On December 13, 2021 Ryvu Therapeutics (WSE: RVU) a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported updated clinical and preclinical data demonstrating the single-agent activity of its two lead oncology drug candidates, RVU120 and SEL24 (MEN1703) at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held December 11 – December 14, 2021, in Atlanta, as well as at the 44th Annual San Antonio Breast Cancer Symposium (SABCS) held December 7 – December 10, 2021 (Press release, Ryvu Therapeutics, DEC 13, 2021, View Source [SID1234596993]).

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Presented data included updated clinical results for RVU120, a selective CDK8/19 inhibitor being developed for the treatment of hematological malignancies and solid tumors. The first-in-human (FIH) Phase 1b dose-escalation trial (CLI120-001), which is currently enrolling patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS), has thus far demonstrated an acceptable safety profile and preliminary signs of efficacy for RVU120.

With a data cutoff of November 16, 2021, data highlights include:

A Complete Remission (CR) in an AML patient harboring mutations in DNMT3A and NPM1. Supportive translational data were also presented demonstrating the anti-leukemic activity of RVU120 in PDX AML models bearing DNMT3A and NPM1 mutations.
An erythroid response (ER) in a HR-MDS patient who had relapsed after several lines of previous treatment; as of the data cutoff, this patient remains on study treatment with stable disease for more than 15 months. Supportive translational data were also presented demonstrating that RVU120 induces erythroid differentiation in (Lin-) CD34+ cells.
Acceptable safety profile in 6 patients completing safety evaluations for cycle 1. None of these patients experienced dose-limiting toxicity (DLT). A total of 12 serious adverse events (SAEs) have been reported – none were deemed to be related to the study drug.
An additional poster on the potential efficacy of RVU120 in hormone-negative breast cancer models was presented at the 2021 San Antonio Breast Cancer Symposium, which showed that oral administration of RVU120 demonstrated strong anticancer activity in a TNBC xenograft model.

Ryvu licensee Menarini Group presented updated Phase 2 data for SEL24 (MEN1703) (DIAMOND-01, ClinicalTrials.gov identifier: NCT03008187), showing pharmacodynamics (PD) and genomic profiling in the First-in-Human Diamond-01 trial.

"We are delighted to present data update at the ASH (Free ASH Whitepaper) and SABCS conferences, including clinical responses in the Phase Ib trial of RVU120, and exciting translational data for this project", said Pawel Przewiezlikowski, Chief Executive Officer of Ryvu Therapeutics. "We have managed to achieve several important development milestones across our pipeline in 2021, highlighting our commitment to challenge current treatment paradigms and develop therapeutics that address clinical limitations of current treatments in oncology. In 2022, we expect to achieve additional clinical milestones for our two lead oncology drug candidates, RVU120 and SEL24, as we remain focused on developing new and innovative therapeutics for patients suffering from cancer."

Posters presented at the 63rd ASH (Free ASH Whitepaper) Annual Meeting & Exposition included:

CLI120-001 Phase Ib Study of RVU120 (SEL120) in Patients with AML and High-Risk MDS: Updated Safety/Efficacy Results from Initial Dose Escalation (Publication Number: 3418)
RVU120 (SEL120) CDK8/19 Inhibitor – a Drug Candidate for the Treatment of MDS Can Induce Erythroid Differentiation (Publication Number: 1518)
Inhibition of Cyclin Dependent Kinase 8 (CDK8): A Novel Approach to Target the Leukemia Initiating Cells (LICs) in T-Cell Acute Lymphoblastic Leukemia (T-ALL) (Publication Number: 2250)
Preclinical and Clinical Signs of Efficacy of RVU120 (SEL120), a Specific CDK8/19 Inhibitor in DNMT3A-Mutated AML (Publication Number: 2371)
SEL24(MEN1703) Inhibits PIM/FLT3 Downstream Target in Acute Myeloid Leukemia (AML) Patients: Results of the Pharmacodynamics (PD) Assay and Genomic Profiling in the First-in-Human Diamond-01 Trial (Publication Number: 3436)
Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo (#1766), presented at the 2021 San Antonio Breast Cancer Symposium.

On December 13, 2021 Syndax Pharmaceuticals, Inc. ("Syndax," the "Company" or "we") (Nasdaq: SNDX), a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported updated positive data from the Phase 1 dose escalation portion of the AUGMENT-101 trial of SNDX-5613 in patients with mutant nucleophosmin (mNPM1) or mixed lineage leukemia rearranged (MLLr) relapsed/refractory (R/R) acute leukemias (Press release, Syndax, DEC 13, 2021, View Source [SID1234596992]). SNDX-5613 is the Company’s highly selective oral menin inhibitor. The data are being featured during an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on Monday, December 13, 2021 at 3:15 p.m. ET.

