On June 22, 2020 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that the European Medicines Agency (EMA) has validated for review the Type II variation application for BAVENCIO (avelumab) for first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) (Press release, Pfizer, JUN 22, 2020, View Source [SID1234561428]). With this validation, the application is complete, and the EMA will now begin the review procedure.

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The application is based on results from the Phase III JAVELIN Bladder 100 study which showed a statistically significant improvement in overall survival (OS) for BAVENCIO plus best supportive care (BSC) as first-line maintenance treatment following induction chemotherapy versus BSC alone in patients with locally advanced or metastatic UC. The data were presented at the ASCO (Free ASCO Whitepaper) 2020 Virtual Scientific Meeting.

In the European Union alone, nearly 200,000 people are diagnosed each year with bladder cancer.1 Urothelial carcinoma accounts for approximately 90 percent of bladder cancers.2 Urothelial carcinoma becomes harder to treat as it advances, spreading through the layers of the bladder wall.3 Despite available therapies, more than 60,000 Europeans die from bladder cancer each year.1

Earlier this year, the US Food and Drug Administration (FDA) accepted a supplemental Biologics License Application (sBLA) for first-line maintenance treatment of patients with locally advanced or metastatic UC for Priority Review under the agency’s Real-Time Oncology Review (RTOR) pilot program. The FDA also granted Breakthrough Therapy Designation to BAVENCIO for this indication.

In addition, a supplemental new drug application has also been accepted by Japan’s Ministry of Health, Labour and Welfare for BAVENCIO as a first-line maintenance therapy for locally advanced or metastatic UC.

ABOUT JAVELIN BLADDER 100
JAVELIN Bladder 100 (NCT02603432) is a Phase III, multicenter, multinational, randomized, open-label, parallel-arm study investigating first-line maintenance treatment with BAVENCIO plus BSC versus BSC alone in patients with locally advanced or metastatic UC. A total of 700 patients whose disease had not progressed after platinum-based induction chemotherapy as per RECIST v1.1 were randomly assigned to receive either BAVENCIO plus BSC or BSC alone. The primary endpoint was OS in the two primary populations of all patients and patients with PD-L1+ tumors defined by the Ventana SP263 assay.

ABOUT BAVENCIO (AVELUMAB)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.4-6 In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications in the US

BAVENCIO (avelumab) in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Avelumab is currently approved for patients with MCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

BAVENCIO Important Safety Information from the US FDA-Approved Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and axitinib for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with axitinib, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.
BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.
Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.
BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO in combination with axitinib can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

On June 22, 2020 Dana-Farber Cancer Institute reported that a novel liquid biopsy method can detect kidney cancers with high accuracy, including small, localized tumors which are often curable but for which no early detection method exists (Press release, Dana-Farber Cancer Institute, JUN 22, 2020, View Source [SID1234561515]).

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The report in Nature Medicine suggests that if validated in larger trials and applied widely, the non-invasive test could find more early kidney cancers when they haven’t spread, thus reducing the mortality of the disease. "Hopefully we can scale this to a much larger level and detect cancer earlier so we can act earlier," said Toni Choueiri, MD, a co-senior author of the study. He is the director of the Lank Center for Genitourinary Oncology at Dana-Farber.

It’s estimated that 73,750 new kidney cancer cases will be diagnosed in 2020, and about 14,830 will die of the disease. About 35 percent of cancers are diagnosed only after they have spread beyond the kidney and are more difficult to treat. Small, early kidney tumors usually cause no symptoms, and increasingly are found incidentally in scans of the abdomen performed for another purpose. However, there is no imaging or other screening test recommended for the general population to look for early kidney cancers. Initially, a test based on the method described in the new report might be used to screen people with a family history of kidney cancer, or who had a previous kidney cancer, said Choueiri. "We need to be specific first, before making it totally mainstream," he said.

Non-invasive liquid biopsies, which search for cancer-related DNA shed by tumors into blood or other body fluids, are moving rapidly toward clinical use as a means of early detection for some kinds of tumors. However, "kidney cancer is one of the hardest tumors to detect, because it doesn’t shed as much DNA as other tumors," said Matthew Freedman, MD, a medical oncologist at Dana-Farber and co-senior author of the report. "That’s where this test performs really well" because it can identify abnormal patterns in small amounts of tumor-shed DNA. "And it’s a proof of principle that early stage disease is detectable."

