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Leap Therapeutics Presents TRX518 Data at ESMO Immuno-Oncology Congress 2018 and Updated Data from DKN-01 Study in Biliary Tract Cancer

On December 14, 2018 Leap Therapeutics, Inc. (NASDAQ: LPTX) reported its clinical data from its ongoing Phase I/II study of TRX518 in combination with gemcitabine, KeytrudaÒ (pembrolizumab), or OpdivoÒ (nivolumab) in patients with advanced solid tumors at the European Society for Molecular Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Congress 2018 (Press release, Leap Therapeutics, DEC 14, 2018, View Source [SID1234532078]). In addition, Leap provided the top-line final data from the Phase I/II study of DKN-01 in combination with gemcitabine and cisplatin chemotherapy in patients with advanced biliary tract cancer.

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Leap will host a conference call and webcast on Monday, December 17, 2018 at 8:30 AM US Eastern Time with Jason J. Luke, MD, Assistant Professor of Medicine, Pritzker School of Medicine at the University of Chicago and Todd M. Bauer, MD, Sarah Cannon Research Institute/Tennessee Oncology PLLC, TN. Drs. Luke and Bauer will discuss patient outcomes and provide additional perspectives about the TRX518 program.

TRX518

TRX518 is unique among Glucocorticoid-Induced TNF Receptor (GITR) agonist antibodies for its aglycosyl design, permitting activation of GITR signaling without depleting CD8+ T-effector cells. In cancer patients, TRX518 has been shown to increase CD8+ T-effector cell infiltrate and the expression of granzyme B, as well as decrease CD4+ T-regulatory cell infiltrate. The dual function of TRX518 is designed to enhance the anti-tumor activity of chemotherapies and immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies.

TRX518 Clinical Data Presented at ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2018

The clinical trial is a continuation of the TRX518 multi-dose monotherapy study that has been expanded with three combination study arms to evaluate lower (2 mg/kg loading dose with 1 mg/kg maintenance doses) and higher (4 mg/kg loading dose with 1 mg/kg maintenance doses) dose levels of TRX518 in combination with gemcitabine chemotherapy or Keytruda or Opdivo anti-PD-1 immune checkpoint antibodies.

Key Findings:

In monotherapy and combination studies, TRX518 demonstrated safety, tolerability, and clinical benefit in patients with heavily pretreated solid tumors.
TRX518 in combination with Keytruda or Opdivo achieved durable complete and partial responses in patients not expected to respond to anti-PD-1 therapy alone, including a confirmed complete response in an esophageal squamous cell cancer patient and a confirmed partial response in an anti-PD-1 refractory urothelial cancer patient.
TRX518 in combination with gemcitabine achieved meaningful clinical benefit and objective tumor reduction for heavily pretreated patients suffering from pancreatic, biliary tract, mesothelioma, appendiceal, and ovarian cancer.
The biopsies of responding patients demonstrated an increase in CD8+ T-effector cells and granzyme B expression and a reduction in CD4+ T-regulatory cells and FoxP3 expression, hallmarks of immune activation and anti-tumor activity associated with GITR agonism.
TRX518/gemcitabine combination:

The combination arm evaluating TRX518 in combination with gemcitabine enrolled thirty patients who had received one to nine prior therapies. Four patients were treated at the lower dose of TRX518, and twenty-six patients were treated at the higher dose. The study enrolled fourteen patients with pancreatic cancer, five with biliary tract cancer, and eleven with other cancers including ovarian, appendiceal, and mesothelioma. Seventeen patients had previously progressed on gemcitabine therapy, and ten had previously progressed on anti-PD-1/PD-L1 therapy.

Clinical outcomes data as of December 5, 2018 includes:

TRX518 + gemcitabine

Response Evaluable

Stable Disease

Progressive Disease

Disease Control Rate (Response Evaluable)

Overall

52%

Lower dose TRX518

Higher dose TRX518

56.5%

Pancreatic Cancer

50%

Biliary Tract Cancer (BTC)

80%

Other Cancers

40%

Nineteen pancreatic or biliary tract cancer (PBC) patients were enrolled, and nine remain on study. Nearly all of these patients had received prior gemcitabine therapy, and nine (47%) remained on study for more than four cycles. Eight (67%) of twelve evaluable PBC patients previously treated with gemcitabine who received the higher dose of TRX518 have had stable disease, including a fourth-line pancreatic cancer patient who remains on study in Cycle 9 with a 21% reduction in tumor burden. Pancreatic cancer patients who have progressed on gemcitabine have extremely poor outcomes with studies indicating a range of 1.6 to 2.9 months between median progression and median overall survival.

