel for the treatment of cervical cancer.
−Removed: Lifileucel for metastatic cervical cancer was formerly known as LN-145.
−Removed: According to estimates from the SEER program, approximately 14,480 women were diagnosed with cervical cancer, and approximately 4,290 cervical cancer-related deaths occurred in the U.S.
−Removed: C-145-04 is an ongoing Phase 2, multicenter pivotal trial that will assess the safety and efficacy of lifileucel for the treatment of patients with recurrent, metastatic or persistent cervical cancer.
−Removed: In February 2019, lifileucel received Fast Track designation from the FDA for development in the treatment of cervical cancer with disease progression on or after chemotherapy.
−Removed: In March 2019, the protocol for this trial was amended to modify the primary endpoint of ORR to be determined by IRC.
−Removed: In May 2019, lifileucel received BTD from the FDA for development in the treatment of cervical cancer.
−Removed: Results from the C-145-04 clinical trial were reported at ASCO in June 2019.
−Removed: In 27 patients with metastatic cervical cancer, treatment with lifileucel resulted in an ORR of 44%.
−Removed: In the study there were 3 complete responses and 9 partial responses.
−Removed: The DCR was 85%.
−Removed: Patients were heavily pretreated and had a mean of 2.4 prior therapies.
−Removed: The median DOR had not been reached.
−Removed: The median follow-up was 7.4 months.
−Removed: The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.
−Removed: Based on an EOP2 meeting held with the FDA in June 2019, the FDA has acknowledged that results from the C-145-04 clinical trial may be sufficient to support registration of lifileucel in the treatment of patients with metastatic cervical cancer.
−Removed: In accordance with the FDA’s recommendations, the protocol was amended, to further define the patient population in Cohort 1 as outlined below.
−Removed: In November 2019, in order to evaluate lifileucel in additional lines of therapy in cervical cancer and to address the emerging treatment landscape, we amended the C-145-04 trial to collect additional data on combination therapy in early-line patients as well as TIL alone in late-line patients.
−Removed: These additional cohorts also allowed access to TIL therapy when the pivotal Cohort 1 was completed.
−Removed: The C-145-04 trial currently consists of the following cohorts of cervical cancer patients with recurrent, persistent, or metastatic disease:
−Removed: ● Cohort 1 has completed enrollment in patients who have progressed during or after systematic chemotherapy;
−Removed: ● Cohort 2 has closed enrollment to patients for treatment with lifileucel who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor in addition to systematic chemotherapy;
−Removed: ● Cohort 3 is enrolling patients who have not received prior systemic therapy for recurrent, metastatic, or persistent disease , and will explore safety and efficacy of the combination of the lifileucel regimen with pembrolizumab;
−Removed: ● Cohort 4 includes patients who have been previously enrolled but do not fit Cohort 1-3, including patients dosed with product produced by our Gen 1 TIL manufacturing process;
−Removed: ● Cohort 5 is enrolling patients for retreatment with LN-145 for patients who have progressed after initial treatment with lifileucel .
−Removed: Given the emerging treatment landscape in cervical cancer, including the approval of pembrolizumab in combination with chemotherapy as a first-line treatment, we are engaging with the FDA to discuss our planned BLA submission and intend to execute our strategy based on feedback from the FDA for the BLA.
−Removed: LN-145 for NSCLC
−Removed: We are developing LN-145 alone and in combination with approved therapies to treat NSCLC.
−Removed: According to estimates from the SEER program, approximately 235,760 people were diagnosed with lung and bronchus cancers, and approximately 131,880 deaths occurred related to these cancers in the U.S.
−Removed: In November 2020, we announced that we had finalized the protocol for our potential registrational clinical trial in NSCLC, IOV-LUN-202, to investigate LN-145 in patients with recurrent or metastatic NSCLC, without driver mutations, who previously received a single line of approved systemic therapy of combined checkpoint inhibitor and chemotherapy.
−Removed: The IOV-LUN-202 clinical trial, which continues to enroll patients, includes three cohorts.
−Removed: Cohorts 1 and 3 of the IOV-LUN-202 clinical trial are enrolling patients who presented with a PD-L1 tumor proportion score, or TPS, of less than one percent at the time they started front-line therapy.
−Removed: Cohort 2 is enrolling patients with a PD-L1 TPS of greater than or equal to one percent at the time they started front-line therapy.
−Removed: In Cohort 3 we are exploring LN-145 manufactured from core biopsy using our Gen 3 manufacturing process.
−Removed: Patient dosing commenced in IOV-LUN-202 in the second quarter of 2021 and we intend to continue to enroll patients in the IOV-LUN-202 clinical trial throughout 2022.
−Removed: LN-145 for Head and Neck Cancer
−Removed: We are also developing LN-145 to treat head and neck cancer.
−Removed: According to estimates from the SEER program, approximately 66,630 people were diagnosed with head and neck-related cancers, which are referred to by the SEER program as oral cavity, pharynx and larynx cancers, and approximately 14,620 head and neck-related cancer deaths occurred in the U.S.
−Removed: In June 2017, we enrolled our first patient in our ongoing Phase 2 trial, C-145-03, for the treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, who have failed one prior therapy.
−Removed: In 2018, preliminary data for 13 patients who were administered a mix of Gen 1 and Gen 2 products, was released showing an ORR of 31%, with 4 partial responses, with the DOR ranging from 2.8 to 7.6 months.
−Removed: Patients in the study had a median of three prior therapies.
−Removed: The safety findings from this study were also consistent with previous reports.
−Removed: The most common TEAEs observed at the time of that data cut included chills, hypotension, pyrexia, hyponatremia, and anemia.
−Removed: As additional results are reported for the C-145-03 study, the safety profile of LN-145 may change.
−Removed: We changed the design of our C-145-03 trial in 2020 so that enrolled patients would also be treated using either LN-145 produced from the Gen 3 manufacturing process or PD-1 selected TIL, known as LN-145-S1, from the PD-1 selected TIL manufacturing process in two separate cohorts.
−Removed: In January 2021, we announced that we are closing the C-145-03 clinical trial after the trial reached its pre-specified enrollment target.
−Removed: Lifileucel and LN-145 in Combination with Pembrolizumab and Other Immunotherapies
−Removed: In addition to the trials for lifileucel and LN-145 mentioned above, we are developing these products alone or in combination with pembrolizumab or other ICIs for melanoma, head and neck and NSCLC in our clinical trial IOV-COM-202, a Phase 2, multicenter trial that is composed of seven cohorts.
−Removed: In May 2019, we reported that the first patient was dosed in the IOV-COM-202 trial.
−Removed: In addition to the U.S., the IOV-COM-202 trial has active sites in Canada and in certain European countries.
−Removed: The IOV-COM-202 trial now consists of the following cohorts of patients:
−Removed: patients with advanced unresectable or metastatic melanoma who have not received prior immunotherapy, including checkpoint inhibitors such as anti-PD-1/anti-PD-L1 therapy , for treatment with lifileucel in combination with pembrolizumab ;
−Removed: ● C ohort 1B:
−Removed: melanoma patients who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy for treatment with LN-145-S1;
−Removed: ● C ohort 1C:
−Removed: melanoma patients who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy, for treatment with LN-145 manufactured using our Gen 3 process;
−Removed: ● C ohort 2A:
−Removed: patients with advanced, recurrent, or metastatic HNSCC who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy, for treatment with LN-145 in combination with pembrolizumab ;
−Removed: ● C ohort 3A:
−Removed: patients with NSCLC who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy , for treatment with LN-145 in combination with pembrolizumab ;
−Removed: ● C ohort 3B:
−Removed: patients with NSCLC who have previously received systemic therapy, which could include checkpoint inhibitors or tyrosine kinase inhibitors, for treatment with LN-145 alone;
−Removed: ● C ohort 3C:
−Removed: patients with NSCLC who have progressed after one prior systemic therapy for treatment with LN-145 in combination with ipilimumab/nivolumab.
−Removed: IOV-2001 PBL for CLL or SLL
−Removed: In November 2019, we announced that our IND for IOV-2001 was approved by the FDA and that our sponsored clinical trial using this therapy, IOV-CLL-01, was cleared to proceed.
−Removed: IOV-2001 is a non-genetically modified, polyclonal T cell product that is manufactured using a nine-day process from 50 mL of a patient's blood sample.
−Removed: IOV-2001 is under investigation in a Phase 1/2 clinical trial for the treatment of CLL or SLL.
−Removed: Patients experiencing disease relapse during ibrutinib or acalabrutinib therapy treatment are eligible for this clinical trial.
−Removed: Preclinical studies of IOV-2001 have shown activity against autologous leukemia cancer cells, while treatment with ibrutinib and acalabrutinib has been demonstrated to improve the proliferation and effector functions of the IOV-2001 manufactured product.
−Removed: Investigator-Sponsored Clinical Trials
−Removed: TIL Therapy in Other Solid Tumor Indications
−Removed: We are collaborating with MDACC on a clinical trial to evaluate TIL therapy in sarcomas, ovarian, and thyroid cancers.
−Removed: These trials, including NCT03449108, began enrolling patients in 2018.
−Removed: Patients in these trials are being treated with LN-145 or LN-145-S1 manufactured by us.
−Removed: We are also collaborating with Yale University on a clinical trial to evaluate TIL therapy in triple-negative breast cancer, or TNBC, NCT04111510, which opened for enrollment in 2020.
−Removed: Patients in this trial will be treated with LN-145 manufactured by us.
−Removed: We are also collaborating with Moffitt on a clinical trial, NCT04052334, to explore MCC TIL in adolescent and young adult patients with soft tissue sarcoma.
−Removed: TIL Therapy in Combination with Other Immunotherapy Drugs and/or in Earlier Lines of Therapy
−Removed: We provide funding for a clinical trial, NCT03215810, conducted by Moffitt, which seeks to evaluate TIL therapy in combination with the checkpoint inhibitor nivolumab in NSCLC.
−Removed: This study is closed to enrollment.
−Removed: An additional clinical trial, NCT02652455, is being conducted by Moffitt to evaluate TIL therapy in combination with nivolumab in metastatic melanoma.
−Removed: We have also previously collaborated with Moffitt on a clinical trial, NCT01701674, to evaluate TIL therapy in combination with the CTLA-4 checkpoint inhibitor ipilimumab.
−Removed: In 2019, we entered into a collaboration with Moffitt to fund a Phase 1 trial of lymphodepletion plus TIL therapy with high-dose IL-2 in adolescent and young adult patients with soft tissue sarcoma in clinical trial NCT04052334.
−Removed: Under our CRADA, we are collaborating with the NCI on a clinical trial, NCT02621021, to evaluate TIL therapy in combination with the checkpoint inhibitor pembrolizumab in a 170-patient clinical trial in patients with advanced melanoma.
−Removed: We are collaborating with The Ohio State University to evaluate TIL therapy in high-risk melanoma in the neoadjuvant setting.
−Removed: This trial, NCT05176470, is expected to begin recruiting patients in 2022 who are diagnosed with stage IIIB-D melanoma that has spread to nearby tissue or lymph nodes (locally advanced).
−Removed: Patients in this trial will be treated with lifileucel manufactured by Iovance.
−Removed: The purpose of the study is to assess the feasibility of TIL expansion from all screened eligible patients who have had tumor-involved lymph nodes removed.
−Removed: TIL Therapy Background
−Removed: Immune System
+Added: According to estimates from the SEER program, in 2022 approximately 14,100 women would be diagnosed with cervical cancer and approximately 4,280 cervical cancer-related deaths would occur in the U.S.
+Added: We are developing lifileucel alone and in combination with pembrolizumab for the treatment of advanced, unresectable or metastatic, cervical cancer.
+Added: Lifileucel for advanced cervical cancer was formerly known as LN-145.
+Added: C-145-04 is an ongoing Phase 2, multicenter pivotal clinical trial.
+Added: In March 2019, the protocol for this clinical trial was amended to modify the primary endpoint of from ORR by investigator to ORR based on IRC assessment.
+Added: Initial results from the C-145-04 clinical trial were reported at ASCO in June 2019.
+Added: In anticipation of a changing landscape, we amended the protocol for the C-145-04 clinical trial in November 2019 from a single cohort design into a multicohort study.
+Added: Cohort 1 was defined to include patients who had progressed during or after systemic chemotherapy excluding ICI.
+Added: Cohort 2 was newly added to include patients who have progressed during or after treatment with anti-PD-1/-L1 checkpoint inhibitor in addition to systemic chemotherapy.
+Added: Cohort 3 was added to enroll patients who had not received prior systemic therapy to investigate lifileucel in combination with pembrolizumab.
+Added: Cohort 3 results from 14 initial patients were included as part of an oral presentation at SITC in November 2021.
+Added: The ORR was 57.1 % with eight out of 14 patients achieving an objective response, including one complete response, six partial responses and one unconfirmed partial response.
+Added: The TEAE profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion, and IL-2 regimens.
+Added: In the C-145-04 trial, we completed enrollment of Cohort 1 in 2020, Cohort 2 in 2021 and Cohort 3 in 2022.
