Unresectable Pleural Malignant Mesothelioma

The Norwegian biotech is now eligible for extra scientific advice on its drug, fee reductions, and the potential for ten years of market exclusivity in Europe. Image credit: Shutterstock/Esra Pekdemir. The European Medicines Agency (EMA) has granted orphan drug designation to Ultimovacs for its universal cancer vaccine UV1 for the treatment of mesothelioma. The positive opinion follows a similar move by the US Food and Drug Administration, which granted an orphan drug designation for UV1 in October 2023. The Norwegian biotech is now eligible for extra scientific advice on its drug, fee reductions, and the potential for ten years of market exclusivity, as per European orphan drug incentives. The EMA based its decision on positive results from Ultimovacs’ Phase II NIPU trial evaluating the vaccine in malignant pleural mesothelioma patients, according to a 19 February press release. UV1 works by inducing T cell response against telomerase reverse transcriptase (hTERT) – a protein that provides the limitless self-renewal hallmark in cancer progression. The antigen is present in around 85-90% of cancers, according to Ultimovacs. Mesothelioma is an aggressive cancer that develops in the lining of internal organs and is most commonly caused by exposure to asbestos. See Also: The randomised, multi-centre, open-label, proof of concept Phase II study (NCT04300244) compared patients receiving UV1 in addition to the checkpoint inhibitors Yervoy (ipilimumab) and Opdivo (nivolumab)—both marketed by Bristol Myers Squibb (BMS)— to patients receiving Yervoy and Opdivo alone. All participants had already received platinum-based chemotherapy as first-line treatment. The trial has been conducted in collaboration with BMS. Ultimovacs has reported a clinically meaningful improvement in overall survival for the group receiving the cancer vaccine with a good safety and tolerability profile observed. According to a ClinicalTrials.gov entry, 118 participants are estimated to enrol. The aim of the study, according to Ultimovacs, is to evaluate adding a therapeutic cancer vaccine to an immune checkpoint inhibitor regimen. In addition to orphan designations in mesothelioma, UV1 also has FDA orphan drug status for the treatment of stage IIB-stage IV melanoma . The candidate has been granted two fast track designations by the FDA – one for unresectable malignant pleural mesothelioma to improve overall survival and the other for the treatment of unresectable or metastatic melanoma. The company says it has Phase II trials in five cancer indications in total. Ultimovacs will face competition from big pharma as cancer vaccines gain traction across the industry. mRNA-based vaccines being developed by Pfizer/BioNTech and Moderna/MSD’s have gained the most attention, showcasing high efficacy in reducing cancer spreading and death. Whilst mRNA vaccines are tailored to specific cancers, Ultimovacs says its off-the-shelf has the potential to treat a broad range of cancers.

The Orphan Drug Designation (ODD) from the European Medicines Agency (EMA) was granted based on results from the randomized Phase II clinical trial NIPU, which showed improved overall survival with UV1 in combination with ipilimumab and nivolumab in patients with malignant pleural mesothelioma UV1 has also received U.S. Food and Drug Administration ODD for UV1 in the treatment of patients with mesothelioma and malignant stage IIB-stage IV melanoma Oslo, February 19, 2024: Ultimovacs ASA (“Ultimovacs”) (OSE ULTI), a clinical-stage biotechnology leader in novel immunotherapeutic cancer vaccines, today announced that the European Medicines Agency (EMA) has issued a positive opinion on the company’s application for Orphan Drug Designation (ODD) for its therapeutic cancer vaccine UV1 for the treatment of mesothelioma. The designation was granted based on results from the Phase II clinical trial, NIPU evaluating UV1 added to ipilimumab and nivolumab treatment in patients with malignant pleural mesothelioma. “The EMA’s Orphan Drug Designation for UV1 in mesothelioma is an important step forward in the development of our cancer vaccine in this indication,” said Carlos de Sousa, CEO of Ultimovacs. “It allows for important regulatory and commercial benefits and provides us with the potential to rapidly advance UV1 for a patient population with poor prognosis and a high unmet medical need.” To qualify for orphan designation in the EU, an investigational medicine must be intended to treat a seriously debilitating or life-threatening condition affecting fewer than five in 10,000 people in the EU, based on data that support that the investigational medicine may produce clinically significant benefits over existing treatments. ODD provides companies with certain benefits and