Additional reductions in tumor burden and durable clinical benefit have been noted in appendiceal cancer (-4% in Cycle 7), mesothelioma (-5% in Cycle 6), and two in ovarian cancer (-15% in Cycle 5, -9% off after 4 cycles).

TRX518/Keytruda or Opdivo combination

The combination arms evaluating TRX518 in combination with Keytruda or Opdivo enrolled fourteen patients in the dose escalation cohorts as of December 5, 2018. Both patients treated with the higher dose of TRX518 plus Keytruda have had clinical benefit. An esophageal squamous cell carcinoma patient has had a confirmed complete response, which remains ongoing for seven months, and an ocular melanoma patient has had a 23% reduction in tumor volume and six months of ongoing stable disease. In the low dose TRX518 plus Opdivo combination arm, a patient with urothelial carcinoma who had failed prior Keytruda had a confirmed partial response and remained on therapy for six months.

Enrollment is now complete in the dose escalation cohort for TRX518 and Keytruda and continues in the high dose escalation cohort of TRX518 and Opdivo. Leap anticipates that dose expansion cohorts for both combinations will initiate in the first quarter 2019.

DKN-01

DKN-01 is a humanized monoclonal antibody targeting the Dickkopf-1 (DKK1) protein, a Wnt pathway modulator. DKN-01 is in clinical trials in patients with esophagogastric cancer, hepatobiliary cancer, and gynecologic cancers.

At the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting, Leap announced that the combination of DKN-01 and paclitaxel generated a 46.7% overall response rate, 19.6 weeks median progression free survival, and 61.1 weeks median overall survival in fifteen evaluable esophagogastric cancer patients as a second-line therapy. In the subgroup of twelve evaluable patients with heavily pre-treated esophageal squamous cell carcinoma, DKN-01 and paclitaxel produced a 33.3% overall response rate, 13.7 weeks median progression free survival, and 31.0 weeks median overall survival.

At the ESMO (Free ESMO Whitepaper) 2018 Annual Meeting, Leap announced that the combination of DKN-01 and Keytruda demonstrated promising clinical activity with a 23.5% overall response rate and 58.8% disease control rate in evaluable gastric or gastroesophageal junction cancer patients who have been heavily pretreated and have not had prior anti-PD-1/PD-L1 therapy. The combination has generated durable responses in subgroups less likely to respond to pembrolizumab monotherapy, for example, patients whose tumors are microsatellite stable and/or PD-L1 negative. Additional data from the DKN-01/Keytruda combination is expected in the second quarter of 2019.

DKN-01 in combination with gemcitabine and cisplatin in Advanced Biliary Tract Cancer

The open-label, Phase I/II study enrolled fifty-one patients with advanced biliary tract cancer (BTC). Seven patients received one of two dose levels (150 mg or 300 mg) of DKN-01 in combination with gemcitabine and cisplatin during Part A, with forty-four additional patients treated at the 300 mg dose level of DKN-01 in the Part B expansion cohort. Forty-two patients were chemotherapy treatment-naïve, and nine patients had received 1-2 prior therapies. The primary objective of this study was to evaluate the safety, pharmacokinetics, and efficacy of DKN-01 in combination with gemcitabine and cisplatin.

In the study, DKN-01 in combination with gemcitabine and cisplatin was well tolerated with no new emerging safety trends. Forty-seven patients overall were treated at the 300 mg DKN-01 dose level, and their median overall survival was 53.7 weeks (12.4 months). Median progression free survival was 37.7 weeks (8.7 months). Ten patients (21.3%) had a partial response and thirty-one patients (66.0%) experienced a best response of stable disease, representing a disease control rate of 87.2%. Two patients (4.3%) had progressive disease, and four patients (8.5%) were non-evaluable for response. The one-year probability of overall survival was 0.51, and the six-month probability of progression free survival was 0.58. The median number of cycles of DKN-01 was seven (range of 1 to 23), and the median duration on study was 331 days.