+Added: During 2022, following the FDA discussions and feedback on a registration strategy to address the shift in standard of care following the FDA approval of pembrolizumab in the frontline cervical cancer setting, we reopened Cohort 2 to enroll additional patients and to be a pivotal cohort to support a BLA for cervical cancer following progression on chemotherapy and pembrolizumab.
+Added: We expect to continue enrollment in Cohort 2 in 2023.
+Added: LN-145 for Advanced, or Metastatic or Unresectable NSCLC
+Added: According to SEER program estimates, approximately 236,740 people would be diagnosed with lung and bronchus cancers, and approximately 130,180 deaths would occur related to these cancers in the U.S.
+Added: We are developing our TIL therapy LN-145 alone and in combination with approved therapies to treat advanced NSCLC in the IOV-LUN-202 and IOV-COM-202 clinical trials.
+Added: IOV-LUN-202 is investigating LN-145 monotherapy in patients with metastatic NSCLC who previously received approved systemic therapy of combined or sequential ICI and chemotherapy in three cohorts.
+Added: The programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, in patients at the time they started frontline therapy was less than one percent or unknown in patients in Cohort 1 and greater than or equal to one percent in patients in Cohort 2.
+Added: In Cohort 3, we are exploring treatment with TIL that is extracted from core biopsy and manufactured using our Gen 3 process.
+Added: In June 2021, the first patient was treated in the IOV-LUN-202 clinical trial.
+Added: In a poster on IOV-LUN-202 at the American Association for Cancer Research, or AACR, Annual Meeting in April 2022, we featured protocol updates including changes to eligibility criteria, and the option for pre-progression tumor harvest, to broaden enrollment in reflection of the unmet need in NSCLC.
+Added: We enrolled patients during 2022 and intend to continue enrollment in 2023.
+Added: IOV-COM-202 is a clinical trial that includes 2 active cohorts and one previously completed cohort in patients with recurrent or metastatic NSCLC as follows:
+Added: ● Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs.
+Added: Cohort 3B was previously completed and investigated LN-145 monotherapy in patients who had progressed on or after prior ICI therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor, or TKI, therapy.
+Added: ● Cohort 3C is investigating LN-145 in combination with ipilimumab or nivolumab in patients who previously received only a prior line of approved systemic ICI monotherapy.
+Added: We have reported full results from Cohort 3B and initial results from Cohort 3A in the IOV-COM-202 study.
+Added: Cohort 3B results were reported in June 2021 and presented at SITC in November 2021.
+Added: For the completed Cohort of 28 patients in the analysis population, the ORR was 21.4%, including one complete response and five partial responses.
+Added: All patients had received prior anti-PD-1/-L1 therapy, and all six responding patients had also received prior chemotherapy.
+Added: The TEAE profile was consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and IL-2.
+Added: As of a data extract in November 2022 provided in a corporate slide deck, one complete response remained ongoing at 37 months following treatment with LN-145.
+Added: In a January 2023 press release, we shared initial topline results in 17 patients from Cohort 3A which comprises three distinct clinical subsets of anti-PD-1 naïve patients:
+Added: 1) treatment-naïve, 2) post-chemotherapy, and 3) estimated glomerular filtration rate, or EGFR, -mutant after prior treatment with TKIs.
+Added: Confirmed ORR by RECIST v1.1 was 47%, with an objective response observed in 8 patients treated with LN-145 in combination with pembrolizumab.
+Added: Responses were observed regardless of PD-L1 status.
+Added: Two patients achieved complete responses and remain on study, including one patient who was post-chemotherapy and anti-PD-1 naive, and one patient who was EGFR-mutant after prior treatment with TKI.
+Added: Safety was consistent with other studies of Iovance TIL therapies in combination with pembrolizumab.
+Added: Study enrollment remains ongoing.
+Added: Observed differences between the patient subsets are informing the design of a subsequent potential registration study.
+Added: Detailed clinical results will be shared at a future medical meeting.
+Added: We plan to continue to discuss registrational strategies for LN-145 with the FDA in 2023.
+Added: Based on initial results from Cohort 3A, we plan to meet with the FDA in 2023 to discuss Cohort 3A results and a potential registration clinical trial of lifileucel in frontline advanced NSCLC.
+Added: IOV-4001 for Advanced Melanoma and NSCLC
+Added: Our lead genetically modified TIL therapy, IOV-4001, utilizes the gene-editing TALEN® technology licensed from Cellectis, to inactivate the gene coding for PD-1.
+Added: The worldwide exclusive license enables us to use certain TALEN® technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL therapies.
+Added: We are investigating the safety and efficacy of IOV-4001 in the IOV-GM1-201 multicenter, first-in-human Phase 1/2 clinical trial in previously treated patients with advanced melanoma, who have progressed following anti-PD-1/PD-L1 blocking antibody therapy and, in those patients with BRAF mutations, after BRAF/MEK inhibitor therapy in Cohort 1, or metastatic NSCLC who have received no more than three prior lines of therapy, with or without oncogene driver mutations in Cohort 2.
+Added: We treated the first patient with IOV-4001 in the third quarter of 2022.
+Added: We published posters that highlight the “trial in progress” for IOV-GM1-201 at SITC in November 2022 and preclinical results for antitumor activity of IOV-4001 at the AACR Annual Meeting in April 2022.
+Added: TIL Therapy for HNSCC
+Added: In metastatic head and neck cancer squamous cell carcinoma, or HNSCC, we are evaluating LN-145 as monotherapy and in combination with pembrolizumab.
+Added: The Phase 2 C-145-03 trial began in June 2017 and closed in January 2021 after reaching its pre-specified enrollment target to investigate LN-145 using various manufacturing processes.
+Added: Cohort 2A in IOV-COM-202 is evaluating
+Added: LN-145 in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy.
+Added: Initial and updated Cohort 2A results were presented at the SITC Annual Meetings in November 2020 and 2021, respectively.
+Added: PBL Therapy in Blood Cancers
+Added: In blood cancers, our clinical trial IOV-CLL-01 is a Phase 1/2 clinical trial evaluating the safety and efficacy of IOV-2001, our polyclonal PBL therapy, in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL, to receive IOV-2001.
+Added: Next-Generation Product Candidates
+Added: We are committed to innovating individualized T-cell therapies that may recognize a multitude of diverse patient-specific cancer cells.
+Added: Our current next-generation technology platforms are designed to optimize TIL therapy across four key initiatives:
+Added: genetic modifications, potency, process optimization and new treatment regimens.
+Added: ● Genetic modifications:
+Added: We are pursuing several targets for genetic modification that utilize the gene-editing TALEN® platform licensed from the clinical-stage biotechnology company, Cellectis.
+Added: Single- and multiple- knockouts may further harness the immune system response to cancer and potentially increase the efficiency, potency and application of TIL therapy.
+Added: Preclinical development is also ongoing with cytokine-tethered TIL products and additional TIL products and TIL-cell lines using transient and stable gene insertion and inactivation, which may expand and activate TIL to achieve better efficacy while avoiding systemic side effects of cytokines.
+Added: We are exploring potential approaches to increase potency of the final TIL product through sorting and selection of specific TIL, such as PD-1+ selected TIL and CD39/69 double-negative TIL, and the use of certain inhibitors or other reagents in TIL expansion cultures.
+Added: Our TIL candidate LN-145-S1 is manufactured from TIL selected for PD-1 expression and has been investigated in patient cohorts in our clinical trials.
+Added: ● Process optimization:
+Added: We are committed to further improving and streamlining the processes for TIL therapy manufacturing and tumor sample collection.
+Added: We are investigating a 16-day Gen 3 manufacturing process in patient cohorts included in the C-145-03 clinical trial in HNSCC and the IOV-COM-202 clinical trial.
+Added: We are also exploring our Gen 3 process to manufacture TIL from core biopsy as a less-invasive collection of tumor samples in a cohort of patients with NSCLC in our IOV-LUN-202 clinical trial.
+Added: ● New treatment regimens:
+Added: We are exploring potential avenues to improve aspects of the TIL treatment regimen.
+Added: In 2020, we licensed an antibody cytokine-engrafted protein, or IL-2 analog, which we refer to as IOV-3001, from Novartis.
+Added: IOV-3001 is in IND-enabling studies supporting its use as part of the TIL treatment regimen following TIL infusion.
+Added: Collaborations for New Tumor Types and Treatment Settings
+Added: Our ongoing academic collaborations with leading cancer research centers as well as government and corporate partners are exploring the potential for TIL therapy in other tumor types and treatment settings, such as in the following example studies:
+Added: ● MDACC has sponsored two Phase 2 clinical trials that were initiated in 2018.
+Added: The first clinical trial, NCT03449108, is underway to investigate LN-145 or LN-145-S1 manufactured using our proprietary processes to treat patients with soft tissue sarcoma, osteosarcoma, platinum resistant ovarian cancer, anaplastic thyroid cancer, and triple negative breast cancer.
+Added: The second clinical trial, NCT03610490, was previously active to investigate TIL manufactured by MDACC in patients with platinum resistant ovarian cancer, pancreatic and colorectal cancer, which may not be representative of our data using our Iovance manufacturing process.
+Added: ● Yale Comprehensive Cancer Clinical is sponsoring a trial, NCT04111510, exploring LN-145 in triple-negative breast cancer.
+Added: ● Memorial Sloan Kettering Cancer Center, or MSKCC, is investigating TIL therapy LN-144 manufactured by Iovance in patients with uveal melanoma in the NCT05607095 clinical trial, and asymptomatic melanoma brain metastases in the NCT05640193 clinical trial.
+Added: ● Moffitt is conducting several clinical trials with funding from Iovance.
+Added: Two clinical trials, which have closed to enrollment, are evaluating TIL therapy in combination with the checkpoint inhibitor nivolumab in NSCLC in the NCT03215810 clinical trial and metastatic melanoma in the NCT02652455 clinical trial.
+Added: We previously collaborated on the NCT01701674 clinical trial to evaluate TIL therapy in combination with the CTLA-4 checkpoint inhibitor ipilimumab.
+Added: A Phase 1 clinical trial, NCT04052334, completed enrollment in 2022 and is investigating TIL therapy manufactured by Moffitt in adolescent and young adult patients with soft tissue sarcoma.
+Added: ● The Ohio State University is investigating lifileucel manufactured by Iovance in high-risk melanoma patients in the neoadjuvant setting in the NCT05176470 clinical trial.
+Added: The trial began recruiting in 2022 to assess the feasibility of TIL expansion from tumor-involved lymph nodes patients who are diagnosed with stage IIIB-D melanoma that has spread to nearby tissue or locally advanced lymph nodes.
+Added: ● NCI, under our CRADA, is conducting the NCT02621021 clinical trial to evaluate TIL therapy in combination with the checkpoint inhibitor pembrolizumab in a 170-patient clinical trial in patients with advanced melanoma.
+Added: Immune System and Cancer Surveillance
The immune system recognizes danger signals and responds to threats at a cellular level.
1 unchanged sentence
T-cells can be distinguished from other white blood cells by T-cell receptors present on their cell surface.
−Removed: These receptors contribute to tumor surveillance by helping T cells recognize infected cells as well as cancerous cells.
+Added: These receptors contribute to tumor surveillance by helping T-cells recognize infected as well as cancerous cells.
T-cells are involved in both sensing and killing infected or cancerous cells, as well as coordinating the activation of other cells in an immune response.
−Removed: Cancer Immunotherapy
−Removed: Despite the progress that has been made over the past several decades, effective treatment of cancer, especially solid tumors, continues to be challenging.
−Removed: Some reasons solid tumors are so difficult to treat are:
−Removed: (i) in many solid tumors, there are multiple genomic mutations, as well as intratumoral heterogeneity, (ii) there are numerous tumor neoantigens, with <1% of them being shared across patients with the same tumor histology and it is not always clear which particular mutations are critical, and (iii) solid tumors can adapt and find a way to evade treatments that target a single mutation.
+Added: Challenges for Cancer Immunotherapy
+Added: Despite progress over the past several decades, effective treatment of solid tumors continues to be challenging for several reasons, including:
+Added: (i) intratumoral heterogeneity, (ii) numerous mutations and tumor neoantigens, with <1% shared across patients and lack of clarity on which mutations or neoantigens are critical, and (iii) ability to adapt and evade treatments that target a single mutation.
In addition, the tumor itself and the tumor microenvironment can suppress the patient’s natural immune response.
1 unchanged sentence
In addition, standard of care treatments for cancer can be deleterious to T-cells’ ability to kill cancer.
−Removed: We believe that adoptive cell therapy, specifically with the use of human polyclonal TIL cells as therapeutic entities to reengage the immune system, may be a significant advancement in the treatment of cancer.
−Removed: These one-time cellular therapies may avoid the long-term side effects associated with current treatments and have the potential to be effective.
−Removed: TIL therapy has the potential to treat solid tumors by increasing the effectiveness and number of a patient’s cancer-specific T cells.
−Removed: TIL therapy is polyclonal, and we believe that it is capable of targeting multiple tumor antigens on cancer cells.
