On May 1, 2019 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a biotechnology company developing novel immunotherapy treatments for cancer and autoimmune diseases, reported an update for the ongoing development of its product candidates (Press release, Immutep, MAY 1, 2019, View Source [SID1234535559]).

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Efti Clinical Update

AIPAC – Phase IIb Clinical Trial

To date, there have been 211 patients enrolled in the Company’s Phase IIb AIPAC clinical trial, which is evaluating eftilagimod alpha ("efti" or "IMP321") in combination with paclitaxel, a chemotherapy, in metastatic breast cancer. Full recruitment of the trial, 226 patients, is expected to occur in the second quarter of this year. The trial is being conducted at 33 clinical trial sites across Germany, the UK, France, Hungary, Belgium, Poland and the Netherlands.

The first read out of Progression Free Survival (PFS) data is expected within the next 11 months, but not before Q4 2019, depending on the number of predefined progression events. Other endpoints include Overall Response Rate (ORR) and Overall Survival (OS).

TACTI-002 – Phase II Clinical Trial

15 patients have been enrolled in Immutep’s Phase II TACTI-002 clinical trial across seven clinical sites in the U.S., Europe and Australia. This figure includes 11 patients in the first line non-small cell lung cancer (NSCLC) cohort, which requires 17 patients to complete recruitment of this initial cohort.

The TACTI-002 study is being conducted in collaboration with Merck & Co., Inc., Kenilworth, NJ, USA (known as "MSD" outside the United States and Canada) and is evaluating the combination of efti with MSD’s KEYTRUDA (or pembrolizumab, an anti-PD-1 therapy) in up to 109 patients with second line head and neck squamous cell carcinoma or NSCLC in first and second line.

Patient recruitment is ongoing and Immutep expects to report first data from the study in mid-2019.

LOGO

TACTI-mel – Phase I Clinical Trial

Immutep reported positive, more mature data from its ongoing and fully recruited TACTI-mel Phase I clinical study in melanoma in March. The trial is evaluating the combination of efti with anti-PD-1 therapy KEYTRUDA (pembrolizumab) in 24 patients with unresectable or metastatic melanoma.

Key findings from the ongoing trial were as follows:

Part A (starting cycle 5 of

pembrolizumab therapy) N=18

Part B (starting day 1 cycle 1 of

pembrolizumab therapy) N=6

Overall Response Rate (ORR)

33% (61%*) 50%
Disease Control Rate (DCR)

66% 66%
*Exploratory ORR when tumour size is measured according to irRC from day 1 of cycle 1 of pembrolizumab and following combination therapy (which starts at cycle 5 of prembrolizumab treatment).

In addition, efti continues to have a very favorable safety profile in doses up to 30 mg administered s.c. every 2 weeks. The data was presented at the World Immunotherapy Congress 2019.

INSIGHT & INSIGHT-004 – Phase I Clinical Trials

INSIGHT-004 is a Phase I clinical trial in collaboration with Merck KGaA, Darmstadt, Germany and Pfizer Inc. and the Institute of Clinical Cancer Research, Krankenhaus Nordwest GmbH (IKF) which is evaluating the combination of efti with avelumab, a human anti-PD-L1 antibody, in patients with advanced solid malignancies. The trial protocol has now been approved by the competent authority and ethics committee and Immutep expects the first patient to be recruited in Q2 2019.

This study is taking place as an extension to the INSIGHT trial, an investigator sponsored explorative trial which is already underway and being run by our partner, IKF.

13 patients are now enrolled in the INSIGHT clinical trial, which is evaluating the potential of efti in different settings in terms of route of administration and indications.

IMP761 Update

IMP761—Preclinical Results

Immutep reported positive results from its preclinical study of IMP761, a novel LAG-3 agonist antibody being developed for the treatment of autoimmune diseases, in March. The preclinical results showed that IMP761 decreases inflammation at the tissue site, demonstrating its potential as a new therapy that could treat the cause of autoimmune disease, rather than just the symptoms.

Specifically, in vitro results showed that IMP761 caused the down-regulation of human T cell proliferation and activation. In addition, the in vivo studies showed that IMP761 causes down-modulation of T cell infiltration in a non-human-primate animal model. These results were presented at the 14th Congress of European Crohn’s and Colitis Organisation (ECCO) Conference.