"Patients with metastatic biliary tract cancer have a poor prognosis with an unmet medical need, with median overall survival of less than one year. We are very pleased by the progression-free survival, overall survival, and favorable safety profile demonstrated by DKN-01 in combination with gemcitabine and cisplatin in this single arm study," commented by Andrew X. Zhu, M.D., Director of Liver Cancer Research at Massachusetts General Hospital Cancer Center and Professor of Medicine at Harvard Medical School. "The activity of DKN-01 in biliary tract cancer warrants further development in the front-line setting as well as in second-line in combination with anti-PD-1/PD-L1 antibodies."

TRX518 Clinical Perspectives Conference Call and Webcast

On Monday, December 17, 2018 at 8:30AM ET, Leap will be hosting a conference call and webcast for the investment community. To access the conference call, please dial (866) 589-0108 (US/Canada Toll-Free) or (409) 231-2048 (international) and refer to conference ID 9187987. The presentation will also be webcast live and will be available on Leap’s website, View Source A replay of the webcast will be available on Leap’s website after the event and will be available for a limited time.

RadioMedix presented at the 2018 Bio Investor Forum

On December 14, 2018 RadioMedix Inc reported that it has been selected by the National Cancer Institute (NCI) Small Business Innovation Research Development Center (SBIR) to participate in 2018 Bio Investor Forum (Press release, RadioMedix, DEC 14, 2018, View Source [SID1234532075]). The company received federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (HHSN261201600015C, HHS261201800048C/75N91018C00048) for the development of radiotherapeutic alpha-emitter labeled agents.

Dr. Izabela Tworowska, Chief Science Officer of RadioMedix, presented the corporate overview of the company pipeline at the 2018 Bio Investor Forum held in San Francisco, California. The presentation was sponsored by NCI SBIR Development Center’s Investor Initiatives program. Dr. Tworowska provided an overview of the research and financial growth of the RadioMedix, discussed the company pipeline and the status of the clinical development of radiotheranostic drugs.

"We have been invited to attend the Bio Investor Forum in San Francisco for two consecutive years and we are grateful the NCI SBIR Investor Initiatives for this invitation and also for the feedback on our presentation", said Dr. Tworowska. "It is a great opportunity to attend One-on-One Partnering meetings and gain the interest of the pharmaceutical companies and investors", added Dr. Tworowska.

"RadioMedix’s rich clinical stage pipeline of innovative radiopharmaceuticals makes an attractive case for investors, and large companies, familiar with our space", said Dr. Delpassand, Chairman and CEO of RadioMedix. "Targeted radioligand therapy will be the strongest segment in the field of nuclear medicine and RadioMedix is well-positioned to take advantage of this opportunity", added Dr. Delpassand.

Astellas Acquires Potenza Therapeutics – Acquisition adds clinical stage novel immuno-oncology programs to Astellas’ oncology pipeline

On December 14, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported that it exercised, and closed on its exclusive option to acquire Potenza Therapeutics, Inc. ("Potenza") on December 13, 2018, U.S. Eastern Time (Press release, Astellas Pharma, DEC 14, 2018, View Source [SID1234532074]). This acquisition marks the successful outcome of a collaboration agreement entered into in 2015 to build a portfolio of novel immuno-oncology (IO) therapies. The clinical IO therapies developed through this collaboration may also provide a platform for IO combinations with Astellas’ existing non-IO programs for life cycle management and future novel IO combinations.

"This transaction underscores Astellas’ commitment to innovation and scientific partnerships to advance our creation of value for patients," said Kenji Yasukawa, Ph.D., President and CEO, Astellas. "In oncology, Astellas has focused on developing treatments for unmet medical needs with novel mechanisms of action and modalities. We believe the novel assets we have developed with Potenza have the potential to make an even more pronounced difference for patients in need."

Through the research and development collaboration over the past three and a half years, Astellas and Potenza have discovered and developed three novel investigational new drugs (INDs) with the potential to treat various cancers that are non-responsive or resistant to the current generation of IO therapies. This portfolio of programs targeting immune stimulation, immune checkpoint inhibition, and regulatory T cell function includes:

ASP8374/PTZ-201, an anti-TIGIT antibody (immune checkpoint inhibitor) and ASP1948/PTZ-329, an anti-NRP1 antibody (Treg function inhibitor), both of which are currently in Phase 1 clinical studies;
ASP1951/PTZ-522, a novel format GITR agonistic antibody (T cell priming & costimulation), which has recently achieved IND clearance.
Upon the closing of this transaction, Potenza became a wholly-owned subsidiary of Astellas, establishing a competitive and fully owned clinical IO pipeline.