−Removed: Furthermore, the non-myeloablative, or NMA, lymphodepleting chemotherapy administered prior to TIL infusion is capable of suppressing the hostile tumor microenvironment, which we believe will enhance the efficacy of TIL therapy.
−Removed: Tumor-Infiltrating Lymphocytes
−Removed: Our Gen 2 TIL therapy involves the following steps:
−Removed: Remove tumor sample:
−Removed: A surgical biopsy is conducted to remove about 1.5 cm of the tumor.
−Removed: Expand and rejuvenate patient-specific T cells using proprietary process:
−Removed: The tumor is fragmented to facilitate a clear path for TIL to leave the tumor tissue and placed in media.
−Removed: The ingredients and conditions in the culture media optimize the growth of TIL rather than other cell types.
−Removed: TIL are expanded exponentially ex vivo to yield billions (10 9 – 10 11 ) of TIL using our Gen 2 process.
−Removed: Our Gen 2 manufacturing process takes 22 days from receipt of the patient’s tumor at the manufacturing facility until cryopreservation of a product ready for shipping of the final TIL product to the institution for infusion of the TIL back into the patient.
−Removed: Initially cells grow slowly during the pre-rapid expansion, or pre-rep, phase (day 0-11) followed by a rapid expansion, or REP phase (day 11-22).
−Removed: Following the pre-rep phase, the cells are transferred to a larger bioreactor and feeder cells are introduced to further activate the TIL to proliferate during the REP phase.
−Removed: On Day 16 the TIL are harvested while maintaining a closed system before they are counted and placed into multiple bioreactors which are incubated one last time until Day 22.
−Removed: TIL are filtered, washed, concentrated and finally formulated with cryopreservation media on Day 22.
−Removed: Up to four final product bags are then prepared on Day 22, depending on total cell count.
−Removed: Lymphodepletion and infusion:
−Removed: To prepare for TIL infusion, patient receives NMA lymphodepletion to eliminate potentially suppressive tumor microenvironment and maximize engraftment and potential potency of TIL therapy;
−Removed: the patient is infused with their expanded TIL and subsequently administered up to 6 doses of IL 2 to promote T-cell activity.
−Removed: We currently treat patients with a single infusion of TIL product, although our protocols allow for more than one administration of TIL product.
−Removed: After infusion, TIL can potentially infiltrate the tumor microenvironment to eliminate large numbers of cancer cells.
−Removed: TIL can also further proliferate in the body.
−Removed: TIL therapy can potentially overcome several mechanisms of tumor escape to which endogenous T cells may be susceptible due to the hostile tumor microenvironment.
−Removed: In September 2020, we reported data at the European Society for Medical Oncology conference highlighting the reinvigoration of TIL during the Gen 2 manufacturing process.
−Removed: Historical Clinical Results with TIL in Metastatic Melanoma
−Removed: To date, hundreds of metastatic melanoma patients have already been treated with TIL therapy produced locally using different manufacturing methods at different academic institutions and hospitals in the U.S., Europe, Canada, and Israel.
−Removed: At the NCI, clinical responses have been relatively consistent in several trials that were conducted prior to anti-PD-1 treatment becoming the available standard of care for melanoma patients:
−Removed: over 50% of the melanoma patients treated with TIL achieved an objective response (i.e., tumor regression of 30% or more, as defined by RECIST criteria) and approximately 22-24% of patients have a complete response (tumor regression of 100%) with no evidence of disease remaining after only one administration.
+Added: Advancing Immuno-Oncology with Our Tumor-Infiltrating Lymphocyte Technology Platforms
+Added: Our T-cell-based immunotherapy technology platforms are potentially applicable to many solid tumor types and blood cancers.
+Added: Each platform is focused on leveraging patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.
+Added: Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, our polyclonal T-cells are personalized therapies designed to target a variety of neoantigens that are unique to the patient or tumor .
+Added: We believe that adoptive cell therapy, specifically with the use of human polyclonal TIL cells to reengage the immune system, may be a significant advancement in the treatment of cancer.
+Added: Using our lead TIL immunotherapy platform, our initial strategy is to deliver polyclonal T-cell-based therapies for patients with late-stage solid tumor cancers.
+Added: After infusion, TIL can potentially infiltrate the tumor to eliminate cancer cells, further proliferate in the body and potentially overcome several mechanisms of tumor escape to which endogenous T-cells may be susceptible due to the immune-suppressive tumor microenvironment.
+Added: For earlier intervention, we are investigating the potential of our TIL therapy in combination with a class of immunotherapy drugs called ICIs that seek to overcome one of the main escape mechanisms of cancer against an immune system attack.
+Added: TIL therapy and ICIs may work synergistically to target and attack cancer cells while breaking down barriers for the immune system to mount a response.
+Added: There are three key steps in the TIL therapy process.
+Added: Sample Collection.
+Added: A tumor sample of about 1.5 cm in diameter is removed during a surgical biopsy and shipped to our centralized manufacturing facility, where the TIL are isolated.
+Added: Manufacturing.
+Added: Patient-specific TIL are amplified and reinvigorated using our proprietary Gen 2 manufacturing process, reflecting our successful efforts to centralize and streamline TIL manufacturing from several weeks to 22 days.
+Added: Additional detail on Gen 2 is provided below in the Manufacturing Process section of our Annual Report on Form 10-K.
+Added: The patient begins with a preparative regimen of non-myeloablative lymphodepletion, or NMA-LD, to suppress the immunosuppressive tumor microenvironment, which we believe will enhance the efficacy of TIL therapy.
+Added: After NMA-LD, the expanded and rejuvenated, patient-specific TIL cells are delivered back into the body by infusion.
+Added: The treatment regimen is completed with a short course of IL-2 of up to 6 doses to promote T-cell activity in the body after TIL infusion.
+Added: If a patient is receiving TIL as a monotherapy, their treatment may be complete.
+Added: If a patient is receiving TIL therapy as part of the combination approach, they will continue treatment with ICIs following TIL infusion.
+Added: Historical Clinical Results with Other TIL Therapies in Metastatic Melanoma
+Added: To date, more than 600 patients have been treated with TIL therapies manufactured using our proprietary processes.
+Added: Prior to our clinical trials, hundreds of advanced melanoma patients were treated with TIL therapy produced locally using different manufacturing methods at different academic institutions and hospitals in the U.S., Europe, Canada, and Israel.
+Added: At the NCI, clinical responses have been relatively consistent in several trials of TIL therapy in anti-PD-1 naïve melanoma patients that were conducted prior to anti-PD-1 treatment becoming the available standard of care for melanoma patients.
+Added: Over 50% of patients achieved an objective response, and approximately 22-24% of patients had a complete response, as defined by RECIST v1.1 criteria.
Most patients who have had a complete response remained in response in 3-7 years of follow up.
−Removed: Furthermore, patients can respond to TIL therapy regardless of their prior therapies.
−Removed: In September 2015, Dr.
−Removed: Steven Rosenberg, a recognized pioneer in immuno-oncology and adoptive cell therapy using TIL, presented updated findings from a Phase 2 clinical trial of TIL therapy in metastatic melanoma at the American Association for Cancer Research Inaugural International Cancer Immunotherapy Conference.
−Removed: Data was presented from a 101 patient, Phase 2 clinical trial conducted at the NCI.
−Removed: In the trial, patients with advanced metastatic melanoma were equally divided in two groups.
−Removed: Both groups were treated according to a standard TIL protocol using NMA chemotherapy, with the second group also receiving total body irradiation, or TBI.
−Removed: 54% of the patients treated with TIL therapy achieved an objective response.
−Removed: Out of the 101 patients, 24, or 24%, had experienced a complete response and 23 of the 24, or 96%, showed ongoing durability of this response at 30 to 47 months following treatment, at the time of publication.
−Removed: Median follow-up time was approximately 40.9 months.
−Removed: Overall survival, or OS, was approximately 80% at 12 months, and median OS had not yet been achieved.
−Removed: Median progression-free survival was approximately 8-10 months.
−Removed: This observation was also presented by Dr.
−Removed: Stephanie Goff at the 2016 ASCO meeting and published in the Journal of Clinical Oncology in June 2016.
−Removed: At the ASCO 2018 meeting, Dr.
−Removed: Goff presented updated findings from the trial.
−Removed: Notably, patients that had prior anti PD-1 treatment had an ORR of 20-25%.
−Removed: In August 2021, Seitter, et al., in a collaboration led by Dr.
−Removed: Rosenberg from the Surgery Branch of the NCI, published in Clinical Cancer Research the patient outcomes based on two decades of experience with TIL therapy in metastatic melanoma.
−Removed: The ORR in the entire cohort of 226 patients was 51%, with a complete response rate of 22%.
−Removed: The median overall survival and median melanoma-specific survival were 20.6 months and 22.2 months, respectively.
−Removed: The patients achieving a complete response (n=49) had a 10-year melanoma-specific survival of 96%.
−Removed: The ORR in the 192 patients who had not received anti-PD-1 therapy as a prior line of therapy was 56% with a median melanoma-specific survival of 28.5 months.
−Removed: Of the 43 patients who were refractory to anti-CTLA-4 therapy without exposure to anti-PD-1, there was no difference in the response rate (60%), when compared to those naïve to any immune checkpoint therapy (55%).
+Added: In August 2021, patient outcomes based on two decades of experience with TIL therapy in a cohort of 226 patients with metastatic melanoma were published by Seitter, et al., in a collaboration led by Dr.
+Added: Steven Rosenberg from the Surgery Branch of the NCI, in Clinical Cancer Research.
+Added: The ORR was 51%, with a complete response rate of 22%.
+Added: The 49 patients achieving a complete response had a 10-year melanoma-specific survival of 96%.
+Added: In the 192 patients who had not received prior anti-PD-1 therapy, ORR was 56% with a median melanoma-specific survival of 28.5 months.
+Added: Of the 43 patients who were refractory to anti-CTLA-4 therapy without exposure to anti-PD-1, the 60 % response rate showed no difference when compared to the 55% response rate in those naïve to any immune checkpoint therapy.
Baseline demographic features, including BRAF status, did not influence outcome.
−Removed: Prior therapies including refractoriness to anti-PD-1 and BRAF/MEK inhibitors affected outcome compared to patients who had no exposure to these agents.
−Removed: Out of the 226 patients reported, 34 were refractory to anti-PD-1 therapy and had an ORR of 24%, with a median melanoma-specific survival of 11.6 months.
−Removed: Decreased melanoma-specific survival was seen in patients refractory to BRAF/MEK inhibitors regardless of prior anti-PD-1 exposure with a median survival of 8.7 months (refractory to both anti-PD-1) and 12.1 months (naïve to anti-PD-1).
−Removed: Clinical Results with TIL in Other Solid Tumor Indications
−Removed: Under our CRADA with the NCI, we are providing research, development and clinical funding for the development of unmodified TIL therapy for a variety of solid tumor indications, including HPV-associated cancers (cervical, head and neck), melanoma, bladder, breast, lung cancers, glioblastoma multiforme, colorectal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma and cholangiocarcinoma.
−Removed: Depending on results from the research and development and clinical trials conducted at the NCI under our CRADA, we may pursue the development and regulatory approval of TIL therapy for additional indications.
−Removed: We continue to enroll patients in our ongoing clinical programs and we closely monitor our studies to learn about all safety events occurring, as described elsewhere in this Annual Report on Form 10-K.
−Removed: Some of these events may be associated with TIL therapy.
−Removed: Historically, the largest set of data for TIL therapy was generated by the NCI as part of their multiple clinical studies.
−Removed: Per publications from the NCI, toxicities or adverse events during TIL therapy have been mostly associated with either the lymphodepletion regimen or the IL-2 therapy given after TIL infusion as described by Goff et al.
−Removed: in the Journal of Clinical Oncology in June 2016.
−Removed: The historical approach to the administration of IL-2 is to continue dosing until intolerance.
−Removed: Our trials, however, have limited administration of IL-2 to up to 6 doses.
−Removed: Next Generation TIL Product Strategies
−Removed: We are developing next generation TIL products using owned and licensed intellectual property rights, in some cases in combination with collaborators such as Cellectis, as described elsewhere in this Annual Report on Form 10-K.
−Removed: These products include selected TIL therapies, genetically-modified and cytokine-tethered TIL therapies.
−Removed: We are also developing PBL therapy for CLL and SLL.
−Removed: Process Development, Manufacturing, and Manufacturing Agreements
−Removed: Our first generation TIL manufacturing process was based on the NCI’s original manufacturing and processing of TIL, which we modified so that it could be reproduced in a cGMP environment.
−Removed: This first-generation process expanded the number of TIL over a 5-to-6-week period and produced a non-cryopreserved product for administration to the patient.
−Removed: Our Gen 2 TIL manufacturing process, which was developed by our internal research and process development team, shortens the manufacturing process to 22 days while allowing for a cryopreserved product.
−Removed: The Gen 2 process is currently in use in almost all of our trials in which we manufacture TIL products, including lifileucel and LN- 145.