The Company is continuing cell line development and GMP manufacturing preparations for IMP761 to progress the antibody towards clinical development.

Update on programs fully funded by Immutep’s licensing partners

GlaxoSmithKline – GSK2831781 / IMP731

GlaxoSmithKline (GSK) has announced that it will be pursuing a proof-of-concept study in ulcerative colitis for GSK2831781, which is derived from Immutep’s IMP731 antibody. This Phase II clinical study is expected to commence shortly.

Novartis—LAG525 / IMP701

Novartis is continuing its clinical development program for LAG525, or IMP701, in oncology. Currently, there are five ongoing Phase I/II clinical trials evaluating this product candidate.

CYTLIMIC—efti

Immutep is working with CYTLIMIC to prepare for CYTLIMIC’s clinical trials to evaluate efti as part of a therapeutic cancer vaccine, called CYT001. The vaccine contains cancer antigens to boost a patient’s own immune cells to recognise and kill cancer cells related to the antigens.

Eddingpharm (EOC Pharma)—efti

Immutep’s partner and Chinese licensee, EOC Pharma, is continuing the recruitment of patients for its Phase I clinical study of efti for the treatment of metastatic breast cancer. Immutep expects further progress from EOC Pharma later in 2019.

On May 1, 2019 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported that members of its senior management team are scheduled to participate in the following investor conferences later this month (Press release, CRISPR Therapeutics, MAY 1, 2019, View Source [SID1234535492]):

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SunTrust Robinson Humphrey 5th Annual Life Sciences Summit
Date: Wednesday, May 8, 2019
Location: New York, NY

Bank of America Merrill Lynch 2019 Health Care Conference
Date: Wednesday, May 15, 2019
Presentation: 1:00 p.m. PT
Location: Las Vegas, NV

UBS Global Healthcare Conference
Date: Tuesday, May 21, 2019
Presentation: 11:00 a.m. ET
Location: New York, NY

A live webcast of the Bank of America Merrill Lynch and UBS events will be available on the "Events & Presentations" page in the Investors section of the Company’s website at View Source A replay of the webcasts will be archived on the Company’s website for 14 days following each presentation.

On May 1, 2019 Exelixis, Inc. (NASDAQ: EXEL) reported that it is initiating COSMIC-313, a phase 3 pivotal trial of cabozantinib (CABOMETYX) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) versus nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (Press release, Exelixis, MAY 1, 2019, View Source [SID1234535508]). The primary endpoint of the trial is progression-free survival, and the secondary endpoints are overall survival and objective response rate.

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"Clinical observations suggest cabozantinib promotes an immune-permissive environment, which could present an opportunity for additive or synergistic effects with immune checkpoint inhibitors," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "The mechanisms of action of single agent cabozantinib and the combination of nivolumab and ipilimumab are complementary, and each has demonstrated efficacy in advanced renal cell carcinoma. The further combination of these agents as a triplet regimen may offer promise to previously untreated patients with intermediate- or poor-risk disease, who are known to have poor treatment outcomes."

COSMIC-313 is a multicenter, randomized, double-blinded, controlled phase 3 pivotal trial that aims to enroll approximately 676 patients at 150 sites globally. Patients will be randomized 1:1 to the experimental arm of cabozantinib in combination with nivolumab and ipilimumab and to the control arm of nivolumab and ipilimumab in combination with matched placebo.

Design of this phase 3 pivotal trial was informed by results from the ongoing phase 1b study of cabozantinib plus nivolumab with or without ipilimumab in patients with previously treated advanced genitourinary cancers, including RCC. The phase 1b trial is being conducted by the U.S. National Cancer Institute and includes centers from its Experimental Therapeutics Clinical Trials Network.

Bristol-Myers Squibb is providing nivolumab and ipilimumab for use in this trial.

Please see Important Safety Information below and full U.S. prescribing information at View Source

About RCC

The American Cancer Society’s 2019 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.1 Approximately 32,000 patients in the U.S. and 70,000 globally require treatment, and an estimated 15,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.3

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.4,5 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6,7,8,9 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC and for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

The combination of CABOMETYX with nivolumab and ipilimumab is not indicated for previously untreated advanced RCC.

