NovoCure Stock

NovoCure Limited operates as a global oncology company. The company has a proprietary platform technology called Tumor Treating Fields (TTFields), which are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. The company’s key priorities are to drive commercial adoption of Optune Gio and Optune Lua, its commercial TTFields therapy devices, and to advance clinical and product development programs intended to extend overall survival in some of the most aggressive forms of cancer.

Optune Gio is approved by the U.S. Food and Drug Administration (FDA) under the Premarket Approval (PMA) pathway for the treatment of adult patients with newly diagnosed glioblastoma (GBM) together with temozolomide, a chemotherapy drug, and for adult patients with GBM following confirmed recurrence after chemotherapy as monotherapy treatment. The company also has a CE certificate to market Optune Gio for the treatment of GBM in the European Union (EU), as well as approval or local registration in the United Kingdom (U.K.), Japan, Canada and certain other countries. Optune Lua is approved by the FDA under the Humanitarian Device Exemption (HDE) pathway to treat malignant pleural mesothelioma and pleural mesothelioma (together, MPM) together with standard chemotherapies. The company has also received CE certification in the European Union (EU) and approval or local registration to market Optune Lua in certain other countries. The company markets Optune Gio and Optune Lua in multiple countries around the globe with the majority of its revenues coming from the use of Optune Gio in the U.S., Germany and Japan. The company is actively evaluating opportunities to expand its international footprint.

The company focuses its research and development activities in areas of greatest anticipated value creation. This includes non-small cell lung cancer, brain cancers, and pancreatic cancer. In 2023, the company announced results from its phase 3 LUNAR study evaluating the use of TTFields together with standard therapies following platinum-based treatment failure in the treatment of patients with metastatic non-small cell lung cancer (NSCLC). Patients treated with TTFields therapy and standard therapies demonstrated a statistically significant and clinically meaningful improvement in overall survival over standard therapies alone. The LUNAR study also showed a statistically significant and clinically meaningful improvement in overall survival when patients were treated with TTFields therapy and immune checkpoint inhibitors, as compared to those treated with immune checkpoint inhibitors alone, and a positive trend in overall survival when patients were treated with TTFields therapy and docetaxel versus docetaxel alone. In December 2023, the company filed a PMA application with the FDA seeking approval for the use of TTFields therapy together with standard systemic therapies for the treatment of NSCLC following progression on or after platinum-based therapy. In January 2024, the company announced the FDA had accepted this submission for filing. The company is investing in pre-commercial launch activities and anticipate a decision in the second half of 2024.

The company has several ongoing or planned trials which will further explore the use of TTFields therapy in the treatment of NSCLC, including the phase 3 METIS and LUNAR-2 trials, as well as the phase 2 KEYNOTE B36 and LUNAR-4 trials. In addition to its trials in NSCLC, the company has multiple ongoing or planned trials in its brain and pancreatic cancer programs, including the phase 3 TRIDENT, KEYNOTE D58 and PANOVA-3 trials, and the phase 2 PANOVA-4 trial.

The company’s therapy is delivered through a medical device and it continues to advance its Products with the intention to extend survival and maintain quality of life for patients. The company has several product development programs underway that are designed to optimize the delivery of TTFields to the target tumor and enhance patient ease of use. The company’s intellectual property portfolio contains hundreds of issued patents and numerous patent applications pending worldwide. The company possesses global commercialization rights to its Products in oncology and are well-positioned to extend those rights into the future as it continues to find innovative ways to improve its Products.

In 2018, the company granted Zai Lab (Shanghai) Co., Ltd. (Zai) a license to commercialize its Products in China, Hong Kong, Macau and Taiwan (Greater China) under a License and Collaboration Agreement (the Zai Agreement). The Zai Agreement also establishes a development partnership intended to accelerate the development of TTFields therapy in multiple solid tumor cancer indications.

Commercial Business

Optune Gio is marketed for the treatment of GBM, the most common form of primary brain cancer and an aggressive disease for which there are few effective treatment options. Optune Lua is marketed for the treatment of MPM, a rare cancer that has been strongly linked to asbestos exposure. The company markets Optune Gio and Optune Lua in multiple countries around the globe with the majority of its revenues coming from the use of Optune Gio in the U.S., Germany and Japan.

Treatment of newly diagnosed GBM

In 2015, the company received FDA approval to market Optune Gio (then known as Optune) for the treatment of adult patients with newly diagnosed supratentorial GBM in combination with temozolomide. The FDA approved Optune Gio for newly diagnosed GBM based on the EF-14 study (EF-14), which was a randomized phase 3 clinical study which compared, post radiation, Optune Gio plus temozolomide versus temozolomide alone for the treatment of newly diagnosed GBM. The primary endpoint of the study was progression-free survival and a powered secondary endpoint was overall survival.

