What changed in this filing

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Item 1. Business

2025-02-27 compared with 2024-02-29 · 187 added, 154 removed, 943 unchanged (27% of the section changed)

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Unless otherwise provided in this Annual Report, references to the “ Company, ” “ we, ” “ us, ” and “ our ” refer to Puma Biotechnology, Inc.

and our wholly owned subsidiaries.

and our wholly owned subsidiary.

We are a biopharmaceutical company that develops and commercializes innovative products to enhance cancer care and improve treatment outcomes for patients.

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Therapeutic strategies have been developed to block HER2 in order to improve the treatment of this type of breast cancer.

Trastuzumab, pertuzumab, lapatinib, T-DM1, fam‐trastuzumab deruxtecan and tucatinib are all drugs are used as single agents, in combination with other drugs and in combination with chemotherapy to treat patients with HER2-positive breast cancer at various stages.

Neratinib is a potent irreversible TKI that blocks signal transduction through the epidermal growth factor receptors, HER1, HER2 and HER4.

Trastuzumab, pertuzumab, lapatinib, T-DM1, fam‐trastuzumab deruxtecan and tucatinib are all drugs that are used as single agents, in combination with other drugs and in combination with chemotherapy to treat patients with HER2-positive breast cancer at various stages.

Neratinib is a potent irreversible tyrosine kinase inhibitor (“TKI”) that blocks signal transduction through the epidermal growth factor receptors, HER1, HER2 and HER4.

Based on pre-clinical studies and clinical trials to date, we believe that neratinib may offer an advantage over existing treatments that are used in the treatment of patients with HER2-positive breast cancer.

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NERLYNX, the commercial name for neratinib, is currently approved in the United States for two indications:

the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer following adjuvant trastuzumab-based therapy and for use in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in metastatic setting.

We also believe neratinib has potential clinical application in the treatment of several other cancers as well, including other tumor types that over-express or have a mutation in HER2 or epidermal growth factor receptor (“EGFR”), such as cervical cancer, lung cancer or other solid tumors.

We currently market NERLYNX in the United States using our direct specialty sales force consisting of approximately 38 sales specialists as of December 31, 2023.

We currently market NERLYNX in the United States using our direct specialty sales force consisting of approxima tely 35 sales specialists as of December 31, 2024.

Our sales specialists are supported by an experienced sales leadership team consisting of regional managers and directors, as well as a commercial team of experienced professionals in marketing, access and reimbursement, managed markets, marketing research, commercial operations and sales force planning and management.

Outside the United States, we have entered into exclusive sub-license agreements with third parties to pursue regulatory approval, if necessary, and commercialize NERLYNX, if approved.

As of December 31, 2023, NERLYNX has received approval for the treatment of certain patients with extended adjuvant or metastatic HER2-positive breast cancer in more than 20 countries outside the United States, including the European Union (“EU”), China, Latin America, Australia, Canada, and Hong Kong.

We are currently a party to several sub-licenses in various regions outside the United States, including Europe (excluding Russia and Ukraine), Australia, Canada, China, Southeast Asia, Israel, South Korea, and various countries and territories in Central America, South America and Africa.

We have also implemented a managed access program for NERLYNX.

Managed access programs provide physicians and patients access to medicines when there are limited or no other therapeutic options available.

Our managed access program for NERLYNX enables participation from countries outside the United States where permitted by applicable rules, procedures and regulatory authorities.

The program provides access to NERLYNX for the treatment of early stage HER2-positive breast cancer (extended adjuvant setting), HER2-positive metastatic breast cancer and HER2-mutated solid tumors.

In order for patients to qualify for our managed access program they must be unable to participate in any ongoing NERLYNX clinical trial.

As of December 31, 2024, NERLYNX has received approval for the treatment of certain patients with extended adjuvant and/or metastatic HER2-positive breast cancer in more than 40 countries outside the United States, including the European Union (“EU”), China, Latin America, Australia, Canada, and Hong Kong.

In September 2022, we entered into an exclusive license agreement with a subsidiary of Takeda Pharmaceutical Company Limited (“Takeda”) to license the worldwide research and development and commercial rights to alisertib.

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Successfully execute our NERLYNX commercial plan.

An important near-term objective is to continue to execute our NERLYNX commercial plan by driving market penetration and duration of therapy consistent with the current NERLYNX label.

An important near-te rm objective is to continue to execute our NERLYNX commercial plan by driving market penetration and duration of therapy consistent with the current NERLYNX label.

We continue to focus our efforts on commercializing NERLYNX in the United States.

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We also plan to evaluate alisertib in biomarker focused populations where it has shown a higher degree of activity, such as patients with c-Myc amplification and RB1 loss/RB1 mutations, as we believe that this may provide a point of differentiation from the other drugs being developed in the treatment of these diseases.

In the first half of 2024, we plan to initiate our ALI-4201 clinical trial, a Phase II clinical trial in up to 60 patients designed to evaluate the safety and efficacy of alisertib in extensive small cell lung cancer.

Maximize the value of our programs by maintaining the flexibility to commercialize our drug candidates independently or through collaborative relationships with third parties.

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In-license or acquire additional commercial drugs and/or drug candidates and technologies in order to build a sustainable product pipeline by employing multiple therapeutic approaches and disciplined decision criteria based on clearly defined proof of principal goals.

We seek to build a sustainable portfolio including commercial drugs where we can successfully leverage our existing commercial infrastructure and a product pipeline by employing multiple therapeutic approaches and by acquiring drug candidates belonging to known drug classes.

We seek to build a sustainable portfolio including commercial drugs where we can successfully leverage our existing c ommercial infrastructure and a product pipeline by employing multiple therapeutic approaches and by acquiring drug candidates belonging to known drug classes.

In addition, we employ disciplined decision criteria to assess drug candidates.

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The median cumulative duration of grade 3 diarrhea ranged from 2 – 2.5 days across the CONTROL DE study cohorts for the entire 12-month treatment period (compared with 5.0 days for ExteNET).

The proportion of patients discontinuing neratinib because of diarrhea was decreased both DE cohorts (DE1 3%;

The proportion of patients discontinuing neratinib because of diarrhea was decreased in both DE cohorts (DE1 3%;

DE2 6%) compared with ExteNET (17%).

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In February 2013, we reached agreement with the FDA under a Special Protocol Assessment (“SPA”) for our Phase III clinical trial (PUMA-NER-1301 or the NALA trial) of neratinib in patients with HER2-positive metastatic breast cancer who have failed two or more prior treatments (third-line disease).

An SPA is a written agreement between the trial’s sponsor and the FDA regarding the design, endpoints, and planned statistical analysis of the Phase III trial with respect to the effectiveness of neratinib for the indication to be studied to support a NDA.

The European Medicines Agency (“EMA”) also provided follow-on Scientific Advice (“SA”) consistent with that of the FDA regarding our Phase III trial design and endpoints used for such design to support the submission of an marketing authorization application (“MAA”) in the EU.

The European Medicines Agency (“EMA”) also provided follow-on Scientific Advice (“SA”) consistent with that of the FDA regarding our Phase III trial design and endpoints used for such design to support the submission of a marketing authorization application (“MAA”) in the EU.

Pursuant to the SPA and SA, the Phase III NALA trial was designed as a randomized controlled trial of neratinib plus capecitabine versus Tykerb® (lapatinib) plus capecitabine in patients with third-line HER2-positive metastatic breast cancer.

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The current antibody-based treatments, including trastuzumab and pertuzumab, do not enter the brain and therefore are not believed to be effective in treating these patients.

Neratinib is currently being tested in a clinical trial in collaboration with Translational Breast Cancer Research Consortium referred to as TBCRC 022.

The purpose of this study is to determine how well neratinib works in treating breast cancer that has spread to the brain.

In this research study, the investigators are looking to see how well neratinib works to decrease the size of or stabilize breast cancer that has metastasized to the brain.

In June 2017, we presented interim data from the TBCRC 022 at the ASCO 2017 Annual Meeting.