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"Patients with relapsed or refractory leukemia harboring NPM1 mutations or MLL-rearrangements face a particularly poor prognosis," said Eytan M. Stein, M.D., Assistant Attending Physician and Director, Program for Drug Development in Leukemia, Department of Medicine at Memorial Sloan Kettering Cancer Center, and the trial’s principal investigator. "Data being reported today show highly encouraging clinical activity and favorable tolerability across a heavily pretreated population. In addition to very high MRD negative rates in those patients achieving complete response (CR) or CR with partial hematologic recovery (CRh), we are also seeing response durations greater than six months."

"The updated data presented today at ASH (Free ASH Whitepaper) from our ongoing AUGMENT-101 trial strongly support the potential of SNDX-5613 to serve as a best-in-class treatment option for patients with NPM1 or MLLr leukemia, which together represents approximately 40% of all acute leukemias," said Briggs W. Morrison, M.D., Chief Executive Officer of Syndax. "We are also very pleased that discussions with the U.S. Food and Drug Administration (FDA) have confirmed that the ongoing Phase 2 AUGMENT-101 trial may potentially serve as the basis for regulatory filings in each of its three indication-specific cohorts of NPM1 mutant acute myeloid leukemia (AML), MLLr AML, and MLLr acute lymphoblastic leukemia (ALL), and that patients will be able to restart treatment with SNDX-5613 following a stem cell transplant."

Dr. Morrison continued, "We also remain focused on executing on our strategy to expand into earlier lines of therapy and pediatric populations, and we look forward to initiating the BEAT AML trial in frontline MLLr and mNPM1 AML in combination with venetoclax and azacitidine, the INTERCEPT trial in AML patients with MRD positive disease, and the AUGMENT-102 trial in combination with chemotherapy in adult and pediatric relapsed/refractory MLLr and mNPM1 acute leukemia patients."

As of an October 18, 2021 data cutoff date, a total of 59 patients with a median of four prior therapies, including 42% who received a prior stem cell transplant and 59% who received prior venetoclax, were dosed in the Phase 1 portion of the trial. Across evaluable patients with mNPM1 (n=13) or MLLr (n=38) acute leukemia who received at least one dose of SNDX-5613, the overall response rate1 (ORR) was 55%, with a CR/CRh rate of 24% and nine patients proceeding to stem cell transplant (two patients achieving a CR with incomplete platelet recovery [CRp] with no evidence of minimal residual disease [MRD], and seven patients who achieved MRD- CR or CRh). The ORR in evaluable patients harboring an NPM1 mutation was 38% (5/13), with a CR/CRh rate of 23% (3/13). The ORR in evaluable patients harboring an MLL-rearrangement was 61% (23/38), with a CR/CRh rate of 24% (9/38).

The overall MRD negative rate was 31% (16/51). Among those patients who achieved CR/CRh, 92% (11/12) were MRD negative, including 100% (3/3) of NPM1 patients and 89% (8/9) of MLLr patients. Median time to response for patients achieving a CR/CRh was two months. Median duration of response (DOR) was not reached, inclusive of patients who received stem cell transplant, and 6/12 patients who achieved CR/CRh had a duration of response greater than six months.

SNDX-5613 was well-tolerated, with no discontinuations due to treatment-related adverse events observed in heavily pretreated patients. The only dose limiting toxicity observed was Grade 3 QT prolongation, which occurred in 7% (3/43) of patients treated at the four doses that met the study’s pre-defined recommended Phase 2 dose criteria. Differentiation syndrome was reported in 14% of patients (8/59) with all cases being Grade 1 or 2 and readily managed with standard therapies.

As data from the Phase 1 portion of the trial have continued to mature, the results have demonstrated consistent and compelling anti-leukemic activity with favorable tolerability in patients with both R/R MLLr and NPM1 acute leukemias. The following table summarizes select efficacy and safety data that has been presented by the Company throughout 2021.