In EF-14, Optune Gio plus temozolomide demonstrated unprecedented five-year survival results. Median overall survival was extended by nearly five months (median overall survival of 20.9 months versus 16.0 months for temozolomide alone). Median progression-free survival was extended by 2.7 months to 6.7 months for Optune Gio plus temozolomide from 4.0 months for temozolomide alone. The final EF-14 data were published in the Journal of the American Medical Association in 2017.

The extension of progression-free and overall survival in patients receiving Optune Gio in combination with temozolomide in EF-14 was not specific to any prognostic subgroup or tumor genetic marker and was consistent regardless of MGMT methylation status, extent of resection, age, performance status or gender. Optune Gio was safely combined with temozolomide with no significant increase in serious adverse events compared with temozolomide alone. The most common side effect related to Optune Gio was mild to moderate skin irritation.

Treatment of recurrent GBM

The company initially received FDA approval for Optune Gio in 2011 for use as a monotherapy treatment for adult patients with GBM, following confirmed recurrence after chemotherapy. The FDA approved Optune Gio based on the EF-11 study (EF-11), a randomized, phase 3 clinical study.

EF-11 was a multi-center, active controlled clinical study of 237 adults with recurrent GBM. Participants received either Optune Gio as a monotherapy (n=120) or the physician’s choice of chemotherapy (n=117). Chemotherapies chosen for the active control arm included mainly bevacizumab, nitrosoureas and temozolomide. The primary endpoint was superiority in overall survival. Overall survival for patients treated with Optune Gio alone and active chemotherapy was 6.6 months and 6.0 months, respectively (p=0.27: HR = 0.86). The study demonstrated that Optune Gio provided clinically comparable survival with an overall better quality of life.

In 2020, the EF-19 post-approval registry, which was a post-approval study required as a condition of FDA approval, confirmed the effectiveness and safety of Optune Gio as monotherapy and further strengthened Optune Gio's clinical profile in recurrent GBM. The EF-19 study studied Optune Gio as a monotherapy for the treatment of recurrent GBM in 192 patients compared to the 117 recurrent GBM patients who received best standard of care chemotherapy in the company’s EF-11 registration study. Optune Gio as monotherapy reduced the risk of death with fewer adverse events compared to best standard of care chemotherapy. For patients who received at least one course of therapy, Optune Gio prolonged survival by a median 1.7 months.

Treatment of MPM

In 2019, the company received FDA approval via the HDE pathway to market Optune Lua (then known as NovoTTF-100L) for the treatment of adult patients with unresectable, locally advanced or metastatic MPM concurrent with pemetrexed and platinum-based chemotherapy. The FDA approved Optune Lua for MPM based on the STELLAR study (STELLAR). STELLAR was a single-arm, open-label, multi-center study designed to test the safety and efficacy of Optune Lua in combination with pemetrexed combined with cisplatin or carboplatin in patients with unresectable, previously untreated MPM. The study was powered to prospectively determine the overall survival in patients treated with Optune Lua plus chemotherapy. Secondary endpoints included overall response rate (per mRECIST criteria), progression-free survival and safety.

STELLAR investigated safety and efficacy among 80 patients treated with Optune Lua plus standard of care chemotherapy. In STELLAR, the median overall survival was 18.2 months (95% CI, 12.1-25.8 months) across all patients treated with Optune Lua plus chemotherapy. The median overall survival was 21.2 months for patients with epithelioid MPM (n=53) and 12.1 months for patients with non-epithelioid MPM (n=27). 62% of patients enrolled in STELLAR who used Optune Lua plus chemotherapy were still alive at one year, with 42% of patients alive at two years. The disease control rate in patients with at least one follow-up CT scan performed (n=72) was 97%. 40% of patients had a partial response, 57% had stable disease, and 3% had progressive disease. The median progression-free survival was 7.6 months (95% CI, 6.7-8.6 months).

Commercial Markets

The company has built a commercial organization and market Optune Gio for the treatment of GBM in multiple countries in North America, Europe and Asia.

Commercial Execution

The company has sales force colleagues globally. Healthcare providers must undergo a certification training in order to prescribe the company’s Products. The company’s sales and marketing efforts are principally focused on driving adoption of Optune Gio for the treatment of GBM among both neuro-oncologists and radiation oncologists. In certain countries, neurosurgeons and medical oncologists also drive adoption. The company continues to focus on driving key academic center engagements.

The company operates as a direct-to-patient distributor of its Products, except for Japan. In Japan, the company distributes Optune Gio through hospitals and provide patient support services under a contractual arrangement with the hospital. Once an eligible patient is identified by a certified prescriber, the healthcare provider’s office submits a prescription order form and supporting documentation to the company. The company provides the healthcare provider and the patient with a usage report for monitoring patient time on therapy.

