On April 29, 2019 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported financial results for the first quarter ended March 31, 2019 (Press release, CRISPR Therapeutics, APR 29, 2019, View Source [SID1234535456]).

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"This past quarter, we began an important new period for CRISPR Therapeutics with the treatment of the first patient in our clinical trial for CTX001 in hemoglobinopathies," said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. "This is a significant landmark for the Company and we continue to enroll patients in our trials for both beta thalassemia and sickle cell disease. With the acceptance of our IND and CTA for CTX110, we look forward to the initiation of our clinical trials for our allogeneic CAR-T programs in the near-term and hope to bring other CAR-T programs to the clinic in the next six to twelve months."

Recent Highlights and Outlook

Hemoglobinopathies

Beta thalassemia
In April 2019, CRISPR Therapeutics and its partner, Vertex, announced that the U.S. Food and Drug Administration (FDA) had granted Fast Track Designation for CTX001, an investigational, autologous, gene-edited hematopoietic stem cell therapy, for the treatment of transfusion-dependent beta thalassemia (TDT). In February 2019, CRISPR and Vertex announced that the first patient had been treated with CTX001 in a Phase 1/2 clinical study of patients with TDT, marking the first company-sponsored use of a CRISPR/Cas9 therapy in a clinical trial. Enrollment in the Phase 1/2 study in patients with TDT is ongoing.

Sickle Cell Disease
The companies are also evaluating CTX001 for the treatment of sickle cell disease (SCD) and received Fast Track Designation for CTX001 from the FDA in January 2019 for SCD. The companies announced in February 2019 that the first patient had been enrolled in a Phase 1/2 clinical study of CTX001 in severe SCD in the U.S. and is expected to be infused with CTX001 in mid-2019. Enrollment in the Phase 1/2 study in patients with SCD is ongoing.
Immuno-Oncology

CTX110
Earlier this year, the FDA approved CRISPR Therapeutics’ Investigational New Drug (IND) application for CTX110, its wholly-owned allogeneic CAR-T cell therapy targeting CD19+ malignancies. Additionally, the Company has obtained approval from Health Canada for its Clinical Trial Application (CTA). CRISPR Therapeutics remains on track to initiate a Phase 1/2 trial to assess the safety and efficacy of CTX110 in the first half of 2019 and continues to work closely with various clinical sites to begin the trial. The Company’s proprietary CRISPR-based allogeneic CAR-Ts have the potential to create the next-generation of cell therapies that may have a superior product profile compared to current autologous therapies and allow accessibility to broader patient populations.

CRISPR Therapeutics continues to advance additional allogeneic CAR-T candidates including: CTX120, targeting B-cell maturation antigen (BCMA) for the treatment of multiple myeloma; and CTX130, targeting CD70 for the treatment of solid tumors and hematologic malignancies. Earlier this month, the Company presented preclinical data targeting multiple solid tumor types with anti-CD70 allogeneic CAR-T cells, further demonstrating consistent expression, durability, selectivity and potent cell killing. The Company also presented data targeting CD33 that showed potent preclinical activity against acute myeloid leukemia (AML) cells. These data were presented during poster sessions at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

CRISPR Therapeutics will present additional data at the upcoming 2019 American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting demonstrating the potential of CRISPR/Cas9 allogeneic CAR-T cell candidates for multiple oncology targets. CRISPR/Cas9 allogeneic CAR-T cells show consistently high percent CAR expression, while maintaining durable potency, low exhaustion, and lack of alloreactivity (#841). The Company will also present data evaluating homology-independent CRISPR/Cas9 off-target assessments methods (#134).
Corporate Development

The U.S. Patent Office issued four patents to Dr. Emmanuelle Charpentier, together with The Regents of the University of California and University of Vienna (collectively, CVC). Additionally, CVC was recently granted its third patent in Europe. These patents expand CVC’s wide-ranging CRISPR-Cas9 gene-editing patent portfolio.

Earlier this year, CRISPR Therapeutics announced strategic collaborations with StrideBio, Inc. and ProBioGen. The Company continues to examine new technologies and capabilities in support of existing programs.