incentives, including ten years of market exclusivity upon reaching the market, clinical protocol assistance, access to a centralized marketing authorization procedure, and reduced regulatory fees. Mesothelioma is a rare and aggressive form of cancer with a high mortality rate and few therapeutic options. Patients with mesothelioma commonly have a history of occupational or environmental exposure to asbestos, and it typically takes decades for this specific form of cancer to develop. The impact of UV1 vaccination in patients with malignant pleural mesothelioma has been evaluated in a randomized Phase II clinical trial, NIPU. In the study, UV1 was combined with checkpoint inhibitors ipilimumab and nivolumab and compared to ipilimumab and nivolumab alone as a second-line treatment, after first-line treatment with platinum-based chemotherapy. The results from the study, presented at the European Society for Molecular Oncology (“ESMO”) Congress 2023, demonstrated a clinically meaningful improvement in overall survival for UV1 treatment in combination with ipilimumab and nivolumab versus ipilimumab and nivolumab alone. In addition, UV1 maintained its positive safety and tolerability profile in this combination with no added toxicities. Oslo University Hospital sponsored the NIPU study with support from Bristol Myers Squibb and Ultimovacs. On February 5, 2024, the FDA granted Fast Track designation for UV1 in combination with ipilimumab and nivolumab for the treatment of patients with unresectable malignant pleural mesothelioma to improve overall survival. In October 2023, UV1 received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with mesothelioma. In December 2021, the FDA granted Orphan Drug Designation for UV1 for the treatment of stage IIB-stage IV melanoma. In October 2021, the FDA granted Fast Track designation for UV1 as add-on therapy to ipilimumab or pembrolizumab for the treatment of unresectable or metastatic melanoma. ==ENDS== About NIPUNIPU (Nivolumab and Ipilimumab Plus/minus UV1 vaccination) is a randomized, multi-center phase II trial in which Ultimovacs’ universal cancer vaccine, UV1, is evaluated in combination with Bristol-Myers Squibb’s checkpoint inhibitors, nivolumab and ipilimumab, as second-line treatment of malignant pleural mesothelioma. The trial sponsor is Oslo University Hospital, supported in the preparation and execution of the trial by Ultimovacs and Bristol Myers Squibb. The 118 patients are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every two weeks) and ipilimumab (1 mg/kg every six weeks) until disease progression, unacceptable toxicity, or for a maximum of 2 years. Patients randomized to the experimental arm received eight intradermal injections of UV1 vaccine during the first three months of treatment. The objective of the study is to achieve a clinically meaningful progression-free survival (PFS) benefit in patients with malignant pleural mesothelioma (MPM) after progression on first-line standard platinum doublet chemotherapy. Subsequent events emerging in patients in both arms of the NIPU study will continue to be monitored beyond the read-out of the primary endpoint. The ipilimumab and nivolumab combination has been approved as first-line treatment for patients with malignant pleural mesothelioma in Europe and the U.S. About Mesothelioma Mesothelioma is a rare and aggressive type of cancer that occurs in the thin layer of tissue that surrounds the lungs and inside of the chest. Mesothelioma accounted for 30 870 new cancer cases and 26 278 cancer deaths worldwide in 2020, according to International Agency for Research on Cancer (Globocan 2020). Pleural mesothelioma is a disease with a high unmet medical need, especially in industrialized countries. The median overall survival is approximately one year. Occupational asbestos exposure is the No. 1 cause of the disease, and several occupations, like firefighters, military veterans, construction, and industry workers, are at risk. This cancer usually takes several decades to develop after a person’s first exposure to asbestos. Most patients are diagnosed after age 70 because of the long latency period. Even though the use of asbestos to a large extent is banned in many countries today, new incidences of mesothelioma will continue to be a medical and public health challenge because of the long latency period typical of the illness. For patients with inoperable disease, few treatment options are available after first-line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond, and improvements are called for. Telomerase is expressed in mesothelioma cells and is therefore a relevant target for therapeutic vaccination. About UltimovacsUltimovacs is a clinical-stage biotechnology leader in novel immunotherapeutic cancer vaccines with broad