"We are extremely proud of what the experienced Potenza team has accomplished to discover and create innovative therapeutics for the treatment of cancers," said Dan Hicklin, Ph.D., President and CEO, Potenza. "Over the past three and a half years, we have enjoyed a successful and productive partnership with Astellas. I am pleased that these therapies will now have access to the resources of a large international company, with world-class R&D and the strategic and financial backing to support the development of these innovative potential new medicines for cancer patients in need."

By exercising its options under the Warrant Purchase Agreement, Astellas paid an upfront fee of $164.6 million to acquire Potenza and Potenza’s shareholders will be eligible for additional payments that total up to $240.1 million, depending on the progress of various programs in clinical development.

Astellas is reviewing the impact of the acquisition on its financial result for the fiscal year ending March 31, 2019.

Acquisition Summary

Acquiring company: Astellas Pharma Inc.
Major shareholders of Potenza Therapeutics:
MPM Capital, InterWest Partners, Astellas Pharma Inc., Founders and others (including stock options)
Payment: Cash on hand
Amount:
$164.6 million to make Potenza a wholly-owned subsidiary of Astellas
Up to $240.1 million in future contingent payments based on the advances in clinical programs
Overview of Acquired Company

Corporate Name: Potenza Therapeutics, Inc.
Location: Cambridge, MA
Representative: President and CEO Dan J. Hicklin, Ph.D.
Founded year: 2014
Number of employees: 19
Relationship with Astellas: Equity-method affiliate, research and development partner

Celltrion and Teva Announce FDA Approval of HERZUMA® (trastuzumab-pkrb), a Biosimilar to HERCEPTIN®, for the Treatment of HER2-Overexpressing Breast Cancer for Certain Indications

On December 14, 2018 Celltrion, Inc. (KRX:068270) and Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) reported that the U.S. Food and Drug Administration (FDA) has approved HERZUMA (trastuzumab-pkrb), a HER2/neu receptor antagonist biosimilar to HERCEPTIN1 (trastuzumab) for the following indications (Press release, Celltrion, DEC 14, 2018, View Source [SID1234532069]):

Adjuvant Breast Cancer of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer
as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
as part of a treatment regimen with docetaxel and carboplatin
Metastatic Breast Cancer
in combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
In these indications, patients should be selected for therapy based on an FDA-approved companion diagnostic for a trastuzumab product
"Biosimilars are of growing importance to the oncology community and the approval of HERZUMA may provide more patients access to this important therapy," stated Woosung Kee, Chief Executive Officer of Celltrion. "This is our second oncology biosimilar approval in the United States in the past month, which reinforces the goal for all of our approved products — providing broader treatment options for patients and the providers who treat them."

HERZUMA meets the FDA’s rigorous standards as a biosimilar to the reference product for the approved indications based on a totality of evidence. The FDA approval is based on a review of a comprehensive data package inclusive of foundational analytical similarity data, nonclinical data, clinical pharmacology, immunogenicity, clinical efficacy and safety data. The results of the clinical development program for HERZUMA demonstrated that there were no clinically meaningful differences in purity, potency and safety between HERZUMA and HERCEPTIN for the treatment of HER2-overexpressing breast cancer for the approved indications.

"We are excited about building Teva’s presence in biosimilars," said Brendan O’Grady, Executive Vice President and Head of North America Commercial at Teva. "The addition of HERZUMA to our biosimilars portfolio will allow us to leverage our strengths from Oncology and Generics."

Trastuzumab products have a Boxed Warning which states that treatment with trastuzumab may be associated with cardiomyopathy, infusion reactions, pulmonary toxicity and embryo-fetal toxicity. Please see the full Boxed Warning and additional Important Safety Information in this release and accompanying Prescribing Information.

Celltrion and Teva Pharmaceutical Industries Ltd. entered into an exclusive partnership in October 2016 to commercialize HERZUMA in the U.S. and Canada.