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On May 1, 2019 United Therapeutics Corporation (Nasdaq: UTHR) reported its financial results for the quarter ended March 31, 2019 (Press release, United Therapeutics, MAY 1, 2019, View Source [SID1234535560]).

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"I’m very pleased to report that last quarter we helped more pulmonary arterial hypertension (PAH) patients with our Remodulin, Tyvaso and Orenitram medicines than ever before," said Martine Rothblatt, Ph.D., Chairman and Chief Executive Officer of United Therapeutics. "While we did also experience the disappointment of being unable to prove a morbidity/mortality benefit of esuberaprost in our BEAT phase III trial, it is of course the nature of science that hypotheses are disproven as well as proven. No string of successes is without its setbacks, and we are confident of positive results being proven amongst our many other pivotal studies including the DISTINCT study of dinutuximab for small cell lung cancer, the INCREASE study of Tyvaso in pulmonary hypertension (PH) associated with interstitial lung disease, the PERFECT study of Tyvaso in PH associated with COPD, the SOUTHPAW study of Orenitram in PH associated with heart failure, the ADVANCE OUTCOMES study of ralinepag in PAH, the SAPPHIRE study of autologous gene therapy in PAH and our lung transplantation study."

Revenues for the three months ended March 31, 2019 decreased by $26.6 million as compared to the same period in 2018.

Remodulin net product sales for the three months ended March 31, 2019 increased by $28.7 million as compared to the same period in 2018. U.S. Remodulin net product sales increased by $18.8 million, primarily due to an increase in the number of patients being treated with Remodulin and a price increase implemented in April 2018, which was the first price increase for Remodulin since 2010. International Remodulin net product sales increased by $9.9 million, primarily due to an increase in quantities shipped to international distributors.

Tyvaso net product sales for the three months ended March 31, 2019 increased by $9.2 million as compared to the same period in 2018. This increase was primarily due to an increase in the number of patients being treated with Tyvaso and a price increase implemented in January 2019.

Orenitram net product sales for the three months ended March 31, 2019 increased by $6.2 million as compared to the same period in 2018. This increase was primarily due to an increase in the number of patients being treated with Orenitram and a price increase implemented in January 2019.

Unituxin net product sales for the three months ended March 31, 2019 increased by $6.9 million as compared to the same period in 2018. This increase was primarily due to an increase in the number of vials sold.

Adcirca net product sales for the three months ended March 31, 2019 decreased by $77.6 million as compared to the same period in 2018. This decrease was due to a decrease in bottles sold following the onset of generic competition for Adcirca beginning in August 2018.

Refer to Share-based compensation below for discussion.

Cost of product sales, excluding share-based compensation. The decrease in cost of product sales of $31.1 million for the three months ended March 31, 2019, as compared to the same period in 2018, was primarily attributable to a $32.8 million decrease in royalty expense for Adcirca because fewer bottles were sold due to the onset of generic competition for Adcirca beginning in August 2018.

Research and development expense, excluding share-based compensation. The increase in research and development expense of $835.6 million for the three months ended March 31, 2019, as compared to the same period in 2018, was driven by continued investment in our product pipeline. Research and development expense for the treatment of cardiopulmonary diseases increased by $829.2 million for the three months ended March 31, 2019, as compared to the same period in 2018, due to: (1) an $800.0 million upfront payment to Arena Pharmaceuticals under our license agreement related to ralinepag, and $8.9 million of expenditures associated with the phase III ADVANCE studies of ralinepag during the three months ended March 31, 2019; (2) a $12.5 million payment under our license and collaboration agreement with MannKind; (3) increased spending of $5.6 million on the development of drug delivery devices, including the Implantable System for Remodulin; and (4) increased spending on several clinical and non-clinical studies.

Share-based compensation. The increase in share-based compensation expense of $130.3 million for the three months ended March 31, 2019, as compared to the same period in 2018, was primarily due to: (1) a $126.0 million increase in STAP expense (benefit) driven by an 8% increase in our stock price for the three months ended March 31, 2019, as compared to a 24% decrease in our stock price for the same period in 2018; and (2) a $3.0 million increase in stock option expense due to additional awards granted and outstanding in 2019.