In February, CRISPR Therapeutics proposed to elect John T. Greene and Katherine A. High, M.D. to its Board of Directors at the Company’s upcoming annual general meeting to be held later this year. Together, they will bring significant strategic and operational experience to CRISPR Therapeutics.
First Quarter 2019 Financial Results

Cash Position: Cash as of March 31, 2019, was $437.5 million, compared to $456.6 million as of December 31, 2018, a decrease of $19.1 million. Cash used in operations drove the decrease, offset by $25.7 million in net cash provided by financing activities during the quarter.

Revenues: Total collaboration revenues were $0.3 million for the first quarter of 2019 compared to $1.4 million for first quarter of 2018. CRISPR’s collaboration revenue is attributable to its research partnerships with Casebia and Vertex. Cost sharing on the Vertex co-development and co-promotion agreement related to hemoglobinopathies is not included in revenue, but instead as an offset to expense in R&D.

R&D Expenses: R&D expenses were $33.8 million for the first quarter of 2019 compared to $19.5 million for the first quarter of 2018. The increase was driven by headcount and services expense supporting the advancement of the hemoglobinopathies program, the broadening of the wholly-owned immuno-oncology portfolio, as well as increased investment in the Company’s CRISPR/Cas9 platform research.

G&A Expenses: General and administrative expenses were $14.9 million for the first quarter of 2019 compared to $8.8 million for the first quarter of 2018. The increase was driven by headcount-related expense and external professional and consulting service expense.

Net Loss: Net loss was $48.4 million for the first quarter of 2019 compared to a loss of $28.3 million for the first quarter of 2018, driven predominantly by increased R&D expense in the quarter.

On Apri 29, 2019 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported that it will webcast management presentations as follows (Press release, Regeneron, APR 29, 2019, View Source [SID1234535452]):

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Bank of America Merrill Lynch 2019 Healthcare Conference at 8:00 a.m. Pacific Time (11:00 a.m. Eastern Time) on Wednesday, May 15, 2019
Barclays 2019 Biopharmaceuticals CEO/CFO Conference Call Series at 11:00 a.m. Eastern Time on Friday, May 17, 2019
UBS 2019 Global Healthcare Conference at 10:00 a.m. Eastern Time on Monday, May 20, 2019
The sessions may be accessed from the "Investors & Media" page of Regeneron’s website at View Source Replays of the conference call and webcasts will be archived on the Company’s website and will be available for 30 days.

On April 29, 2019 Neurocrine Biosciences, Inc. (NASDAQ: NBIX) reported its financial results for the quarter ended March 31, 2019 and provided an update on the launch of INGREZZA (valbenazine) and its clinical development programs (Press release, Neurocrine Biosciences, APR 29, 2019, View Source [SID1234535451]).

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"We remain focused on building awareness of tardive dyskinesia and are encouraged by the continued adoption of INGREZZA among healthcare providers and the patient community. Importantly, a record number of new patients started treatment with INGREZZA during the first quarter," said Kevin Gorman, Ph.D., Chief Executive Officer of Neurocrine Biosciences. "Within our product pipeline, we remain on track for the NDA submission of opicapone for Parkinson’s disease, plan to discuss the registration program for congenital adrenal hyperplasia with the FDA, and look forward to making progress on the Parkinson’s disease and Friedreich’s ataxia gene therapy programs in collaboration with Voyager Therapeutics. We have laid the foundation to make meaningful strides throughout 2019 and work towards our goal of having three FDA-approved treatments in four indications by 2020."

Financial Results

Total revenue was $138.4 million for the first quarter of 2019, compared to $71.1 million for the same period in 2018.

INGREZZA received U.S. Food and Drug Administration (FDA) approval in 2017, becoming the first medicine approved in the United States for the treatment of adults with tardive dyskinesia. ORILISSA (elagolix) was approved by the FDA for the treatment of endometriosis with associated moderate to severe pain during the third quarter of 2018, with AbbVie sales beginning in August 2018.

