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Item 1. Business

2022-02-24 compared with 2021-02-25 · 209 added, 196 removed, 388 unchanged (51% of the section changed)

We are a global oncology company with a proprietary platform technology called Tumor Treating Fields ("TTFields"), which are electric fields tuned to specific frequencies that disrupt cancer cell division.

Our key priorities are to drive commercial adoption of Optune and Optune Lua, our commercial TTFields delivery systems, and to advance clinical and product development programs intended to extend overall survival in some of the most aggressive forms of cancer.

Our key priorities are to drive commercial adoption of Optune and Optune Lua, our commercial TTFields devices, and to advance clinical and product development programs intended to extend overall survival in some of the most aggressive forms of cancer.

Optune 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 gioblastoma ("GBM") in combination with temozolomide, a chemotherapy drug, and for adult patients with GBM following confirmed recurrence after chemotherapy as monotherapy treatment.

We also have approval or a CE certificate to market Optune for the treatment of GBM in the European Union ("EU"), Japan and certain other countries.

We market Optune in the U.S., Austria, Germany, Israel, Japan, Sweden and Switzerland, which we refer to as our "active markets." With respect to GBM, our sales and marketing efforts are principally focused on driving adoption with both neuro-oncologists and radiation oncologists.

We are expanding our commercial operations into France with an initial focus on developing key opinion leader relationships in GBM and establishing a path to reimbursement for our Products.

Optune Lua is approved by the FDA under the Humanitarian Device Exemption ("HDE") pathway to treat malignant pleural mesothelioma ("MPM") in combination with standard chemotherapies.

We have received CE certification to market Optune Lua (under the name " NovoTTF-100L ") in the EU and Switzerland.

We currently market Optune Lua in the U.S., and are evaluating plans to expand access to our therapy for MPM patients in other markets.

With respect to MPM, our commercial efforts are principally focused on generating awareness and on establishing a dialogue with third-party payers around access to Optune Lua.

We believe the mechanism of action behind TTFields therapy may be broadly applicable to solid tumor cancers.

Currently, we are conducting phase 3 pivotal trials evaluating the use of TTFields in brain metastases from non-small cell lung cancer ("brain metastases"), non-small cell lung cancer ("NSCLC"), ovarian cancer and pancreatic cancer.

In 2020, we enrolled our first patient in our global phase 4 TRIDENT trial to test the potential survival benefit of initiating Optune concurrent with radiation therapy versus following radiation therapy in patients with newly diagnosed GBM.

We are also conducting phase 2 pilot trials evaluating the use of TTFields in liver cancer and gastric cancer, as well as testing the potential incremental survival benefit of TTFields delivered using high-intensity arrays versus standard arrays.

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.

We also have a CE certificate to market Optune for the treatment of GBM in the European Union ("EU"), as well as approval or local registration in the United Kingdom ("UK"), Japan and certain other countries.

Optune Lua is approved by the FDA under the Humanitarian Device Exemption ("HDE") pathway to treatment malignant pleural mesothelioma ("MPM") together with standard chemotherapies.

We have also received CE certification in the EU and approval or local registration to market Optune Lua in certain other countries.

We market Optune and Optune Lua in multiple countries around the globe with the majority of our revenues coming from the use of Optune in the U.S., Germany and Japan.

We are actively evaluating and executing upon opportunities to expand our international footprint.

We believe the physical mechanism of action behind TTFields therapy may be broadly applicable to solid tumor cancers.

Currently, we are conducting phase 3 pivotal studies evaluating the use of TTFields in non-small cell lung cancer ("NSCLC"), ovarian cancer, brain metastases from non-small cell lung cancer ("brain metastases") and pancreatic cancer.

In 2021, we completed patient enrollment in our phase 3 pivotal NSCLC and ovarian cancer studies with data anticipated in 2022 and 2023, respectively.

Additionally, we have multiple ongoing phase 2 pilot studies evaluating the use of TTFields in gastric cancer, for which patient enrollment is complete, and stage 3 NSCLC, as well as testing the potential incremental survival benefit of TTFields delivered using high-intensity arrays versus standard arrays.

We are designing several phase 2 pilot studies in partnership with oncology leaders to further explore the capabilities of TTFields.

We are also currently conducting a global phase 4 post-marketing study testing the potential survival benefit of initiating Optune concurrent with radiation therapy versus following radiation therapy in patients with newly diagnosed GBM.

In 2021, we presented data from our phase 2 pilot study studying the use of TTFields in liver cancer and are currently evaluating protocol design options for a large, randomized study in this indication.

We anticipate expanding our clinical pipeline over time to study the safety and efficacy of TTFields for additional solid tumor indications and combinations with other cancer treatment modalities.

In the second quarter of 2021, we plan to launch the KEYNOTE B36 trial ("KEYNOTE B36"), a phase 2 pilot trial to study TTFields with pembrolizumab in first-line NSCLC through our clinical trial collaboration with MSD (a tradename of Merck & Co., Inc.).

Our therapy is delivered through a medical device and we continue to advance our Products with the intention to extend survival and maintain quality of life for patients.

We have several product development programs underway that prioritize impact on both TTFields dose and patient ease of use.

Our intellectual property portfolio contains over 185 issued patents and numerous patent applications pending worldwide.

We believe we own global commercialization rights to our Products in oncology and are well-positioned to extend those rights into the future as we continue to find innovative ways to improve our Products.

We have several product development programs underway that are designed to optimize TTFields delivery to the target tumor and enhance patient ease of use.

Our intellectual property portfolio contains hundreds of issued patents and numerous patent applications pending worldwide.

We believe we possess global commercialization rights to our Products in oncology and are well-positioned to extend those rights into the future as we continue to find innovative ways to improve our Products.

In 2018, we granted Zai Lab (Shanghai) Co., Ltd.

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interference.

TTFields therapy is a cancer treatment that uses electric fields tuned to specific frequencies to disrupt cancer cell division.

TTFields therapy is a treatment that uses electric fields tuned to specific frequencies to disrupt cancer cell division.

All cells are surrounded by a bilipid membrane, which separates the interior of the cell, or cytoplasm, from the space around it.

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Interfering with these key processes disrupts mitosis and can lead to cell death.

Our track record of fundamental scientific research extends across two decades and, in all of our preclinical research to date, TTFields has demonstrated a consistent anti-mitotic effect.

Research is ongoing to further refine our understanding of the multi-pronged mechanism of action of TTFields.

In addition to its anti-mitotic effect, TTFields has been shown to inhibit DNA damage repair, to induce autophagy, to reduce cell migration and invasion, to increase cell membrane permeability and disrupt the blood-brain barrier, and to induce immunogenic cell death.

Our track record of fundamental scientific research extends across more than two decades and, in all of our preclinical research to date, the application of TTFields has demonstrated a consistent anti-mitotic effect.

Recent preclinical work suggests that the well-established impairment created by the physical effect of TTFields to tumor cells results in a series of changes to cell processes that inhibit DNA damage repair, induce autophagy, reduce cell migration and invasion, and increase anti-tumor immunity.

Research is ongoing to further refine and build upon our understanding of TTFields' several mechanisms of action.

Beyond our internal research efforts, we provide independent researchers with preclinical laboratory bench systems, known as inovitro™ and inovivo™, and we grant funding to support basic and translational research on TTFields.

We also support independent research through our Investigator-Sponsored Trials and Preclinical Material Transfer Agreement programs in order to enhance our understanding of the optimal use of TTFields.

TTFields is intended principally for use in combination with other standard-of-care cancer treatments.

TTFields is intended principally for use together with other standard-of-care cancer treatments.