applicability. Ultimovacs’ lead candidate, UV1, is an off-the-shelf therapeutic cancer vaccine directed against human telomerase (hTERT), an antigen that is present in 85-90% of cancers in all stages of tumor growth. A broad clinical program, with Phase II trials in five cancer indications enrolling more than 670 patients, aims to demonstrate UV1’s impact in combination with other immunotherapies in multiple cancer types expressing telomerase and where patients have unmet medical needs. UV1 is a patented technology owned by Ultimovacs. In addition, Ultimovacs holds all rights of the proprietary TET technology platform for any possible future use of formulations in various solid tumor indications. The Company is listed on Euronext Oslo Stock Exchange (OSE:ULTI). About UV1 Phase II programThe immunotherapeutic off-the-shelf cancer vaccine UV1 is investigated in combination with checkpoint inhibitors in patients with various cancer indications with diverse tumor biology. The diversity of the UV1 Phase II program places Ultimovacs in a favorable position to capture the cancer vaccine’s potential broad applicability when combined with checkpoint inhibitors: INITIUM: Evaluating UV1 in combination with ipilimumab and nivolumab as first-line treatment for patients with malignant melanoma. Enrollment of 156 patients completed in July 2022. Expected readout in March 2024. Sponsored by Ultimovacs.NIPU: Evaluating UV1 in combination with ipilimumab and nivolumab as second-line treatment for patients with malignant pleural mesothelioma. Enrollment of 118 patients completed in January 2023. Data presented at the ESMO Congress in October 2023, showed that UV1 as add-on to ipilimumab and nivolumab, demonstrated a statistically significant and clinically meaningful improvement of overall survival versus ipilimumab and nivolumab alone. 31% of the patients receiving UV1 vaccine experienced an objective response, compared to 16% in the control arm. The investigator-initiated trial is led by Oslo University Hospital and supported by Bristol-Myers Squibb and Ultimovacs.FOCUS: Evaluating UV1 in combination with pembrolizumab as first-line treatment for patients with head and neck cancer. Enrollment of 75 patients completed in August 2023, expected readout H2 2024. The investigator-initiated trial is led by Halle University in Germany, supported by Ultimovacs.DOVACC: Evaluating UV1 in combination with olaparib and durvalumab as maintenance therapy in non-BRCA mutated patients with advanced ovarian cancer. More than 40% of the 184 patients enrolled as of Q4 2023 reporting, expected readout H1 2025. The investigator-initiated trial is led by NSGO-CTU and supported by ENGOT, AstraZeneca, and Ultimovacs.LUNGVAC: Evaluating UV1 combined with cemiplimab as first-line treatment of non-small cell lung cancer patients. More than 15% of 138 patients enrolled as of Q4 2023 reporting, expected readout H1 2026. The investigator-initiated trial is led by Vestre Viken (Drammen Hospital) and supported by Ultimovacs. About UV1UV1 is an off-the-shelf therapeutic cancer vaccine designed to induce a specific T cell response against telomerase. UV1 consists of long, synthetic peptides representing a sequence in the reverse transcriptase subunit of telomerase (hTERT), shown to induce CD4+ T cells. These CD4+ T cells have the potential to provide inflammatory signals and T cell support believed to be critical for triggering a strong anti-tumor immune response. Following intradermal injection, antigen presenting cells (APCs) in the skin are exposed to the vaccine peptides. These APCs will process the peptides, and present vaccine epitopes on Human Leukocyte Antigen (HLA) molecules to naïve T cells in the lymph nodes. Activated vaccine specific T cells will then enter the circulation and search for cells displaying their cognate antigen in the context of HLA molecules. The UV1 peptides contain several epitopes, shown to be non-restrictive in terms of (HLA) alleles for presentation. It is therefore not required to perform HLA pre-screening of patients, which potentially enables broad population utilization of the vaccine. UV1 is administered over three months as eight intradermal injections together with the immune-modulator GM-CSF. For further information, please see www.ultimovacs.com or contact: Carlos de Sousa, CEO Email: carlos.desousa@ultimovacs.comPhone: +47 908 92507 Anne Worsøe, Head of IREmail: anne.worsoe@ultimovacs.comPhone: +47 90686815 This information is considered to be inside information pursuant to the EU Market Abuse Regulation and is subject to the disclosure requirements pursuant to Section 5-12 in the Norwegian Securities Trading Act.This stock exchange announcement was published by Anne Worsøe, Head of Investor Relations at Ultimovacs ASA, on February 19, 2024 at 07:00 CET.