The multicenter Phase II clinical trial enrolled patients with HER2-positive metastatic breast cancer who have brain metastases.

The trial enrolled three cohorts of patients.

Neratinib was evaluated in a clinical trial with the Translational Breast Cancer Research Consortium, referred to as TBCRC 022.

The purpose of the study was to determine how well neratinib worked in treating breast cancer that had spread to the brain.

In this research study, the investigators looked to see how well neratinib worked to decrease the size of or stabilize breast cancer that had metastasized to the brain.

In June 2017, we presented interim data from TBCRC 022 at the ASCO 2017 Annual Meeting.

The multicenter Phase II clinical trial enrolled patients with HER2-positive metastatic breast cancer who had brain metastases.

The trial initially enrolled three cohorts of patients.

Patients in the second cohort (n=5) represent patients who had brain metastases which were amenable to surgery and who were administered neratinib monotherapy prior to and after surgical resection.

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No patients had received prior treatment with lapatinib.

The primary endpoint of the trial was CNS Objective Response Rate according to a composite criteria that included volumetric brain MRI measurements, steroid use, neurological signs and symptoms, and Response Evaluation Criteria in Solid Tumors (“RECIST”) evaluation for non-CNS sites.

The primary endpoint of the trial was CNS Objective Response Rate according to composite criteria that included volumetric brain MRI measurements, steroid use, neurological signs and symptoms, and Response Evaluation Criteria in Solid Tumors (“RECIST”) evaluation for non-CNS sites.

The secondary endpoint of the trial was CNS response by Response Assessment in Neuro-Oncology-Brain Metastases (“RANO-BM”) criteria.

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Among the 37 patients evaluable for safety, 32% of the patients had grade 3 diarrhea and 41% had grade 2 diarrhea.

Updated results from TBCRC-022 were presented in December 2022 at the 2022 San Antonio Breast Cancer Symposium This presentation outlined updates from three cohorts:

Updated results from an additional TBCRC 022 cohort were presented in December 2022 at the 2022 San Antonio Breast Cancer Symposium.

This presentation outlined updates from three sub-cohorts of cohort 4:

4A – patients with previously untreated Breast Cancer Brain Metastases (“BCBM”);

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The efficacy results from the trial showed that CNS Objective Response Rate by RANO-BM was 33.3% of patients in cohort 4A, 29.4% in cohort 4B, and 28.6% in cohort 4C.

Rates of response + stable disease greater than or equal to 6 months were 50% in cohort 4A, 35.3% in cohort 4B, and 33.3% in cohort 4C.

Rates of response + stable disease greater than or equal to six months were 50% in cohort 4A, 35.3% in cohort 4B, and 33.3% in cohort 4C.

Intracranial activity was observed for the combination of neratinib plus T-DM1 in all three cohorts, including in patients with prior T-DM1 exposure, suggesting a reversal of resistance to T-DM1.

Overall, the most frequently observed adverse event was diarrhea, grade 2 (32%) and grade 3 (23%).

In April 2018, we announced that NERLYNX has been included as a recommended treatment option in the latest NCCN, Clinical Practice Guidelines in Oncology Central Nervous System Cancers for Breast Cancer patients with brain metastases.

The NCCN designated NERLYNX in combination with capecitabine as a category 2B treatment option and NERLYNX in combination with paclitaxel as a category 2B treatment option.

Use, as designated for breast cancer patients with brain metastases, is outside the FDA-approved indication for NERLYNX and considered investigational, and we do not market or promote NERLYNX for these uses.

In April 2018, we announced that NERLYNX has been included as a recommended treatment option in the latest NCCN Clinical Practice Guidelines in Oncology Central Nervous System Cancers for patients with breast cancer and brain metastases.

The NCCN designated NERLYNX in combination with capecitabine as a category 2A treatment option and NERLYNX in combination with paclitaxel as a category 2B treatment option.

Use of NERLYNX for breast cancer patients with brain metastases is outside the FDA-approved indication for NERLYNX and considered investigational, and we do not market or promote NERLYNX for these uses.

Neratinib — Other Potential Applications

While we believe neratinib has potential applications in other diseases, such as HER2 Mutation-Positive Solid Tumors, HER2-Mutated, Non-Amplified Breast Cancer and EGFR Exon 18 Mutated Non Small Cell Lung Cancer, we are not currently pursuing additional development in these indications at this time.

While we believe neratinib has potential applications in other diseases, such as HER2 -mutated solid tumors, as well as EGFR exon 18-mutated non-small cell lung cancer, we are not currently pursuing additional development in these indications at this time.

NERLYNX combinations are included in the body of the NCCN Practice Guidelines for Breast Cancer for patients with HER2-negative metastatic (stage IV) breast cancer and activating mutations in the HER2 gene as detected by next generation sequencing of tumor tissue or ctDNA under the heading Useful in Certain Circumstances (BINV-Q).

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Dose escalation of neratinib is included as an approach to improve the tolerability of neratinib in the treatment of metastatic HER2-positive breast cancer.

NERLYNX monotherapy is also included in the body of the NCCN Practice Guidelines for Cervical Cancer for use as a second-line or subsequent therapy for patients with recurrent or metastatic cervical cancer and a mutation in the HER2 gene.

NERLYNX is included in CERV-F under the heading Useful in Certain Circumstances and designated as a category 2A treatment option.

Use of NERLYNX in cervical cancer patients is outside the FDA-approved indication for NERLYNX and considered investigational, and we may not market or promote NERLYNX for these uses.

Neratinib is also being investigated in an ongoing Phase 1 trial (NCT05372614) that is sponsored by the National Cancer Institute to evaluate the combination of neratinib and fam-trastuzumab deruxtecan (Enhertu) in patients with metastatic solid tumors.

The Phase 1 trial includes patients with metastatic solid tumors harboring HER2-overexpression (immunohistochemistry 3+), ERBB2 amplifications, or activating HER2 mutations.

The primary objectives are to assess safety and tolerability of the combination, and the secondary objectives include evaluating pharmacokinetics, preliminary efficacy, and potential biomarkers of response.

Alisertib is an investigational reversible, ATP-competitive inhibitor that is designed to be highly selective for Aurora Kinase A.

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During 2023, we met with the FDA to discuss our alisertib clinical development plan in both proposed indications and discussed potential dosing schedules for alisertib.

Following comments from the FDA on the proposed clinical development plans, we initiated clinical trials for both small cell lung cancer and breast cancer in 2024 and are currently enrolling.

Alisertib in Small Cell Lung Cancer

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The trial also incorporated an analysis of patients with alterations in cell cycle genes including cyclin-dependent kinase 6 gene (CDK6), retinoblastoma-like 1 gene (RBL1), retinoblastoma-like 2 gene (RBL2), and retinoblastoma 1 gene (RB1).

Of note RB1 mutations were the most frequently mutation with approximately 60% of the patients having RB1 mutations while CDK6, RBL1 and RBL2 mutations were found with very low frequency.

Of note RB1 mutations were the most frequent mutation with approximately 60% of the patients having RB1 mutations while CDK6, RBL1 and RBL2 mutations were found with very low frequency.

For patients with cell cycles mutations (RB1, CDK6, RBL1 and RBL2), the PFS in the paclitaxel plus alisertib arm was 3.68 months while the placebo plus paclitaxel arm was 1.8 months and the hazard ratio was 0.395 with a p value of 0.003.

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According to the published biomarker data from the alisertib clinical trial, approximately 72% of small cell lung cancer patient samples had c-Myc amplifications and approximately 60-80% of small cell lung cancer patient samples had RB1 mutations.

In August 2023, we announced that we had been notified by the FDA that we can proceed under our Investigational New Drug application (“IND”) with the clinical development of alisertib monotherapy for the treatment of patients with extensive stage small cell lung cancer (“SCLC”).

Our Phase II trial ALISertib in CAncer (ALISCA™-Lung1) Phase II trial (PUMA-ALI-4201)) will enroll up to 60 patients with extensive stage small cell lung cancer who have progressed after first-line platinum-based chemotherapy and immunotherapy.