The Company reported a net loss of $102.1 million, or $1.12 net loss per share, for the first quarter of 2019, compared to $41.8 million, or $0.47 net loss per share, for the same period in 2018. The increase in net loss for the first quarter of 2019 is primarily due to $113.1 million of in-process research and development (IPR&D) in connection with the strategic collaboration with Voyager. This was partially offset by increased INGREZZA net product sales.

Research and development (R&D) expenses decreased to $37.7 million for the first quarter of 2019, from $48.9 million for the same period in 2018. The decrease in R&D expenses is primarily due to a prior year $8 million non-recurring share-based compensation charge and a prior year $10 million event-based payment to BIAL – Portela & CA, S.A. (BIAL) for opicapone.

In connection with the closing of the Voyager transaction in March 2019, the Company made an upfront payment of $115 million and purchased $50 million of Voyager’s common stock. The Company accounted for this transaction, including related transaction costs, as an asset acquisition and expensed $113.1 million as IPR&D and recorded the $50 million equity investment at $54.7 million as an asset on the Company’s balance sheet based upon the fair value at the timing of closing. The equity investment will be marked to market each quarter with gains and losses recorded to other income/expense.

Sales, general and administrative (SG&A) expenses increased to $87.5 million for the first quarter of 2019, from $58.6 million for the same period in 2018. The increase in SG&A expenses is primarily due to the sales force expansion in the third quarter of 2018, the national launch of a patient-focused disease state awareness campaign, Talk About TD, and an increase in the Branded Pharmaceutical Drug fee expense.

The Company’s balance sheet at March 31, 2019, reflected total assets of $957.7 million, including cash and available for sale investments of $700.8 million, compared to total assets of $993.2 million at December 31, 2018.

Pipeline Highlights

ORILISSA (elagolix) Update

On July 24, 2018, AbbVie, in collaboration with Neurocrine, announced FDA approval and in October 2018 Health Canada approval for ORILISSA for the management of endometriosis with associated moderate to severe pain. The FDA granted priority review to ORILISSA. The FDA grants priority review designation to medicines that, if approved, would provide a significant improvement in the safety or effectiveness of treatment of a serious condition. AbbVie began commercialization of ORILISSA in the United States in August 2018.

AbbVie provided positive top-line efficacy data from two Phase III studies in women with uterine fibroids in the first quarter of 2018 and from the associated six-month safety extension study during the third quarter of 2018. The ELARIS UF-I and UF-II studies of elagolix met all primary and ranked secondary endpoints at month six. These replicate Phase III studies were randomized, parallel, double-blind, placebo-controlled clinical trials evaluating elagolix alone or in combination with low-dose hormone (add-back) therapy in women with heavy uterine bleeding associated with uterine fibroids. The studies enrolled approximately 400 patients each for an initial six-month placebo-controlled dosing period. At the end of the six months of placebo-controlled evaluation, patients were eligible to enter an additional six-month safety extension study. The primary efficacy endpoint of the study was an assessment of the change in menstrual blood loss utilizing the alkaline hematin method comparing baseline to month six. Additional secondary efficacy endpoints were evaluated including the change in fibroid volume and hemoglobin. Bone mineral density was assessed via dual-energy x-ray absorptiometry (DEXA) scan at baseline at the conclusion of dosing and at six months post-dosing. Results from these studies will form the basis for an anticipated New Drug Application (NDA) submission to the FDA for the approval of elagolix in the treatment of uterine fibroids in the middle of 2019.

Opicapone Update

In February 2017, the Company entered into an exclusive licensing agreement with BIAL for the development and commercialization of opicapone in the United States and Canada. Opicapone is a once-daily, oral, peripherally-acting, highly-selective catechol-O-methyltransferase inhibitor, being developed as an adjunct therapy to preparations of levodopa/DOPA decarboxylase inhibitors for adult patients with Parkinson’s disease and motor fluctuations. The Company met with the FDA in January 2018 and based upon the BIPARK-I and BIPARK-II pivotal Phase III studies conducted by BIAL, the FDA did not require additional Phase III trials to form an NDA submission. The Company remains on track for an NDA submission in the second quarter of 2019.

