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Acorda Provides Financial and Pipeline Update for Fourth Quarter and Year End 2017

On February 15, 2018 Acorda Therapeutics, Inc. (Nasdaq:ACOR) reported a financial and pipeline update for the fourth quarter and full year ended December 31, 2017 (Press release, Acorda Therapeutics, FEB 15, 2018, View Source [SID1234523984]).

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"We continue to prepare for the potential approval and launch of INBRIJA, our investigational inhaled levodopa treatment for symptoms of OFF periods in people with Parkinson’s disease. We look forward to working with the FDA during the NDA review process, and to bringing this new treatment option to the Parkinson’s community to help address an important unmet need," said Ron Cohen, M.D., Acorda’s President and CEO. "Based on our continued market research, as well as the strength of our Phase 3 data, we believe INBRIJA’s US market opportunity to be greater than $800 million."

Fourth Quarter 2017 Financial Results

AMPYRA (dalfampridine) Extended Release Tablets, 10 mg – For the quarter ended December 31, 2017, the Company reported AMPYRA net revenue of $167.2 million compared to $132.3 million for the same quarter in 2016.

Royalty Revenue – For the quarter ended December 31, 2017, the Company reported royalty revenue of $16.1 million as compared to $4.4 million for the same quarter in 2016. The Company reported FAMPYRA royalties from sales outside of the U.S. of $3.1 million compared to $2.7 million for the same quarter in 2016. Additionally, the Company completed a transaction that provides a fully paid-up, royalty-free license for Selincro in exchange for $13.0 million which was recorded as royalty revenue in the quarter ended December 31, 2017. During the quarter ended December 31, 2017, the Company completed a royalty purchase transaction for its Fampyra royalty revenue in exchange for an upfront payment of $40 million. The transaction was recorded as a liability in accordance with US GAAP which will be reduced over time as royalty revenue is recognized.

Research and development (R&D) expenses for the quarter ended December 31, 2017 were $35.1 million, including $2.2 million of share-based compensation compared to $53.8 million, including $3.0 million of share-based compensation for the same quarter in 2016.

Sales, general and administrative (SG&A) expenses for the quarter ended December 31, 2017 were $39.5 million, including $5.4 million of share-based compensation compared to $59.0 million, including $6.0 million of share-based compensation for the same quarter in 2016.

The Company recorded non-cash asset impairment charges of $233.5 million for tozadenant as a result of the termination of this program, and $23.8 million for SYN120 as a result of the trial not meeting key primary and secondary endpoints. The Company assessed the valuation assumptions for both programs and determined the assets were fully impaired. Both of these charges were recorded in the quarter ended December 31, 2017.

Benefit from income taxes for the quarter ended December 31, 2017 was $51.9 million, including $2.7 million of cash taxes, compared to a provision for income taxes of $1.0 million, including $0.7 million of cash taxes for the same quarter in 2016.

The Company reported a GAAP net loss attributable to Acorda of $(171.1) million for the quarter ended December 31, 2017, or $(3.70) per diluted share. GAAP net loss in the same quarter of 2016 was $(3.1) million, or $(0.07) per diluted share.

Non-GAAP net income for the quarter ended December 31, 2017 was $28.5 million, or $0.61 per diluted share. Non-GAAP net income in the same quarter of 2016 was $2.5 million, or $0.05 per diluted share. This quarterly non-GAAP net income measure, more fully described below under "Non-GAAP Financial Measures," excludes share-based compensation charges, non-cash interest charges on our debt, restructuring expenses, changes in the fair value of acquired contingent consideration, asset impairment charges, gain on sale of assets and acquisition-related expenses. A reconciliation of the GAAP financial results to non-GAAP financial results is included with the attached financial statements.

Financial Results – Full Year Ended December 31, 2017

AMPYRA (dalfampridine) Extended Release Tablets, 10 mg – For the full year ended December 31, 2017 net revenue was $543.3 million compared to $492.8 million for full year 2016. Full year 2017 net revenue increased 10.2% over 2016.

Royalty Revenue – For the full year ended December 31, 2017, the Company reported royalty revenue of $29.5 million compared to $17.2 million for the full year 2016. The Company reported FAMPYRA royalties from sales outside of the U.S. of $11.6 million compared to $10.6 million for the full year 2016. Royalty revenue related to the authorized generic version of Zanaflex was $2.6 million compared to $3.9 million for the full year 2016. Additionally, the Company reported $15.3 million in royalties for Selincro for the full year 2017, which includes $13.0 million of royalty revenue related to the Selincro royalty transaction.