−Removed: We have selected Gen 2 for product registration and ongoing and future TIL clinical development, although we continue to develop new TIL manufacturing processes.
−Removed: For example, at the SITC meeting in November 2021, we presented a poster on the expansion of TIL demonstrating the use of static bags for the clinical TIL manufacturing process.
−Removed: Furthermore, we have developed a third-generation manufacturing process, known as Gen 3 which has a shorter manufacturing process than Gen 2.
−Removed: We are testing Gen 3 in multiple clinical trials, as described elsewhere in this Annual Report on Form 10-K.
−Removed: We have also developed next generation manufacturing processes to genetically modify TIL using the TALEN technology licensed from Cellectis, including our lead preclinical program IOV-4001, as well as selections for TIL that are PD-1 positive, such as our product known as LN-145-S1.
−Removed: The Gen 2 manufacturing process begins with the collection of the patient’s tumor, which is then sent to a central manufacturing facility, where the T cells are isolated.
−Removed: These cells are stimulated to proliferate, then propagated in cell culture flasks until sufficient cells are available for infusion back into the patient.
−Removed: The TIL is then washed and put in media suitable for cryopreservation and infusion.
−Removed: The final product is shipped back to the clinical center where it can be administered to the patient.
+Added: Exposure to prior therapies, including refractoriness to anti-PD-1 and BRAF/MEK inhibitors, affected outcome.
+Added: In the population most comparable to Cohorts 2 and 4 of our C-144-01 trial, 34 of the reported patients were refractory to anti-PD-1 therapy and had an ORR of 24%, with a median melanoma-specific survival of 11.6 months.
+Added: Decreased melanoma-specific survival was seen in patients that are refractory to BRAF/MEK inhibitors regardless of prior anti-PD-1 exposure with a median survival of 8.7 months in patients who were refractory to anti-PD-1 and 12.1 months in patients who were naïve to anti-PD-1.
+Added: In December 2022, in the New England Journal of Medicine, a team from The Netherlands Cancer Institute and the National Center for Cancer Immune Therapy, Department of Oncology, of the Copenhagen University Hospital published the results of a multicenter, open-label phase 3 clinical trial of 168 patients with unresectable stage IIIC-IV melanoma randomized 1:1 to TIL or single agent ipilimumab.
+Added: The study began in 2014.
+Added: Patients in the study had received a maximum of one line of prior therapy, of which 86% were refractory to anti-PD-1 therapy.
+Added: With a median follow-up of 33.0 months, median PFS was 7.2 months for TIL compared to 3.1 months for ipilimumab.
+Added: ORR was 49% for TIL with 20% complete responses, compared to 21% ORR and 7% complete response rate for ipilimumab.
+Added: mOS for TIL was 25.8 months compared to 18.9 months for ipilimumab.
+Added: Grade 3 and higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients.
+Added: Manufacturing Processes
+Added: Iovance was founded to deliver broad access to TIL therapy for people with cancer by conducting multicenter clinical trials and developing centralized, scalable manufacturing processes to enable regulatory approvals and commercial launches.
+Added: The NCI and other academic centers have historically manufactured TIL therapies for research purposes.
+Added: To date, these site-specific processes have not been scalable or standardized to serve sizeable patient populations.
+Added: Our Gen 1 TIL manufacturing process modified the NCI’s original TIL manufacturing and processing so that it could be reproduced in a current good manufacturing practice, or cGMP, environment.
+Added: TIL expansion occurred over a 5-to-6-week period and produced a non-cryopreserved product.
+Added: Our internal research and process development team developed our proprietary Gen 2 technology to include manufacturing and logistical efficiencies aimed at further optimizing treatment and streamlining distribution processes.
+Added: Gen 2 manufacturing takes 22 days while allowing for a cryopreserved product.
+Added: We currently use Gen 2 in almost all Iovance clinical trials for product registration and our BLA submission.
+Added: We also continue to develop new processes.
+Added: We have developed a shorter, 16-day, Gen 3 manufacturing process as well as next generation manufacturing processes to genetically modify TIL and to select for TIL that potentially more potent.
+Added: Gen 2 Manufacturing Process
+Added: During the Gen 2 process, TIL are expanded exponentially ex vivo to yield billions or 10 9 – 10 11 of TIL.
+Added: The process begins with the collection of the patient’s tumor by surgical biopsy, which is sent to a central manufacturing facility.
+Added: The tumor is fragmented to facilitate a clear path for TIL to leave the tumor tissue and placed in media that optimizes the growth of TIL rather than other cell types.
+Added: Initially, from days 0-11, cells grow slowly during the pre-rapid expansion, or pre-rep phase.
+Added: Following the pre-rep phase, the cells are transferred to a larger bioreactor and feeder cells are introduced to further activate the TIL to proliferate during the rapid expansion, or REP phase, from days 11-22.
+Added: During the REP phase, on day 16, the TIL are harvested while maintaining a closed system before they are counted and placed into multiple bioreactors which are incubated one last time until day 22.
+Added: On day 22, TIL are filtered, washed, concentrated and finally formulated with cryopreservation media before being placed in up to four final product bags, depending on total cell count.
+Added: The final product is shipped back to the center where it can be administered to the patient.
The following diagram illustrates our Gen 2 TIL manufacturing process.
−Removed: To meet projected needs for commercial quantities of TIL products, we have built our own commercial manufacturing facility, the i CTC, to manufacture TIL product using the Gen 2 manufacturing process.
−Removed: As of the end of 2021, we had completed the commissioning activities at the i CTC and successfully manufactured and delivered the first clinical batch of LN-145 for the IOV-COM-202 trial, representing our first internally manufactured TIL product, as we continue our launch readiness activities to supply commercial TIL upon potential BLA approval.
−Removed: In addition, we have entered into MSAs with WuXi, Moffitt, and PharmaCell, which was acquired by Lonza, pursuant to which they have agreed to manufacture, package, ship and handle quality assurance and quality control of certain clinical trials for our TIL products working closely with our employees.
−Removed: We have two suites for clinical manufacturing at WuXi, and one of two suites is also available to manufacture TIL for commercial use.
−Removed: Cell processing activities are conducted at all facilities under cGMP, using qualified equipment and materials.
−Removed: We believe that all materials and components utilized in the production of the final TIL product are readily available from qualified suppliers.
−Removed: We expect to rely on our own manufacturing facility and these CMOs to meet anticipated clinical trial and if approved, commercial demands.
+Added: Our Iovance Cell Therapy Center, or iCTC, for Large-Scale Centralized Manufacturing
+Added: Our i CTC is the first centralized and scalable cGMP manufacturing facility dedicated to producing TIL as a potential therapy for patients with solid tumors.
+Added: At 136,000 square feet, the i CTC is among the largest cell therapy manufacturing facilities in existence.
+Added: It currently supplies investigational TIL therapy for Iovance clinical trials, with commercial manufacturing expected to begin after initial product approval.
+Added: The proximity of the i CTC to multiple airports facilitates delivery of TIL therapies to treatment centers, with the i CTC expected to cover logistics and delivery of TIL therapy in both North America and Europe.
+Added: This location may also offer future tax savings under Pennsylvania’s Keystone Opportunity Improvement Zone, or KOIZ.
+Added: Clinical Manufacturing
+Added: In 2021, we completed the commissioning activities at the i CTC and successfully initiated manufacturing of clinical batches of lifileucel and LN-145.
+Added: In addition, we have entered into MSAs with WuXi Advanced Therapies, Inc., or WuXi, and Moffitt pursuant to which they have agreed to manufacture, package, ship and handle quality assurance and quality control of certain clinical trials for our TIL products working closely with our employees.
In the future, we may rely on them or other third parties, or our own manufacturing capabilities, for the manufacturing and processing of TIL-based product candidates for our clinical trials.
+Added: Commercial Manufacturing Preparations
+Added: To meet projected needs for commercial quantities, we continue our launch readiness and scale up activities to supply commercial TIL upon potential BLA approval.
+Added: We expect to rely primarily on our own i CTC facility for commercial supply, with flexibility to use CMOs to meet anticipated clinical trial and, if approved, commercial demands.
+Added: For example, we expect to be able to use two suites for clinical or commercial manufacturing at WuXi in Philadelphia if needed based on demand.
If we are unable to meet manufacturing capabilities and demand at our own commercial manufacturing facility, we may need to rely on CMOs, including both current and alternate suppliers, to ensure sufficient capacity is available for commercial purposes.
−Removed: Orphan Drug Designations
−Removed: During 2015, we received an Orphan Drug Designation, or ODD, for lifileucel in the U.S.
−Removed: to treat malignant melanoma stages IIB-IV.
−Removed: If approved, an ODD provides seven years of market exclusivity in the U.S., subject to certain limited exceptions.
−Removed: an ODD does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.
−Removed: The benefits and limitations of ODD are described in more detail elsewhere in this Annual Report on Form 10-K.
−Removed: During 2018, we received an ODD from the FDA for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.
−Removed: Fast Track Designations
−Removed: In August 2017, we announced that the FDA had granted Fast Track designation for lifileucel for the treatment of advanced metastatic melanoma.
−Removed: In February 2019, we announced that the FDA had granted Fast Track designation for lifileucel in the treatment of metastatic cervical cancer.
−Removed: Additionally, in November 2021, we announced that the FDA granted Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI naïve metastatic melanoma based on the unmet medical need and potential advantages for this combination over available care.
−Removed: The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.
−Removed: Fast Track designation allows more frequent meetings and communications with the FDA to discuss the drug’s development plans and review process.
−Removed: The Fast Track designation also allows for the possibility for rolling review of a BLA by FDA, and also potential eligibility if certain criteria are met for accelerated approval.
−Removed: Regenerative Medicine Advanced Therapy Designation
−Removed: In October 2018, we announced that the FDA had granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma.
−Removed: The RMAT designation is based on data provided to the FDA from our C-144-01 trial.
−Removed: RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development.
−Removed: Under this designation, surrogate endpoints can be used to receive approval for a product, accelerated approval may be granted, and a rolling review of a BLA may be permitted by FDA.
−Removed: Breakthrough Therapy Designation
−Removed: In May 2019, we announced that the FDA had granted Breakthrough Therapy Designation, or BTD, for lifileucel for the treatment of patients with metastatic cervical cancer.
−Removed: The BTD was granted based on data provided to the FDA from our C-145-04 trial.
−Removed: Under a BTD, the FDA may take actions that help expedite the development and review of the application for a product candidate, including seeking to provide timely advice and interactive communications to the sponsor with intensive guidance during development, to help the sponsor design and conduct a more efficient development program.
−Removed: Product candidates with BTD may be suitable for alternative clinical trial designs when scientifically appropriate, which may result in smaller trials or more efficient trials that require less time to complete.
−Removed: BTD also allows the sponsor to file sections of the BLA on an ongoing basis for rolling review where the FDA may consider beginning review portions of a marketing application before the full submission is complete.
−Removed: In addition, BTD status allows for the potential to request priority review of our BLA at the time of BLA submission if supported by clinical data.
−Removed: The clinical evidence needed to support breakthrough designation is preliminary, and the FDA has authority to rescind a BTD if a product candidate no longer meets the qualifying criteria.
−Removed: Commercialization Plan
−Removed: We currently have limited sales, marketing or commercial product distribution capabilities and as a company we have no experience in commercializing cell therapy products.
−Removed: We are continuing to build our U.S.
−Removed: commercial and medical affairs infrastructure and intend to build our own global commercialization capabilities over time in certain geographies for our TIL product candidates including lifileucel for metastatic melanoma and cervical cancer.
−Removed: If any of our TIL product candidates are approved, we expect to commercialize those products in the U.S.
−Removed: with an experienced sales, marketing, payer access and distribution organization including a national specialty oncology sales force.
−Removed: We have started and continue to build a dedicated team of medical affairs professionals to help educate health professionals about our TIL therapy and to assist in any training necessary for individual centers to administer our therapy.
−Removed: Outside the U.S., we are in the process of defining our regulatory and commercial strategy.
−Removed: As additional product candidates advance through our pipeline, our commercial plans will evolve as we consider elements such as the market potential.
−Removed: The five primary areas of our pre-launch efforts include:
−Removed: ● engagement with potential authorized treatment centers, or ATCs, for commercial launch;
−Removed: ● development of a close collaboration with healthcare professionals, or HCPs, who will be handling or administering our product;
−Removed: ● operational excellence by us in provision of our product;
−Removed: ● communication with payors;
−Removed: ● building a patient-centric organization.
−Removed: To date, in the U.S., lifileucel has been administered in 19 clinical trial centers for melanoma.
−Removed: We anticipate that these clinical trial centers will be among the initial 40 ATCs at launch upon approval.
+Added: Our CMO relationship is described in more detail in the Research, Development, Manufacturing and License agreements section of this Annual Report on Form 10-K.
+Added: Cell processing activities are conducted at all facilities under cGMP, using qualified equipment and materials.
+Added: We believe that all materials and components utilized in the production of the final TIL product are readily available from qualified suppliers.