Best Response in Response Evaluable Patients

April ’21

May ’21

Dec ’21

n = 31 (%)

n = 31 (%)

n = 51 (%)

Overall Response Rate* (ORR)

15/31 (48%)

15/31 (48%)

28/51 (55%)

CR/CRh

5 (16%)

7 (23%)

12 (24%)

CRp

5 (16%)

4 (13%)

7 (14%)

CRi/MLFS

5 (16%)

4 (13%)

9 (18%)

Received HSCT

4

4

9

MLLr ORR

13/24 (54%)

13/24 (54%)

23/38 (61%)

mNPM1 ORR

2/7 (29%)

2/7 (29%)

5/13 (38%)

≥Gr3 QTc prolonged (all doses)

14%

14%

12%

≥Gr3 QTc prolonged (RP2D doses)

9%

9%

7%

* Overall Response Rate = CR + CRh + CRp + CRi + MLFS

The Phase 2 portion of AUGMENT-101, which will assess 163 mg every 12 hours of SNDX-5613 in patients receiving concomitant strong CYP3A4 inhibitor treatment, is currently underway. A total of 64 adult and up to ten pediatric patients will be enrolled across each of the following three distinct trial populations: patients with NPM1 mutant AML, patients with MLLr AML, and patients with MLLr ALL. Discussions with the FDA have confirmed that AUGMENT-101 may potentially serve as the basis for regulatory filings in each of the three distinct trials. The primary endpoint for each of the three trials will be efficacy as measured by complete remission rate (CR + CRh), with key secondary endpoints including DOR and overall survival.

A copy of today’s presentation will be available in the Publications and Meeting Presentations section of Syndax’s website.

About SNDX-5613

SNDX-5613 is a potent, selective, small molecule inhibitor of the menin-MLL binding interaction that is being developed for the treatment of mixed lineage leukemia rearranged (MLLr) acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1 mutant AML. In preclinical models of MLLr acute leukemias, SNDX-5613 demonstrated robust, dose-dependent inhibition of tumor growth, resulting in a marked survival benefit. Menin-MLL interaction inhibitors have also demonstrated robust treatment benefit in multiple preclinical models of NPM1 mutant AML, which represents the most frequent genetic abnormality in adult AML. SNDX-5613 is currently being evaluated in the Company’s AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. SNDX-5613 was granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of patients with AML, and Fast Track designation for the treatment of adult and pediatric patients with relapsed or refractory acute leukemias harboring a mixed lineage leukemia rearranged MLLr or NPM1 mutation.

About Mixed Lineage Leukemia Rearranged Acute Leukemias

Rearrangements of the MLL gene give rise to mixed lineage leukemia rearranged (MLLr) acute leukemias known to have a poor prognosis, with less than 25% of adult patients surviving past five years. MLL rearrangements produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-MLLr interaction has been shown to halt the growth of MLLr leukemic cells. MLLr leukemias, which are routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques, occur in approximately 80% of infant acute leukemias and up to 10% of all acute leukemias. There are currently no approved therapies indicated for MLLr leukemias.

About NPM1 Mutant Acute Myeloid Leukemia

NPM1 mutant acute myeloid leukemia (AML), which is distinguished by point mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%. Similar to mixed lineage leukemia rearranged (MLLr) leukemias, NPM1 mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-MLL interaction. NPM1 mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1 mutant AML.

On December 13, 2021 Novartis reported the introduction of T-Charge, the company’s next-generation CAR-T platform that will serve as the foundation for various new investigational CAR-T cell therapies in the Novartis pipeline (Press release, Novartis, DEC 13, 2021, View Source [SID1234596991]). At the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper) 2021, Novartis will present early clinical data from ongoing Phase I clinical trials with YTB323 (anti-CD19) and PHE885 (anti-BCMA), the first Novartis CAR-T cell therapies developed using this platform. Notably, initial efficacy data show a complete response rate of 73% (95% CI: 44.9, 92.2) at month three for the 15 patients with diffuse large B-cell lymphoma (DLBCL) who received dose level two of YTB3231. For the 11 patients with multiple myeloma who received the two highest doses of PHE885, the best overall response was 100%2.

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The T-Charge platform preserves T cell stemness, the ability to self-renew and mature, which results in a product containing greater proliferative potential and fewer exhausted T cells3,4. With T-Charge, CAR-T cell expansion occurs primarily within a patient’s body (in-vivo), eliminating the need for an extended culture time outside of the body (ex-vivo)3,4. These unique characteristics of the T-Charge platform may lead to better and more durable responses, improved long-term outcomes and a reduced risk of severe adverse events1-4.