There is a growing body of evidence that supports TTFields' broad applicability with certain other cancer therapies, including radiation therapy, certain chemotherapies and certain immunotherapies.

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TTFields therapy is delivered through a portable medical device.

The complete delivery system, called Optune or Optune Lua, includes a portable electric field generator, arrays, rechargeable batteries and accessories.

The complete devices, called Optune and Optune Lua (for GBM and MPM treatment, respectively), include a portable electric field generator, arrays, rechargeable batteries and accessories.

Sterile, single-use arrays are placed directly on the skin in the region surrounding the tumor and connected to the electric field generator to deliver therapy.

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We plan to specifically target individual solid tumor types by optimizing field generator parameters such as frequency and power output.

Our arrays have been developed and are in use, either commercially or clinically, for application on the head, chest and abdomen.

Our arrays have been developed and are in use, either commercially or clinically, for application on the head, thorax and abdomen.

Through engineering efforts, we plan to continue to advance our Products to optimize TTFields therapy for patients.

We have several product development programs underway intended to extend survival and maintain quality of life.

Our development programs will prioritize impact on both TTFields dose and patient ease of use and are primarily focused on enhancements to the field generator, arrays and software applications.

We are developing a third generation device to optimize the use of electric fields to treat tumors, next generation arrays to be more flexible and deliver higher intensities, next generation array layout planning software, and patient-centered software to support larger patient populations in multiple indications.

Over time, we may have the opportunity to optimize the energy delivered to individual patients, potentially improving efficacy.

We have several product development programs underway designed to extend survival and enhance quality of life.

Our product development programs are primarily focused on enhancements to the field generator, arrays and software applications.

Our product development initiatives include, but are not limited to:

next generation arrays that are more flexible and deliver higher intensities, next generation array layout planning software, development of a third generation device that optimizes the use of electric fields to treat tumors, and patient-centered software that enables scaled patient support as we prepare to treat larger patient populations across multiple indications.

ultimate goal is to optimize the energy delivered to patients' tumors, potentially improving efficacy.

Any enhancements will be subject to applicable regulatory reviews and approvals.

Our commercial business

Optune is currently marketed in our active markets 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 currently marketed in the U.S.

for the treatment of MPM, a rare cancer that has been strongly linked to asbestos exposure.

Our first commercial priority in each active market is to generate awareness of our Products and our clinical trial data.

Optune is currently 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 currently marketed for the treatment of MPM, a rare cancer that has been strongly linked to asbestos exposure.

We market Optune and Optune Lua in multiple countries around the globe with the majority of our revenues coming from the use of Optune in the U.S., Germany and Japan.

Treatment of newly diagnosed GBM

In 2015, we received FDA approval to market Optune for the treatment of adult patients with newly diagnosed supratentorial GBM in combination with temozolomide.

The FDA approved Optune for newly diagnosed GBM based on the EF-14 trial ("EF-14"), which was a randomized, phase 3 pivotal clinical trial which compared, post radiation, Optune plus temozolomide versus temozolomide alone for the treatment of newly diagnosed GBM.

The primary endpoint of the trial was progression-free survival and a powered secondary endpoint was overall survival.

The FDA approved Optune for newly diagnosed GBM based on the EF-14 study ("EF-14"), which was a randomized, phase 3 pivotal clinical study which compared, post radiation, Optune 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 plus temozolomide demonstrated unprecedented five-year survival results.

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Median progression-free survival was extended by 2.7 months to 6.7 months for Optune plus temozolomide from 4.0 months for temozolomide alone.

The final EF-14 data were published in JAMA in 2017.

The final EF-14 data were published in the Journal of the American Medical Association in 2017.

The following graph presents the overall survival data in the intent-to-treat population from our five-year analysis:

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Physical, role, social, emotional and cognitive functioning for patients treated with Optune and temozolomide all remained stable and comparable with patients treated with temozolomide alone.

In 2018, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology® (NCCN Guidelines®) for Central Nervous Systems Cancers were updated to include alternating electric fields therapy (Optune) in combination with temozolomide following standard brain radiation therapy with concurrent temozolomide as a Category 1 recommended postoperative adjuvant treatment option for patients with newly diagnosed supratentorial GBM.

The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology® (NCCN Guidelines®) for Central Nervous Systems Cancers were updated to include alternating electric fields therapy (Optune) in combination with temozolomide following standard brain radiation therapy with concurrent temozolomide as a

Category 1 recommended postoperative adjuvant treatment option for patients with newly diagnosed supratentorial GBM.

A post-hoc analysis of EF-14 showed that more time on Optune predicted increased survival in GBM patients.

An Optune monthly usage threshold as low as 50 percent correlated with significantly improved outcomes in patients

treated with Optune together with temozolomide compared to patients treated with temozolomide alone.

An Optune monthly usage threshold as low as 50 percent correlated with significantly improved outcomes in patients treated with Optune together with temozolomide compared to patients treated with temozolomide alone.

The greater the patients’ monthly usage of Optune, the better their outcomes.

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a median survival of 24.9 months from randomization and a five-year probability of survival of 29.3 percent.

In 2019, a separate post-hoc analysis of EF-14 showed that higher intensities at the tumor bed were associated with increased survival in GBM patients.

A separate post-hoc analysis of EF-14 showed that higher intensities at the tumor bed were associated with increased survival in GBM patients.

Patients treated with Optune at higher intensities (greater than or equal to 1.06 V/cm;

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We initially received FDA approval for Optune in 2011 for use as a monotherapy treatment for adult patients with GBM, following confirmed recurrence after chemotherapy.

The FDA approved Optune based on the EF-11 trial ("EF-11"), a randomized, phase 3 pivotal clinical trial.

EF-11 was a multi-center, active controlled clinical trial of 237 adults with recurrent GBM.

The FDA approved Optune based on the EF-11 study ("EF-11"), a randomized, phase 3 pivotal clinical study.

EF-11 was a multi-center, active controlled clinical study of 237 adults with recurrent GBM.

Participants received either Optune as a monotherapy (n=120) or the physician’s choice of chemotherapy (n=117).

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Overall survival for patients treated with Optune alone and active chemotherapy was 6.6 months and 6.0 months, respectively (p=0.27:

The trial demonstrated that Optune provided clinically comparable survival with an overall better quality of life.

The study demonstrated that Optune provided clinically comparable survival with an overall better quality of life.

More objective radiological responses were observed in the Optune group than in the active control chemotherapy group (14 patients versus 7 patients).

Three patients in the Optune alone arm had a complete response versus no patients in the active chemotherapy arm.

In 2020, the FDA-mandated EF-19 post-approval registry trial confirmed the effectiveness and safety of Optune as monotherapy and further strengthened Optune's clinical profile in recurrent GBM.

The EF-19 trial studied Optune 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 Novocure’s EF-11 registration trial.

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 as monotherapy and further strengthened Optune's clinical profile in recurrent GBM.

The EF-19 study studied Optune 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 Novocure’s EF-11 registration study.

Optune as monotherapy reduced the risk of death with fewer adverse events compared to best standard of care chemotherapy.

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In 2019, we 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 trial ("STELLAR").

STELLAR was a single-arm, open-label, multi-center trial designed to test the safety and efficacy of Optune in combination with pemetrexed combined with cisplatin or carboplatin in patients with unresectable, previously untreated MPM.

The trial was powered to prospectively determine the overall survival in patients treated with Optune Lua plus 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 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.

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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.

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).

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Our commercial markets

We have built a commercial organization and market Optune for the treatment of GBM in the U.S., Austria, Germany, Israel, Japan, Sweden and Switzerland, which we refer to as our active markets.