Research and development (R&D) expenses for the full year ended December 31, 2017 were $166.1 million, including $9.7 million of share-based compensation, compared to $203.4 million, including $10.6 million of share-based compensation for the full year 2016

Sales, general and administrative (SG&A) expenses for the full year ended December 31, 2017 were $181.6 million, including $23.1 million of share-based compensation, compared to $235.4 million, including $25.8 million of share-based compensation for the full year 2016.

Asset impairment charges for the full year ended December 31, 2017 include $233.5 million for tozadenant, $23.8 million for SYN120, and $39.4 million for Selincro.

Benefit from income taxes for the full year ended December 31, 2017 was $28.5 million, including $14.1 million of cash taxes compared to a benefit from income taxes of $6.7 million, including $4.3 million of cash taxes for the full year 2016.

For the full year ended December 31, 2017, the Company reported a GAAP net loss of $(223.4) million, or $(4.86) per diluted share. GAAP net loss for the full year 2016 was $(34.6) million, or $(0.76) per diluted share.

Non-GAAP net income for the full year ended December 31, 2017 was $80.7 million, or $1.75 per diluted share. Non-GAAP net income for the full year ended December 31, 2016 was $11.5 million, or $0.25 per diluted share. This full year non-GAAP net income measure, more fully described below under "Non-GAAP Financial Measures," excludes share-based compensation charges, non-cash interest charges on our debt, restructuring expenses, changes in the fair value of acquired contingent consideration, asset impairment charges, gain on sale of assets, realized foreign currency loss (gain) and acquisition related expenses. A reconciliation of the GAAP financial results to non-GAAP financial results is included with the attached financial statements.

At December 31, 2017, the Company had cash and cash equivalents of $307.1 million.

2018 Financial Guidance

AMPYRA net revenue is expected to be $330-$350 million. The Company expects to maintain exclusivity of AMPYRA at least through July 30, 2018; this guidance is subject to change based on the appellate court’s decision.
R&D expenses for the full year 2018 are expected to be $100-$110 million and include manufacturing expenses associated with INBRIJA. This guidance is a non-GAAP projection that excludes share-based compensation as more fully described below under "Non-GAAP Financial Measures."
SG&A expenses for the full year 2018 are expected to be $170-$180 million. This guidance is a non-GAAP projection that excludes share-based compensation as more fully described below under "Non-GAAP Financial Measures."
Year-end cash balance for 2018 is projected to be over $300 million
Fourth Quarter 2017 Pipeline and Corporate Updates

INBRIJA (levodopa inhalation powder) Next Steps
The Company resubmitted the NDA for INBRIJA in December 2017. The FDA is expected to inform the Company if the submission has been deemed complete and permits a full review in February 2018.
The Company expects to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) in Q1 2018.
AMPYRA (dalfampridine) Patent Appeal
In November, 2017, the Company and the defendants filed reply briefs for the appeal to the U.S. Court of Appeals for the Federal Circuit of the District Court’s decision in the AMPYRA patent litigation. The date for oral argument is expected in the first half of 2018.
Both BIO and PhRMA filed amicus briefs in support of the Company’s appeal, raising important issues in conjunction with biopharmaceutical innovation.
Royalty Monetization Transactions/ZANAFLEX (tizanidine hydrochloride) Franchise Sale
In November, 2017, the Company announced royalty monetization transactions of $53 million for FAMPYRA and SELINCRO.
The Company also announced the sale of ZANAFLEX and ZANAFLEX CAPSULES for $4 million.
SYN120 Phase 2 Data in Parkinson’s disease
Data from the Phase 2 proof-of-concept study for SYN120 showed that several of the outcome measures trended in favor of drug versus placebo; neither the primary nor key secondary endpoints achieved statistical significance.
The Company continues to review the data, which will be presented at an upcoming medical meeting.
Tozadenant Program Discontinued
In November, 2017, the Company discontinued its clinical development program for tozadenant, an investigational treatment for Parkinson’s disease. The Company made this decision based on the emergence of serious adverse events in its Phase 3 program.
Webcast and Conference Call

The Company will host a conference call today at 8:30 a.m. ET. To participate, dial (866) 393-4306 (domestic) or (734) 385-2616 (international); access code 8789908. The presentation will be available on the Investors section of www.acorda.com.

A replay of the call will be available from 11:30 a.m. ET on February 15, 2018 until 11:59 p.m. ET on March 15, 2018. To access the replay, dial (855) 859-2056 (domestic) or (404) 537-3406 (international); reference code 8789908. The archived webcast will be available in the Investor Relations section of the Acorda website.