"With T-Charge, we aim to build on the vast knowledge gleaned from early investment in CAR-T research and trials. Our ambition now is to go beyond incremental advances, to further reimagine CAR-T cell therapy and give patients a higher likelihood of durable responses with the ultimate potential for a cure," said Jay Bradner, President of the Novartis Institutes for BioMedical Research. "We are encouraged by these promising early clinical data from the first CAR-T cell therapies produced using the T-Charge platform as we look to accelerate their development and delivery to patients."

Phase I YTB323 clinical study1
YTB323, an investigational, autologous CD19-directed CAR-T cell therapy developed using the T-Charge platform, showed promising results in the diffuse large B-cell lymphoma arm of a first-in-human, multicenter, Phase I dose-escalation study. Patients received a single treatment of YTB323 at two dose levels (DL). The median administered doses were 2.5×106 CAR+ cells (DL1; n=4) and 12.5×106 CAR+ cells (DL2; n=16). Of the 15 patients who received YTB323 treatment at DL2 at least three months prior to the data cut-off, the complete response (CR) rate was 73% (95% CI: 44.9, 92.2), including two patients who were in CR prior to treatment with YTB323.

For the 20 patients evaluable for safety, there were no new safety signals beyond those previously known to be related to CD19-directed CAR-T cell therapy. All AEs were reported regardless of the study drug relationship. Six patients experienced CRS including five of grade 1/2 and one of grade 4. Five patients had neurological adverse reactions (AR), of which two events were considered serious (both at DL2; one experienced grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and the other experienced grade 2 seizure that resulted in a grade 3 ICANS). Recruitment for this trial is ongoing. These data will be presented in an oral session at the ASH (Free ASH Whitepaper) annual meeting (Abstract #740; Monday, December 13, 3:00 PM EST).

"The introduction of CAR-T cell therapy led to unprecedented efficacy results for patients facing limited treatment options and a poor prognosis. Unfortunately, some patients with late-stage B-cell malignancies relapse or do not respond after initial response when treated with traditional CAR-T cell therapies," said principal investigator Ian W. Flinn, MD, PhD, Director of the Lymphoma Research Program at Sarah Cannon Research Institute in Nashville. "As part of a community of researchers, physicians and patient advocates, I am hopeful about the promise of novel and next-generation CAR-T cell therapies."

Phase I PHE885 clinical study2
PHE885, an investigational, autologous BCMA-directed CAR-T cell therapy developed using the T-Charge platform, demonstrated promising results in patients with relapsed or refractory multiple myeloma in a first-in-human Phase I, multicenter, dose-escalation study. Fifteen patients were evaluated for efficacy and safety and the fixed doses received were 2.5×106 (n=4), 5×106 (n=10) and 14.3×106 CAR-T cells (n=1). Although the follow-up period was brief, PHE885 shows encouraging initial clinical activity with a best overall response of 100% for patients receiving the 5×106 or 14.3×106 CAR-T cell dose, with responses deepening over time. With a median follow-up of 3.5 months, eight of 15 patients had ongoing responses at the time of data cutoff. Of the evaluable patients at three months post administration, 34% (2/6) were MRD-negative by next-generation sequencing (NGS) at 10-6; 43% (3/7) were MRD-negative at 10-5.

All patients experienced CRS with two patients experiencing grade ≥3 CRS. No patients experienced grade 4 or 5 CRS. All neurotoxicity events (n=4) were nonserious, grade 1-2, reversible, and temporally associated with CRS. Recruitment for this trial is ongoing. These data will be presented in a poster presentation session at the ASH (Free ASH Whitepaper) annual meeting (Abstract #3864; Monday, December 13, 6:00 PM EST).

Results from pre-clinical studies of YTB323 and PHE885 that served as the scientific rationale to initiate these Phase I clinical trials will also be presented at the meeting (Abstracts #2848 and #2770).

About T-Charge1-4
T-Charge is a next-generation CAR-T platform, innovated at the Novartis Institutes for BioMedical Research (NIBR), that will serve as the foundation for various new investigational CAR-T cell therapies in the Novartis pipeline. By implementing the T-Charge platform, we aim to revolutionize CAR-T cell therapy with new products that have the potential to offer patients a higher likelihood of better and more durable responses, improved long-term outcomes and a reduced risk of severe adverse events. The T-Charge platform preserves T cell stemness (T cell ability to self-renew and mature), an important T cell characteristic closely tied to its therapeutic potential, which results in a product containing greater proliferative potential and fewer exhausted T cells. With T-Charge, CAR-T cell expansion occurs primarily within the patient’s body (in-vivo), eliminating the need for an extended culture time outside of the body (ex-vivo). The T-Charge platform, which implements important process efficiencies, will be rapid, compared with traditional CAR-T, and reliable, through simplified processes and streamlined quality control. Multiple CAR-T therapies, including YTB323 and PHE885, are being developed using the Novartis T-Charge platform.