CAH Program (NBI-74788) Update

In the second quarter of 2017, the Company successfully completed the Phase I investigational new drug (IND)-opening study of NBI-74788 in healthy volunteer participants. The study was a randomized, open-label, two-period crossover study to evaluate the pharmacokinetics, the effect of food on pharmacokinetics, and the safety of NBI-74788 in a total of 16 healthy adults.

The Company began a Phase II proof-of-concept study examining the pharmacokinetics, pharmacodynamics, and safety of NBI-74788 in adult males and females with classic 21-hydroxylase deficiency CAH in November of 2017. This study will evaluate the safety and tolerability of NBI-74788 in patients with CAH together with the relationship between exposure and specific steroid hormone levels in these patients. In March 2019, positive interim results from this ongoing study demonstrated a clinically meaningful reduction in key biomarkers associated with the management of CAH. NBI-74788 was shown to be well tolerated with no serious adverse events reported to date. The Company plans to meet with the FDA during the third quarter of 2019 to discuss the registration program for NBI-74788 in adult and pediatric patients with CAH.

Voyager Collaboration and VY-AADC Program

Neurocrine Biosciences formed a strategic collaboration with Voyager Therapeutics focused on the development and commercialization of Voyager’s gene therapy programs, VY-AADC for Parkinson’s disease and VY-FXN01 for Friedreich’s ataxia, as well as rights to two programs to be determined. This collaboration combines Neurocrine’s expertise in neuroscience, drug development and commercialization with Voyager’s innovative gene therapy programs targeting severe neurological diseases. The collaboration became effective in March 2019 following the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976.

Based on the results from the VY-AADC Phase I programs in Parkinson’s disease, RESTORE-1, a Phase II, randomized, placebo-surgery controlled, double-blinded, multi-center, clinical trial was initiated to evaluate the safety and efficacy of VY-AADC in patients who have been diagnosed with Parkinson’s disease for at least four years, are not responding adequately to oral medications, and have at least three hours of OFF-time during the day as measured by a validated self-reported patient diary.

Conference Call and Webcast Today at 4:30 PM Eastern Time

Neurocrine will hold a live conference call and webcast today at 4:30 p.m. Eastern Time (1:30 p.m. Pacific Time). Participants can access the live conference call by dialing 877-876-9173 (US) or 785-424-1667 (International) using the conference ID: NBIX. The webcast can also be accessed on Neurocrine’s website under Investors at www.neurocrine.com. A replay of the webcast will be available on the website approximately one hour after the conclusion of the event and will be archived for approximately one month.

About INGREZZA (valbenazine) Capsules
INGREZZA, a selective VMAT2 inhibitor, is the first FDA-approved product indicated for the treatment of adults with tardive dyskinesia, a condition associated with uncontrollable, abnormal and repetitive movements of the face, torso, and/or other body parts.

INGREZZA is thought to work by reducing the amount of dopamine released in a region of the brain that controls movement and motor function, helping to regulate nerve signaling in adults with tardive dyskinesia. VMAT2 is a protein in the brain that packages neurotransmitters, such as dopamine, for transport and release from presynaptic neurons. INGREZZA, developed in Neurocrine’s laboratories, is novel in that it selectively inhibits VMAT2 with no appreciable binding affinity for VMAT1, dopaminergic (including D2), serotonergic, adrenergic, histaminergic, or muscarinic receptors. Additionally, INGREZZA can be taken for the treatment of tardive dyskinesia as one capsule, once-daily, together with psychiatric medications such as antipsychotics or antidepressants.

Important Safety Information

Contraindications
INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

Warnings & Precautions
Somnolence
INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.

QT Prolongation
INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.

Adverse Reactions
The most common adverse reaction (≥5% and twice the rate of placebo) is somnolence. Other adverse reactions (≥2% and >placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, vomiting, nausea, and arthralgia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088.