Development Pipeline

Based on the results of its preclinical research, the company has developed a pipeline strategy to advance TTFields therapy through phase 2 and phase 3 studies across multiple solid tumor types. The company anticipates expanding its clinical pipeline over time to include additional solid tumor cancer indications.

The solid tumor cancers subject to its phase 2 and phase 3 studies, as well as the studies themselves, are described in greater detail below. In addition to its studies in tumors of the head, thorax and abdomen, the company continues to conduct research in its approved indications to further advance the scientific evidence supporting the use of TTFields therapy in GBM and to gather additional information about its therapy's optimal use.

In January 2024, the final patient was enrolled in its TRIDENT trial (TRIDENT), a phase 3 study testing the potential survival benefit of initiating Optune Gio concurrent with radiation therapy and maintenance temozolomide in patients with newly diagnosed GBM. The primary endpoint is overall survival. Secondary endpoints include, but are not limited to, progression-free survival, survival rates at one and two years, overall radiological response, severity and frequency of adverse effects, pathological changes in resected GBM tumors post treatment, quality of life, and correlation of overall survival to TTFields dose. TRIDENT was designed to accrue 950 patients with a 24-month minimum follow-up period after the last patient is enrolled. Final data from the TRIDENT trial is anticipated in 2026.

In 2021, the company enrolled the last patient in its UNAR trial (LUNAR), a phase 3 study testing the effectiveness of TTFields therapy in combination with immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone for patients with stage 4 NSCLC who progressed during or after platinum-based therapy. It is estimated that approximately 30,000 patients actively seek treatment for stage 4 NSCLC after progressing during or after platinum-based therapy each year in the U.S. The primary endpoint was superior overall survival of patients treated with TTFields therapy plus immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone.

In June 2023, the company presented positive results from the LUNAR study which met its primary endpoint with a statistically significant and clinically meaningful 3-month improvement in median overall survival with TTFields therapy added to standard therapies (hazard ratio=0.74, P=0.035). Patients randomized to receive TTFields therapy together with standard therapies (n=137) demonstrated median overall survival of 13.2 months compared to 9.9 months in patients treated with standard therapies alone (n=139).

In July 2023, the FDA accepted the investigation device exemption for the LUNAR-2 clinical trial (LUNAR-2), a randomized, phase 3 study evaluating the efficacy of TTFields therapy concomitant with pembrolizumab and platinum-based chemotherapy for the treatment of patients with metastatic NSCLC. The two primary endpoints of LUNAR-2 are overall survival and progression-free survival. Secondary endpoints include, but are not limited to, progression-free survival and overall survival according to patient histology, progression-free survival and overall survival according to patient tumor proportion score, one-, two-, and three-year survival rates, objective response rate, duration of response, disease control rate and severity and frequency of adverse effects. LUNAR-2 is designed to accrue 734 patients with a 21-month follow-up following the enrollment of the last patient.

In 2022, the first patient was enrolled in the company’s KEYNOTE B36 trial (KEYNOTE B36), a phase 2 study evaluating the safety and efficacy of TTFields therapy together with the anti-PD-1 therapy pembrolizumab for the treatment of first-line metastatic NSCLC.

In March 2023, the company enrolled the final patient in its METIS study (METIS), a phase 3 study testing the effectiveness of SRS plus TTFields therapy compared to SRS alone in patients with brain metastases resulting from NSCLC. It is estimated that between 20 to 40% of patients with NSCLC develop brain metastases, with an estimated 38,000 to 77,000 patients diagnosed each year in the U.S. with brain metastases resulting from NSCLC.

In February 2023, the final patient was enrolled in the company’s PANOVA-3 trial (PANOVA-3), a phase 3 study evaluating the efficacy of TTFields therapy together with nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine alone as a front-line treatment for unresectable locally advanced pancreatic cancer. It is estimated that approximately 48,000 patients are diagnosed with unresectable pancreatic cancer each year in the U.S.

In 2023, the first patient was enrolled in the phase 2 PANOVA-4 trial (PANOVA-4) evaluating the safety and efficacy of TTFields therapy together with atezolizumab, gemcitabine and nab-paclitaxel in the treatment of metastatic pancreatic cancer.

In addition to its development pipeline, the company has conducted phase 2 and phase 3 clinical trials exploring the use of TTFields therapy in a variety of other solid tumor cancers.

In 2022, the company announced the final results from its EF-31 phase 2 study, a single-arm study evaluating the safety and efficacy of TTFields therapy together with XELOX chemotherapy (and trastuzumab for HER2-positive patients) as first-line treatment for patients with unresectable gastric adenocarcinoma or gastroesophageal junction adenocarcinoma in partnership with Zai.