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Alisertib will be dosed at 50 mg BID on days 1-7 of every 21-day cycle.

In February 2024 we announced that we initiated the Phase II ALISCA-Lung1 trial.

The primary endpoint of the trial will be objective response rate with secondary endpoints of duration of response, disease control rate, progression free survival and overall survival.

We will also be looking at each of these endpoints within selected pre-specified biomarker subgroups as well as to assess whether there is enhanced efficacy in any biomarker subgroup.

We will be performing a biomarker analysis of the ALI-4201 trial in parallel with the execution of the clinical trial.

In February 2024 we announced that we initiated the Phase II ALISCA TM -Lung1 trial.

This study is ongoing and actively recruiting.

The primary endpoint of the trial is objective response rate with secondary endpoints of duration of response, disease control rate, PFS and overall survival.

We will look at each of these endpoints within selected pre-specified biomarker subgroups to assess whether there is enhanced efficacy in any biomarker subgroup.

We will perform a biomarker analysis of the ALI-4201 trial in parallel with the execution of the clinical trial.

We plan to perform an initial interim analysis for the evaluation of the biomarkers as well as an evaluation of the efficacy.

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The median PFS in the paclitaxel plus alisertib arm was 10.2 months and the median PFS in the paclitaxel alone arm was 7.1 months.

Treatment with paclitaxel plus alisertib resulted in a numerically higher but not statistically significant improvement in overall survival with the median OS for the paclitaxel plus alisertib arm was 26.3 months versus 25.1 months for the single agent paclitaxel arm of the trial which resulted in a hazard ratio of 0.89 and a p value of 0.61.

Treatment with paclitaxel plus alisertib resulted in a numerically higher but not statistically significant improvement in overall survival where the median OS for the paclitaxel plus alisertib arm was 26.3 months versus 25.1 months for the single agent paclitaxel arm of the trial which resulted in a hazard ratio of 0.89 and a p value of 0.61.

The standard of care for the first line treatment of hormone receptor positive, HER2-negative metastatic breast cancer in the United States is treatment with Cyclin-dependent kinases (CDK) 4/6 inhibitors (CDK 4/6 inhibitors).

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The median PFS in the paclitaxel plus alisertib arm was 9.6 months and the median PFS in the paclitaxel plus placebo arm was 5.7 months.

Treatment with paclitaxel plus alisertib resulted in a higher but not statistically significant improvement in overall survival with the median OS for the paclitaxel plus alisertib arm was 16 months versus 12.7 months for the paclitaxel alone arm of the trial which resulted in a hazard ratio of 0.51 and a p value of 0.09.

Treatment with paclitaxel plus alisertib resulted in a higher but not statistically significant improvement in overall survival where the median OS for the paclitaxel plus alisertib arm was 16 months versus 12.7 months for the paclitaxel alone arm of the trial which resulted in a hazard ratio of 0.51 and a p value of 0.09.

Higher rates of grade 3 or higher AEs were seen in the paclitaxel plus alisertib arm for neutropenia, leukopenia, diarrhea, mucositis and stomatitis.

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No mutations were significantly associated with response or resistance to alisertib plus paclitaxel, including those in PIK3CA, TP53, AKT1, HER2, and CDH1.

Increased MYC RNA expression was observed in tumors from patients who did not derive clinical benefit from paclitaxel alone (defined as PFS less than 6 months) compared to those with benefit from paclitaxel alone (defined as PFS greater than or equal to 6 months).

Increased MYC RNA expression was observed in tumors from patients who did not derive clinical benefit from paclitaxel alone (defined as PFS less than six months) compared to those with benefit from paclitaxel alone (defined as PFS greater than or equal to six months).

Increased MYC RNA expression was not observed in patients who did not appear to benefit from alisertib plus paclitaxel.

Elevated expression of genes involved in MYC activation and in unfolded protein response (a pro- survival mechanism) were enriched in alisertib plus paclitaxel responders compared to paclitaxel responders and were associated with poor response to paclitaxel alone.

In 12 patients with exceptional response to alisertib plus paclitaxel (defined as PFS greater than or equal to 12 months), increased expression of genes involved in MYC activation and in epithelial to mesenchymal transition (a hallmark of cancer progression and metastasis) was observed in comparison to cancers from patients whose disease progressed within 6 months of initiating alisertib + paclitaxel (n=11) or those with exceptional response to paclitaxel alone (n=4).

In 12 patients with exceptional response to alisertib plus paclitaxel (defined as PFS greater than or equal to 12 months), increased expression of genes involved in MYC activation and in epithelial to mesenchymal transition (a hallmark of cancer progression and metastasis) was observed in comparison to cancers from patients whose disease progressed within six months of initiating alisertib + paclitaxel (n=11) or those with exceptional response to paclitaxel alone (n=4).

Development plan.

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According to biomarker analyses from clinical trials, approximately 50% of hormone receptor positive breast cancer tumors may have c-Myc amplifications and approximately 2-9% of hormone receptor positive HER2-negative breast cancer samples have RB1 mutations detected at the time of resistance to CDK 4/6 inhibitors.

Based on the our interactions with the FDA in 2023, we plan to initiate a Phase II trial of alisertib in combination with endocrine treatment (consisting of either anastrozole, exemestane, letrozole, fulvestrant or tamoxifen) in patients with chemotherapy-naïve HER2-negative, hormone receptor-positive metastatic breast cancer (ALISCA-Breast1).

Based on our interactions with the FDA, we initiated a Phase II trial of alisertib in combination with endocrine treatment (consisting of either anastrozole, exemestane, letrozole, fulvestrant or tamoxifen) in patients with chemotherapy-naïve HER2-negative, hormone receptor-positive metastatic breast cancer (ALISCA™-Breast1).

Patients must have been previously treated with CDK 4/6 inhibitors and received at least two prior lines of endocrine therapy in the recurrent or metastatic setting to be eligible for the trial.

We plan to initiate this trial in the second half of 2024.

The ALISCA-Breast1 trial is designed to dose patients with alisertib given at either 30 mg, 40 mg or 50 mg twice daily (BID) on days 1-3, 8-10 and 15-17 on a 28-day cycle in combination with the endocrine therapy of the investigator’s choice.

In November 2024, we announced that we initiated the Phase II ALISCA TM -Breast1 trial, and the study is actively enrolling patients.

The ALISCA TM -Breast1 trial is designed to dose patients with alisertib given at either 30 mg, 40 mg or 50 mg twice daily (BID) on days 1-3, 8-10 and 15-17 on a 28-day cycle in combination with the endocrine therapy of the investigator’s choice.

Patients must not have been previously treated with the endocrine treatment that will be given in combination with alisertib in the trial.

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Patients must provide blood samples and tissue-based biopsies so that biomarkers can be evaluated.

The primary efficacy end points will include objective response rate, duration of response, disease control rate and PFS.

As a secondary objective, the we plan to evaluate each of these efficacy endpoints within biomarker subgroups in order to determine whether any biomarker subgroup correlates with more favorable efficacy results, such as though observed in preclinical and clinical studies in other cancers including breast cancer and small cell lung cancer.

Pending the outcome of this planned study, we may then look to focus the future clinical development of alisertib in combination with endocrine therapy for patients with HER2-negative hormone receptor-positive breast cancer in patients with any potential biomarkers.

The primary objective is to determine the optimal alisertib dose level administered in combination with selected endocrine therapy to be used in future studies.

The primary efficacy end points include objective response rate, duration of response, disease control rate and PFS.

As a secondary objective, we will evaluate each of these efficacy endpoints within biomarker subgroups in order to determine whether any biomarker subgroup correlates with more favorable efficacy results, such as through observed in preclinical and clinical studies in other cancers including breast cancer and small cell lung cancer.

Pending the outcome of this study, we may then look to focus the future clinical development of alisertib in combination with endocrine therapy for patients with HER2-negative hormone receptor-positive breast cancer in patients with any potential biomarkers.

Based on our interactions with the FDA, we believe that this trial design could find the optimal dose of alisertib in combination with endocrine therapy in patients with HER2-negative, hormone receptor-positive metastatic breast cancer, and pending sufficiently positive results, allow us to move into a pivotal Phase III trial.