On April 29, 2019 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a clinical-stage targeted oncology company, reported financial results for the first quarter ended March 31, 2019 (Press release, Mirati, APR 29, 2019, View Source [SID1234535450]).

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First Quarter Highlights

January 7th, we announced a clinical collaboration with Bristol-Myers Squibb Company to evaluate the combination of sitravatinib and nivolumab (OPDIVO), in our planned Phase 3 clinical trial in second line NSCLC patients who have progressed following prior treatment. Mirati will sponsor and fund the clinical trial and Bristol-Myers Squibb will provide nivolumab at no cost.
January 15th, we announced that we had dosed the first patient in the Phase 1/2 clinical trial of MRTX849, a novel KRAS G12C inhibitor.
January 22nd, we announced the successful completion of a public offering of common stock that provided net cash proceeds of $107.9 million.
February 19th, we announced the appointment of Faheem Hasnain as Chairman of the Board of Directors.
"In the first quarter we made significant advances across our pipeline, including the dosing of the first patient with our KRAS G12C inhibitor, MRTX849. We also strengthened our operational and strategic capabilities, highlighted by a successful public offering and the appointment of Faheem Hasnain as Chairman of the Board," said Charles M. Baum, M.D., Ph.D., President and Chief Executive Officer. "Our clinical programs continue to advance, and we are on track for a second quarter initiation of the Phase 3 randomized trial of sitravatinib plus nivolumab, versus docetaxel, in second line non-small cell lung cancer (NSCLC). The Phase 1/2 clinical trial of our KRAS G12C inhibitor, MRTX849, is ongoing and enrollment is proceeding well. We will provide an initial clinical update on MRTX849 in the second half of 2019."

Financial Results for the First Quarter 2019

Cash, cash equivalents, and short-term investments were $301.0 million at March 31, 2019, compared to $222.8 million at December 31, 2018. In January 2019, we completed a public offering of common stock that provided net cash proceeds of $107.9 million.

License and collaboration revenues relate to the Collaboration and License Agreement between the Company and BeiGene, Ltd. ("BeiGene"), dated January 7, 2018. License and collaboration revenues for the first quarter of 2019 were $1.2 million and relate to revenues earned in connection with a manufacturing supply services agreement with BeiGene. License and collaboration revenues for the first quarter of 2018 were $9.5 million and relate to the license the Company granted to BeiGene under the Collaboration and License Agreement.

Research and development expenses for the first quarter of 2019 were $34.2 million, compared to $19.7 million for the same period in 2018. The increase in research and development expenses is due to an increase in expense associated with sitravatinib and MRTX849, as well as an increase in salaries and related expense, including an increase in share-based compensation expense. The increase in sitravatinib expense is due to increased costs to support the expansion of existing and new clinical trials, and the increase in MRTX849 expense relates to the Phase 1 clinical trial, which was initiated in the first quarter of 2019. The Company recognized research and development-related share-based compensation expense of $5.2 million during the first quarter of 2019, compared to $1.5 million for the same period in 2018.

General and administrative expenses for the first quarter of 2019 were $9.8 million, compared to $5.2 million for the same period in 2018. The increase is primarily due to an increase in share-based compensation expense due to an increase in the fair value of stock options granted during the three months ended March 31, 2019 compared to the same period in 2018. The Company recognized general and administrative-related share-based compensation expense of $5.9 million during the first quarter of 2019, compared to $2.2 million for the same period in 2018.

Net loss for the first quarter of 2019 was $40.9 million, or $1.17 per share basic and diluted, compared to net loss of $14.7 million, or $0.51 per share basic and diluted for the same period in 2018.

About Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in patients whose cancers have progressed despite treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion clinical trial emphasizing enrollment of patients whose tumors harbor specific mutations in the CBL protein. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma. Sitravatinib potently inhibits these RTKs and is being investigated as a treatment option for cancer patients with CBL mutations.