Readout of topline result expected in March 2024 from UV1 randomized Phase II trial INITIUM in Ultimovacs’ lead indication, advanced malignant melanomaTopline result will report primary endpoint of progression-free survival (PFS) of UV1 vaccination combined with standard of care immunotherapy over immunotherapy alonePositive results from the INITIUM trial will be further presented at an international medical conference and published in a reputable medical journalUV1 granted Fast Track designation from FDA based on clinically meaningful survival results in Phase II trial NIPU in mesothelioma, presented at ESMO Congress 2023 Sustained long-term survival data reported in UV1-103 trial in advanced malignant melanomaExploratory study TENDU based on TET technology met primary endpoint Conference call and webcast scheduled for February 14, 2024, at 13:00 (CET) Oslo, February 14, 2024: Ultimovacs ASA ("Ultimovacs") (OSE ULTI), a clinical-stage biotechnology leader in novel immunotherapeutic cancer vaccines, announces its fourth quarter 2023 results today. “The upcoming significant milestone is the announcement of the topline result from the INITIUM trial next month. If the trial meets the primary endpoint and demonstrates a clinical benefit over the current gold standard of immunotherapy for this indication, ipilimumab and nivolumab, it represents a significant accomplishment. From an industry perspective, it will be the first time an off-the-shelf cancer vaccine shows such an additional clinical benefit in a randomized trial in the most serious form of skin cancer”, said Carlos de Sousa, CEO of Ultimovacs. “Our mission is to demonstrate UV1’s value for patients. Because of the ground-breaking potential of a positive topline result, we will seek to present the full analysis at a major oncology conference and publish the results in a top-tiered medical journal. Sharing clinical trial results in peer-reviewed forums represents a validation from experts in the field, as well as an effective outreach to leaders in the global medical, investment and pharmaceutical sectors. We look forward to communicating the topline result in March and to share the full study results at the best peer-reviewed opportunity thereafter.” Fourth Quarter 2023 Highlights Near-term readout of UV1 Phase II study INITIUM in unresectable or metastatic malignant melanoma On January 16, 2024, Ultimovacs announced that the last patient enrolled in the INITIUM trial has now been followed for 18 months, thereby enabling readout of the primary endpoint. The Company expects to announce topline results from the randomized Phase II clinical trial in March this year. With a positive topline result from the trial, the ambition is to present the study results at an upcoming international oncology conference and in a high impact medical journal.On October 31, 2023, Ultimovacs announced that a suggested INITIUM study protocol amendment allowing data cut-off 18 months after inclusion of last patient if 70 endpoints have not occurred was accepted by relevant regulatory authorities. The amendment followed the observation that very few endpoints occurred during 2023. By mid-January 2024, the last enrolled patient had completed follow-up time of 18 months triggering data cut-off. The protocol amendment maintains the integrity of the study statistics without materially affecting the scientific value of the clinical trial. The topline result from the study is expected in March 2024.On November 2, 2023, the Company announced the completed enrollment of 21 patients in the INITIUM supplementary single-arm study in malignant melanoma. Study objectives are to investigate how immune responses against telomerase transfers into anti-tumor activity and further to clinical benefit for patients. Clinically meaningful survival data reported at the ESMO Congress in UV1 Phase II study NIPU in malignant mesothelioma NIPU trial principal investigator, Professor Åslaug Helland, MD, PhD, reported the results from the study in second-line treatment of patients with malignant mesothelioma as an oral presentation at the ESMO Congress 2023 in Madrid in October. The data presented showed that UV1, as add-on to the checkpoint inhibitors ipilimumab and nivolumab, demonstrated a clinically meaningful overall survival benefit after a relevant observation period, with no added toxicities compared to ipilimumab and nivolumab alone. The study also reported that 31% of the patients treated with UV1 experienced an objective response, as compared to 16% in the control arm. An analysis of the Hazard Ratio in Overall Survival showed that UV1 cancer vaccination combined with ipilimumab and nivolumab reduced the risk of death by 27%. On October 9, 2023, Ultimovacs announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation (ODD) to the Company’s therapeutic cancer vaccine UV1 for the treatment of patients with mesothelioma. On February 5, 2024, Ultimovacs announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the Company’s therapeutic cancer vaccine UV1 in combination with ipilimumab and nivolumab for the treatment of patients with unresectable malignant pleural mesothelioma to improve overall survival. Demonstrated