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Clinical Testing of Our Drug Candidates

Any drug candidates we seek to develop will require extensive pre-clinical and clinical testing to determine its safety and efficacy in the potential applications prior to seeking and obtaining regulatory approval.

Any drug candidates we seek to develop will require extensive pre-clinical and clinical testing to determine its safety and efficacy in the potential applications before seeking and obtaining regulatory approval.

This process is expensive and time consuming.

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All of the other competitors are developing their drugs for the treatment of early stage and/or metastatic HER2-positive breast cancer and/or for cancers that have a HER2 mutation.

We are aware of the DESTINY-Breast11 neoadjuvant trial and DESTINY-Breast05 adjuvant trial of trastuzumab deruxtecan in early stage HER2-positive breast cancer, as well as the CompassHER2 RD trial of tucatinib in early stage HER2-positive breast cancer.

In addition, we are also competing with academic institutions, governmental agencies and private organizations that are conducting research in the field of cancer.

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United States

We currently have an oncology sales force in the United States comprised of approximately 38 sales specialists, 8 clinical nurse educators and four strategic account managers and one national account director who are focused on promoting NERLYNX to oncologists and the oncology care team.

This sales force is supported by an experienced leadership team consisting of 6 regional business leaders and a VP of sales.

We currently have an oncology sales force in the United States comprised of approximately 35 sales specialists, three clinical nurse educators, two strategic account managers and one national account director who are focused on promoting NERLYNX to oncologists and the oncology care team.

This sales force is supported by an experienced leadership team consisting of six regional business leaders and a VP of sales.

In addition, the broader commercial team is comprised of experienced professionals in marketing, training, sales operations, global product strategy as well as access and reimbursement.

In addition, our commercial infrastructure includes capabilities in manufacturing, regulatory, quality control, and compliance.

It is also supported from a clinical expertise and cancer landscape perspective by our medical affairs group.

Our commercial infrastructure includes capabilities in manufacturing, regulatory, quality control, and compliance.

It is also supported from a clinical and cancer landscape perspective by our medical affairs group.

We launched NERLYNX in the United States in July 2017 with the goal of establishing NERLYNX as the standard of care for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer to follow adjuvant trastuzumab-based therapy.

In Feb 2020, NERLYNX was also approved in the United States in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.

We believe that the key commercial priorities to achieve for NERLYNX include:

Educating healthcare providers about the evolving clinical data for NERLYNX and its ability to reduce the risk of recurrence in the extended adjuvant setting for woman battling HER2-positive breast cancer;

We believe that the key commercial priorities for NERLYNX include:

Educating healthcare providers about the evolving clinical data for NERLYNX and its ability to reduce the risk of recurrence in the extended adjuvant setting for patients battling HER2-positive breast cancer;

Educating HER2-positive breast cancer patients about the risks of recurrence and empowering them to ask their MDs if NERLYNX is an appropriate option for them;

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In the United States, we sell our products through a specialty pharmacy network and special distributor network.

The specialty pharmacy network sells directly to patients and consists of Acaria Health, Accredo, CVS, ONCO 360, Optum/Diplomat and Biologics.

The specialty pharmacy network sells directly to patients and consists of Acaria Health, Accredo, CVS, ONCO 360, Optum and Biologics.

Our specialty distributor network sells to hospitals, physician practices and other sites of care and consists of McKesson, ASD/Oncology Supply, Cardinal Health and DMS Pharmaceutical Group.

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December 2024

December 2021

February 2023

September 2023

November 2024

December 2024

We currently have sub-licenses in each of these regions with third parties that are commercializing NERLYNX in their respective geography.

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We hold a worldwide exclusive license under our license agreement with Pfizer, as amended (the “Pfizer Agreement”) to 21 granted U.S.

patents and four pending U.S.

patents and three pending U.S.

patent applications, as well as foreign counterparts thereof, and other patent applications and patents claiming priority therefrom to develop and commercialize certain compounds, including neratinib.

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We also have a license to an issued U.S.

patent for the use of neratinib in the treatment of breast cancer, which is currently set to expire in 2025, an issued patent for the use of neratinib in the extended adjuvant treatment of early stage HER2-positive breast cancer that has previously been treated with a trastuzumab containing regimen that expires in 2030, two issued patents for the use of neratinib in combination with capecitabine, the latter of which is set to expire in 2031, and two issued patents for the formulation of NERLYNX® that are set to expire in 2030, two issued patents for the polymorphic forms of neratinib which are set to expire in 2028, one issued patent for the preparation of the polymorphic forms of neratinib which is set to expire in 2028, and three issued patents for the use of the polymorphic forms of neratinib in the treatment of breast cancer which are set to expire in 2028.

patent for the use of neratinib in the treatment of breast cancer, which is currently set to expire on October 8, 2025, an issued patent for the use of neratinib in the extended adjuvant treatment of early stage HER2-positive breast cancer that has previously been treated with a trastuzumab containing regimen that expires in 2030, two issued patents for the use of neratinib in combination with capecitabine, the latter of which is set to expire in 2031, and two issued patents for the formulation of NERLYNX® that are set to expire in 2030, two issued patents for the polymorphic forms of neratinib which are set to expire in 2028, one issued patent for the preparation of the polymorphic forms of neratinib which is set to expire in 2028, and three issued patents for the use of the polymorphic forms of neratinib in the treatment of breast cancer which are set to expire in 2028.

In jurisdictions which permit such, we will seek patent term extensions where possible for certain of our patents (discussed further below, including in “Government Regulation”).

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7,399,865 is eligible for five years of patent term extension.

7,399,865 Patent Term Extension (PTE) Certificate issued on November 19, 2021.

7,399,865 Patent Term Extension (PTE) Certificate was issued on November 19, 2021.

7,399,865 will expire December 29, 2030.

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If we obtain marketing approval in the United States for new uses or combination therapies for neratinib, we may be eligible for additional periods of regulatory exclusivity, such as three-year market exclusivity covering the new use.

If we obtain market approval for neratinib or other drug candidates or in certain jurisdictions outside the United States, we may be eligible for regulatory protection, such as eight to eleven years of data and marketing exclusivity are potentially available for new drugs in the EU;

up to five years of patent extension are potentially available in Europe (Supplemental Protection Certificate), and eight years of data exclusivity are potentially available in Japan.

up to five years of patent extension potentially available in Europe (Supplemental Protection Certificate), and eight years of data exclusivity potentially available in Japan.

In Europe, marketing approval for neratinib was obtained on August 31, 2018, which provided 10 years of regulatory exclusivity.

Between 2019 and 2022, marketing approval for neratinib was obtained in Argentina, Brazil, Brunei, Canada, Chile, China, Ecuador, Hong Kong, Israel, Malaysia, Mexico, Singapore and Taiwan.

Where available and eligible, regulatory or data exclusivity has been obtained, or is currently being pursued in these jurisdictions outside the United States and Europe.

Between 2019 and 2024, marketing approval for neratinib was obtained in Argentina, Brazil, Brunei, Canada, Chile, China, Ecuador, Hong Kong, Israel, Malaysia, Mexico, Singapore, Taiwan, Brazil and Thailand.

Where available a nd eligible, regulatory or data exclusivity has been obtained, or is currently being pursued in these jurisdictions outside the United States and Europe.

Patent term extension or supplemental protection certificate are being, or will be, pursued in jurisdictions where available and eligible, including Chile, Europe and Taiwan.

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We have filed Supplemental Protection Certificate applications in the countries the EP1848414 patent was validated.

Of these Supplemental Protection Certificate applications, five have been granted, one is pending grant, four have been abandoned and the remaining are in active prosecution.

Of these Supplemental Protection Certificate applications, seven have been granted, one is undergoing appeal proceedings, six have been abandoned, five proceedings have been stayed, and the remaining six are in active prosecution.

An Opposition was filed by Hexal AG (“Hexal”) on August 3, 2016 against European Patent No.