About Novartis commitment to Oncology Cell Therapy
Novartis has a mission to reimagine medicine by bringing curative cell therapies to patients worldwide. Novartis has a deep CAR-T pipeline and ongoing investment in manufacturing and supply chain process improvements. With active research underway to broaden the impact of cell and gene therapy in oncology, Novartis is going deeper in hematological malignancies, reaching patients with other cancer types and evaluating next-generation CAR-T cell therapies that focus on new targets and utilize new platforms.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials.

On December 12, 2021 The board of directors of Eli Lilly and Company (NYSE: LLY) reported a 15 percent increase in its quarterly dividend and declared a dividend for the first quarter of 2022 of $0.98 per share on outstanding common stock (Press release, Eli Lilly, DEC 13, 2021, View Source [SID1234596990]).

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The dividend is payable on March 10, 2022 to shareholders of record at the close of business on Feb. 15, 2022.

On December 13, 2021 Curaleaf Holdings, Inc. (CSE: CURA /OTCQX: CURLF) ("Curaleaf" or the "Company"), a leading international provider of consumer products in cannabis, reported that it has received commitments for a private placement of 8.0% Senior Secured Notes due 2026 (the "Notes") for aggregate gross proceeds of US$425 million (the "Offering") (Press release, Curaleaf Holdings, DEC 13, 2021, View Source [SID1234596989]).

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The Notes, which will be issued at 100% of face value, will be senior secured obligations of the Company and will bear interest at a rate of 8.0% per annum, payable semi-annually in equal installments until the maturity date, unless earlier redeemed or repurchased. The Notes will be governed by a trust indenture to be entered into on closing of the Offering (the "Indenture"). The Indenture enables the Company to issue additional notes on an ongoing basis as needed, subject to maintaining leverage ratios and complying with the other terms and conditions of the Indenture. In addition, the Indenture permits up to an additional US$200 million of senior bank financing. Curaleaf intends to use the net proceeds from the Offering to refinance existing indebtedness, for working capital, and to pay transaction fees and expenses. The Notes will mature on December 15, 2026. The Offering is expected to close on December 15, 2021, subject to customary closing conditions.

"We are pleased to announce what we believe is the largest debt financing of any publicly-traded MSO to date," said Joseph Bayern, Chief Executive Officer of Curaleaf. "This offering will allow us to refinance our existing debt at a materially lower interest rate and provides us with additional financial flexibility to execute our strategic growth initiatives. While this initial offering provides more than enough liquidity to refinance our existing debt and meet current needs, the new Indenture provides us a new degree of flexibility to raise debt financing to ensure we have ample liquidity to meet our needs now and into the future."

Seaport Global Securities LLC and Canaccord Genuity Corp. (the "Agents") acted as placement agents for the Notes in the United States and Canada, respectively.

The Notes are being offered on a private placement basis in certain provinces and territories of Canada pursuant to applicable exemptions from the prospectus requirements of Canadian securities laws. The Notes may also be sold in the United States to or for the account or benefit of "U.S. persons" (as defined in the United States Securities Act of 1933, as amended (the "U.S. Securities Act")), on a private placement basis to "qualified institutional buyers" and "accredited investors" pursuant to an exemption from the registration requirements of the U.S. Securities Act, and in such jurisdictions outside of Canada and the United States as may be agreed upon by the Agents and the Company, in each case in accordance with applicable laws. The Notes to be issued will be subject to a customary four-month hold period under Canadian securities laws.

No securities regulatory authority has either approved or disapproved of the contents of this news release. The Notes have not been and will not be registered under the U.S. Securities Act or any state securities laws. Accordingly, the Notes may not be offered or sold within the United States or to or for the account or benefit of "U.S. persons" unless registered under the U.S. Securities Act and applicable state securities laws or pursuant to exemptions from the registration requirements of the U.S. Securities Act and applicable state securities laws. This news release does not constitute an offer to sell or a solicitation of an offer to buy any securities of the Company in any jurisdiction in which such offer, solicitation or sale would be unlawful.