We have also built a commercial organization to market Optune Lua for the treatment of MPM in the U.S.

We have built a commercial organization and market Optune and Optune Lua for the treatment of GBM and MPM in multiple countries in North America, Europe and Asia.

In 2022, we estimate that approximately:

• 15,000 people will be diagnosed with GBM or tumors that typically progress to GBM in the U.S.

Of this population, we estimate that approximately 11,200 patients are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility.

We estimate that approximately 8,200 of eligible patients will actively seek treatment.

Of this population, we estimate that approximately 8,200 patients who are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility will actively seek treatment.

• 4,600 people will be diagnosed with GBM or tumors that typically progress to GBM in Germany.

Of this population, we estimate that approximately 3,400 patients are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility.

We estimate that approximately 2,500 of eligible patients will actively seek treatment.

Of this population, we estimate that approximately 2,500 patients who are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility will actively seek treatment.

• 2,200 people will be diagnosed with GBM or tumors that typically progress to GBM in Japan.

Of this population, we estimate that approximately 1,600 patients are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility.

We estimate that approximately 1,200 of eligible patients will actively seek treatment.

• 1,600 people will be diagnosed with GBM or tumors that typically progress to GBM in our other active markets:

Austria, Israel, Sweden and Switzerland.

Of this population, we estimate that approximately 1,200 patients are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility.

We estimate that approximately 900 of eligible patients will actively seek treatment.

Of this population, we estimate that approximately 1,200 patients who are candidates for treatment with Optune based upon the rate of disease progression and medical eligibility will actively seek treatment.

In 2022, we estimate that approximately 3,000 people are diagnosed with malignant mesothelioma in the U.S.

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We believe there are many more patients who could benefit from treatment with TTFields than are currently on therapy.

We continue to focus on increasing penetration for GBM in our active markets and on successfully expanding our MPM business in the U.S.

We continue to focus on increasing penetration for GBM and MPM.

In the future, we anticipate strategically expanding into additional geographic markets and additional indications, pending regulatory approval.

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Healthcare providers must undergo a certification training in order to prescribe our Products.

As of December 31, 2020, we trained more than 3,700 GBM prescribers in our active markets.

With respect to the treatment of GBM, our sales and marketing efforts are principally focused on driving adoption with both neuro-oncologists and radiation oncologists.

In certain countries, neurosurgeons and medical oncologists also drive adoption.

We continue to focus on driving key academic center engagement in our active markets.

As of December 31, 2020, we trained more than 130 MPM prescribers in the U.S.

With respect to the treatment of MPM, our sales and marketing efforts are principally focused on certification training, supporting the required Institutional Review Board approval process, and driving awareness among radiation oncologists and thoracic oncologists.

We continue to focus on driving key academic center engagements.

With respect to the treatment of MPM, our sales and marketing efforts are principally focused on certification training, supporting the required Institutional Review Board approval process in certain geographies, and driving awareness among radiation oncologists and thoracic oncologists.

We believe the benefit of our education efforts will extend beyond MPM to future indications treated by the same prescribers and that radiation oncologists will continue to play an increasingly important role in driving adoption of our Products in both current and future indications.

We currently operate as a direct-to-patient distributor of our Products in all active markets except for Japan.

We currently operate as a direct-to-patient distributor of our Products, except for Japan.

In Japan, we distribute Optune through hospitals and provide patient support services under a contractual arrangement with the hospital.

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Once treatment is initiated, we provide 24/7 technical support for patients and caregivers as well as assistance with insurance reimbursement.

We also provide the healthcare provider and the patient with a usage report for monitoring patient

time on therapy.

We believe we have the experience, expertise and infrastructure to scale our sales and marketing efforts in our active markets.

In addition to our commercial organization, we believe we have established a scalable supply chain.

We also provide the healthcare provider and the patient with a usage report for monitoring patient time on therapy.

We believe we have the experience and expertise to scale our sales and marketing efforts.

Billing and reimbursement

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Currently, the monthly list price for our therapy in the U.S.

is $21,000 and we have set list prices in our other active markets that are approximately equivalent to this price, subject to currency fluctuations.

is $21,000 and we have set list prices outside of the United States that are approximately equivalent to this price, subject to currency fluctuations.

We typically negotiate discounts from our list price with healthcare payers, and in certain cases we accept government-mandated discounts from our list prices in order to secure reimbursement for our Products.

We continue to work with payers to expand access to Optune for patients with GBM.

As of December 31, 2020, we have received national reimbursement for Optune in Austria, Germany, Israel, Japan, Sweden and Switzerland, where coverage becomes effective on April 1, 2021.

As of December 31, 2021, we have received national reimbursement for Optune in Austria, Germany, Israel, Japan, Sweden and Switzerland.

In the U.S., a substantial majority of Americans with private health insurance had coverage of Optune for newly diagnosed GBM and/or recurrent GBM as of December 31, 2021.

As of September 2019, Americans who are beneficiaries of the Medicare fee-for-service program also have coverage of Optune for newly diagnosed GBM.

Our team is focused on working through the typical administrative ramp-up with Medicare to ensure that we realize the full financial benefit as soon as possible.

We believe we have completed our administrative ramp-up towards processing Medicare claims and are efficiently pursuing appeals.

We are actively appealing Medicare fee-for-service coverage denials up to and including the Administrative Law Judge ("ALJ") process with Centers for Medicare and Medicaid Services ("CMS").

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Our development pipeline

Based on the results of our preclinical research, we have developed a pipeline strategy to advance TTFields through phase 2 pilot, phase 3 pivotal trials and phase 4 post-marketing studies across multiple solid tumor types.

Based on the results of our preclinical research, we have developed a pipeline strategy to advance TTFields through phase 2 pilot, phase 3 pivotal studies and phase 4 post-marketing studies across multiple solid tumor types.

We anticipate expanding our clinical pipeline over time to include additional solid tumor cancer indications.

Current Development Pipeline

The solid tumor cancers subject to our phase 2 pilot, phase 3 pivotal, and phase 4 post-marketing trials, as well as the trials themselves, are described in greater detail below.

The solid tumor cancers subject to our phase 2 pilot, phase 3 pivotal, and phase 4 post-marketing studies, as well as the studies themselves, are described in greater detail below.

We continue to conduct research in our approved indications to further advance the scientific evidence supporting the use of TTFields in GBM and to gather additional information about our therapy's optimal use.

EF-33 phase 2 pilot trial

In 2020, we enrolled the first patient in our EF-33 trial, an open-label, single-arm phase 2 pilot clinical trial to study if Optune delivered at 200 kHz to the brain using high-intensity arrays in the treatment of recurrent GBM significantly improves the clinical outcomes of patients compared to using standard transducer arrays.

2-THE-TOP phase 2 pilot study

In November 2021, Dr.

David Tran, Chief of the Division of Neuro-Oncology at the McKnight Brain Institute at the University of Florida, presented updated data from the phase 2 pilot 2-THE-TOP study testing the safety and efficacy of TTFields together with pembrolizumab and temozolomide for the treatment of adult patients with newly diagnosed GBM.

As of May 24, 2021 25 patients with a median age of 61 years were enrolled in the study, with a median follow-up of 14.7 months.

32% had biopsy only and 16% had partial resection.

72% had unmethylated MGMT and 12% had an IDH mutation.

48% were progression-free, and 60% were still alive.

Of the 19 patients with follow-up greater than 9 months, the median progression-free survival was at least 11.2 months compared to 6.7 months from the historical control study, EF-14, in which patients received TTFields and adjuvant temozolomide.