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Tiefenbacher (GmbH & Co.

KG) on November 28, 2023 and by Generics [UK] Limited on December 1, 2023.

EP3000467 is used as the basic patent for Supplementary Protection Certificate applications for the EMA-approved NERLYNX® product.

Responses to the notices of opposition need to be filed by April 15, 2024.

KG) on November 28, 2023 and by Generics (UK) Limited (“Generics”) on December 1, 2023.

EP3000467 is used as the basic patent for Supplementary Protection Certificate applications for the EMA-approved NERLYNX® product, 17 of which have been granted, three proceedings have been stayed, and eleven are in active prosecution.

The patentee response to the notice of opposition was filed on April 15, 2024, following which, all three opponents filed additional arguments in reply to the patentee’s submission.

On February 6, 2025, we filed our response to the summons to attend oral proceedings.

Oral proceedings are currently scheduled for April 9, 2025.

One European divisional application is pending in the same family, namely EP 23157078.8.

Substantive examination thereof has not yet commenced.

A response to the European Search Opinion (ESO) for this application was filed February 14, 2024.

On October 6, 2017, Hexal also filed an Opposition against European Patent No.

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A divisional application, EP16203986.1 was granted with the patent number EP3175853 on November 1, 2023.

This patent was also opposed by Sandoz AG on July 2, 2024.

The patentee’s response was filed on December 12, 2024.

On December 19, 2024, Sandoz AG requested the opposition division to delay issuance of their preliminary opinion by two months since they intend to respond to the patentee’s submission.

A divisional application, EP23206402.2, remains pending in this family.

Claims for this pending divisional need to be filed by January 8, 2024.

Substantive examination thereof has not yet commenced.

Substantive examination has commenced and a response to the European Search Opinion (ESO) is due by May 20, 2025.

On May 21, 2020, Dr.

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Hexal, has not appealed the decision within the prescribed time and the Interlocutory Decision became final.

There are two pending divisional applications, namely EP19154710.8 and EP22169771.7, wherein the latter received Third Party Observations on December 1, 2023.

An Opposition was filed by Generics (UK) Ltd.

(“Generics”) on September 3, 2015 against European Patent No.

A divisional application for EP19154710.8 has been granted as EP3566697, and EP22169771.7 has received a decision to grant, taking effect on March 5, 2025.

An Opposition was filed by Generics on September 3, 2015 against European Patent No.

EP2656844, which was licensed from Pfizer in 2011, and which claims, inter alia, a pharmaceutical pack containing 50 to 300 mg of neratinib and pharmaceutically acceptable salts thereof and vinorelbine for use in a method of treating a neoplasm.

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We hold a worldwide exclusive license under our license agreement with Takeda (the “Takeda Agreement”), to 22 granted U.S.

patents and 5 pending U.S.

patent applications, as well as foreign counterparts thereof, and other patent applications and patents claiming priority therefrom for a total of approximately 363 foreign patents and patent applications to develop and commercialize alisertib.

patents and five pending U.S.

patent applications, as well as foreign counterparts thereof, and other patent applications and patents claiming priority thereof for a total of approximately 368 foreign patents and patent applications to develop and commercialize alisertib.

We have a license to issued U.S.

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We were also obligated to commence a new clinical trial for a product containing one of these compounds within a specified period of time and use commercially reasonable efforts to complete such trial and achieve certain milestones as provided in a development plan.

If certain of our out-of-pocket costs in completing such studies exceed a mutually agreed amount, Pfizer was obligated to pay for certain additional out-of-pocket costs to complete such studies.

If certain of our out-of-pocket costs in completing such studies exceeded a mutually agreed amount, Pfizer was obligated to pay for certain additional out-of-pocket costs to complete such studies.

We must use commercially reasonable efforts to develop and commercialize products containing these compounds in specified major-market countries and other countries in which we believe it is commercially reasonable to develop and commercialize such products.

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Under the terms of the Takeda Agreement, we assumed sole responsibility for the global development and commercialization of alisertib.

We paid Takeda an upfront license fee of $7 million in October 2022 and is eligible to receive potential future milestone payments of up to $287.3 million upon our achievement of certain regulatory and commercial milestones during the term of the exclusive license agreement, as well as tiered royalty payments for any net sales of alisertib.

We paid Takeda an upfront license fee of $7.0 million in October 2022 and Takeda is eligible to receive potential future milestone payments of up to $287.3 million upon our achievement of certain regulatory and commercial milestones during the term of the exclusive license agreement, as well as tiered royalty payments for any net sales of alisertib.

Under the Takeda Agreement, we must use commercially reasonable efforts to develop and commercialize one product containing alisertib in specified major-market countries.

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On March 30, 2018, we entered into a sub-license agreement (the “Pint Agreement”), with Pint Pharma International SA (“Pint”).

Pursuant to the Pint Agreement, we granted to Pint, under certain of our intellectual property rights relating to neratinib, an exclusive, sublicensable (under certain circumstances) license to develop and commercialize any product containing neratinib and certain related compounds in Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama, Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay, and Venezuela, French Guiana, the Falkland Islands, and Mexico (the “Pint Territory”).

Pursuant to the Pint Agreement, we granted to Pint, under certain of our intellectual property rights relating to neratinib, an exclusive, sublicensable (under certain circumstances) license to develop and commercialize any product containing neratinib and certain related compounds in Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama, Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay, Venezuela, French Guiana, the Falkland Islands and Mexico (the “Pint Territory”).

The Pint Agreement sets forth the parties’ respective obligations with respect to the development, commercialization, and supply of the licensed product.

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Pursuant to the Pierre Fabre Agreement, we received an upfront payment and will potentially receive additional regulatory and sales-based milestone payments based on regulatory and sales activities in the Licensee Territory (as such term is defined in the Third Pierre Fabre Amendment).

Pursuant to the Third Pierre Fabre Amendment, we received an upfront payment of $50.0 million and will potentially receive additional regulatory and sales-based milestone payments up to $240.0 million based solely on regulatory and sales activities in the Third Pierre Fabre Territory.

Pursuant to the Third Pierre Fabre Amendment, we received an upfront payme nt of $50.0 million an d will potentially receive additional regulatory and sales-based milestone payments u p to $240.0 million based sole ly on regulatory and sales activities in the Third Pierre Fabre Territory.

In addition, we will receive double-digit royalties based on net sales of the licensed products in the Licensee Territory, on the one hand, and double-digit royalties based on net sales of the licensed products in the Third Pierre Fabre Territory, on the other hand.

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Assuming successful completion of the required clinical testing, the results of pre-clinical studies and of clinical trials, together with other detailed information, including information on the manufacture and composition of the drug, are submitted to the FDA in the form of an NDA requesting approval to market the product for one or more indications.

An NDA must be accompanied by a significant user fee, which may be waived in circumstances, such as where the drug is approved for an orphan-designated indications, or for the first NDA submitted by a qualifying small business.

An NDA must be accompanied by a significant user fee, which may be waived in circumstances, such as where the drug is approved for an orphan-designated indication, or for the first NDA submitted by a qualifying small business.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review.

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Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity.

Under the Prescription Drug User Fee Act (“PDUFA”) guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

Under the Prescription Drug User Fee Act (“PDUFA”) guidelines that are currently in effect, the FDA has a goal of 10 months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted.

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The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase I and an organizational commitment to expedite the development and review of the drug candidate, including involvement of senior managers.

Any drug candidate submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

Any drug candidate submitted to the FDA for approval, including a product with a fast track designation or breakthrough therapy designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review.

An NDA is eligible for priority review if the drug candidate is designed to treat a serious condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available products.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review.

The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

Drug products intended for serious or life threatening conditions may also be eligible for accelerated approval upon a determination that the drug candidate has an effect on a surrogate endpoint, which is a laboratory measurement or physical sign used as an indirect or substitute measurement representing a clinically meaningful outcome, or an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA generally requires that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled confirmatory clinical trials to verify or characterize the anticipated effect on irreversible morbidity or mortality or other clinical benefit and may require that such confirmatory trials be underway prior to granting any accelerated approval.