In 2021, the company announced the final results of its HEPANOVA phase 2 trial, a single-arm study evaluating the safety and efficacy of TTFields therapy in combination with sorafenib for the treatment of advanced hepatocellular cancer.

In August 2023, the company announced preliminary results from the phase 3 INNOVATE-3 trial (INNOVATE-3), studying the effectiveness of TTFields therapy with paclitaxel in patients with platinum-resistant ovarian cancer. INNOVATE-3 did not meet its primary endpoint of overall survival at the final analysis. Patients randomized to receive TTFields therapy plus paclitaxel (n=280) demonstrated a median overall survival of 12.2 months compared to a median overall survival of 11.9 months in patients treated with paclitaxel alone (n=278) (hazard ratio=1.008).

Zai License and Collaboration Agreement

In 2018, the company announced a strategic collaboration with Zai. The collaboration agreement grants Zai a license to commercialize the company’s Products in Greater China and establishes a development partnership intended to accelerate the development of TTFields therapy in multiple solid tumor cancer indications. Zai has launched Optune Gio for the treatment of newly diagnosed GBM in Hong Kong and mainland China and is seeking marketing authorization for GBM in Taiwan.

Intellectual property

The company’s robust global patent and intellectual property portfolio consists of hundreds of issued patents in multiple jurisdictions covering various aspects of its devices and related technology. In the U.S., the company’s patents have expected expiration dates between 2024 and 2041. The company has also filed several hundred additional patent applications worldwide, that, if issued, may protect aspects of its platform beyond the current last-to-expire patent in the relevant market. These pending applications cover innovations relating to its arrays, field generators and software platform, in addition to other topics related to TTFields therapy.

Pursuant to its strategic collaboration with Zai, the company granted Zai a license to commercialize TTFields therapy in Greater China.

Research, Development and Clinical Studies Expenses

The company’s research, development and clinical studies expenses included $223.1 million for the year ended December 31, 2023.

Government regulation

In the U.S., the company’s Products and its operations are subject to extensive regulation by the FDA under the Federal Food, Drug, and Cosmetic Act (FDCA). In the EU member states where it markets the company’s Products and operates, it is subject to, inter alia, the Medical Device Regulation (MDR) as implemented into national legislation by the EU member states, and as amended from time to time, as well as local applicable law. The MDR replaced the Medical Device Directive (MDD) on May 26, 2021. In Switzerland, the company’s Products and operations are subject to, inter alia, the Medical Devices Ordinance, which implements the MDR into Swiss law. In Japan, the company’s Products and operations are subject to regulation by the Pharmaceuticals and Medical Device Agency (PMDA) under the Pharmaceuticals and Medical Devices Act (PMD Act). In the U.K., the company’s Products and operations are subject to, inter alia, the Medical Devices Regulations 2002 and the Medical Devices (Amendment etc.) (EU Exit) Regulations 2020 (the UK Regulations), which implements the MDR and MDR like provisions into the U.K. law. The company has registered three of its facilities with the FDA. The company is subject to announced and unannounced inspections by the FDA to determine its compliance with the Quality System Regulation (QSR) and other regulations and these inspections include the manufacturing facilities of its suppliers. In Japan, the company must obtain approvals from the Ministry of Health, Labour, and Welfare (MHLW) to market its devices. Each regulatory approval process outside of the U.S. includes all the risks associated with FDA regulation, as well as country-specific regulations.

As a DME supplier, the company is subject to the Stark law, which is a strict liability law that prohibits Medicare payments for certain designated health services (DHS), including DME ordered by physicians who, personally or through an immediate family member, have an ownership interest in or a compensation arrangement with the furnishing DHS entity. In the U.S., the company is subject to accreditation and licensing requirements as a durable medical equipment (DME) supplier in most states and must meet the supplier standards of Medicare, Medicaid and other federal healthcare programs.

Numerous federal and state laws and regulations, including the Health Insurance Portability and Accountability Act of 1996 as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH and collectively HIPAA), govern the collection, dissemination, use, security and privacy of individually identifiable health information. The company is in substantial compliance with such applicable laws and regulations, including HIPAA.

The company has adopted policies and codes of conduct regarding its interactions with Covered Recipients and is in material compliance with the Sunshine Act. However, the company’s failure to adhere to these requirements could materially adversely impact its business and financial results. Additionally, a number of states have transparency reporting requirements similar to (and in some cases broader than) the Sunshine Act, and regulations similar to the Sunshine Act have been adopted in foreign countries including a number of EU member states.

History

NovoCure Limited was founded in 2000. The company was incorporated under the laws of Jersey (Channel Islands) in 2000.