24% patients with measurable tumors achieved partial or complete response.

193,760 peripheral blood mononuclear cells were sequenced in 12 patients before pembrolizumab and detected robust post-TTFields T cell activation in 11 of 12 patients via the T1IFN trajectory with a strong correlation with the TCRαβ clonal expansion Simpson index (Spearman coefficient r=-0.8, P=0.014).

The study defined a T cell-based gene signature of TTFields effects on TCRαβ clonal expansion.

The most common adverse events were thrombosis (16%), seizure (12%), and metabolic disturbances (8%).

2-THE-TOP concluded that the triple combination of TTFields, temozolomide, and pembrolizumab is well tolerated and shows early evidence of efficacy in newly diagnosed GBM patients.

Patients will continue follow-up with survival and molecular data to be updated.

EF-33 phase 2 pilot study

In 2020, we enrolled the first patient in our EF-33 study, an open-label, single-arm phase 2 pilot clinical study to study if Optune delivered at 200 kHz to the brain using high-intensity arrays in the treatment of recurrent GBM significantly improves the clinical outcomes of patients compared to using standard transducer arrays.

The primary endpoint is progression-free survival.

Secondary endpoints include overall survival, progression-free survival rate at six months, overall survival rate at one year and two years, overall radiological response, and severity and frequency of adverse events.

Secondary endpoints include overall survival, progression-free survival rate at six months, overall survival rate at one year and two years, overall radiological response, and severity and

frequency of adverse events.

All comparisons will be made against historical control data from the EF-11 study.

EF-33 is expected to enroll 25 patients and we anticipate data will be available in 2022.

TRIDENT phase 4 post-marketing trial

In 2020, we enrolled the first patient in our TRIDENT trial ("TRIDENT"), a phase 4 post-marketing trial testing the potential survival benefit of initiating Optune concurrent with radiation therapy in patients with newly diagnosed GBM.

TRIDENT phase 4 post-marketing study

In 2020, we enrolled the first patient in our TRIDENT study ("TRIDENT"), a phase 4 post-marketing study testing the potential survival benefit of initiating Optune concurrent with radiation therapy in patients with newly diagnosed GBM.

The primary endpoint is overall survival.

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TRIDENT is designed to accrue 950 patients with 24 months minimum follow-up after the last patient enrolled.

Brain metastases

Metastatic cancer is cancer that has spread from the place where it first started to another place in the body.

In metastasis, cancer cells break away from where they first formed (the primary cancer), travel through the blood or lymph system, and form new tumors (the metastatic tumors) in other parts of the body.

The exact incidence of brain metastases is unknown because no national cancer registry documents brain metastases, and estimates from scientific literature vary greatly based on the study methodology applied.

It is estimated that between 100,000 and

240,000 new cases are diagnosed in the U.S.

each year with brain metastases estimated to occur in between 10% to 40% of all cancer patients.

Brain metastases are commonly treated with a combination of surgery and radiation.

Chemotherapy is often given for the primary tumor, but many chemotherapy agents do not cross the blood brain barrier and are thus ineffective in the treatment of brain metastases.

When brain metastases appear, they are either surgically removed or treated with radiation using stereotactic radiosurgery ("SRS") when possible.

Whole brain radiation therapy, although effective in delaying progression or recurrence of brain metastases when given either before or after SRS, is associated with neurotoxicity with a significant decline in cognitive functioning.

Thus, whole brain radiation therapy is often delayed until later in the disease course and is often used as a last resort.

This practice results in a window of unmet need after localized surgery and SRS are used and before whole brain radiation therapy is administered to delay or prevent the additional spread of brain metastases.

METIS phase 3 pivotal trial

In 2016, we enrolled the first patient in our METIS trial ("METIS"), a phase 3 pivotal trial testing the effectiveness of SRS plus TTFields 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.

The primary endpoint of METIS is time to first intracranial progression.

Secondary endpoints include, among others, time to neurocognitive failure, overall survival and radiological response rate following study treatments.

The study is designed to accrue 270 patients with data analyzed 12 months after the last patient in.

We anticipate data will be available in 2022.

Non-small cell lung cancer

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The standard of care for second line treatment is also evolving and may include platinum-based chemotherapy for patients who received immune checkpoint inhibitors as their first line regimen, pemetrexed, docetaxel or immune checkpoint inhibitors.

EF-15 phase 2 pilot trial

In 2013, we published the results of our phase 2 pilot trial, the EF-15 trial ("EF-15"), evaluating the safety and efficacy of TTFields in the treatment of advanced NSCLC.

EF-15 phase 2 pilot study

In 2013, we published the results of our phase 2 pilot study, the EF-15 study ("EF-15"), evaluating the safety and efficacy of TTFields in the treatment of advanced NSCLC.

EF-15 focused on the effects of treatment with TTFields in combination with standard of care pemetrexed chemotherapy.

Results of the pemetrexed Phase 3 FDA registration trial were used as a historical control in this trial.

Results of the pemetrexed phase 3 pivotal FDA registration study were used as a historical control in this study.

A total of 42 patients were recruited to the study with a minimum follow-up of six months.

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Adverse events reported in this combination study were comparable to those reported with pemetrexed alone, suggesting minimal added toxicities due to TTFields.

KEYNOTE B36 phase 2 pilot trial

In July 2020, we entered into a clinical trial collaboration with MSD, a trade name of Merck & Co., Inc.

through a subsidiary, to develop TTFields together with MSD’s anti-PD-1 therapy pembrolizumab for treatment of first-line NSCLC, expanding our research in the lung cancer space.

We plan to conduct a phase 2 pilot study.

KEYNOTE B36, evaluating TTFields concomitant with pembrolizumab for first-line treatment of intrathoracic advanced or

metastatic, PD-L1 positive NSCLC.

KEYNOTE B36 is expected to enroll its first patient in the second quarter of 2021.

LUNAR phase 3 pivotal trial

In 2017, we enrolled the first patient in our LUNAR trial ("LUNAR"), a phase 3 pivotal trial testing the effectiveness of TTFields 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.

LUNAR phase 3 pivotal study

In 2017, we enrolled the first patient in our LUNAR study ("LUNAR"), a phase 3 pivotal study testing the effectiveness of TTFields 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 46,000 patients receive second-line treatment for stage 4 NSCLC each year in the U.S.

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TTFields is intended principally for use in combination with other standard-of-care treatments, and LUNAR was designed to generate data that contemplates multiple outcomes, all of which we believe will be clinically meaningful.

LUNAR is designed to enroll 534 patients with data analyzed 18 months after the last patient in.

We anticipate final data will be available in 2023.

The protocol specifies an enrollment-driven interim analysis at 432 patients, which we anticipate will occur in the fourth quarter of 2021.

In April 2021, we announced that an independent Data Monitoring Committee ("DMC") informed us that the pre-specified interim analysis for the LUNAR study was accelerated given the length of accrual and the number of events observed, to date.

The interim analysis included data from 210 patients accrued through February 2021.

After review of the interim analysis, the DMC concluded that the LUNAR study should continue with no evidence of increased systemic toxicity.

The DMC went on to comment that the continued accrual to 534 patients as proposed in the original protocol, given the current rate of accrual and the interim data presented, is likely unnecessary and

possibly unethical for patients randomized to control.

For this reason, the DMC recommended an adjustment of accrual to approximately 276 patients with a 12-month follow-up following the enrollment of the last patient.

The DMC believed this amended protocol would provide adequate data regarding toxicity and efficacy, providing sufficient overall power, as well as potentially providing important information regarding efficacy within treatment subgroups.

