On March 23, 2023 Sirona Biochem Corp. (TSX-V: SBM) (FSE: ZSB) (OTC: SRBCF) ("Sirona" or the "Company") reported a non-brokered private placement offering of unsecured, convertible debentures (the "Convertible Debentures") (Press release, Sirona Biochem, MAR 23, 2023, View Source [SID1234629262]). The Company is offering Convertible Debentures units (the "Debenture Units") at a price of $1,000 per Debenture Unit for aggregate gross proceeds of up to $1,500,000 (the "Offering").

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Each Debenture Unit will have a face value of (the "Face Value") of $1,120, consisting of $1,000 in principal (the "Principal") and $120 in prepaid interest (the "Prepaid Interest"). The Principal of the Debenture Units will accrue interest at a rate of 12% per annum, which accrued interest ("Accrued Interest") will be paid semi-annually, in arrears. The Company will pay the Prepaid Interest and Accrued Interest in cash or, subject to TSX Venture Exchange ("TSXV") acceptance, may elect to satisfy payment in kind by issuing Shares ("Interest Shares"). In the event of payment in kind, the number of Interest Shares due will be calculated using a conversion price (the "Interest Conversion Price") equal to, subject to acceptance by the TSXV, the maximum Discounted Market Price (as defined in TSXV policies) on the applicable payment due date.

The holder may, at its option, convert in full or in part, the Principal at any time prior to the maturity date (the "Maturity Date"), being the third anniversary of the issue date, into units (the "Units") of the Company at $0.10 per Unit (the "Conversion Price"). Upon conversion of the Principal, the Company will pay Prepaid Interest and unpaid Accrued Interest in cash or, subject to acceptance by the TSXV, in Interest Shares issued at the Interest Conversion Price.

Each Unit will consist of one Share and one non-transferable share purchase warrant (a "Warrant"). Each Warrant will be exercisable by the holder thereof to purchase one Share (a "Warrant Share") at an exercise price of $0.15 at any time prior to the Maturity Date.

The Company shall have the right to redeem the Convertible Debentures prior to the Maturity Date at any time after 6 months from the issue date, by paying holders in cash the Face Value of the Convertible Debentures, together with all Prepaid and Accrued Interest and a redemption penalty payment of 8% of the Face Value. The Company shall give the holders 30 business days’ notice (the "Redemption Notice") to do so. On receipt of a Redemption Notice, a holder may elect to convert all or part of the Principal of the Convertible Debenture into Units at the Conversion Price. All Prepaid and Accrued Interest in respect of the Principal amount so converted shall be, at the election of the holder, either paid in cash or, subject to acceptance by the TSXV, converted into Shares at the Interest Conversion Price, by giving the Company notice (the "Conversion Notice") within 10 business days of receipt of the Redemption Notice.

The closing of the Offering is subject to the receipt of necessary regulatory approvals, including the approval of the TSXV. The Convertible Debentures, Shares, Warrants and any Warrant Shares will be subject to a four-month hold period under applicable securities laws and TSXV policies. The Company may pay eligible finders a fee in connection with the Offering.

The Company plans to use approximately 1/3 of the net proceeds from the Offering for general corporate purposes, and the remainder of the proceeds will used for research and development expenses (including but not limited to, laboratory staff salaries, laboratory materials and intellectual property costs).

Dr. Howard Verrico, the Chief Executive Officer, has agreed to subscribe for $500,000 of Debenture Units. Dr. Verrico’s participation is a "related party transaction" within the meaning of Multilateral Instrument 61-101 Protection of Minority Security Holders in Special Transactions. The Company intends to rely on the exemptions from the formal valuation and minority shareholder-approval requirements of MI 61-101 in respect of related party participation in the Offering. The MI 61-101 exemptions are available as the fair market value of the Debenture Units, and the fair market value of the consideration for the Debenture Units, insofar as it involves Dr. Verrico and other interested parties, will not exceed 25% of the Company’s market capitalization.