Intellectual Property
+Added: We aim to lead in the field of T-cell-based immunotherapy by building and augmenting the patent rights for our proprietary TIL technology platform, which we have developed internally and licensed from third parties.
Intellectual property is of importance in our field and in biotechnology generally.
−Removed: We seek to protect and enhance proprietary technology, inventions, and improvements that are commercially important to the development of our business by seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties.
−Removed: We also plan to rely on regulatory protection afforded through ODDs, available regulatory exclusivities and patent term extensions where available.
−Removed: To achieve this objective, a strategic focus for us has been to develop our own intellectual property, while also identifying and licensing patents that provide protection and serve as an optimal platform to enhance our intellectual property and technology base.
+Added: We seek to protect and enhance proprietary technology, inventions, and improvements that are commercially important to the development of our business by seeking, maintaining, and defending patent rights.
+Added: We also plan to rely on regulatory protection afforded through Orphan Drug Designation, or ODD, available regulatory exclusivities and patent term extensions where available.
+Added: To achieve this objective, our strategic focus has been to develop our own intellectual property, while also identifying and licensing patents from third parties that provide protection and serve as an optimal platform to enhance our intellectual property and technology base.
We expect to further develop our patent portfolio as a strategic focus in 2023.
−Removed: We have developed our own patent portfolio based on internal research and development activities.
−Removed: As a result, we now own a number of pending patent applications and granted patents in the fields of TIL therapy, MIL therapy, and PBL therapy, TIL, MIL, and PBL manufacturing processes, and TIL, MIL, and PBL expansion methods.
−Removed: For example, we currently own more than 35 U.S.
+Added: We currently own more than 60 U.S.
patents related to TIL therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.
2 unchanged sentences
More than 35 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to January 2038, not including any patent term extensions or adjustments that may be available.
−Removed: Our owned and licensed intellectual property portfolio also includes patent applications relating to TIL, MIL, and PBL therapies;
+Added: Our owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, MIL, and PBL therapies;
frozen tumor-based TIL technologies;
remnant TIL and digest TIL compositions, methods and processes;
−Removed: methods of treatment of a broad range of cancers using TIL therapies;
methods of manufacturing TIL, MIL, and PBL therapies;
−Removed: the use of costimulatory molecules in TIL therapy and manufacturing;
−Removed: stable and transient genetically-modified TIL therapies;
+Added: the use of costimulatory and T-cell modulating molecules in TIL therapy and manufacturing;
+Added: stable and transient genetically-modified TIL therapies, including genetic knockouts of immune
+Added: cytokine-tethered TIL therapies;
methods of using ICIs in combination with TIL therapies;
1 unchanged sentence
and methods of treating patient subpopulations.
−Removed: Research, Development and License Agreements
−Removed: Currently, preclinical research and development is conducted primarily at our own internal research and development laboratory in Tampa, Florida, and additionally with the NCI, Moffitt, and MDACC, as described below.
−Removed: We sponsor our own clinical trials and also collaborate on investigator-sponsored clinical trials with the NCI, Moffitt, and MDACC.
−Removed: In addition, we hold exclusive, co-exclusive, and non-exclusive licenses to certain patent and other intellectual property rights with the NIH, an agency of the U.S.
−Removed: Public Health Service within the Department of Health and Human Services, Moffitt, MDACC, Novartis, and Cellectis as described in this Annual Report on Form 10-K.
+Added: Research, Development, Manufacturing and License Agreements
+Added: WuXi Advanced Therapies, Inc.
+Added: Manufacturing and Services Agreements
+Added: In November 2016, we entered into a three-year manufacturing services agreement, or the First WuXi MSA, with WuXi, pursuant to which WuXi agreed to provide manufacturing and other services, which has since been amended and assigned to our subsidiary Iovance Biotherapeutics Manufacturing LLC.
+Added: Under the First Wuxi MSA, we entered into two statements of work for two cGMP manufacturing suites to be operated by WuXi for us.
+Added: The terms of one of these statements of work was extended to December 2022.
+Added: In October 2022, Iovance Biotherapeutics Manufacturing LLC entered into an additional three-year MSA, or the Second WuXi MSA, with WuXi and its parent company WuXi Apptec, Co, Ltd.
+Added: The Second WuXi MSA and its related statement of work will supersede the statement of work under the First WuXi MSA with respect to commercial and clinical manufacturing for the two existing manufacturing suites.
+Added: Both suites are expected to be capable of being used for the commercial manufacture of our products.
National Institutes of Health and the National Cancer Institute
Cooperative Research and Development Agreement
−Removed: In August 2011, we signed a five-year CRADA with the NCI, to work with Dr.
−Removed: Steven Rosenberg on developing adoptive cell immunotherapies that are designed to destroy metastatic melanoma cells.
−Removed: In January 2015, we executed an amendment to the CRADA to include four new indications.
−Removed: As amended, in addition to metastatic melanoma, the CRADA included the development of TIL therapy for the treatment of patients with bladder, lung, triple-negative breast, and cancers associated with HPV.
−Removed: In August 2016, the NCI and we entered into a second amendment to the CRADA.
−Removed: The principal changes effected by the second amendment included (i) extending the term of the CRADA by another five years to August 2021, and (ii) modifying the focus on the development of unmodified TIL as a stand-alone therapy or in combination with products licensed by the FDA, and commercially available reagents routinely used for adoptive cell therapy.
+Added: We entered into a CRADA with the NCI to develop adoptive cell immunotherapies in multiple solid tumor types, including unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL with anti-tumor reactivity, and strategies for more potent TILs.
+Added: In August 2011, we signed a five-year CRADA with the NCI, to work on the development of adoptive cell immunotherapies that are designed to destroy metastatic melanoma cells.
+Added: The CRADA was amended in 2015 and 2016, to, among other things, extend the term of the CRADA through August 2023, include new indications such as bladder, lung, triple-negative breast, and Human Papilloma Virus, or HPV, -associated cancers and modify the focus on the development of unmodified TIL as a stand-alone therapy or in combination.
The parties have continued the development of improved methods for the generation and selection of TIL with anti-tumor reactivity in metastatic melanoma, bladder, lung, breast, and HPV-associated cancers.
−Removed: In August 2021, the NCI and we entered into a third amendment to the CRADA.
−Removed: The third amendment, among other things, extended the term of the CRADA by three years to August 2024.
−Removed: The research plan in this amendment includes the evaluation in clinical trials of strategies for development of more potent TILs, such as selection of CD39/69 double negative cells and the use of certain inhibitors or other reagents in TIL expansion cultures.
+Added: In August 2021, a third amendment extended the term of the CRADA by three years to August 2024, among other things.
+Added: The research plan in this third amendment includes the evaluation in clinical trials of strategies for development of more potent TILs, such as selection of CD39/69 double negative cells and the use of certain inhibitors or other reagents in TIL expansion cultures.
Pursuant to the terms of the CRADA, as amended, we are required to make quarterly payments of $0.5 million to the NCI for support of research activities.
−Removed: To the extent we license patent rights relating to a TIL-based product candidate, we will be responsible for all patent-related expenses and fees, past and future, relating to the TIL-based product candidate.
−Removed: In addition, we may be required to supply certain test articles, including TIL, grown and processed under cGMP conditions, suitable for use in clinical trials.
+Added: To the extent we license patent rights relating to a TIL-based product candidate, we will be responsible for all patent-related expenses and fees, past and future.
+Added: In addition, we may be required to supply certain test articles, including TIL, grown and processed under Current Good Manufacturing, or cGMP, conditions, suitable for use in clinical trials.
We or the NCI may unilaterally terminate the CRADA for any reason or for no reason, at any time, by providing written notice at least 60 days before the desired termination date.
−Removed: Patent License Agreement Related to the Development and Manufacture of TIL
−Removed: Effective October 5, 2011, we entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, which was subsequently amended on February 9, 2015 and October 2, 2015.
−Removed: Pursuant to the Patent License Agreement as amended, the NIH granted us licenses, including exclusive, co-exclusive, and non-exclusive licenses, to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products for the treatment of metastatic melanoma, lung, breast, bladder and HPV-positive cancers, or collectively the Indications.
−Removed: The Patent License Agreement requires us to pay royalties based on a percentage of net sales (which percentage is in the mid-single digits), a percentage of revenues from sublicensing arrangements, and lump sum benchmark royalty payments on the achievement of certain clinical and regulatory milestones for each of the Indications and other direct costs incurred by the NIH pursuant to the agreement.
−Removed: Effective May 6, 2021, we entered into an Amended and Restated Patent License Agreement with NIH, or the Amended and Restated Patent License Agreement, which includes the grant of additional exclusive, worldwide patent rights in the Indications to cytokine-tethered TIL technology, and expands the non-exclusive, worldwide field of use to all cancers.
−Removed: The Amended and Restated Patent License Agreement requires us to pay royalties based on a percentage of net sales in jurisdictions where patent rights exist, which percentage can fall into a tier that may be less than one percent to mid-single digits depending upon certain events, including the exclusivity of the rights, and we expect lower overall royalty payments as a result.
−Removed: We also agreed to pay potential milestone payments on the achievement of certain clinical, regulatory, and commercial sales milestones for each of the Indications and other direct costs incurred by the NIH pursuant to the Amended and Restated Patent License Agreement, as well as a percentage of revenues from sublicensing arrangements.
−Removed: We anticipate making milestone payments, including a payment in the low single-digit millions of dollars, in conjunction with the approval of a BLA for any of our product candidates covered by the Amended and Restated Patent License Agreement.
−Removed: The term of the Amended and Restated Patent License Agreement continues until the expiry of the last-to-expire patent rights licensed thereunder, and the agreement contains standard termination provisions.
+Added: Patent License Agreement Related to the Development and Manufacture of TIL Therapies
+Added: We have licensed exclusive, co-exclusive, and non-exclusive licenses from NIH to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products.
+Added: We entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, in 2011, which was amended in 2015.
+Added: Pursuant to the Patent License Agreement, as amended, the NIH granted us licenses, including exclusive, co-exclusive, and non-exclusive licenses, to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products for the treatment of metastatic melanoma, lung, breast, bladder and HPV-positive cancers.
+Added: In May 2021, we entered into an Amended and Restated Patent License Agreement with NIH, which included the grant of additional exclusive, worldwide patent rights in the indications to interleukin-15 and interleukin-21 cytokine-tethered TIL technology, and expanded the non-exclusive, worldwide field of use to all cancers.
+Added: Effective August 1, 2022, we entered into a Second Amended and Restated Patent License Agreement with NIH to include additional exclusive, worldwide patent rights to TIL products expressing interleukin-12, expanded rights to TIL selection technologies previously licensed under the Exclusive Patent License Agreement below, and additional non-exclusive, worldwide patent rights to certain technologies related to enhancing TIL potency.
+Added: The Second Amended and Restated Patent License Agreement requires us to pay royalties based on a percentage of net sales in jurisdictions where patent rights exist, which percentage can fall into a tier that may be less than one percent to mid-single digits depending upon certain events, including the exclusivity of the rights, and we expect lower overall royalty payments as a result.
+Added: We also agreed to pay potential milestone payments on the achievement of certain clinical, regulatory, and commercial sales milestones for each of the indications and other direct costs incurred by the NIH pursuant to the Second Amended and Restated Patent License Agreement.
+Added: We anticipate making milestone payments, including payments ranging from several hundred thousand dollars to the mid-single-digit millions of dollars, in conjunction with certain development milestones, the approval of a BLA or its foreign equivalent, or the first U.S.
+Added: and foreign commercial sales of any of our product candidates covered by the Second Amended and Restated Patent License Agreement.
+Added: The term of the Second Amended and Restated Patent License Agreement continues until the expiry of the last-to-expire patent rights licensed thereunder, and the agreement contains standard termination provisions.
Exclusive Patent License Agreement Related to TIL Selection
−Removed: On February 10, 2015, we entered into an exclusive patent license agreement, or the Exclusive Patent License Agreement, with the NIH under which we received an exclusive license to the NIH’s rights to patent-pending technologies related to methods for improving adoptive cell therapy through more potent and efficient production of TIL from melanoma tumors by selecting for T cell populations that express various inhibitory receptors.
−Removed: Unless terminated sooner, the license shall remain in effect until the last licensed patent right expires.
−Removed: Under the Exclusive Patent License Agreement, we agreed to pay customary royalties based on a percentage of net sales of a licensed product (which percentage is in the mid-single digits), a percentage of revenues from sublicensing
−Removed: arrangements, and lump sum benchmark payments upon the successful completion of clinical studies involving licensed technologies, the receipt of the first FDA approval or foreign equivalent for a licensed product or process resulting from the licensed technologies, the first commercial sale of a licensed product or process in the U.S., and the first commercial sale of a licensed product or process in any foreign country.
+Added: In February 2015, we entered into an exclusive patent license agreement, or the Exclusive Patent License Agreement, with the NIH under which we received an exclusive worldwide license under the selected TIL patents.
+Added: This license was superseded and replaced by the Second Amended and Restated Patent License Agreement.