In May 2021, the FDA approved our investigational device exemption supplement incorporating the recommended protocol changes and we enrolled our last LUNAR patient in November 2021.

We anticipate data in 2022.

KEYNOTE B36 phase 2 pilot study

In July 2020, we entered into a clinical study collaboration with MSD, a trade name of Merck & Co., Inc.

through a subsidiary, to study TTFields together with MSD’s anti-PD-1 therapy pembrolizumab for treatment of first-line NSCLC, expanding our research in the lung cancer space.

In April 2021, the FDA approved our IDE application to initiate the KEYNOTE B36 phase 2 pilot study to study TTFields with pembrolizumab in first-line NSCLC.

As of December 31, 2021 there were nine KEYNOTE B36 clinical study sites actively evaluating patients for enrollment.

Brain metastases

Metastatic cancer is cancer that has spread from the place where it first started to another place in the body.

It is estimated that between 100,000 and 240,000 new cases are diagnosed in the U.S.

each year with brain metastases estimated to occur in between 10% to 40% of all cancer patients.

Brain metastases are commonly treated with a combination of surgery and radiation.

Chemotherapy is often given for the primary tumor, but many chemotherapy agents do not cross the blood brain barrier and are thus ineffective in the treatment of brain metastases.

When brain metastases appear, they are either surgically removed or treated with radiation using stereotactic radiosurgery ("SRS") when possible.

Whole brain radiation therapy, although effective in delaying progression or recurrence of brain metastases when given either before or after SRS, is associated with neurotoxicity and a significant decline in cognitive functioning.

Thus, whole brain radiation therapy is often delayed until later in the disease course and is often used as a last resort.

METIS phase 3 pivotal study

In 2016, we enrolled the first patient in our METIS study ("METIS"), a phase 3 pivotal study testing the effectiveness of SRS plus TTFields 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.

The primary endpoint of METIS is time to first intracranial progression.

Secondary endpoints include, among others, time to neurocognitive failure, overall survival and radiological response rate following study treatments.

The study is designed to accrue 270 patients with data analyzed 12 months after the last patient in.

We anticipate data will be available in 2023.

Liver cancer is a leading cause of cancer deaths worldwide and is the sixth leading cause of cancer deaths annually in the U.S.

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The current common standard treatment for patients with advanced disease and those who progressed on loco-regional therapy is systemic therapy with sorafenib, lenvatinib, or atezolizumab plus bevacizumab.

HEPANOVA phase 2 pilot trial

In 2018, we opened our HEPANOVA trial, a single-arm, phase 2 pilot clinical trial in liver cancer testing the safety and efficacy of TTFields in combination with sorafenib for the treatment of advanced hepatocellular cancer that are not eligible for standard local therapies or surgery.

In September 2021, we announced that the FDA granted breakthrough designation to the NovoTTF-200T System, a TTFields device intended for use together with atezolizumab and bevacizumab for the first-line treatment of patients with unresectable or metastatic liver cancer.

The designation offers us an opportunity to interact with FDA experts throughout the premarket review phase and allows for prioritized review of regulatory submissions.

HEPANOVA phase 2 pilot study

In 2018, we opened our HEPANOVA study, a single-arm, phase 2 pilot clinical study in liver cancer testing the safety and efficacy of TTFields in combination with sorafenib for the treatment of advanced hepatocellular cancer that are not eligible for standard local therapies or surgery.

The primary endpoint is overall response rate, and secondary endpoints include progression-free and overall survival at one year.

We have completed enrollment of 25 patients at multiple centers across Europe and anticipate data will be available in the second quarter of 2021.

In July 2021, we announced the final results of the HEPANOVA study.

Historical control data showed a 4.5% objective response rate and a 43% disease control rate for patients treated with sorafenib alone.

In 21 evaluable patients, HEPANOVA showed a 9.5% objective response rate and 76% disease control rate, as well as 5.8 months of progression free survival.

These results are even more encouraging when considering the poor prognosis of the study population.

52% of the patients in HEPANOVA were categorized as Child-Pugh Class B, compared to 5% in the historical control, indicating significant liver functional compromise.

Additionally, research conducted to date has shown that TTFields anti-mitotic effect requires extended exposure to the therapy for maximum impact.

This was a challenge given median patient treatment duration of only 10 weeks during the study.

Of the patients who received at least 12 weeks of therapy, the disease control rate reached 91% with an objective response rate of 18%.

These data demonstrate that TTFields have the potential to extend survival in advanced liver cancer.

Our team, along with study investigators, are actively designing a phase 3 pivotal study that contemplates TTFields therapy together with the current standard of care, including immunotherapy.

Gastric cancer

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In patients diagnosed with advanced gastric cancer that is no longer operable, combination chemotherapy extends progression-free survival and overall survival to 3-6 months and 8-14 months, respectively.

EF-31 phase 2 pilot trial

In 2020, we opened our EF-31 trial, a single-arm, phase 2 pilot clinical trial in gastric cancer in partnership with Zai testing the safety and efficacy of TTFields and XELOX chemotherapy as first-line treatment for patients with unresectable gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

EF-31 phase 2 pilot study

In 2020, we opened our EF-31 study, a single-arm, phase 2 pilot clinical study in gastric cancer in partnership with Zai testing the safety and efficacy of TTFields together with XELOX chemotherapy as first-line treatment for patients with unresectable gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

The primary endpoint is investigator-assessed objective response rate, and secondary endpoints include progression-free and overall survival.

The trial is expected to enroll a total of 28 patients in multiple centers across Greater China, and we anticipate data will be available in 2022.

The protocol is designed to include 25 evaluable patients who receive at least one tumor assessment.

In October 2021, we announced the final patient was enrolled in the study and data is anticipated in 2022.

Ovarian cancer

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Almost all patients with recurrent disease ultimately develop platinum resistance, and the prognosis for this population remains poor.

INNOVATE phase 2 pilot trial

In 2018, we published the results of our phase 2 pilot trial in recurrent ovarian cancer, the INNOVATE trial ("INNOVATE"), examining TTFields in combination with standard of care chemotherapy.

INNOVATE was a multi-center, non-randomized, open-label trial designed to test the feasibility, safety and preliminary efficacy of TTFields in combination with weekly paclitaxel.

The paclitaxel control arm from the bevacizumab phase 3 FDA registration trial was used as a historical control in this trial.

INNOVATE phase 2 pilot study

In 2018, we published the results of our phase 2 pilot study in recurrent ovarian cancer, the INNOVATE study ("INNOVATE"), examining TTFields in combination with standard of care chemotherapy.

INNOVATE was a multi-center, non-randomized, open-label study designed to test the feasibility, safety and preliminary efficacy of TTFields in combination with weekly paclitaxel.

The paclitaxel control arm from the bevacizumab phase 3 pivotal FDA registration study was used as a historical control in this study.

A total of 31 patients were recruited to the study with a minimum follow-up of six months.

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Efficacy results based on the 31 evaluable patients suggested more than doubling of the progression-free survival and an improvement in overall survival among patients who received TTFields therapy with paclitaxel compared to paclitaxel alone.

INNOVATE-3 phase 3 pivotal trial

In 2019, we enrolled the first patient in our INNOVATE-3 trial ("INNOVATE-3"), a phase 3 pivotal trial testing the effectiveness of TTFields with paclitaxel in patients with platinum-resistant ovarian cancer.