Non-GAAP Financial Measures

This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP), and also certain historical and forward-looking non-GAAP financial measures. In particular, Acorda has provided non-GAAP net income, adjusted to exclude the items below, and has provided 2018 guidance for R&D and SG&A expenses on a non-GAAP basis. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, the Company believes the presentation of non-GAAP net income, when viewed in conjunction with our GAAP results, provides investors with a more meaningful understanding of our ongoing and projected operating performance because this measure excludes (i) non-cash compensation charges and benefits that are substantially dependent on changes in the market price of our common stock, (ii) non-cash interest charges related to the accounting for our outstanding convertible debt which are in excess of the actual interest expense owing on such convertible debt as well as non-cash interest related to the Fampyra monetization, non-cash interest charges related to our asset based loan which was terminated in 2017 and acquired Biotie debt, (iii) changes in the fair value of acquired contingent consideration which do not correlate to our actual cash payment obligations in the relevant periods, (iv) acquisition related expenses and related foreign currency losses and gains that pertain to a non-recurring event, (v) corporate restructuring expenses that pertain to a non-recurring event, (vi) asset impairments which are non-cash charges that relate to program terminations that are not routine to the operation of the business, and (vii) gain on sale of assets that pertains to a non-recurring event. The Company believes its non-GAAP net income measure helps indicate underlying trends in the Company’s business and is important in comparing current results with prior period results and understanding projected operating performance. Also, management uses this non-GAAP financial measure to establish budgets and operational goals, and to manage the Company’s business and to evaluate its performance.

In addition to non-GAAP net income, we have provided 2018 guidance for R&D and SG&A expenses on a non-GAAP basis. Due to the forward looking nature of this information, the amount of compensation charges and benefits needed to reconcile these measures to the most directly comparable GAAP financial measures is dependent on future changes in the market price of our common stock and is not available at this time. The Company believes that these non-GAAP measures, when viewed in conjunction with our GAAP results, provide investors with a more meaningful understanding of our ongoing and projected R&D and SG&A expenses. Also, management uses these non-GAAP financial measures to establish budgets and operational goals, and to manage the Company’s business and to evaluate its performance..

Oncoceutics and Calvert Research Announce Development/Investment Agreement for ONC 206

On February 14, 2018 Oncoceutics Inc. and Calvert Research, LLC reported that the two companies have entered into a second product development and investment partnership agreement, this time to further develop and enable the submission of an investigational new drug (IND) application for ONC206, Oncoceutics’ next generation molecule (Press release, Oncoceutics, FEB 14, 2018, View Source [SID1234558372]).

As a part of this second agreement, Calvert Research will enlist the capabilities of its CRO affiliate, Calvert Laboratories, Inc. to conduct certain GLP animal safety and pharmacology studies on ONC206 in its GLP certified facilities. In addition, Calvert Research has made a second equity investment in Oncoceutics. This agreement follows the same successful investment-development partnership model established between Oncoceutics and Calvert Research in 2013 that lead to Oncoceutics being able to open an IND application for ONC201, its lead molecule.

ONC206 is a member of a family of drug candidates called "imipridones" that possess the same core structure of ONC201 and that have demonstrated the same favorable drug characteristics, including efficacy in pre-clinical models against cancer with high levels of safety. Given these attractive attributes, Oncoceutics filed a pre-IND application with the FDA describing its plans for a clinical trial with ONC206 and received positive written feedback to the pre-IND submission from the FDA. Based on the FDA written response, Oncoceutics has defined all of the studies required to have an IND accepted by the FDA. These include manufacturing ONC206 in quantity and at quality sufficient to treat people, and the toxicology work necessary to open an investigational new drug application (IND) that will be completed by Calvert Laboratories. Oncoceutics expects to complete all studies by the end of 2018 and to file the IND and begin first-in-human studies for ONC206 in 2019.

Previously, Oncoceutics has announced that the United States Patent and Trademark Office (USPTO) has issued a patent providing the company with composition of matter protection for ONC206.

"We are pleased to enter into a second investment partnership agreement with Calvert Research, a firm that possesses excellent capabilities in the field of GLP-compliant animal safety studies," said Martin Stogniew Ph.D., Chief Development Officer of Oncoceutics. "By bringing the second member of the imipridone family towards a clinical trial, we are continuing our transformation of Oncoceutics from a company with one drug in development into a company developing a portfolio of drugs."

10-K – Annual report [Section 13 and 15(d), not S-K Item 405]

Seattle Genetics has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission .

FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint

On February 14, 2018 The U.S. Food and Drug Administration reported the approval of Erleada (apalutamide) for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant) (Press release, US FDA, FEB 14, 2018, View Source [SID1234523990]). This is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer.

"The FDA evaluates a variety of methods that measure a drug’s effect, called endpoints, in the approval of oncology drugs. This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment," said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "In the trial supporting approval, Erleada had a robust effect on this endpoint. This demonstrates the agency’s commitment to using novel endpoints to expedite important therapies to the American public."

According to the National Cancer Institute (NCI) at the National Institutes of Health, prostate cancer is the second most common form of cancer in men in the U.S.. The NCI estimates approximately 161,360 men were diagnosed with prostate cancer in 2017, and 26,730 were expected to die of the disease. Approximately 10 to 20 percent of prostate cancer cases are castration-resistant, and up to 16 percent of these patients show no evidence that the cancer has spread at the time of the castration-resistant diagnosis.

Erleada works by blocking the effect of androgens, a type of hormone, on the tumor. These androgens, such as testosterone, can promote tumor growth.

The safety and efficacy of Erleada was based on a randomized clinical trial of 1,207 patients with non-metastatic, castration-resistant prostate cancer. Patients in the trial either received Erleada or a placebo. All patients were also treated with hormone therapy, either with gonadotropin-releasing hormone (GnRH) analog therapy or with surgery to lower the amount of testosterone in their body (surgical castration). The median metastasis-free survival for patients taking Erleada was 40.5 months compared to 16.2 months for patients taking a placebo.

Common side effects of Erleada include fatigue, high blood pressure (hypertension), rash, diarrhea, nausea, weight loss, joint pain (arthralgia), falls, hot flush, decreased appetite, fractures and swelling in the limbs (peripheral edema).

Severe side effects of Erleada include falls, fractures and seizures.

This application was granted Priority Review, under which the FDA’s goal is to take action on an application within 6 months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The sponsor for Erleada is the first participant in the FDA’s recently-announced Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals and more transparency into the FDA’s decision-making process. Soon after approval, certain information from the clinical summary report will post with the Erleada entry on Drugs@FDA and on the new pilot program landing page.

The FDA granted the approval of Erleada to Janssen Pharmaceutical Companies.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

ERLEADA&#8482 (apalutamide), a Next-Generation Androgen Receptor Inhibitor, Granted U.S. FDA Approval for the Treatment of Patients with Non-Metastatic Castration-Resistant Prostate Cancer

On February 14, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the U.S. Food and Drug Administration (FDA) has approved ERLEADA (apalutamide), a next-generation androgen receptor inhibitor,1 for the treatment of patients with non-metastatic castration-resistant prostate cancer (NM-CRPC) (Press release, Johnson & Johnson, FEB 14, 2018, View Source [SID1234523973]). ERLEADA is the first FDA-approved treatment for these patients. Today’s approval follows an FDA Priority Review designation based upon data from the Phase 3 SPARTAN study, which demonstrated a 72 percent reduction in risk of distant metastasis or death, and an increase in median metastasis-free survival (MFS) by more than two years (difference of 24.31 months) in patients with NM-CRPC.

"The need to delay metastasis is critical to the treatment of prostate cancer. Nearly 90 percent of patients with castration-resistant prostate cancer will eventually develop bone metastases, at which point the prognosis sharply worsens," said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, LLC. "We are excited about what this approval means for patients living with prostate cancer, and that physicians now have an important and much-needed treatment option that has been shown to delay the progression of castration-resistant prostate cancer."

ERLEADA received FDA approval based on the Phase 3 data from the SPARTAN clinical trial, which assessed the efficacy and safety of ERLEADA versus placebo in patients with NM-CRPC who had a rapidly rising PSA while receiving continuous androgen deprivation therapy.2 The study was recently presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (ASCO GU) on Thursday, February 8, 2018 in San Francisco and published in The New England Journal of Medicine.2,3

"The SPARTAN trial results demonstrated impressive clinical benefits in patients with non-metastatic castration-resistant prostate cancer," said Matthew Smith, M.D., Ph.D., Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, Professor of Medicine at Harvard Medical School, and co-principal investigator of the SPARTAN study. "As an oncologist and clinical investigator, I know how devastating it can be for patients and their families to hear that the cancer has spread. With this approval, doctors now have the chance to offer hope for delaying metastases in patients with castration-resistant prostate cancer."