Lee Moffitt Cancer Center
−Removed: Research Collaboration and Clinical Grant Agreements with Moffitt
−Removed: In December 2016, we entered into a three-year Sponsored Research Agreement with Moffitt, which expired in December 2019.
−Removed: In June 2020, we entered into a new Sponsored Research Agreement with Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner, and under which immaterial payments will be made to Moffitt in connection with the research services thereunder.
+Added: Sponsored Research Agreement
+Added: In June 2016, we entered into a Sponsored Research Agreement with Moffitt, which expired in December 2019.
+Added: In June 2020, we entered into a new Sponsored Research Agreement with Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner.
+Added: In June 2022, this agreement was extended until the later of December 19, 2022 or a mutually acceptable completion of the Research Agreement, which is currently expected in mid-2023.
+Added: Clinical Grant Agreements
In December 2016, we entered into a clinical grant agreement with Moffitt to support an ongoing clinical trial at Moffitt that combines TIL therapy with nivolumab for the treatment of patients with metastatic melanoma.
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Under both clinical grant agreements with Moffit, we have non-exclusive rights to clinical data arising from the respective clinical trials.
−Removed: Exclusive License Agreements with Moffitt
−Removed: We entered into a license agreement with Moffitt, or the First Moffitt License, effective as of June 28, 2014, under which we received a world-wide license to Moffitt’s rights to patent-pending technologies related to methods for improving TIL for adoptive cell therapy using toll-like receptor agonists.
+Added: Exclusive License Agreements
+Added: We have exclusive license agreements to Moffitt’s patent-pending technologies related to methods for improving TIL for adoptive cell therapy using toll-like receptor, or TLR, agonists, the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies, and tumor digests in conjunction with TIL manufacturing processes and therapies.
+Added: We entered into a license agreement with Moffitt, or the First Moffitt License, effective as of June 28, 2014, under which we received a worldwide license to Moffitt’s rights to patent-pending technologies related to methods for improving TIL for adoptive cell therapy using TLR agonists.
Unless earlier terminated, the term of the license extends until the earlier of the expiration of the last issued patent related to the licensed technology or 20 years after the effective date of the license agreement.
−Removed: Pursuant to the First Moffitt License, we paid an upfront licensing fee in the amount of $0.1 million.
−Removed: A patent issuance fee will also be payable under the First Moffitt License, upon the issuance of the first U.S.
+Added: Pursuant to the First Moffitt License, we paid an upfront licensing fee, and a patent issuance fee will also be payable under the First Moffitt License, upon the issuance of the first U.S.
patent covering the subject technology.
−Removed: In addition, we agreed to pay milestone license fees upon completion of specified milestones, customary royalties based on a specified percentage of net sales (which percentage is in the low single digits) and sublicensing payments, as applicable, and annual minimum royalties beginning with the first sale of products based on the licensed technologies, which minimum royalties will be credited against the percentage royalty payments otherwise payable in that year.
+Added: In addition, we agreed to pay
+Added: milestone license fees upon completion of specified milestones, customary royalties based on a specified percentage of net sales, which percentage is in the low single digits, and sublicensing payments, as applicable, and annual minimum royalties beginning with the first sale of products based on the licensed technologies, which minimum royalties will be credited against the percentage royalty payments otherwise payable in that year.
We will also be responsible for all costs associated with the preparation, filing, maintenance and prosecution of the patent applications and patents covered by the First Moffitt License related to the treatment of any cancers in the U.S., Europe and Japan and in other countries designated by us in agreement with Moffitt.
−Removed: We entered into a second license agreement with Moffitt effective as of May 7, 2018, or the Second Moffitt License, under which we received an exclusive license to Moffitt’s rights to patent-pending technologies related to the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies.
−Removed: Pursuant to the Second Moffitt License, we paid an upfront licensing fee in the amount of $0.1 million in 2018.
−Removed: An annual license maintenance fee is also payable commencing on the first anniversary of the effective date.
−Removed: In addition, we agreed to pay an annual commercial use payment for each indication for which a first sale has occurred.
−Removed: We subsequently exercised an option to exclusively license Moffitt’s rights to patent pending technologies related to the use of tumor digests in conjunction with TIL manufacturing processes and therapies, and we and Moffitt amended and restated the Second Moffitt License in October 2021, or the Amended & Restated Second Moffit License, to include these rights.
−Removed: Pursuant to the Amended & Restated Second Moffitt License, we paid an upfront licensing fee in the amount of $0.2 million in 2021.
−Removed: In addition, we agreed to pay an annual commercial use payment for each indication for which a first sale has occurred for products relating to the use of 4-1BB antagonists and for products relating to the use of tumor digests covered by the license.
+Added: In May 2018, we entered into a second license agreement with Moffitt, or the Second Moffitt License, under which we received an exclusive license to Moffitt’s rights to patent-pending technologies related to the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies.
+Added: Pursuant to the Second Moffitt License, we paid an upfront licensing fee, and an annual license maintenance fee is also payable commencing on the first anniversary of the effective date.
+Added: We also agreed to pay an annual commercial use payment for each indication for which a first sale has occurred.
+Added: We subsequently exercised an option to exclusively license Moffitt’s rights to patent pending technologies related to the use of tumor digests in conjunction with TIL manufacturing processes and therapies and entered into an amended and restated Second Moffitt License in October 2021, or the Amended & Restated Second Moffit License, to include these rights.
+Added: Pursuant to the Amended & Restated Second Moffitt License, we paid an upfront licensing fee in 2021.
+Added: We also agreed to pay an annual commercial use payment for each indication for which a first sale has occurred for products relating to the use of 4-1BB agonists and for products relating to the use of tumor digests covered by the license.
The University of Texas M.D.
−Removed: Anderson Cancer Center
+Added: Anderson Cancer Center, or MDACC
Strategic Alliance Agreement
−Removed: In April 2017, we entered into a Strategic Alliance Agreement, or the SAA, with MDACC agreed to conduct clinical and preclinical research studies.
+Added: In April 2017, we entered into a Strategic Alliance Agreement, or the SAA, with MDACC, under which we and MDACC agreed to conduct clinical and preclinical research studies.
We agreed in the SAA to provide total funding not to exceed approximately $14.2 million for the performance of the multi-year studies under the SAA.
−Removed: In return, we acquired all rights to inventions resulting from the studies and have been granted a non-exclusive, sub-licensable, royalty-free, and perpetual license to specified background intellectual property of
−Removed: MDACC reasonably necessary to exploit, including the commercialization thereof.
−Removed: We have also been granted certain rights in clinical data generated by MDACC outside of the clinical trials to be performed under the SAA.
+Added: In return, we acquired all rights to inventions resulting from the studies and have been granted a non-exclusive, sub-licensable, royalty-free, and perpetual license to specified background intellectual property of MDACC reasonably necessary to exploit, including the commercialization thereof.
+Added: We have also been granted certain rights to clinical data generated by MDACC outside of the clinical trials to be performed under the SAA.
The SAA’s term shall continue in effect until the later of the fourth anniversary of the SAA or the completion or termination of the research and receipt by us of all deliverables due from MDACC thereunder.
−Removed: In May 2017, we made a prepayment of $1.4 million under this agreement.
−Removed: In light of the disease caused by the novel coronavirus, SARS-CoV-2, which was declared a public health emergency on January 31, 2020, under section 319 of the Public Health Service Act (42 U.S.C.
−Removed: 247d) by the Secretary of Health and Human Services, and which we refer to herein as the COVID-19 pandemic, MDACC temporarily suspended their research programs and decommissioned their research labs, and as a result, enrollment in our MDACC-sponsored studies under the SAA was temporarily paused in the first half 2020, but has since been restarted.
−Removed: WuXi Advanced Therapies, Inc.
−Removed: In November 2016, we entered into a three-year manufacturing and services agreement, or MSA, with WuXi, pursuant to which WuXi agreed to provide manufacturing and other services, which has since been amended and assigned to our subsidiary Iovance Biotherapeutics Manufacturing LLC.
−Removed: Under the agreement, we entered into two statements of work for two cGMP manufacturing suites to be established and operated by WuXi for us, and both of the suites are expected to be capable of being used for the commercial manufacture of our products.
−Removed: The first statement of work was amended in June 2019, September 2020, and February 2021, and the second statement of work was amended in July 2019 and July 2021.
−Removed: Both statements of work provide for adjustments to the targeted production capacity levels and the corresponding fixed fees upon written notice from us of 30 days and 90 days for the first and second suites, respectively.
−Removed: The terms of the related statements of work currently extend to February 2022 for the first statement of work and were extended to December 2022 for the second statement of work.
Cellectis S.A.
−Removed: In December 2019, we entered into a research collaboration and exclusive worldwide license agreement under which we license gene-editing technology from Cellectis.
−Removed: Financial terms of the license include development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN-modified TIL products.
+Added: Research Collaboration and Exclusive Worldwide License Agreement
+Added: In December 2019, we entered into a research collaboration and exclusive worldwide license agreement whereby we will license gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop TIL therapies that have been genetically edited, including a PD-1 inactivated product that we refer to as IOV-4001.
+Added: Financial terms of the license include annual license payments and development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN® modified TIL products.
Novartis Pharma AG
−Removed: In January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.
+Added: License Agreement
+Added: In January 2020, we obtained a license from Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.
Under the agreement, we have paid an upfront payment to Novartis and may pay future milestones related to initiation of patient dosing in various phases of clinical development for IOV-3001 and approval of the product in the U.S., the European Union, or EU, and Japan.
Novartis is also entitled to low-to-mid single digit percentage royalties from commercial sales of the product.
−Removed: The biotechnology and pharmaceutical industries put significant resources in developing novel and proprietary therapies for the treatment of cancer.
+Added: Regulatory Designations
+Added: The FDA has granted ODD for lifileucel in the U.S.
+Added: to treat malignant melanoma stages IIB-IV and for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter;
+Added: Fast Track and RMAT designations for lifileucel to treat advanced metastatic melanoma;
+Added: Fast Track and Breakthrough Therapy Designations, or BTD, for lifileucel to treat metastatic cervical cancer;
+Added: and Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI naïve metastatic melanoma.
+Added: Orphan Drug Designations
+Added: During 2015, we received ODD for lifileucel in the U.S.
+Added: to treat malignant melanoma stages IIB-IV, and in 2018, we received an ODD for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.
+Added: If approved, an ODD provides seven years of market exclusivity in the U.S., subject to certain limited exceptions.
+Added: However, an ODD does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.
+Added: The benefits and limitations of ODD are described in more under the Government Regulations section in this Annual Report on Form 10-K.
+Added: Fast Track Designations
+Added: In August 2017, we announced that the FDA had granted Fast Track designation for lifileucel for the treatment of advanced metastatic melanoma.
+Added: In February 2019, we announced that the FDA had granted Fast Track designation for lifileucel in the treatment of metastatic cervical cancer.
+Added: Additionally, in November 2021, we announced that the FDA granted Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI-naïve metastatic melanoma.
+Added: The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.
+Added: Fast Track designation allows more frequent meetings and communications with the FDA to discuss the drug’s development plans and review process.
+Added: The Fast Track designation also allows for the possibility for rolling review of a BLA by FDA, where the FDA may consider beginning review portions of a marketing application before the full submission is complete, and also potential eligibility if certain criteria are met for accelerated approval.
+Added: Regenerative Medicine Advanced Therapy Designation
+Added: In October 2018, we announced that the FDA had granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma.
+Added: The RMAT designation is based on data provided to the FDA from our C-144-01 trial.
+Added: RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development.
+Added: Under this designation, surrogate endpoints can be used to receive approval for a product, accelerated approval may be granted, and a rolling review of a BLA may be permitted by FDA.
+Added: Breakthrough Therapy Designation
+Added: In May 2019, we announced that the FDA had granted BTD for lifileucel for the treatment of patients with metastatic cervical cancer.
+Added: The BTD was granted based on data provided to the FDA from our C-145-04 clinical trial.
+Added: Under a BTD, the FDA may take actions that help expedite the development and review of the application for a product candidate, including seeking to provide timely advice and interactive communications to the sponsor with intensive guidance during development, to help the sponsor design and conduct a more efficient development program.
+Added: Product candidates with BTD may be suitable for alternative clinical trial designs when scientifically appropriate, which may result in smaller clinical trials or more efficient clinical trials that require less time to complete.
+Added: BTD also allows the sponsor to submit portions of the BLA on an ongoing basis for rolling review.
+Added: In addition, BTD status allows for the potential to request priority review of our BLA at the time of BLA submission if supported by clinical data.
+Added: The clinical evidence needed to support breakthrough designation is preliminary, and the FDA has authority to rescind a BTD if a product candidate no longer meets the qualifying criteria.
+Added: The biotechnology and pharmaceutical industries put significant resources into developing novel and proprietary therapies for the treatment of cancer.
We compete with multiple entities who have developed and are developing immuno-oncology therapies, including large and specialty pharmaceutical and biotechnology companies, academic research institutions and governmental agencies and public and private research institutions, as well as companies developing novel targeted therapies for cancer.
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and Europe are also potential competitors.