INNOVATE-3 phase 3 pivotal study

In 2019, we enrolled the first patient in our INNOVATE-3 study ("INNOVATE-3"), a phase 3 pivotal study testing the effectiveness of TTFields with paclitaxel in patients with platinum-resistant ovarian cancer.

It is estimated that approximately 16,000 patients are diagnosed with platinum-resistant ovarian cancer each year in the U.S.

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The study is designed to accrue 540 patients with data analyzed 18 months after the last patient in.

We anticipate final data in 2023.

The protocol specifies an enrollment-driven interim analysis at last patient in, which we anticipate will occur in the third quarter of 2021.

The European Network for Gynaecological Oncological Trial groups ("ENGOT") and The GOG Foundation, Inc.

("GOG"), third-party clinical trial networks, are collaborating with us on the trial.

ENGOT and GOG were involved in the development of the trial, and the collaborations are intended to facilitate enrollment of INNOVATE-3 at leading cancer centers in Europe and the United States.

In October 2021, we announced that the final patient was enrolled in the pivotal INNOVATE-3 study.

A DMC will conduct the pre-specified interim analysis pursuant to the study protocol in 2022 and data is anticipated in 2023.The European Network for Gynaecological Oncological Trial groups ("ENGOT") and The GOG Foundation, Inc.

("GOG"), third-party clinical study networks, are collaborating with us on the study.

Pancreatic cancer

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It is estimated that approximately 53,000 patients are diagnosed with pancreatic cancer each year in the U.S.

Pancreatic cancer has a five-year relative survival rate in the single digits, at just 10 percent.

Pancreatic cancer has a five-year relative survival rate of just 10 percent.

Physicians use different combinations of surgery, radiation and pharmacological therapies to treat pancreatic cancer, depending on the stage of the disease.

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Unfortunately, the majority of locally advanced cases are diagnosed once the cancer is no longer operable, generally leaving chemotherapy with or without radiation as the only treatment option.

PANOVA phase 2 pilot trial

In 2018, we published the results of our phase 2 pilot trial in advanced pancreatic adenocarcinoma, the PANOVA trial ("PANOVA"), examining TTFields in combination with standard of care chemotherapy.

PANOVA was a multicenter, non-randomized, open-label trial.

The trial included 40 patients with locally advanced or metastatic pancreatic cancer whose tumors could not be removed surgically and who had not received chemotherapy or radiation therapy prior to the clinical trial.

PANOVA phase 2 pilot study

In 2018, we published the results of our phase 2 pilot study in advanced pancreatic adenocarcinoma, the PANOVA study ("PANOVA"), examining TTFields in combination with standard of care chemotherapy.

PANOVA was a multicenter, non-randomized, open-label study.

The study included 40 patients with locally advanced or metastatic pancreatic cancer whose tumors could not be removed surgically and who had not received chemotherapy or radiation therapy prior to the clinical study.

Patients were enrolled between 2014 and 2016 in two cohorts:

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Patients with metastatic disease experienced a median overall survival of 8.3 months.

One-year survival was 55% (compared to 22% in the gemcitabine historical control).

survival was 55% (compared to 22% in the gemcitabine historical control).

Of 11 patients with available CT scans, 5 (45%) had a partial response (compared to 7% with gemcitabine alone), 5 (45%) had stable disease, which means that the cancer is neither decreasing nor increasing in extent or severity, and 1 (10%) had progressive disease.

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Patients reported no serious adverse events related to TTFields.

PANOVA-3 phase 3 pivotal trial

In 2018, we enrolled the first patient in our PANOVA-3 trial ("PANOVA-3"), a phase 3 pivotal trial testing the effectiveness of TTFields with nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine alone as a front-line treatment for unresectable locally advanced pancreatic cancer.

PANOVA-3 phase 3 pivotal study

In 2018, we enrolled the first patient in our PANOVA-3 study ("PANOVA-3"), a phase 3 pivotal study testing the effectiveness of TTFields 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 43,000 patients are diagnosed with unresectable pancreatic cancer each year in the U.S.

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The study is designed to accrue 556 patients with data analyzed 18 months after the last patient in.

We anticipate final data will be available in 2023.

The protocol specifies an enrollment-driven interim analysis at last patient in, which we now anticipate will occur in 2022.

A DMC will conduct a pre-specified interim analysis pursuant to the study protocol and final data is anticipated in 2024.

Zai License and Collaboration Agreement

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The collaboration agreement grants Zai a license to commercialize our Products in Greater China and establishes a development partnership intended to accelerate the development of TTFields in multiple solid tumor cancer indications.

Zai has launched Optune for the treatment of newly diagnosed GBM in Hong Kong and for the treatment of newly diagnosed and recurrent GBM in mainland China.

Zai has also launched Optune Lua for the treatment of MPM in Hong Kong and intends to file a Marketing Authorization Application in mainland China in 2021.

Zai has launched Optune for the treatment of newly diagnosed GBM in Hong Kong and mainland China and is seeking marketing authorization for GBM in Taiwan.

Zai has also launched Optune Lua for the treatment of MPM in Hong Kong and has filed a Marketing Authorization Application for MPM in mainland China.

For additional information, see Note 12 to the Consolidated Financial Statements.

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Intellectual property

Our robust global patent and intellectual property portfolio consists of over 185 issued patents covering various aspects of TTFields and our Products.

Our robust global patent and intellectual property portfolio consists of hundreds of issued patents in multiple jurisdictions covering various aspects of our devices and related technology.

In the U.S., our patents have expected expiration dates between 2023 and 2038.

We have also filed over 125 additional patent applications worldwide, including 45 new U.S.

patent applications in 2020, that, if issued, may protect aspects of our platform beyond the current last-to-expire patent in the relevant market.

These pending applications cover innovations relating to our arrays, field generators and software platform, in addition to other topics related to TTFields.

We have also filed several hundred additional patent applications worldwide, that, if issued, may protect aspects of our platform beyond the current last-to-expire patent in the relevant market.

pending applications cover innovations relating to our arrays, field generators and software platform, in addition to other topics related to TTFields.

Our reliance on intellectual property involves certain risks, as described under the heading "Risk factors—Risks relating to intellectual property."

In addition to our patent portfolio, we further protect our intellectual property by maintaining the confidentiality of our trade secrets, know-how and other confidential information.

Given the length of time and expense associated with bringing delivery systems candidates through development and regulatory approval to the market place, the healthcare industry has traditionally placed considerable importance on obtaining patent protection and maintaining trade secrets, know-how and other confidential information for significant new technologies, products and processes.

Given the length of time and expense associated with bringing device candidates through development and regulatory approval to the market place, the healthcare industry has traditionally placed considerable importance on obtaining patent protection and maintaining trade secrets, know-how and other confidential information for significant new technologies, products and processes.

Our policy is to require each of our employees, consultants and advisors to execute a confidentiality agreement before beginning their employment, consulting or advisory relationship with us.

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Our intellectual property portfolio is continuously expanding as we find new and unique ways to improve TTFields therapy.

We believe these intellectual property rights would provide an obstacle to the introduction of state of the art

TTFields delivery systems by a competitor.

However, competitors may be able to offer less sophisticated TTFields delivery systems that utilize technology described in expired patents and/or choose to market their system(s) in countries where we have limited or no enforceable intellectual property rights.

We believe these intellectual property rights would provide an obstacle to the introduction of state of the art TTFields devices by a competitor.

However, competitors may be able to offer less sophisticated TTFields devices that utilize technology described in expired patents and/or choose to market their system(s) in countries where we have limited or no enforceable intellectual property rights.

Competitors could also pursue alternative technologies for the application of TTFields into a patient that we did not foresee or protect.