"As the impact of prostate cancer continues to grow, we are reminded every day of the critical need for therapeutic options that offer patients with prostate cancer more time with their loved ones," Mark Scholz, M.D., Executive Director of the Prostate Cancer Research Institute. "Today’s approval is significant, as it means that patients with non-metastatic castration-resistant prostate cancer now have a treatment option that offers renewed hope."

SPARTAN, a Phase 3, randomized, double-blind, placebo-controlled, multi-center study, enrolled 1,207 patients with non-metastatic castration-resistant prostate cancer.4 Patients were randomized 2:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=806), or placebo once daily (n=401).4 All patients in the SPARTAN trial received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy.4

ERLEADA decreased the risk of distant metastasis or death by 72 percent compared to placebo (HR = 0.28; 95% CI, 0.23-0.35; P<0.0001).4 The median MFS was 40.51 months for ERLEADA compared to 16.20 months for placebo, prolonging MFS by more than two years (difference of 24.31 months).4 MFS benefit was consistently seen across patient subgroups including prostate specific antigen doubling time (PSADT) (≤6 months or >6 months), use of a prior bone-sparing agent (yes or no), and locoregional disease (N0 or N1).4

The major efficacy outcome was supported by statistically significant improvements for the following secondary endpoints: time to metastasis (TTM), progression-free survival (PFS) and time to symptomatic progression.4 The median TTM was 40.51 months for ERLEADA compared to 16.59 months for placebo (HR=0.27; 95% CI, 0.22-0.34; P<0.0001) and the median PFS was 40.51 months compared to 14.72 months for placebo (HR=0.29; 95% CI, 0.24-0.36; P<0.0001).4 Overall survival data were not mature at the time of final MFS analysis (24% of the required number of events).4

Warnings and Precautions include seizure, falls and fractures.4 In the SPARTAN trial, the most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.4

About Non-Metastatic Castration-Resistant Prostate Cancer
Non-metastatic castration-resistant prostate cancer (NM-CRPC) refers to a disease state when the cancer no longer responds to medical or surgical treatments that lower testosterone, but has not yet been discovered in other parts of the body using a total body bone scan or CT scan.5 Features include: lack of detectable metastatic disease;5 rapidly rising prostate-specific antigen while on androgen deprivation therapy (ADT) and serum testosterone level below 50 ng/dL.6,7 Ninety percent of patients with CRPC will eventually develop bone metastases, which can lead to pain, fractures and spinal cord compression.8 The relative 5-year survival rate for patients with distant stage prostate cancer is 30 percent.9 It is critical to delay the onset of metastasis in patients with NM-CRPC.

About ERLEADA
ERLEADA (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.4

ERLEADA is an AR inhibitor that binds directly to the ligand-binding domain of the AR. ERLEADA inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.4 A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of ERLEADA in an in vitro transcriptional reporter assay.4 ERLEADA administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.4

Full prescribing information will be available soon at www.ERLEADA.com.

Important Safety Information4

CONTRAINDICATIONS

Pregnancy – ERLEADA can cause fetal harm and potential loss of pregnancy.

WARNINGS AND PRECAUTIONS

Falls and Fractures – In the SPARTAN study, falls and fractures occurred in 16% and 12% of patients treated with ERLEADA compared to 9% and 7% treated with placebo respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.

Seizure – In a randomized study (SPARTAN), two patients (0.2%) treated with ERLEADA experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

ADVERSE REACTIONS

Adverse Reactions – The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

Laboratory Abnormalities

Hematology: anemia ERLEADA 70% (Grade 3-4 0.4%) placebo 64% (Grade 3-4 0.5%) leukopenia ERLEADA 47% (Grade 3-4 0.3%) for, placebo 29% (Grades 3-4 0%), lymphopenia ERLEADA 41% (Grade 3-4 2%), placebo 21% (Grade 3-4 2%);
Chemistry – hypercholesterolemia ERLEADA 76%(Grade3-4 0.1%), placebo 46% (Grade 3-4 0%); hypertriglycemia ERLEADA 70%(Grade 3-4 2%) Placebo 59% (0.8%); hypertriglyceridemia ERLEADA 67%(Grade 3-4 2%) placebo 49%(Grade 3-4 0.8%); Hyperkalemia ERLEADA 32%(Grade 3-4 2%) Placebo 22%(Grade 3-4 0.5%)
Rash – Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (5%) versus placebo (0.3%).

The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four (4%) of patients treated with ERLEADA received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA.

Hypothyroidism – Hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was Day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

Effect of Other Drugs on ERLEADA – Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].

DRUG INTERACTIONS

Effect of ERLEADA on Other Drugs – ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 substrates – Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.