−Removed: For example, a Phase 3 study comparing TIL to standard ipilimumab in patients with metastatic melanoma is currently being conducted in Europe by the Netherlands Cancer Institute, the Copenhagen University Hospital at Herlev, and the University of Manchester.
−Removed: While these universities and public and private research institutions primarily have educational objectives, they may develop proprietary technologies that lead to other FDA-approved therapies or that secure patent protection.
−Removed: We anticipate that we will face possibly increasing competition as new drugs and therapies enter the market and advanced technologies become available.
−Removed: Due to the promising clinical therapeutic effect of their therapies in clinical exploratory trials, we anticipate substantial direct competition from other organizations developing advanced T cell therapies targeting patients who have received prior anti-PD-1/PD-L1 therapies.
−Removed: In particular, we expect to compete with other new therapies for our lead indications developed by companies such as Agenus, BeyondSpring, Bristol-Myers Squibb, Merck, Nektar Therapeutics, Idera Pharmaceuticals, Checkmate Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, Mirati Therapeutics, OncoSec Medical, Replimune, Regeneron Pharmaceuticals, Seagen, and Genmab.
−Removed: We also may compete with other TIL therapies in development by companies such as Instil Bio, Achilles Therapeutics, KSQ
−Removed: Therapeutics, Obsidian Therapeutics, Immatics, TILT Biotherapeutics, WindMIL Therapeutics, GRIT Biotechnology, Lyell Immunopharma, Cellular Biomedicine Group, and others.
−Removed: We also may compete with therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens prior to their administration to patients, as well as TIL therapies that are designed to be specific to neoantigens, including products developed by Adaptimmune Therapeutics, Alaunos Therapeutics, Marker Therapeutics, Turnstone Biologics, Neogene and others.
+Added: For example, a Phase 3 M14TIL clinical
+Added: trial comparing TIL to standard ipilimumab in patients with metastatic melanoma is currently being conducted in Europe by the Netherlands Cancer Institute, the Copenhagen University Hospital at Herlev, and the University of Manchester.
+Added: Results from the M14TIL clinical trial were presented at the European Society for Medical Oncology Congress in September 2022 and published in the New England Journal of Medicine in December 2022, as described in the Historical Clinical Results with Other TIL Therapies in Metastatic Melanoma section of this Annual Report on Form 10-K.
+Added: While these universities and public and private research institutions primarily have educational objectives, they may develop proprietary technologies that lead to other FDA-approved therapies or that secure patent protection that we may need for the development of our technologies and products.
+Added: Due to the promising clinical therapeutic effect of competitor therapies in clinical exploratory trials, we anticipate substantial direct competition from other organizations developing advanced T-cell therapies targeting patients who have received prior anti-PD-1/-L1 therapies.
+Added: In particular, we expect to compete with other new therapies for our lead indications developed by companies such as Agenus, BeyondSpring, Bristol-Myers Squibb, Merck, Nektar Therapeutics, Checkmate Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, Moderna, Mirati Therapeutics, OncoSec Medical, Replimune, Regeneron Pharmaceuticals, Seagen, and Genmab.
+Added: We also may compete with other TIL therapies in development by companies such as Instil Bio, Achilles Therapeutics, KSQ Therapeutics, Obsidian Therapeutics, Immatics, TILT Biotherapeutics, WindMIL Therapeutics, GRIT Biotechnology, Lyell Immunopharma, Cellular Biomedicine Group, and others.
+Added: We also may compete with therapies based on genetically engineered T-cell receptors rendered reactive against tumor-associated antigens prior to their administration to patients, as well as TIL therapies that are designed to be specific to neoantigens, including products developed by Adaptimmune Therapeutics, Alaunos Therapeutics, Intima Bioscience, Marker Therapeutics, Turnstone Biologics, Neogene and others.
To date, these technologies have been primarily applicable to hematologic malignancies, but their application in solid tumor indications may create competition with us.
−Removed: Competition for late-stage melanoma patients may come, if approved, from several therapies currently under clinical development across our lead indications in metastatic melanoma, non-small cell lung and cervical cancers.
−Removed: If we are successful in developing lifileucel for metastatic melanoma, we will compete against other investigational agents in late-stage development for use in combination with approved anti-PD-1 therapies at Bristol-Myers Squibb (relatlimab, a LAG-3-blocking antibody), Idera Pharmaceuticals (IMO-2125, a toll-like receptor, or TLR, 9 agonist), Checkmate Pharmaceuticals (CMP-001, a TLR9 agonist), Eisai (levatinib, a multiple tyrosine kinase inhibitor) and Replimune (RP1, or vusolimogene oderparepvec, an oncolytic virus therapy).
−Removed: Competition for lifileucel in late-stage cervical cancer patients also may arise from approved therapy TIVDAK™ (tisotumab vedotin-tftv) from Seagen/Genmab as well as an investigational agent in clinical development at Agenus (balstilimab, an anti-PD-1 therapy) for use in combination with approved anti-CTLA-4 inhibitor zalifrelimab.
−Removed: In addition, the cervical cancer treatment landscape has further evolved with the approval of KEYTRUDA + chemo + bevacizumab in front-line cervical cancer.
−Removed: We may also face competition for NSCLC patients from a large number of therapies in clinical development that target specific, emerging driver mutations in populations that overlap with our patient populations of interest, including Daiichi Sankyo/Astra Zeneca (datopotamab deruxtecan, an antibody-drug candidate), as well as sponsors with anti-PD-1 combinations in clinical development such as Exelixis (cabozantinib + atezolizumab), Mirati Therapeutics (sitravatinib + nivolumab) and Merck (vibostolimab alone and in combination with pembrolizumab).
−Removed: The studies for these NSCLC therapies are in various stages of the clinical pipeline, including several in Phase 3 trials.
−Removed: While other types of cancer immunotherapies may potentially be used in combination with TIL, such as checkpoint inhibitors, to enhance efficacy, we also expect substantial direct competition from other types of immunotherapies.
−Removed: We face competition from immunotherapy treatments offered by companies such as Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, and Roche.
−Removed: Immunotherapies are also being pursued by several biotechnology companies as well as by large pharmaceutical companies.
−Removed: We cannot predict whether other types of immunotherapies may be enhanced and show greater efficacy.
−Removed: As a result, we may have direct and substantial competition from such immunotherapies in the future.
−Removed: Many potential competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources than we do.
−Removed: Accordingly, our competitors may be more successful than us in obtaining approval for treatments and achieving widespread market acceptance and may render our treatments obsolete or non-competitive.
+Added: We may also face competition from immunotherapy treatments offered by companies such as Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, Roche, and BioNTech.
+Added: We may also face competition from novel IL-2 treatments in development by Alkermes, Werewolf, Nektar Therapeutics, Merck, Sanofi, Neoleukin Therapeutics and others.
+Added: Many of these companies and our other current and potential competitors have substantially greater research and development capabilities and financial, scientific, regulatory, manufacturing, marketing, sales, human resources, and experience than we do.
+Added: Many of our competitors have several therapeutic products that have already been developed, approved and successfully commercialized, or are in the process of obtaining regulatory approval for their therapeutic products in the U.S.
+Added: and internationally.
+Added: Our competitors may obtain regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in competitors establishing a strong market position before we are able to enter the market.
+Added: Our lead product candidate lifileucel is a TIL therapy for the treatment of advanced melanoma and advanced cervical cancer.
+Added: Currently, there are numerous companies that are developing various alternate treatments for melanoma and cervical cancer, including patients that have progressed after prior treatment with checkpoint inhibitors and chemotherapy.
+Added: Accordingly, lifileucel faces significant competition in the melanoma and cervical cancer treatment space from multiple companies.
+Added: Even if we obtain regulatory approval for lifileucel, the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our therapies.
Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of our competitors.
−Removed: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical study sites and patient registration for clinical studies, as well as in acquiring technologies complementary to, or necessary for, our programs.
−Removed: Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
+Added: Early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
+Added: These parties compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business;
7 unchanged sentences
We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors.
−Removed: We also seek to preserve the integrity and confidentiality of our data and
−Removed: trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.
+Added: We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.
While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach.
10 unchanged sentences
generally involves the following:
−Removed: ● completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices, or GLP, regulation, as well as manufacturing development and formulation studies;
+Added: ● completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices, or cGLP, regulation, as well as manufacturing development and formulation studies;
● submission to the FDA of an investigational new drug application, or IND, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;
−Removed: ● approval by an independent Institutional Review Board, or IRB, or ethics committee at each clinical site or centrally, before the trial is begun;
−Removed: ● performance of adequate and well-controlled human clinical trials to establish the safety, and efficacy of the proposed biologic product candidate for its intended purpose;
+Added: ● approval by an independent Institutional Review Board, or IRB, or ethics committee at each clinical site or centrally, before the clinical trial is begun;
+Added: ● performance of adequate and well-controlled human clinical trials, in accordance with the FDA’s current Good Clinical Practices, or cGCP, regulation, to establish the safety, purity, and potency of the proposed biologic product candidate for its intended purpose;
● preparation of and submission to the FDA of a BLA, after completion of pivotal clinical trial(s);
1 unchanged sentence
● a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;
−Removed: ● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical sites to assess compliance with current Good Clinical Practices, or cGCPs;
+Added: ● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical sites to assess compliance with cGCPs;
● FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated periodically when changes are made.
The testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all.
−Removed: Prior to beginning the first clinical trial with a new product candidate, we must submit an IND to the FDA.
+Added: Prior to beginning the first clinical trial with a new
+Added: product candidate, we must submit an IND to the FDA.
An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.
−Removed: The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.
−Removed: The IND also includes results of animal and in vitro studies assessing the toxicology,
−Removed: pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;
+Added: The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials.
+Added: The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;
chemistry, manufacturing, and controls information;
1 unchanged sentence
An IND must become effective before human clinical trials may begin.
−Removed: The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises concerns or questions about the proposed clinical trial.
+Added: The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within that initial 30-day time period, raises concerns or questions about the proposed clinical trial.
In such a case, the IND may be placed on clinical hold and the IND sponsor, and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.
−Removed: Clinical holds also may be imposed by the FDA at any time before or during trials due to safety concerns or non-compliance.
+Added: Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance.
Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
Human immunotherapy products are a new category of therapeutics.
−Removed: Because this is a relatively new and expanding area of novel therapeutic interventions, there can be no assurance as to the length of the trial period, the number of patients the FDA will require to be enrolled in the trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these trials will be acceptable to the FDA to support marketing approval.
−Removed: Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with cGCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.
−Removed: Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated, and a statistical analysis plan.
+Added: Because this is a relatively new and expanding area of novel therapeutic interventions, there can be no assurance as to the length of the clinical trial period, the number of patients the FDA will require to be enrolled in the clinical trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these clinical trials will be acceptable to the FDA to support marketing approval.
+Added: Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with cGCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.
+Added: Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated, and a statistical analysis plan.
A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
Investigators must also provide certain information to the clinical trial sponsors to allow the sponsors to make certain financial disclosures to the FDA.
−Removed: Furthermore, an independent IRB for each site proposing to conduct the clinical trial or centrally must review and approve the plan for any clinical trial, its informed consent form and any subject communications, before the clinical trial begins at that site, and upon amendment of the trial, and must monitor the study until completed.
−Removed: An IRB considers, among other things, whether the risks to individuals participating in the trials are minimized and are reasonable in relation to anticipated benefits and whether the planned human subject protections are adequate.
−Removed: Informed consent must be received from each study subject prior to participation in a clinical study.
+Added: Furthermore, an independent IRB for each site proposing to conduct the clinical trial or centrally must review and approve the plan for any clinical trial, its informed consent documentation and processes, and any subject communications, before the clinical trial begins at that site, and upon amendment of the clinical trial protocol, and must monitor the clinical trial until completed.
+Added: An IRB considers, among other things, whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits and whether the planned human subject protections are adequate.
+Added: Informed consent must be received from each clinical trial subject prior to participation in a clinical trial.
Progress reports detailing the results of the clinical trials must also be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events or other significant safety information is found.
−Removed: Regulatory authorities, the IRB, or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk, that the trial is not being conducted in accordance with regulatory or IRB requirements, or that the trial is unlikely to meet its stated objectives.
+Added: Regulatory authorities, the IRB, or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk, that the clinical trial is not being conducted in accordance with regulatory or IRB requirements, or that the clinical trial is unlikely to meet its stated objectives.
Sponsors may also discontinue studies or development programs for many reasons, including changing business objectives.
−Removed: Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, or DSMB, which provides recommendations and assessments for whether or not a study should move forward at designated check points based on access to certain data from the study.
−Removed: Following a review by a DSMB, the study may be halted if there is an unacceptable safety risk for subjects or on other grounds, such as failure to demonstrate efficacy.
−Removed: There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.
+Added: Some studies also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board, or DSMB, which provides recommendations and assessments for whether or not a clinical trial should move forward at designated check points based on access to certain data from the clinical trial.
+Added: Following a review by a DSMB, the clinical trial may be halted if there is an unacceptable safety risk for subjects or on other grounds, such as failure to demonstrate efficacy.