The test was nearly 100 percent accurate when used with blood samples to distinguish patients with kidney cancer from those known to be free of kidney cancer. The method achieves less accuracy in testing urine samples, but the researchers believe that performance can be improved. If the test is validated in larger trials and becomes widely applicable clinically, a urine sample would be even less-invasive than a blood draw.

The technical name for the testing method is cfMeDIP-seq, which stands for cell-free methylated DNA immunoprecipitation and high-throughput sequencing. Where other liquid biopsy methods search for mutations in tumor-shed DNA that reveal the type and location of cancer, cfMeDIP-seq detects abnormal methylation – the addition of chemical tags to DNA, which doesn’t alter their genetic code but can affect their function.

The method was tested on samples from 99 patients with early and advanced kidney cancer, 15 patients with stage IV urothelial bladder cancer, and 28 healthy, cancer-free control subjects. In analyzing blood serum with the test, the study reported "near-perfect" classification of patients across all stages of kidney cancer. While urine-based classification was not as accurate, "we believe that performance can ben improved through technical and computational optimization," the authors wrote.

Co-first authors of the report are Pier Vitale Nuzzo, Jacob E. Berchuck, Keegan Korthauer, and Sandor Spisak.

This study was conducted with support from Rebecca and Nathan Milikowsky, the Claudia Adams Barr Program for Innovative Cancer Research, the H.L. Snyder Medical Research Foundation, the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute.

On June 22, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported preclinical studies highlighting the potential for its lead drug candidate, repotrectinib, to increase the effectiveness of KRAS-G12C and MEK inhibitors in cancer models, and for its next-generation ALK inhibitor candidate, TPX-0131, to overcome ALK-resistant mutations (Press release, Turning Point Therapeutics, JUN 22, 2020, View Source [SID1234564369]).

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The studies were included as part of three poster presentations at today’s virtual annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"Feedback reactivation and bypass signaling may limit the efficacy of KRAS-G12C and MEK inhibitors against KRAS-driven tumors, and our encouraging preclinical data shows how repotrectinib has the potential to increase the anti-tumor effects by inhibiting SRC, FAK and JAK2 signaling," said Athena Countouriotis, M.D., president and chief executive officer. "We look forward to building upon these preclinical combination studies as we explore the potential for repotrectinib to address a broad set of oncogenic-driven solid tumors.

"In addition, we are excited to share for the first time preclinical data for our fourth drug candidate, TPX-0131, a next generation ALK inhibitor in IND enabling studies. We are encouraged by TPX-0131’s preclinical potency against both wildtype ALK and the most common resistant mutations."

Jessica Lin, M.D., Attending Physician in the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center and Henri and Belinda Termeer Center for Targeted Therapies, and Instructor in Medicine at Harvard Medical School said: "Resistant mutations following treatment with approved ALK inhibitors remain a challenge for patients, especially the difficult to treat G1202R/del solvent front mutation which can occur in up to 42 percent of patients who develop a resistance mutation, and compound mutations that develop after the recently approved agent Lorbrena. The preclinical potency of TPX-0131 against these mutations suggests that it warrants further study."

Repotrectinib Combination Studies
The preclinical antitumor activities of repotrectinib in combination with proxy molecules for AMG510, an investigational KRAS-G12C inhibitor, and trametinib, an approved MEK inhibitor were highlighted for the first time in two poster presentations. The studies show repotrectinib’s inhibition of SRC, FAK and JAK2 at therapeutically relevant concentrations, which in combination with AMG510 or trametinib demonstrated a synergistic effect over the single agent by reducing tumor cell growth and enhancing tumor cell death. The repotrectinib-trametinib combination studies were replicated across panels of KRAS mutant non-small cell lung, colorectal and pancreatic cancer cell lines that harbor a spectrum of KRAS mutations.

The frequently mutated Kirsten Rat Sarcoma (KRAS) viral oncogene is associated with a broad range of human cancers, including approximately 25 percent of non-small cell lung, 45 percent of colorectal and 75 percent of pancreatic cancers. Therapeutic targeting of KRAS has proven challenging, in part due to resistance and adaptive upregulation of alternative signaling pathways that promote tumor cell survival, as well as concurrent secretion of various cytokines and growth factors.

In preclinical models, repotrectinib inhibits SRC and FAK signaling, a key pathway for oncogenic resistance, and JAK2, a driver of cytokine secretion pathways.

TPX-0131, a Next-Generation ALK Inhibitor
TPX-0131 has been internally designed with a compact macrocyclic structure to bind completely within the ATP binding site of ALK. In preclinical studies, TPX-0131 potently inhibits wildtype ALK and numerous ALK mutations, in particular the clinically observed G1202R solvent-front mutation and G1202R/L1196M compound mutation.