About MRTX849

MRTX849 is an investigational, orally-available small molecule that is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12C). KRAS G12C mutations are present in approximately 14% of NSCLC adenocarcinoma patients, 4% of colorectal cancer patients, and subsets of other types of cancer. Tumors characterized by KRAS G12C mutations are commonly associated with poor prognosis and resistance to therapy, and patients with these mutations have few treatment options. MRTX849 is being evaluated in a Phase 1/2 trial treating patients with molecularly-identified, KRAS G12C-positive advanced solid tumors.

On April 29, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking approval of a new indication for ERLEADA (apalutamide) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) (Press release, Johnson & Johnson, APR 29, 2019, View Source [SID1234535449]). The sNDA is based on findings from the Phase 3 TITAN study, whose dual primary endpoints, overall survival (OS) and radiographic progression-free survival (rPFS), were both achieved. These data will be presented at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting during an oral abstract session on Friday, May 31st.

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The sNDA is being reviewed by the FDA through the Real-Time Oncology Review (RTOR) program, which for certain applications allows the FDA to review data before the applicant formally submits the complete application. The program aims to explore a more efficient review process to help ensure treatments are available for patients as soon as possible. Selection into the RTOR program does not guarantee or influence approvability of the application.

"This submission marks an important step in providing a potential treatment option for patients with metastatic castration-sensitive prostate cancer, regardless of prior treatment or the extent of their disease," said Craig Tendler, M.D., Vice President, Oncology Clinical Development and Medical Affairs, Janssen Research & Development, LLC. "We look forward to closely collaborating with the FDA through the efficient Real-Time Oncology Review pilot program with the goal of bringing ERLEADA to an earlier population of patients with metastatic prostate cancer as soon as possible."

About the TITAN Study1
TITAN (NCT02489318) is a Phase 3 randomized, placebo-controlled, double-blind study in patients with mCSPC regardless of extent of disease, and prior treatment with docetaxel or treatment of localized disease. More than 1,050 patients with mCSPC were randomized to receive either ERLEADA plus androgen deprivation therapy (ADT), or placebo plus ADT. The TITAN study included mCSPC patients with both low and high-volume disease, those who were newly diagnosed or those who have received prior definitive local therapy, or prior treatment with up to six cycles of docetaxel. Participants were treated until disease progression or the occurrence of unacceptable treatment related toxicity, or end of treatment. The dual primary endpoints of the study are OS and rPFS. Secondary endpoints include time to chemotherapy, time to pain progression, time to chronic opioid use and time to skeletal related event.1 For additional study information, visit ClinicalTrials.gov.

About ERLEADA
ERLEADA (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). It became the first treatment to receive FDA approval for this disease state on February 14, 2018.2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide as a treatment option for patients with non-metastatic (M0) CRPC with a category 1 recommendation for those with a PSA doubling time ≤10 months*.3 Additionally, the American Urological Association (AUA) Guidelines for Castration-Resistant Prostate Cancer (CRPC) were updated to include apalutamide (ERLEADA) with continued ADT as a treatment option that clinicians should offer to patients with asymptomatic nmCRPC. It is included as one of the options clinicians should offer to patients with nmCRPC who are at high-risk for developing metastatic disease (Standard; Evidence Level Grade A)**.4

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2019. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

**Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.

**Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

About Metastatic Castration-Sensitive Prostate Cancer
Metastatic prostate cancer is cancer that has spread to another part of the body.5 Metastatic castration-sensitive prostate cancer (mCSPC), refers to prostate cancer that still responds to androgen deprivation therapy (ADT).5 Patients with mCSPC tend to have a poor prognosis, with a median OS of less than five years, underscoring the need for new treatment options.6,7,8

ERLEADA IMPORTANT SAFETY INFORMATION2

CONTRAINDICATIONS

Pregnancy — ERLEADA (apalutamide) can cause fetal harm and potential loss of pregnancy.

WARNINGS AND PRECAUTIONS

Falls and Fractures — In a randomized study (SPARTAN), 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), 2 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 — All Grades (Grade 3-4)

Hematology — anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)
Chemistry — hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (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 percent of patients treated with ERLEADA received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA.

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.

DRUG INTERACTIONS

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)].

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.