+Added: There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.
For instance, we are required to register certain clinical trials and post the results of certain completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within specified timeframes, and also to certify to FDA our compliance with these requirements when we make FDA submissions.
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● Phase 1 - The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition.
−Removed: These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.
−Removed: ● Phase 2 - The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and
−Removed: safety risks.
+Added: These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the
+Added: investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.
+Added: ● Phase 2 - The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.
Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.
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Typically, two Phase 3 studies are required by the FDA for product approval.
−Removed: ● Phase 4 - In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product.
+Added: ● Phase 4 - In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product, known as post-approval requirements or commitments, respectively.
These so-called Phase 4 studies may be made a condition to approval of the BLA.
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During the development of a new therapeutic, a sponsor may be able to request a Special Protocol Assessment, or SPA, the purpose of which is to reach an agreement with the FDA on the Phase 3 clinical trial protocol design and analysis that will form the primary basis of product approval and an efficacy claim, as well as preclinical carcinogenicity trials and stability studies.
−Removed: An SPA may only be modified with the agreement of the FDA and the trial sponsor, or if the director of the FDA reviewing division determines that a substantial scientific issue essential to determining the safety or efficacy of the product was identified after the testing began.
+Added: An SPA may only be modified with the agreement of the FDA and the clinical trial sponsor, or if the director of the FDA reviewing division determines that a substantial scientific issue essential to determining the safety or efficacy of the product was identified after the testing began.
An SPA is intended to provide assurance that, in the case of clinical trials, if the agreed upon clinical trial protocol is followed, the clinical trial endpoints are achieved, and there is a favorable risk-benefit profile, the data may serve as the primary basis for an efficacy claim in support of a BLA.
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In addition, under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
−Removed: Also, under the FDA Reauthorization Act of 2017, beginning in 2020, sponsors submitting applications for product candidates intended for the treatment of adult cancer which are directed at molecular targets that the FDA determines to be substantially relevant to the growth or progression of pediatric cancer must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric study data, using appropriate formulations, to inform potential pediatric labeling.
+Added: Also, under the FDA Reauthorization Act of 2017, beginning in 2020, sponsors submitting applications for product candidates intended for the treatment of adult cancer which are directed at molecular targets that the FDA determines to be substantially relevant to the growth or progression of pediatric cancer must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric clinical trial data, using appropriate formulations, to inform potential pediatric labeling.
The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
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The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent commercial production of the product within required specifications.
−Removed: Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with cGCP.
−Removed: If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing, clinical studies, application modifications, or information in a complete response letter, or CRL.
+Added: Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to ensure compliance with cGCP.
+Added: If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing, clinical trials, application modifications, or information in a complete response letter, or CRL.
A CRL indicates that the review cycle for the application is complete, and that the application is not ready for approval.
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An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.
−Removed: However, even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings, or precautions be included in the product labeling, including a boxed warning, require that post-approval studies, including Phase 4 clinical trials, be conducted to
−Removed: further assess a product’s safety and efficacy after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS which can materially affect the potential market and profitability of the product.
+Added: However, even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings, or precautions be included in the product labeling, including a boxed warning, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety and efficacy after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS which can materially affect the potential market and profitability of the product.
The FDA may also not approve label statements that are necessary for successful commercialization and marketing.
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Post-marketing studies or completion of ongoing studies after marketing approval are required to verify the biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.
−Removed: If this trial is not conducted, if it fails to verify the benefit, if other evidence demonstrates that the product is not safe, pure or potent, or if the applicant disseminates false or misleading promotional material, the FDA may withdraw approval of the application on an expedited basis.
+Added: If this clinical trial is not conducted, if it fails to verify the benefit, if other evidence demonstrates that the product is not safe, pure or potent, or if the applicant disseminates false or misleading promotional material, the FDA may withdraw approval of the application on an expedited basis.
Sponsors of products under the Accelerated Approval Pathway must further submit promotional materials to the FDA before dissemination.
−Removed: In addition, the Food and Drug Administration Safety and Innovation Act, or FDASIA, which was enacted and signed into law in 2012, established the new Breakthrough Therapy Designation.
+Added: In addition, the Food and Drug Administration Safety and Innovation Act, or FDASIA, which was enacted and signed into law in 2012, established the new BTD.
A sponsor may seek FDA designation of its product candidate as a Breakthrough Therapy if the product candidate is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the therapy may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
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assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor;
−Removed: and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller trials or more efficient trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment.
−Removed: Breakthrough Therapy designation also allows the sponsor to file sections of the BLA for review on a rolling basis.
+Added: and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller clinical trials or more efficient clinical trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment.
+Added: BTD also allows the sponsor to file sections of the BLA for review on a rolling basis.
Through the 21st Century Cures Act, or Cures Act, Congress also established another expedited program, called a RMAT designation.
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To qualify for this program, the product must be a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or a combination of such products, and not a product solely regulated as a human cell and tissue product.
−Removed: The product must be intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that
−Removed: the product has the potential to address an unmet need for such disease or condition.
+Added: The product must be intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that the product has the potential to address an unmet need for such disease or condition.
Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including early interactions with the FDA.
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After the FDA grants ODD, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.
−Removed: If a product that has ODD subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic, as sameness is defined in the FDA’s regulations, for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
+Added: If a product that has ODD subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, a seven-year period of marketing exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic, as sameness is defined in the FDA’s regulations, for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.
Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.
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Market and Data Exclusivity and Biosimilars
−Removed: While under the Biologics Price Competition and Innovation Act of 2009, or BPCIA, the FDA may eventually license products, as further described below, that are biosimilar to any of our product candidates that are approved, our products may receive periods of regulatory exclusivity, in addition to orphan drug exclusivity for those products with ODDs, providing additional protection from certain forms of competition.
+Added: While under the Biologics Price Competition and Innovation Act of 2009, or BPCIA, the FDA may eventually license products, as further described below, that are biosimilar to any of our product candidates that are approved, our products may receive periods of regulatory exclusivity, separately from orphan drug exclusivity for those products with ODDs, providing additional protection from certain forms of competition.
For instance, our products may receive 12 years of reference product exclusivity that begins running at the time of first licensure.
−Removed: During this 12-year time period, the FDA may not make an approval of a biosimilar product effective and may not accept a biosimilar application until after four years from the date of first licensure.
+Added: During this 12-year time period, the period of marketing exclusivity, the FDA may not make an approval of a biosimilar product effective.
+Added: In addition, the FDA may not accept a biosimilar application until after four years from the date of first licensure, the period of data exclusivity.
However, certain changes and supplements to an approved BLA, and subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the exclusivity period.
The PHSA also includes provisions governing patent litigation over patents that are directed to the reference products.
−Removed: The biosimilar product sponsor and reference product sponsor may, but are not required to, exchange certain patent and product information for the purpose of negotiating and determining the scope of patent litigation, including the patents to be asserted and challenged.
+Added: The biosimilar product sponsor and reference product sponsor may, but are not required to, exchange certain patent and product information for the purpose of negotiating and determining the scope of patent litigation, including the patents to be asserted and
Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit and injunction proceedings against the biosimilar product sponsor.
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There must be no difference between the reference product and a biosimilar in conditions of use, route of administration, dosage form, and strength.
−Removed: A biosimilar product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
+Added: Further, a biosimilar product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
Pediatric Exclusivity and Patent Term Extension
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and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity.
−Removed: Under the Best Pharmaceuticals for Children Act, a six-month exclusivity may be granted if a sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.
+Added: Under the Best Pharmaceuticals for Children Act, a six-month exclusivity may be granted if a sponsor submits pediatric data that fairly responds to a written request from the FDA for such data.
+Added: The FDA may issue such a written request on its own initiative or at the request of the sponsor.
The data do not need to show the product to be effective in the pediatric population studied;
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Post-Approval Requirements
−Removed: Any products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product and deviations, annual reporting and monitoring and providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, certain electronic records and signature requirements, fulfilling post-marketing study and REMS commitments, and complying with FDA promotion and advertising requirements, which include, among other things, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved uses or otherwise consistent with the FDA-approved product labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, rules regarding communication of health care economic information regarding biopharmaceutical products to payors and formularies, and requirements for promotional activities involving the internet.
+Added: Any products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product and deviations, annual reporting and monitoring and providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, certain electronic records and signature requirements, fulfilling post-marketing clinical trial and REMS commitments, and complying with FDA promotion and advertising requirements, which include, among other things, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved uses or otherwise consistent with the FDA-approved product labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, rules regarding communication of health care economic information regarding biopharmaceutical products to payors and formularies, and requirements for promotional activities involving the internet.
Although physicians may prescribe legally available products for off-label use, if they deem such use to be appropriate in their professional medical judgment, manufacturers may not market or promote such off-label uses.
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cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.
−Removed: Manufacturers and other entities involved in the manufacture and distribution of approved products are
−Removed: required to register their establishments and list their products with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other applicable laws.
+Added: Manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments and list their products with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other applicable laws.
Accordingly, manufacturers must continue to expend time, money, and effort in the areas of production and quality control to maintain cGMP compliance.
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Our sales, promotion, medical education and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the U.S., and in addition to the FDA, these entities may include the Federal Trade Commission, the Department of Justice, the Centers for Medicare & Medicaid Services, other divisions of the Department of Health and Human Services and state and local governments.
−Removed: Our promotional and scientific/educational programs must comply with
−Removed: the federal Anti-Kickback Statute, or AKS, the Foreign Corrupt Practices Act, or FCPA, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.
+Added: Our promotional and scientific/educational programs must comply with the federal Anti-Kickback Statute, or AKS, the Foreign Corrupt Practices Act, or FCPA, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.
The federal AKS prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs, in whole or in part.
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Additionally, the FCPA, and similar worldwide anti-bribery laws, generally prohibit companies and their intermediaries from making, offering or authorizing improper payments or other items of value, directly or indirectly, to foreign officials, political parties, or candidates for the purpose of obtaining or retaining business.
−Removed: The FCPA also obligates companies whose securities are listed in the
+Added: The FCPA also obligates companies whose securities are listed in the U.S.
to comply with accounting provisions requiring us to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.
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While we would not be a “covered entity” under HIPAA, it is possible that we may enter into a service or business arrangement that would cause us to serve as a “business associates,” defined as a person or entity that performs certain functions or activities that involve the use or disclosure of protected health information in connection with providing a service for or on behalf of, or provide services to, a covered entity.
−Removed: HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.
+Added: HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil
+Added: actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.
In addition, state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect.
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Companies must still comply with the CCPA during the ramp up period before CPRA goes into effect.
−Removed: The CCPA and CPRA, among other things, create new data privacy obligations for covered companies and provides new privacy rights to California residents, including the right to opt out of certain disclosures of their information.
+Added: The CCPA and CPRA, among other things, create new data privacy obligations for covered companies and provide new privacy rights to California residents, including the right to opt out of certain disclosures of their information.
The CCPA also created a private right of action with statutory damages for certain data breaches, thereby potentially increasing risks associated with a data breach.
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The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.
−Removed: Federal and state enforcement bodies have recently increased their scrutiny of
−Removed: interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.
+Added: Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.
Ensuring that business arrangements with third parties comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert management's attention from the business.
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In addition, significant uncertainty exists as to the reimbursement status of newly approved healthcare products.
−Removed: We may need to conduct expensive clinical studies to demonstrate the comparative cost-effectiveness of our products.
+Added: We may need to conduct expensive clinical trials to demonstrate the comparative cost-effectiveness of our products.
The product candidates that we develop may not be considered cost-effective.
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Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy, and are developing increasingly sophisticated methods of controlling healthcare costs.
−Removed: They may limit coverage to specific drug products on an approved
−Removed: list, or formulary, which might not include all the FDA-approved drug products for a particular indication, or they may control costs, particularly for new expensive therapies, by requiring prior authorization or imposing other restrictions before covering certain products, or they may condition payment based on achieving performance metrics.
+Added: They may limit coverage to specific drug products on an approved list, or formulary, which might not include all the FDA-approved drug products for a particular indication, or they may control costs, particularly for new expensive therapies, by requiring prior authorization or imposing other restrictions before covering certain products, or they may condition payment based on achieving performance metrics.
Legislative proposals to reform healthcare or reduce costs under government programs may result in lower reimbursement for our product candidates or exclusion of our product candidates from coverage.
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We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development programs that enable continued learning and growth and a robust employment package that promotes well-being across all aspects of their lives.
−Removed: In addition to salaries, these programs include potential annual discretionary bonuses, stock awards, a 401(k) plan, healthcare and insurance benefits, health savings and flexible spending accounts, paid time off, family leave, and flexible work schedules, among other benefits.
+Added: In addition to salaries, these programs include potential annual discretionary bonuses, stock awards, Employee Stock Purchase Plan, a 401(k) plan, healthcare and insurance benefits, health savings and flexible spending accounts, paid time off, family leave, and flexible work schedules, among other benefits.
We have taken proactive, aggressive action throughout the COVID-19 pandemic to protect the health and safety of our employees.
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.