sustained long-term survival in Phase I study UV1-103 in malignant melanoma On October 12, 2023, Ultimovacs reported sustained long-term overall survival in patients treated with UV1 cancer vaccine in the UV1-103 Phase I study in malignant melanoma. No confirmed patient deaths occurred in Cohort 1 between the 3-year and 4-year follow-up period. Exploratory Phase I TENDU study of TET technology met primary endpoint On December 18, 2023, Ultimovacs announced that the dose-escalation, first-in-human Phase I trial showed good safety and tolerability across all dose cohorts and met the primary endpoint of the study. Data included observations of immune activation with vaccine specific T cell responses. In addition to the trial results, advancements in preclinical research, technology development and product manufacturing provide a valuable foundation for the future development of the TET technology and TET-based vaccine candidates. Clinical trials update UV1 Phase II program INITIUM (malignant melanoma): Evaluating ipilimumab and nivolumab +/- UV1. The enrollment of 156 patients was completed in July 2022. Topline results are expected in March 2024. INITIUM Supplementary Study: Evaluating UV1 + ipilimumab and nivolumab. Enrollment of the single arm supplementary study, which will not be included in the INITIUM topline results, was completed in October 2023, with a total of 21 patients. NIPU (metastatic pleural mesothelioma): Evaluating ipilimumab and nivolumab +/- UV1. The enrollment of 118 patients was completed in January 2023. The study results were presented at the ESMO Congress in October 2023. FOCUS (head and neck cancer): Evaluating pembrolizumab +/- UV1. The enrollment of 75 patients was completed in August 2023. The readout is expected in the second half of 2024. DOVACC (ovarian cancer): Evaluating olaparib and durvalumab +/- UV1 vs. olaparib alone. 75 out of 184 patients have been enrolled to date, up from 46 as of the previous quarterly report. The multinational trial in ten European countries took longer to initiate than anticipated during the pandemic. The readout is expected in H1 2025 (previously guided to H2 2024).LUNGVAC (non-small cell lung cancer): Evaluating cemiplimab +/- UV1. 23 out of 138 patients have been enrolled to date, up from 13 as of the previous quarterly report. In addition, 3 patients have received treatment with pembrolizumab +/- UV1. The sponsor is currently investigating various possibilities to accelerate the trial enrollment. The readout is expected in H1 2026 (previously guided to H2 2025). TENDU Phase I trial (prostate cancer) based on the TET technology platform: The enrollment of 12 patients was completed in December 2022. The results from the study were announced in December 2023. Financial update Ultimovacs expects that the current cash resources will support operations through 2024 based on current programs and plans. Total operating expenses amounted to MNOK 59.6 in Q4 2023 and MNOK 215.7 FY 2023. Total loss was MNOK 55.9 for the period and MNOK 189.2 in FY2023.Net negative cash flow from operations was MNOK 42.4 in Q4 2023, and net decrease in cash and cash equivalents, not including currency effects, was MNOK 38.9 during Q4 2023. Cash and cash equivalents amounted to MNOK 266.6 as of December 31, 2023. The quarterly report and presentation will be published at 07:00 CET on February 14, 2024 and will be publicly available on the Ultimovacs website. The Company will conduct its fourth quarter conference call and webcast at 13:00 CET the same day. Questions can be submitted throughout the event. The webcast will be archived for replay following the conference call. Link to webcast here. For further information, please see www.ultimovacs.com or contact: Carlos de Sousa, CEO Email: carlos.desousa@ultimovacs.com Phone: +47 908 92507 Hans Vassgård Eid, CFOEmail: hans.eid@ultimovacs.comPhone: +47 482 48632 Anne Worsøe, Head of Investor RelationsEmail: anne.worsoe@ultimovacs.comPhone: +47 906 86815 About UltimovacsUltimovacs is a clinical-stage biotechnology leader in novel immunotherapeutic cancer vaccines with broad applicability. Ultimovacs’ lead candidate, UV1, is an off-the-shelf therapeutic cancer vaccine directed against human telomerase (hTERT), an antigen that is present in 85-90% of cancers in all stages of tumor growth. A broad clinical program, with Phase II trials in five cancer indications enrolling more than 670 patients, aims to demonstrate UV1’s impact in combination with other immunotherapies in multiple cancer types expressing telomerase and where patients have unmet medical needs. UV1 is a patented technology owned by Ultimovacs. In addition, Ultimovacs holds all rights of the proprietary TET technology platform for any possible future use of formulations in various solid tumor indications. The Company is listed on Euronext Oslo Stock Exchange (OSE:ULTI). This information is subject of the disclosure requirements pursuant to Section 5-12 in the Norwegian Securities Trading Act. This stock exchange announcement was published by Joachim Midttun, Financial Manager at Ultimovacs ASA, on February 14, 2024 at 07:00 CET. Attachments Ultimovacs-ASA-Q423-Report Ultimovacs-ASA-Q423-Presentation