We are aware of a few third parties in the United States and China developing devices and filing for intellectual property protection related to TTFields.

Even after the expiration of our U.S.

patents, we believe that potential U.S.

market entrants applying low-intensity, alternating electric fields to solid tumors in the U.S.

will have to undertake their own clinical trials and regulatory submissions to prove equivalence to our Products, a necessary step in receiving regulatory approvals for a competing product.

Beginning in 2021, several of our early patents covering technology included in our Products began expiring in the U.S.

and elsewhere.

Even after the expiration of our patents, we believe that potential market entrants applying low-intensity, alternating electric fields to solid tumors will have to undertake their own clinical studies and regulatory submissions to prove equivalence to our Products, a necessary step in receiving regulatory approvals for a competing product, all while avoiding infringing our unexpired patents.

Presently, the traditional biotechnology, pharmaceutical and medical technology industries expend significant resources in developing novel and proprietary therapies for the treatment of solid tumors, including GBM, MPM and other indications that we are currently investigating.

As we work to increase market acceptance of our Products, we compete with companies commercializing or investigating other anti-cancer therapies, some of which are in clinical trials for GBM or MPM that currently specifically exclude patients who have been or are being treated with our Products.

As we work to increase market acceptance of our Products, we compete with companies commercializing or investigating other anti-cancer therapies, some of which are in clinical studies for GBM or MPM that currently specifically exclude patients who have been or are being treated with our Products.

The introduction of competing therapies could materially impact our business and financial results.

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In the EU member states where we market our Products and operate, we are currently subject to, inter alia, the Medical Device Directive ("MDD") as implemented into national legislation by the EU member states.

From May 26, 2021, the MDD will be replaced and repealed by the Medical Device Regulation ("MDR"), which will apply directly in all EU member states.

On May 26, 2021, the MDD was replaced and repealed by the Medical Device Regulation ("MDR"), which applies directly in all EU member states.

In Switzerland, our Products and operations are subject to, inter alia, the Medical Devices Ordinance, which implements the MDD into Swiss law (See "Foreign approvals and CE mark" below).

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Unless an exemption applies, before we can commercially distribute medical devices in the U.S., we must obtain, depending on the type of device, either prior 510(k) clearance or premarket approval ("PMA") from the FDA.

The FDA classifies medical devices into one of three classes.

FDA classifies medical devices into one of three classes.

Devices deemed to pose lower risks are placed in either class I or II, which typically requires the manufacturer to submit to the FDA a premarket notification requesting permission to commercially distribute the device.

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Devices deemed by the FDA to pose the greatest risks, such as life-sustaining, life-supporting or implantable devices, or devices deemed not substantially equivalent to a previously cleared 510(k) device, are placed in class III, generally requiring PMA.

Premarket approval (PMA) pathway

Premarket approval (PMA) and Humanitarian Device Exemption (HDE) pathways

Optune and Optune Lua are classified as Class III devices as they are deemed to be life-sustaining devices.

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We expect that we will be required to receive PMA for the use of our Products for future indications.

A PMA must be supported by extensive data, including from technical tests, preclinical studies and clinical trials, manufacturing information and intended labeling to demonstrate, to the FDA’s satisfaction, the safety and effectiveness of a medical device for its intended use.

A PMA must be supported by extensive data, including from technical tests, preclinical studies and clinical studies, manufacturing information and intended labeling to demonstrate, to the FDA’s satisfaction, the safety and effectiveness of a medical device for its intended use.

During the PMA review period, the FDA will typically request additional information or clarification of the information already provided.

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Prior to approval of the Optune PMA for the treatment of recurrent GBM, we and our critical component suppliers were each inspected by the FDA.

New PMAs or PMA supplements are required for modifications that affect the safety or effectiveness of our delivery systems, including, for example, certain types of modifications to a delivery system’s indication for use, manufacturing process, labeling and design.

New PMAs or PMA supplements are required for modifications that affect the safety or effectiveness of our devices, including, for example, certain types of modifications to a device’s indication for use, manufacturing process, labeling and design.

PMA supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information needed to support any changes from the device covered by the original PMA and may not require any or as extensive clinical data as the original PMA required, or the convening of an advisory panel.

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For class III devices intended to treat disease affecting 8,000 individuals or less per year in the U.S., called Humanitarian Use Devices ("HUD"), the FDA has a separate marketing authorization pathway called the HDE.

Approval basis for an HDE is a "reasonable assurance of safety" and that the probable benefit to health outweighs risk of injury from its use, which means a traditional phase 3 pivotal trial usually is not required to support approval.

In 2019, the FDA approved Optune Lua (then known as "NovoTTF-100L") for the treatment of MPM under the HDE pathway.

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As part of the approval process, we applied for an exemption from this limitation, which the FDA granted.

Otherwise, HDE approved devices are generally required to follow the same requirements as PMA approved devices.

Clinical trials

Clinical trials are generally required to support approval of a PMA or HDE.

Such trials generally require an Investigational Device Exemption ("IDE") approval from the FDA for a specified number of patients and study sites, unless the product is deemed a non-significant risk device eligible for more abbreviated IDE requirements.

Clinical trials are subject to extensive monitoring, recordkeeping and reporting requirements.

Clinical trials must be conducted under the oversight of an IRB for the relevant clinical trial sites and must comply with FDA regulations, including those relating to current Good Clinical Practices ("cGCPs").

To conduct a clinical trial, we also are required to obtain the patients’ informed consent in form and substance that complies with both FDA requirements and state and federal privacy and human subject protection regulations.

We, the FDA or the respective IRB could suspend a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the anticipated benefits.

Even if a trial is completed, the results of clinical testing may not adequately demonstrate the safety and efficacy of the device or may otherwise not be sufficient to obtain FDA approval to market the product in the U.S.

Otherwise, HDE approved devices are generally required to follow the same requirements as PMA approved devices, including the supplement process.

Clinical studies

Clinical studies are generally required to support approval of a PMA or HDE.

Such studies generally require an Investigational Device Exemption ("IDE") approval from the FDA for a specified number of patients and study sites, unless the product is deemed a non-significant risk device eligible for more abbreviated IDE requirements.

Clinical studies are subject to extensive monitoring, recordkeeping and reporting requirements.

Clinical studies must be

conducted under the oversight of an IRB for the relevant clinical study sites and must comply with FDA regulations, including those relating to current Good Clinical Practices ("cGCPs").

To conduct a clinical study, we also are required to obtain the patients’ informed consent in form and substance that complies with both FDA requirements and state and federal privacy and human subject protection regulations.

We, the FDA or the respective IRB could suspend a clinical study at any time for various reasons, including a belief that the risks to study subjects outweigh the anticipated benefits.

Even if a study is completed, the results of clinical testing may not adequately demonstrate the safety and efficacy of the device or may otherwise not be sufficient to obtain FDA approval to market the product in the U.S.

Post-approval studies are also typically required as a condition of PMA to reinforce the reasonable assurance of safety and effectiveness.

Such studies are conducted in the post-market setting with the approved device, often to address the long-term use of the device or other discrete questions that may have been raised based on the clinical data from the IDE clinical study.

The FDA required a post-approval registry study as a condition of approval for Optune for recurrent GBM.

We have completed this study and the study data have been submitted for presentation at an upcoming medical conference.

The FDA required a post-approval registry study as a condition of approval for Optune for recurrent GBM,which we completed.

Foreign approvals and CE mark

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In the European Economic Area (“EEA”), for Novocure’s devices these include the requirement to obtain a CE Certificate and to affix a CE mark to our Products.