The FDA will attempt to direct additional resources to the evaluation of an application for a drug designated for priority review in an effort to facilitate the review.

The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to 10 months for review of new molecular entity NDAs under its current PDUFA review goals.

Depending on the design of the applicable clinical studies, drug candidates intended for serious or life threatening conditions may also be eligible for accelerated approval upon a determination that the drug candidate has an effect on a surrogate endpoint, which is a laboratory measurement or physical sign used as an indirect or substitute measurement representing a clinically meaningful outcome, or an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality and that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA generally requires that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled confirmatory clinical trials to verify or characterize the anticipated effect on irreversible morbidity or mortality or other clinical benefit and may require that such confirmatory trials be well underway prior to granting any accelerated approval.

Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required clinical trials in a timely manner, or if such trials fail to verify the predicted clinical benefit.

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The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products.

Marketing exclusivity

Data and market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications.

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Foreign Regulation

In addition to regulations in the United States, we are subject to a variety of foreign regulations governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our products.

In addition to regulations in the United States, we are subject to a variety of foreign regulations governing, among other things, clinical trials, marketing authorizati on ( “ MA ” ), co mmercial sales and distribution of our products.

The foreign regulatory approval process includes all of the risks associated with FDA approval set forth above, as well as additional country-specific regulation.

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Once the CTA is approved, clinical study development may proceed.

The CTR foresees a three-year transition period.

The extent to which ongoing and new clinical trials will be governed by the CTR varies.

Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the EU Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the EU Clinical Trials Directive remain governed by said Directive until January 31, 2025.

After this date, all clinical trials (including those which are ongoing) will become subject to the provisions of the CTR.

The CTR transition period ended on January 31, 2025, and all clinical trials (and related applications) are now fully subject to the provisions of the CTR.

Medicines used in clinical trials must be manufactured in accordance with GMP.

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In order to market our drug candidates in the EU and many other foreign jurisdictions, we must obtain separate regulatory approvals.

More concretely, in the EU, medicinal drug candidates can only be placed on the market after obtaining a marketing authorization (“MA”).

To obtain regulatory approval of a drug candidate under EU regulatory systems, we must submit a MA application (“MAA”).

More concretely, in the EU, medicinal drug candidates can only be placed on the market after obtaining a MA.

To obtain regulatory approval of a product candidate under EU regulatory systems, we must submit an MAA.

The process for doing this depends, among other things, on the nature of the medicinal product.

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The centralized procedure is mandatory for certain types of products, such as (i) medicinal products, derived from biotechnology processes, such as genetic engineering, (ii) designated orphan medicinal products, (iii) advanced therapy medicinal products (“ATMPs”) such as gene therapy, somatic cell therapy or tissue-engineered medicines, and (iv) medicinal products containing a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases.

The centralized procedure is optional for products containing a new active substance not yet authorized in the EU or for drug candidates which constitute a significant therapeutic, scientific or technical innovation;

or for which the granting of an MA would be in the interest of public health in the EU.

“National MAs” – are issued by the competent authorities of the EU member states, and only cover their respective territory and are available for drug candidates not falling within the mandatory scope of the centralized procedure.

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After these five years, the authorization may be renewed for an unlimited period on the basis of a reevaluation of the risk-benefit balance.

Under the centralized procedure, the maximum timeframe for the evaluation of a MAA by the EMA is 210 days.

In exceptional cases, the CHMP might perform an accelerated review of a MAA in no more than 150 days (not including clock stops).

Under the centralized procedure, the maximum timeframe for the evaluation of an MAA by the EMA is 210 days.

In exceptional cases, the CHMP might perform an accelerated review of an MAA in no more than 150 days (not including clock stops).

Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the PRIME scheme, which provides incentives similar to the breakthrough therapy designation in the United States.

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Product developers that benefit from PRIME designation can expect to be eligible for accelerated assessment, but this is not guaranteed.

The benefits of a PRIME designation include the appointment of a CHMP rapporteur before submission of a MAA, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review earlier in the application process.

The benefits of a PRIME designation include the appointment of a CHMP rapporteur before submission of an MAA, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review earlier in the application process.

Data and Marketing Exclusivity

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For example, in the EU, new products authorized for marketing (“reference products”) generally receive eight years of data exclusivity and an additional two years of market exclusivity upon MA.

If granted, the data exclusivity period prevents generic or biosimilar applicants from relying on the pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of 8 years from the date on which the reference product was first authorized in the EU.

If granted, the data exclusivity period prevents generic or biosimilar applicants from relying on the pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until ten years have elapsed from the initial MA of the reference product in the EU.

The overall 10-year market exclusivity period can be extended to a maximum of 11 years if, during the first 8 years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

The overall 10-year market exclusivity period can be extended to a maximum of 11 years if, during the first eight years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical entity, and products may not qualify for data exclusivity.

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An EU orphan designation entitles a party to incentives such as reduction of fees or fee waivers, protocol assistance, and access to the centralized procedure.

Upon grant of a MA, orphan medicinal products are entitled to ten years of market exclusivity for the approved indication, which means that the competent authorities cannot accept another MAA, or grant a MA, or accept an application to extend a MA for a similar medicinal product for the same indication for a period of ten years.

Upon grant of an MA, orphan medicinal products are entitled to 10 years of market exclusivity for the approved indication, which means that the competent authorities cannot accept another MAA, or grant an MA, or accept an application to extend an MA for a similar medicinal product for the same indication for a period of 10 years.

The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed pediatric investigation plan (“PIP”).

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Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the member states.

The holder of a MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance (“QPPV”) who is responsible for the establishment and maintenance of that system, and oversees the safety profiles of medicinal products and any emerging safety concerns.

The holder of an MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance (“QPPV”) who is responsible for the establishment and maintenance of that system, and oversees the safety profiles of medicinal products and any emerging safety concerns.

Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (“PSURs”).

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Brexit and the Regulatory Framework in the United Kingdom

Since the end of the Brexit transition period on January 1, 2021, Great Britain (England, Scotland and Wales) has not been directly subject to EU laws, however under the terms of the Ireland/Northern Ireland Protocol, EU laws generally apply to Northern Ireland.

The EU laws that have been transposed into United Kingdom law through secondary legislation remain applicable in Great Britain, however, new legislation such as the EU CTR is not applicable in Great Britain.

Following the end of the Brexit transition period on January 1, 2021, and the implementation of the Windsor Framework on January 1, 2025, the United Kingdom (“UK”) is not generally subject to EU laws in respect of medicines.

The EU laws that have been transposed into United Kingdom law through secondary legislation remain applicable in the UK;

however, new legislation such as the (EU) CTR is not applicable in Great Britain.

Under the Medicines and Medical Devices Act 2021, the Secretary of State or an ‘appropriate authority’ has delegated powers to amend or supplement existing regulations in the area of medicinal products and medical devices.

This allows new rules to be introduced in the future by way of secondary legislation, which aims to allow flexibility in addressing regulatory gaps and future changes in the fields of human medicines, clinical trials and medical devices.

Since January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”), has been the UK’s standalone medicines and medical devices regulator.

As a result of the Northern Ireland protocol, different rules will apply in Northern Ireland than in England, Wales, and Scotland, together, Great Britain (“GB”);

broadly, Northern Ireland will continue to follow the EU regulatory regime, but its national competent authority will remain the MHRA.

On February 27, 2023, the UK Government and the European Commission reached a political agreement on the “Windsor Framework” which will revise the Northern Ireland protocol in order to address some of the perceived shortcomings in its operation.

Under the changes, Northern Ireland will be reintegrated under the regulatory authority of the MHRA with respect to medicinal products.

The Windsor Framework was approved by the European Union-United Kingdom Joint Committee on March 24, 2023, so the UK government and the EU will enact legislative measures to bring it into law.

On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply from January 1, 2025.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, including a 150-day assessment and a rolling review procedure.

Since January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”) is the UK’s standalone medicines and medical devices regulator.