In cell proliferation assays presented at AACR (Free AACR Whitepaper), TPX-0131 exhibited greater potency against wildtype ALK as compared to proxy molecules for approved front-line ALK inhibitors crizotinib, alectinib, brigatinib and ceritinib, and comparable potency to a proxy molecule for approved ALK inhibitor, lorlatinib. TPX-0131 demonstrated more than 100-fold greater potency against the G1202R solvent-front mutation as compared to proxy molecules for the approved ALK inhibitors. Additionally, TPX-0131 is the most potent inhibitor against a range of EML4-ALK compound mutations while prior generation ALK inhibitors tested have shown moderate to no activity.

Anaplastic lymphoma kinase- (ALK) driven tumors are estimated to represent up to 7 percent of driver oncogenes in non-small cell lung cancer and in one study of patients who develop a resistance mutation, G1202R was reported in approximately 42 percent of patients, and compound mutations have been reported in approximately 35 percent of patients who developed resistance following treatment with lorlatinib.

The three posters presented today are:

Title: Repotrectinib increases effectiveness of KRAS-G12C inhibitors in KRAS-G12C mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1958

Title: Repotrectinib increases effectiveness of MEK inhibitor trametinib in KRAS mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1957

Title: TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitorsbstract Number: 5226

On June 22, 2020 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of checkpoint antibodies, cell therapy, adjuvants, and vaccines designed to activate immune response to cancers and infections, reported that it will make a scientific presentation today on optimal anti-cancer combinations with Fc enhanced anti-CTLA-4, AGEN1181, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting (Press release, Agenus, JUN 22, 2020, View Source [SID1234561292]).

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"AGEN1181 is an Fc-engineered anti-CTLA-4 that has shown exciting clinical activity in an early phase 1 clinical trial, which was recently presented at ASCO (Free ASCO Whitepaper)," said Dr. Antoine Tanne, Lead Scientist, Agenus Immune Biology Team. "Today, at AACR (Free AACR Whitepaper), we report that combinations with AGEN1181 demonstrate curative responses in preclinical models resistant to anti-PD-1. These data illustrate the potential of combining allogeneic cell therapies with checkpoint antibodies, such as AGEN1181, to deliver curative benefit in difficult to treat settings."

Title: "Expanding the therapeutic potential of anti-PD-1 and anti-CTLA-4 therapy with innovative Fc engineering and rationale combinations for the treatment of solid tumors"
Presenter: Antoine J. Tanne. Ph.D
Abstract: 922 / 24
Session: Combination Immunotherapies 1
Date/Time: June 22, 2020, 9am-6pm

Presentations will be available for on-demand viewing online at View Source!/9045/sessions/@sessiontype=Virtual%20Symposium/1

On June 22, 2020 Leap Therapeutics, Inc. (NASDAQ:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported the closing of a public offering of 20,250,000 shares of common stock and pre-funded warrants to purchase up to 2,250,000 shares of its common stock (Press release, Leap Therapeutics, JUN 22, 2020, View Source [SID1234561311]). The gross proceeds to Leap from this offering were approximately $45 million, before deducting underwriting discounts and commissions and other offering expenses payable by Leap.

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Piper Sandler & Co. and Raymond James & Associates, Inc. acted as book-running managers for the offering. Robert W. Baird & Co. Incorporated acted as the lead manager for the offering. H.C. Wainwright & Co. and Ladenburg Thalmann & Co. Inc. acted as co-managers for the offering.

The securities were offered and sold pursuant to an effective shelf registration statement on Form S-3 (File No. 333-223419) that was previously filed by Leap with the Securities and Exchange Commission (the "SEC") on March 2, 2018 and was declared effective by the SEC on March 16, 2018. A preliminary prospectus supplement and the related prospectus have been filed with the SEC and are available for free on the SEC’s website at View Source Copies of the final prospectus supplement and the accompanying prospectus relating to the offering may be obtained from: Piper Sandler & Co., 800 Nicollet Mall, J12S03, Minneapolis, MN, 55402, Attention: Prospectus Department, by telephone at (800) 747-3924 or by email at [email protected] or Raymond James & Associates, Inc., Attention: Equity Syndicate, 880 Carillon Parkway, St. Petersburg, Florida 33716, or by telephone at (800) 248-8863, or e-mail at [email protected].