In the EEA, whether or not we have obtained FDA approval, our delivery systems must be subject to conformity assessment procedure involving an EEA notified body, a private organization accredited by an EEA member state to conduct conformity assessment procedures under the MDD/MDR.

Apart from low risk medical devices (Class I with no measuring function and which are not sterile), where the manufacturer can issue a declaration of conformity based on a self-assessment of the conformity of its products with the MDD’s Essential Requirements or the MDR’s General Safety and Performance Requirements, a conformity assessment procedure requires the intervention of a notified body.

In the EEA, whether or not we have obtained FDA approval, our devices must be subject to conformity assessment procedure involving an EEA notified body, a private organization accredited by an EEA member state to conduct conformity assessment procedures under the MDD/MDR.

Apart from low risk medical devices (Class I with no measuring function and which are not sterile), a conformity assessment procedure requires the intervention of a notified body.

The notified body typically audits and examines the device’s technical documentation, including the clinical evaluation, and the quality system for the manufacture, design and final inspection of our devices before issuing a CE Certificate demonstrating compliance with the relevant requirements or the quality system requirements laid down in the relevant Annexes to the MDD/MDR.

Following the issuance of this CE Certificate, we can draw up a declaration of conformity and affix the CE mark to the delivery systems covered by this CE Certificate.

The time required to CE mark our delivery systems or to obtain approval from other non-U.S.

Following the issuance of this CE Certificate, we can draw up a declaration of conformity and affix the CE mark to the devices covered by this CE Certificate.

The time required to CE mark our devices or to obtain approval from other non-U.S.

authorities may be longer or shorter than that required for FDA approval.

Moreover, the MDR, which becomes applicable on May 26, 2021, imposes new stricter requirements that we must comply with in order to renew the CE Certificates for our Products when these expire or May 25, 2025, whichever comes first.

In Switzerland, pursuant to the Mutual Recognition Agreement ("MRA") in place between the EEA and Switzerland, our Products bearing a CE mark may currently be exported from the EEA to Switzerland.

However, this MRA is only valid until May 25, 2021 and if no new MRA has been agreed to by then, Switzerland will be considered a third country with respect to medical devises.

In the EEA, before carrying out a clinical investigation with a device to assess its safety or performance when in accordance with its intend use, the sponsor must receive a positive opinion from the local ethics committee and approval from the national competent authority in the relevant EEA member states in which the clinical investigation will be conducted.

When a CE marked medical device is used in a clinical study in accordance with its intended use,

the approval of the national competent authorities is not required for the use of such medical device in the study.

In Japan, we must obtain approvals from the Ministry of Health, Labour, and Welfare ("MHLW") to market our delivery systems.

Moreover, the MDR, which became applicable on May 26, 2021, imposed new, stricter requirements that we must comply with in order to renew the CE Certificates for our Products when these expire, or May 25, 2025, whichever comes first.

In addition, as of May 25, 2021, in the absence of a new MRA, Switzerland is now considered a non-EU “third country” with respect to medical devices, meaning that movement of our Products bearing a CE mark from the EEA to Switzerland is subject to additional requirements.

In the EEA, before carrying out a clinical investigation with a non-CE marked device to assess its safety or performance when in accordance with its intended use, the study sponsor must receive a positive opinion from the local ethics committee and approval from the national competent authority in the relevant EEA member states in which the clinical investigation will be conducted.

When a CE marked medical device is used in a clinical study in accordance with its intended use, the approval of the national competent authorities is not required for the use of such medical device in the study.

In Japan, we must obtain approvals from the Ministry of Health, Labour, and Welfare ("MHLW") to market our devices.

Each regulatory approval process outside of the U.S.

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• labeling regulations and FDA and equivalent competent authority in other jurisdictions requiring promotion be truthful and non-misleading and prohibiting the promotion of products for uncleared, unapproved or off-label uses;

• approval of product modifications that affect the safety or effectiveness of one of our delivery systems that has been approved or is the subject of a CE Certificate;

• approval of product modifications that affect the safety or effectiveness of one of our devices that has been approved or is the subject of a CE Certificate;

• Medical Device Reporting regulations of the FDCA and medical device vigilance, which require that manufacturers comply with FDA or equivalent competent authority requirements in other jurisdictions to report if their device may have caused or contributed to a death or serious injury, or has malfunctioned in a way that would likely cause or contribute to a death or serious injury if the malfunction of the device or a similar device were to recur;

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• notices of corrections or removals.

Our delivery systems could be subject to voluntary recall if we, the FDA or another applicable regulatory authority determine, for any reason, that our delivery systems pose a risk of injury or are otherwise defective.

Moreover, the FDA and other applicable regulatory authorities can order a mandatory recall if there is a reasonable probability that our delivery system would cause serious adverse health consequences or death.

Our devices could be subject to voluntary recall if we, the FDA or another applicable regulatory authority determine, for any reason, that our devices pose a risk of injury or are otherwise defective.

Moreover, the FDA and other applicable regulatory authorities can order a mandatory recall if there is a reasonable probability that our device would cause serious adverse health consequences or death.

The FDA has broad post-market and regulatory enforcement powers.

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• customer notifications for repair, replacement and/or refunds;

• recall, detention or seizure of our delivery systems;

• recall, detention or seizure of our devices;

• operating restrictions or partial suspension or total shutdown of production;

• refusing or delaying our requests for approval of delivery system candidates or a modified version of Optune;

• refusing or delaying our requests for approval of device candidates or a modified version of Optune;

• withdrawal of PMA/HDE approvals or suspension, variation or withdrawal of CE Certificates that have already been granted;

• refusal to grant export approval for our delivery systems;

• refusal to grant export approval for our devices;

• civil and/or criminal prosecution by the U.S.

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Certain states require that DME providers maintain an in-state location.

Although we believe we are in compliance with all applicable federal and state regulations regarding accreditation and licensure requirements and similar requirements in other jurisdictions, if we are found to be noncompliant, we could lose our accreditation or licensure in such states or our supplier rights under such federal healthcare programs, which could prohibit us from selling our current or future delivery systems to patients in such state or to that federal healthcare program.

Although we believe we are in compliance with all applicable federal and state regulations regarding accreditation and licensure requirements and similar requirements in other jurisdictions, if we are found to be noncompliant, we could lose our accreditation or licensure in such states or our supplier rights under such federal healthcare programs, which could prohibit us from selling our current or future devices to patients in such state or to that federal healthcare program.

Healthcare regulatory matters

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HIPAA also includes a number of federal criminal provisions, including for healthcare fraud and for false statements relating to healthcare matters.

The healthcare fraud provision prohibits knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private third-party payers.

The healthcare fraud provision prohibits knowingly and willfully executing a scheme

to defraud any healthcare benefit program, including private third-party payers.

The false statements provision prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

25 unchanged sentences

• effectively train our personnel on the benefits and risks of our Products and healthcare compliance;

• establish and maintain successful and compliant education programs that educate health care providers so they can appropriately inform their patients about our Products;

• manage geographically disbursed business operations.

1 unchanged sentence

Because our current Products require, and we anticipate our future Products will require, physician training and education, we expect that our sales and marketing and patient support teams will continue to grow substantially as we expand our approved indications and markets.

The ongoing COVID-19 pandemic also creates challenges to our ability to recruit and retain effective and experienced employees.

In 2021, we instituted a COVID-19 vaccine mandate for all employees (subject to certain exceptions).

Some employees chose to leave our company in response to this mandate and while the pandemic continues, this mandate may limit our ability to recruit new employees.

Available information

6 unchanged sentences

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.

What changed 10-K

Item 1. Business