As a result of the Ireland/Northern Ireland protocol, different rules applied in Northern Ireland than in England, Wales, and Scotland, together, Great Britain (“GB”), which continued to follow the EU regulatory regime.

However, on January 1, 2025, a new arrangement called the “Windsor Framework” came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products.

The Windsor Framework removes EU licensing processes and EU labelling and serialization requirements in relation to Northern Ireland and introduces a UK-wide licensing process for medicines.

The UK regulatory framework in relation to clinical trials is governed by the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, which is derived from existing EU legislation (as implemented into UK law, through secondary legislation).

On January 17, 2022, the MHRA launched an eight-week consultation on reframing the UK legislation for clinical trials which aimed to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.

The MHRA published its consultation outcome on March 21, 2023, confirming that it would bring forward changes to the legislation.

The resulting legislative amendments, which are yet to be published, will ultimately determine the extent to which the UK clinical trials framework aligns with or diverges from the (EU) CTR.

In October 2023, the MHRA announced a new Notification Scheme for clinical trials which enables a more streamlined and risk-proportionate approach to initial clinical trial applications for Phase 4 and low-risk Phase 3 CTAs.

MAs in the UK are governed by the Human Medicines Regulations (SI 2012/1916), as amended.

All existing EU MAs for centrally authorized products were automatically converted or grandfathered into UK MAs, effective in GB (only), free of charge on January 1, 2021, unless the MA holder opted-out.

In order to use the centralized procedure to obtain a MA that will be valid throughout the EEA, companies must be established in the EEA.

Under the terms of the Windsor Framework, these MAs became valid for the whole of the UK from January 1, 2025.

In order to use the centralized procedure to obtain an MA that will be valid throughout the EEA, companies must be established in the EEA.

Therefore, since Brexit, companies established in the UK can no longer use the EU centralized procedure and instead an EEA entity must hold any centralized MAs.

In order to obtain a UK MA to commercialize products in the UK, an applicant must be established in the UK and must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures to obtain an MA to commercialize products in the UK.

A new international recognition framework has been in place from January 1, 2024, whereby the MHRA will have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new GB MA.

The UK regulatory framework in relation to clinical trials is derived from existing EU legislation (as implemented into UK law, through secondary legislation).

The MHRA responded to the consultation on March 21, 2023 and confirmed that it would bring forward changes to the legislation.

The final legal texts introduced by the UK Government will ultimately determine the extent to which the UK clinical trials framework aligns with or diverges from the (EU) CTR.

Applications are governed by the Human Medicines Regulations (SI 2012/1916) and are made electronically through the MHRA Submissions Portal.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, a 150-day assessment (subject to clock-stops) and a rolling review procedure.

In addition, since January 1, 2024, the MHRA may rely on the International Recognition Procedure, or IRP, when reviewing certain types of MAAs.

Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g., the regulatory authorities in Australia, Canada, Switzerland, Singapore, Japan, the United States.

The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust.

The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update an MA in the UK or Great Britain.

Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60-day period and the approval from the trusted regulatory partner selected has been granted within the previous two years or if there are such major objections identified or such approval hasn’t been granted within the previous two years within 110 days.

Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.

In the UK, the initial duration of an MA is five years and following renewal will be valid for an unlimited period unless the MHRA decides on justified grounds relating to pharmacovigilance to proceed with only one additional five-year renewal.

Any authorization which is not followed by the actual placing of the drug on the market in the UK within three years shall ease to be in force.

There is no pre-MA orphan designation in the UK.

Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MA application.

The criteria are essentially the same, but have been tailored for the market, i.e., the prevalence of the condition in GB, rather than the EU, must not be more than five in 10,000.

Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in GB.

If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

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For example, the Patient Protection and Affordable Care Act (the “ACA”), enacted in March 2010, substantially changed the way healthcare is financed by both governmental and private insurers.

Among the provisions of the ACA, of greatest importance to the pharmaceutical industry are the following:

an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents;

a new Medicare Part D coverage gap discount program, in which pharmaceutical manufacturers who wish to have their drugs covered under Part D must offer discounts to eligible beneficiaries during their coverage gap period, or the donut hole;

a new formula that increases the rebates a manufacturer must pay under the Medicaid Drug Rebate Program.

Among other provisions, the ACA included an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents and a new formula that increases the rebates a manufacturer must pay under the Medicaid Drug Rebate Program.

Since its enactment, there have been judicial, executive and Congressional challenges to certain aspects of the ACA.

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Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Thus, the ACA will remain in effect in its current form.

In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted.

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The rebate was previously capped at 100% of a drug’s average manufacturer price.

Most significantly, in August 2022, the Inflation Reduction Act of 2022, or the IRA, was signed into law.

Most significantly, in August 2022, President Biden signed the Inflation Reduction Act of 2022 (“IRA”) into law.

This statute marks the most significant action by Congress with respect to the pharmaceutical industry since adoption of the ACA in 2010.

Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;

Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare, with prices that can be negotiated subject to a cap;

imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023);

and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).

redesigns the Medicare Part D benefit (beginning in 2024);

and replaces the Part D coverage gap discount program with a new manufacturer discount program (beginning in 2025).

CMS has published the negotiated prices for the initial 10 drugs, which will first be effective in 2026, and has published the list of the subsequent 15 drugs that will be subject to negotiation.

The IRA permits the Secretary of the Department of Health and Human Services (“HHS”) to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations.

HHS has issued and will continue to issue guidance implementing the IRA, although the Medicare drug price negotiation program is currently subject to legal challenges.

While the impact of the IRA on our business and the pharmaceutical industry cannot yet be fully determined, it is likely to be significant.

HHS has and will continue to issue and update guidance as these programs are implemented, although the Medicare drug price negotiation program is currently subject to legal challenges.

The impact of the IRA on us and the pharmaceutical industry cannot yet be fully determined, but is likely to be significant.

Under the IRA manufacturer discount program that replaced the coverage gap discount program as of January 1, 2025, manufacturers must give a 10 percent discount on Part D drugs in the initial coverage phase, and a 20 percent discount on Part D drugs in the so-called “catastrophic phase” (the phase after the patient incurs costs above the initial phase out-of-pocket threshold, which will be $2,000 beginning in 2025).

The IRA allows the 10 and 20 percent discounts to be phased in over time for certain drugs for “specified manufacturers.” In April 2024, CMS informed us that we are deemed a specified small manufacturer and the discount will be phased in over several years and will increase over time.

We are continuing to evaluate the potential impact of this status on our future revenues.

NERLYNX is reimbursed under Medicare Part D, and the reimbursement amount will be impacted by the 10 and 20 percent discounts under the IRA’s new discounting program (as noted above).

We anticipate that these increased discounts will impact NERLYNX revenues over time, while also having an industry-wide impact on the patient out of pocket costs of Part D drugs.

The impact on NERLYNX revenues could be offset because the IRA’s redesign of certain Part D components, some of which went into effect in 2024, resulted in an increase in the number of patients able to afford this therapy.

The amount of the offset, if any, is inherently uncertain and difficult to predict.

The IRA manufacturer discount program also increases financial obligations of Part D prescription drug plans with respect to beneficiaries in the catastrophic coverage phase.

This may incentivize Part D prescription drug plans to seek greater price concessions from us in order to include NERLYNX on their formularies.

The cost of prescription pharmaceuticals in the United States continues to be the subject of considerable discussion.

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Further to this, in December 2021, Regulation No 2021/2282 on HTA, amending Directive 2011/24/EU, was adopted.

While the Regulation entered into force in January 2022, it will only begin to apply from January 2025 onwards, with preparatory and implementation-related steps to take place in the interim.

Once applicable, it will have a phased implementation depending on the concerned products.

The Regulation entered into force in January 2022 and has been applicable since January 2025, with phased implementation based on the type of product, i.e.

oncology and advanced therapy medicinal products as of 2025, orphan medicinal products as of 2028, and all other medicinal products by 2030.

The Regulation intends to boost cooperation among EU member states in assessing health technologies, including new medicinal products, and provide the basis for cooperation at the EU level for joint clinical assessments in these areas.