Income Tax (Benefit) Expense

The income tax benefit was $156.0 million for the three months ended March 31, 2019, as compared to income tax expense of $64.5 million for the same period in 2018. Our effective income tax rate (ETR) for the three months ended March 31, 2019 and

2018 was 24 percent and 21 percent, respectively. We recognized a loss before income taxes, and a corresponding income tax benefit, for the three months ended March 31, 2019, as a result of the one-time $800.0 million payment to Arena in January 2019. As a result of this loss, our anticipated tax credits, partially offset by non-deductible compensation expense, increase our tax benefit and resulting ETR for the three months ended March 31, 2019, compared to the three months ended March 31, 2018.

Non-GAAP Earnings

Non-GAAP earnings is defined as net income, adjusted for: (1) share-based compensation expense (including expenses relating to stock options, restricted stock units, share tracking awards and our employee stock purchase plan); (2) license-related fees; and (3) tax impact on non-GAAP earnings adjustments.

Conference Call

We will host a half-hour teleconference on Wednesday, May 1, 2019, at 9:00 a.m. Eastern Time. The teleconference is accessible by dialing 1-877-351-5881, with international callers dialing 1-970-315-0533. A rebroadcast of the teleconference will be available for one week by dialing 1-855-859-2056, with international callers dialing 1-404-537-3406, and using access code: 5569533.

This teleconference will also be webcast and can be accessed via our website at View Source

On April 30, 2019, XBiotech Inc. ("we," "us" or the "Company") reported that it has entered into an Equity Distribution Agreement (the "Sales Agreement") with Piper Jaffray & Co ("Piper Jaffray" ) which establishes an at-the-market equity program pursuant to which we may offer and sell shares of our common stock, no par value per share ("Common Stock"), from time to time as set forth in the Sales Agreement (Filing, 8-K, XBiotech, MAY 1, 2019, View Source [SID1234535696]). The Sales Agreement provides for the sale of up to 4,334,453 shares of our Common Stock ("Shares").

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Subject to the terms and conditions set forth in the Sales Agreement, Piper Jaffray will use its commercially reasonable efforts consistent with its normal trading and sales practices to sell the Shares from time to time, based upon our instructions, including any price, time or size limits we specify. We have agreed to pay Piper Jaffray a commission at a fixed rate equal to three percent (3.0%) of the gross proceeds from each sale of Shares. In addition, we have agreed to pay certain expenses incurred by Piper Jaffray in connection with the Sales Agreement, including up to $50,000 of the fees and disbursements of their counsel. However, in the event Piper Jaffray acts as principal in the sale of common stock under the Sales Agreement, such rate of compensation will not apply, but in no event will the total compensation of Piper Jaffray, when combined with the reimbursement of Piper Jaffray for the out-of-pocket reasonable fees and disbursements of its counsel as described above, exceed 8.0% of the gross proceeds received from the sale of the Shares. We have also agreed to provide Piper Jaffray with customary indemnification rights. The Sales Agreement will terminate upon the sale of all of the Shares under the Sales Agreement, unless terminated earlier by either party as permitted under the Sales Agreement.

Sales of the Shares, if any, under the Sales Agreement will be made in transactions that are deemed to be "at the market" offerings as defined in Rule 415 under the Securities Act of 1933, as amended (the "Securities Act"), including sales made from time to time directly on or through the Nasdaq Global Select Market, on any other existing trading market for the Shares, to or through a market maker other than on an exchange or otherwise, in negotiated transactions at market prices prevailing at the time of sale or at prices related to such prevailing market prices, and/or in any other method permitted by law. We have no obligation to sell any of the Shares, and, at any time, we may suspend offers under the Sales Agreement or terminate the Sales Agreement.

Sales of Shares under the Sales Agreement will be made pursuant to the registration statement on Form S-3 (File No. 333-213218), which was declared effective by the U.S. Securities and Exchange Commission (the "SEC") on September 1, 2016, and a related Prospectus Supplement filed with the SEC on April 30, 2019.

This Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to buy any Shares under the Sales Agreement, nor shall there be any sale of such Shares in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state.

The foregoing description of the Sales Agreement does not purport to be complete and is qualified in its entirety by reference to the Sales Agreement, which is filed as Exhibit 10.1 hereto and incorporated by reference herein and into the Registration Statement.

The opinion of our counsel regarding the validity of the Shares that will be issued pursuant to the Sales Agreement is filed herewith as Exhibit 5.1. This opinion is also filed with reference to, and is hereby incorporated by reference into, the Registration Statement.