Important Safety Information and Boxed Warnings

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, AND PULMONARY TOXICITY

Cardiomyopathy – Administration of trastuzumab products can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline- containing chemotherapy regimens.

Evaluate left ventricular function in all patients prior to and during treatment with HERZUMA. Discontinue HERZUMA treatment in patients receiving adjuvant therapy and withhold HERZUMA in patients with metastatic disease for clinically significant decrease in left ventricular function.

Infusion Reactions; Pulmonary Toxicity – Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of HERZUMA administration. Interrupt HERZUMA infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue HERZUMA for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Embryo Fetal Toxicity – Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.

Cardiomyopathy

Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).
There is a 4–6-fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with an anthracycline.
Withhold HERZUMA for ≥ 16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values. The safety of continuation or resumption of HERZUMA in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied.
Patients who receive anthracycline after stopping HERZUMA may also be at increased risk of cardiac dysfunction.
Cardiac Monitoring

Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
Baseline LVEF measurement immediately prior to initiation of HERZUMA.
LVEF measurements every 3 months during and upon completion of HERZUMA.
Repeat LVEF measurement at 4 week intervals if HERZUMA is withheld for significant left ventricular cardiac dysfunction.
LVEF measurements every 6 months for at least 2 years following completion of HERZUMA as a component of adjuvant therapy.
Infusion Reactions

Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia.
In post-marketing reports, serious and fatal infusion reactions have been reported. Severe reactions, which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable, including progressive worsening, initial improvement followed by clinical deterioration, or delayed post-infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.
Interrupt HERZUMA infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered (which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen). Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.
There are no data regarding the most appropriate method of identification of patients who may safely be retreated with trastuzumab products after experiencing a severe infusion reaction. Prior to resumption of trastuzumab infusion, the majority of patients who experienced a severe infusion reaction were pre-medicated with antihistamines and/or corticosteroids. While some patients tolerated trastuzumab infusions, others had recurrent severe infusion reactions despite pre-medications.
Embryo-Fetal Toxicity

Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA. Advise pregnant women and females of reproductive potential that exposure to HERZUMA during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of HERZUMA.
Pulmonary Toxicity

Trastuzumab product use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions.
Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
Exacerbation of Chemotherapy-Induced Neutropenia

In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC Grade 3 to 4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not.
Adverse Reactions

Adjuvant Breast Cancer – Most common adverse reactions (≥5%) are headache, diarrhea, nausea, and chills.
Metastatic Breast Cancer- Most common adverse reactions (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash.

Pulse Biosciences, Inc. Announces Closing of Its $45 Million Rights Offering

On December 14, 2018 Pulse Biosciences, Inc. (Nasdaq: PLSE) ("Pulse Biosciences" or the "Company"), a novel medical therapy company bringing to market its proprietary CellFX Nano-Pulse Stimulation (NPS) platform, reported that its rights offering has closed (Press release, Pulse Biosciences, DEC 14, 2018, View Source [SID1234532068]).

The rights offering resulted in the issuance of 3,581,148 shares of the Company’s common stock at a price of $12.5658 per share for total gross proceeds of $45 million to the Company. Investors who have participated in the rights offering should expect to see the shares issued to them in book-entry or, uncertificated, form. Any excess subscription payments received by Broadridge Corporate Issuer Solutions, Inc. (the "Subscription Agent") will be returned by the Subscription Agent to investors by mail, without interest or penalty, through the same method by which they participated in the rights offering. After giving effect to the rights offering, the Company has 20,578,904 shares of common stock issued and outstanding.

Robert W. Duggan, the chairman of the Company’s board of directors and the beneficial owner of approximately 35% of the Company’s outstanding common stock prior to this rights offering, participated in the rights offering and purchased an aggregate of 3,146,226 shares for an additional investment of approximately $39.5 million. After giving effect to the rights offering, Mr. Duggan is the beneficial owner of approximately 44% of the Company’s outstanding common stock.

A registration statement relating to the shares of common stock was previously filed with the Securities and Exchange Commission (the "SEC") and declared effective on November 6, 2018. A prospectus relating to the offering was filed with the SEC on November 19, 2018 and is available on the SEC’s website. Subscription rights that were not exercised by 5:00 p.m. Eastern Time on December 6, 2018 have expired.