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Medicaid is a joint federal and state program for low-income and disabled beneficiaries.

Medicare is a federal program covering individuals age 65 and over as well as those with certain disabilities.

Medicare is a federal program covering individuals aged 65 and over as well as those with certain disabilities.

As a condition of having federal funds being made available for covered outpatient drugs under Medicaid and Medicare Part B, we have enrolled in the Medicaid Drug Rebate Program (“MDRP”), which requires us to pay a rebate to state Medicaid programs for each unit of our covered outpatient drugs dispensed to a Medicaid beneficiary and paid for by a state Medicaid program.

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Federal law requires that a manufacturer that participates in the MDRP also participate in the Public Health Service’s 340B drug pricing program (the “340B program”) in order for federal funds to be available for the manufacturer’s drugs under Medicaid and Medicare Part B.

We participate in the 340B program, which is administered by the Health Resources and Services Administration (“HRSA”), and requires us to charge statutorily defined covered entities no more than the 340B “ceiling price” for our covered outpatient drugs used in an outpatient setting.

We participate in the 340B program, which is administered by the Health Resources and Services Administration (“HRSA”) that requires us to charge statutorily defined covered entities no more than the 340B “ceiling price” for our covered outpatient drugs used in an outpatient setting.

These 340B covered entities include a variety of community health clinics and other entities that receive health services grants from the Public Health Service, as well as hospitals that serve a disproportionate share of low-income patients.

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HRSA has finalized regulations regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities for 340B-eligible drugs.

HRSA has also finalized an administrative dispute resolution process through which 340B covered entities may pursue claims against participating manufacturers for overcharges, and through which manufacturers may pursue claims against 340B covered entities for engaging in unlawful diversion or duplicate discounting of 340B drugs.

HRSA has also finalized a revised regulation implementing an administrative dispute resolution process through which 340B covered entities may pursue claims against participating manufacturers for overcharges, and through which manufacturers may pursue claims against 340B covered entities for engaging in unlawful diversion or duplicate discounting of 340B drugs.

In order to be eligible to have drug products paid for with federal funds under Medicaid and Medicare Part B and purchased by certain federal agencies and grantees, we also must participate in the U.S.

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Requirements under such laws include advance notice of planned price increases, reporting price increase amounts and factors considered in taking such increases, wholesale acquisition cost information disclosure to prescribers, purchasers, and state agencies, and new product notice and reporting.

Such legislation could limit the price or payment for certain drugs, and a number of states are authorized to impose civil monetary penalties or pursue other enforcement mechanisms against manufacturers who fail to comply with drug price transparency requirements, including the untimely, inaccurate, or incomplete reporting of drug pricing information.

Such legislation could limit the price or payment for certain drugs, and a number of states are authorized to impose civil monetary penalties or pursue other enforcement mechanisms against manufacturers who fail to comply with drug price transparency reporting requirements, including the untimely, inaccurate, or incomplete reporting of drug pricing information.

Some states have enacted legislation creating so-called prescription drug affordability boards, which ultimately may attempt to impose price limits on certain drugs in these states.

Sales and Marketing

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As of December 31, 2024, our workforce consisted of 172 full-time employees.

Throughout 2023, the size of our employee population was fairly consistent, but ending with lower headcount at the end of the year due to reorganization efforts and employee attrition.

Our employee population consists of a field-based commercial team, working from a home office and visiting customers across the country, employees reporting out of our two offices in the United States - Los Angeles, CA and South San Francisco, CA – and employees working remotely from home on a consistent basis.

For our office-based employees, during the latter part of 2022, adopted a virtual work environment, allowing functional management and employees to determine when working virtually is more efficient and productive, and when in-office collaboration is beneficial.

Throughout 2024, the size of our employee population was fairly consistent, but ending with lower headcount at the end of the year due to reorganization/efficiency efforts and employee attrition.

Our employee population consists of a field-based commercial team, working from home offices and visiting customers across the country, employees aligned with our two offices in the United States - Los Angeles, California and South San Francisco, California – and the majority of non-field sales employees working remotely from home on a consistent basis.

For our office-based employees, during the latter part of 2022, we adopted a virtual work environment, allowing functional management and employees to determine when working virtually is more efficient and productive, and when in-office collaboration is beneficial.

We are an equal opportunity employer and believe strongly in hiring and maintaining a diverse, equitable, and inclusive workforce.

This is reflected in our numbers with our total workforce being approximately 50% women and 36% ethnically diverse.

This is reflected in our numbers with our total workforce being approxima tely 49% women and 37% eth nically diverse.

The following table summarizes our workforce by location for the years ended December 31, 2024 and December 31, 2023:

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Field & Remote

We believe that the safety and health of our employees and their families is essential to our business.

We believe that the safety and health of our employees and their families are essential to our business.

Our culture is driven by a desire to do what is right, and we strive to support the well-being of our employees.

Our financial, medical, and mental health benefits are designed to help employees through crisis, and we recently expanded our offerings to create appropriate “work from home” conditions for those employees that are in field positions or choose not to work in the office to include:

ergonomic webinars, 1x1 evaluations, and reimbursement for ergonomic equipment;

phone and internet subsidies;

purchasing additional IT equipment and office supplies;

increasing communications related to our free Employee Assistance Plans, work/life assistance programs, and mental health benefits;

professional resiliency coaching;

subsidized subscriptions to ClassPass – access to fitness, wellness, and mindfulness classes;

hosting a virtual fitness challenge to inspire employees to be more active.

Our financial, health and wellness benefits are designed to assist employees with financial planning, preventative health care, and support when unexpected circumstances arise.

We continue to support employee wellbeing, work flexibility, and work efficiency by offering the following:

a robust offering of benefit options;

periodic reminders of our benefit options to our employees;

a Lifestyle Spending Account to support employee wellness and fitness activities;

programming, including hosting a company-wide “Wellness Week” and “Walking Challenges” to motivate employees to engage with each other for increased physical fitness opportunities;

ergonomic support in the form of training opportunities, 1:1 evaluations, and providing ergonomically compatible equipment when necessary;

subsidies for mobile devices and internet access

Compensation & Benefits

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Employee’s total compensation represents a broad spectrum of plans and programs designed to reward and motivate employees throughout their careers.

Our total rewards package consists of competitive market-based salary and cash target bonus based on geography for every employee.

Our total rewards package consists of competitive market-based salaries and cash target bonuses.

Bonus opportunity and equity compensation increase as a percentage of total compensation based on level of responsibility with actual bonus payout based on performance.

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Culture and Communication

How we conduct our business is just as important as what we do.

How we conduct our business is just as important as what we do and achieve.

Our core values are the principles that guide our company strategy and our individual actions.

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The majority of our employees have obtained advanced degrees in their professions, and we support their continued development with individualized development plans and objectives, mentoring, coaching, training and conference attendance.

In addition, we offer an Educational Reimbursement Program to assist employees who want to further their educations.

Communication is critical in our ability to continuously enhance our company culture and create a more inclusive environment.

The implementation and distribution of quarterly company newsletters have allowed us to share what is important and impactful to us as a business.

It also allows for us to share stories and events that have affected our employees and co-workers across the country on both a personal and professional level.

We hold town halls with our leaders to speak with employees about our vision and to receive feedback on matters important to them.

Additionally, we have dynamic information technology systems, which allow for a more synergistic atmosphere.

We continue to publish a quarterly newsletter to share interesting and useful information through our involvement in cancer-related conferences and causes, such as Breast Cancer Awareness Month.

We also introduce new employees to the organization in our Welcome to Puma section, and profile existing employees in our Get Connected section, where we share information about their roles, motivations to be with Puma, backgrounds, and interests.

In addition, we include information about upcoming employee events and benefit opportunities, as well as previous events like employee team building and Wellness Week participation.

We conduct town hall meetings to share information with employees about what is happening across the business, and often include guest speakers, such as Patient Ambassadors, to motivate and inform our employees.

Lastly, the Human Resources function recently created an employee self-service portal to allow employees to find useful information quickly and easily without assistance.

Corporate Information and History

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business