This news release does not constitute an offer to sell or the solicitation of any offer to buy, nor shall there be any sale of these securities in any jurisdiction in which such offer, solicitation or sale would be unlawful. The Convertible Debentures and the Shares which may be issued on exercise thereof have not been and will not be registered under the United States Securities Act of 1933, as amended (the "U.S. Securities Act") and may not be offered or sold in the United States absent registration or an applicable exemption from the registration requirements of the U.S. Securities Act and applicable state securities laws.

On March 23, 2023 Eisai reporte that it will present two abstracts at the Society of Gynecologic Oncology (SGO) 2023 Annual Meeting on Women’s Cancer (#SGOMtg), which is taking place in-person in Tampa, Florida and virtually from March 25-28 (Press release, Eisai, MAR 23, 2023, View Source [SID1234629260]). Notable research to be featured in the Scientific Plenary IX: The Best of the Rest session includes a presentation of real-world outcomes and healthcare resource utilization in patients with recurrent or advanced endometrial carcinoma who were rechallenged with platinum chemotherapy in Europe (Abstract: #17).

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Also to be presented are data from the LEAP (LEnvatinib And Pembrolizumab) clinical program analyzing tumor-response from the lenvatinib (LENVIMA) plus pembrolizumab (KEYTRUDA) arm of the pivotal Phase 3 Study 309/KEYNOTE-775 trial in patients with advanced endometrial carcinoma following at-least one prior platinum-based regimen in any setting (NCT03517449; Abstract: #518).

"We look forward to sharing our data at this year’s SGO Annual Meeting, particularly a new study that will be presented in an oral scientific plenary session featuring real-world outcomes in patients with recurrent or advanced endometrial cancer who were rechallenged with platinum chemotherapy," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "We believe this research is important to the healthcare providers and patients we aim to serve because it is essential to understand treatment dynamics and related outcomes in clinical practice. As a human health care company, we remain steadfast in our commitment to advance the science of cancer medicine through the generation of real-world evidence."

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of lenvatinib, both as monotherapy and in combination with Merck’s anti-PD-1 therapy pembrolizumab. To date, more than 10 trials have been initiated under the LEAP clinical program, which is evaluating the combination across multiple tumor types.

This release discusses investigational compounds and investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational compounds or investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

The full list of Eisai presentations is included below. Full abstracts will be posted the day of scheduled presentations.

Study/Compound

Abstract Title

Abstract Type & Details

Real World Evidence

Endometrial Cancer Non-Interventional Study

Real-world outcomes and healthcare resource utilization
in recurrent or advanced endometrial cancer patients
rechallenged with platinum chemotherapy in Europe

Oral Scientific Plenary

Abstract #17

March 28, 2023

10:30-11:45 AM EDT

LEAP clinical program

Study 309/KEYNOTE-775

Characterization of tumor response With lenvatinib plus
pembrolizumab in study 309/KEYNOTE-775

Poster Discussion

Abstract #518

March 27, 2023

10:40-11:20 AM EDT

About Endometrial Carcinoma
Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. Worldwide, it was estimated there were more than 417,000 new cases of uterine body cancer diagnosed and more than 97,000 deaths from the disease in 2020 (these estimates include both endometrial carcinomas and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial carcinoma cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be approximately 66,200 new cases of uterine body cancer diagnosed and approximately 13,000 deaths from the disease in 2023. The five-year relative survival rate for metastatic endometrial carcinoma (stage IV) is estimated to be approximately 20%.

About LENVIMA (lenvatinib) Capsules

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC)
In combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
LENVIMA, discovered and developed by Eisai, is a multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation. The combination of LENVIMA and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone. In syngeneic mouse tumor models, the combination of lenvatinib with an anti-PD-1 monoclonal antibody decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity compared to either treatment alone.

Important Safety Information

Warnings and Precautions

Hypertension. In DTC (differentiated thyroid cancer), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC (hepatocellular carcinoma), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis, and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients; 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease, or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

Embryo-Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.

Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥20%) observed in LENVIMA + pembrolizumab-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%). The most common serious adverse reactions (≥2%) were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage. Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%). Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%). Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

In EC, the most common adverse reactions (≥20%) observed in LENVIMA and pembrolizumab–treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar–plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. Serious adverse reactions occurred in 50% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection (3.2%). Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or EC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end-stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or EC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or EC and severe hepatic impairment.

LENVIMA (lenvatinib) is available as 10 mg and 4 mg capsules.

Please see Prescribing Information for LENVIMA (lenvatinib) at View Source

About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in multiple different tumor types across more than 10 clinical trials.

On March 23, 2023 Biohaven Ltd. (NYSE: BHVN) ("Biohaven" or the "Company"), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies for people with debilitating neurological and neuropsychiatric diseases, including ultra-rare disorders, reported financial results for the fourth quarter ended December 31, 2022, and provided a review of recent accomplishments and anticipated upcoming milestones (Press release, Biohaven Pharmaceutical, MAR 23, 2023, View Source [SID1234629259]). For periods prior to the October 3, 2022 spin-off, the reported financial results present, on a historical basis, the combined assets, liabilities, expenses and cash flows directly attributable to the Company, which have been prepared from Biohaven Pharmaceutical Holding Company Ltd., the former parent, consolidated financial statements and accounting records, and are presented on a stand-alone basis as if the operations had been conducted independently from the former parent. The financial statements for all periods presented, including the historical results of the Company prior to October 3, 2022, are now referred to as "Consolidated Financial Statements."

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Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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Vlad Coric, M.D., Chairman and Chief Executive Officer of Biohaven, commented, "2022 was unequivocally the most defining year since our Company’s formation; with the acquisition by Pfizer for a total consideration of approximately $13 billion including retirement of existing debt, Biohaven is well-capitalized to accelerate development across an extraordinary portfolio spanning mid-to-late-stage and promising discovery assets. The acquisition by Pfizer of Biohaven Pharmaceutical Holding Company Ltd. and the CGRP franchise was a testament to our incredible track record of innovating, developing, commercializing and delivering therapeutic breakthrough medicines, propelled by our unwavering patient focus and data-driven methodical approach. We ultimately delivered multiple first cycle FDA approvals of Nurtec ODT and Vydura ODT in both the acute and prevention of migraine as well as the first intranasal CGRP antagonist, Zavzpret—it’s exciting to see Pfizer take the CGRP franchise global and the benefit that this will have for migraine patients around the world."

Dr. Coric continued, "Today, Biohaven is well-capitalized to accelerate development across an extraordinary portfolio spanning mid-to-late-stage and promising discovery assets. Since the launch of our new company in October, we have already made substantial progress in advancing one of the most innovative and exciting neuroscience portfolios. Our Kv7 ion channel platform has the potential to change the treatment paradigm in the management of epilepsy and mood disorders. The first assets from Biohaven’s Kv7 ion channel platform, BHV-7000 and BHV-7010, are selective Kv7.2 and Kv7.3 activators that lack off-target burdensome side effects. We were pleased to complete our SAD/MAD Phase 1 study of BHV-7000 and report preliminary safety, tolerability and pharmacokinetic data last month; in the study, single doses of up to 100 mg and multiple doses of up to 40 mg daily for 15 days were generally well-tolerated. Importantly, we were encouraged by the lack of sedation, dizziness, fatigue, and ataxia observed in this study – side effects that have historically plagued patients taking available anti-seizure medications. With these results, we plan to initiate an EEG study in the first half of 2023 and Phase 2/3 studies in focal epilepsy and bipolar disorder in the second half of 2023. We are also planning an IND submission for BHV-7010, in epilepsy and mood disorders, and an IND submission for our TRPM3 ion channel antagonist, BHV-2100, in chronic pain; both IND submissions are expected in the second half of 2023."

"Beyond our ion channel platform, our team is advancing novel immune-targeting agents to target neuroinflammation with our degrader platform and recent acquisition of the TYK2/JAK1 asset we added to our pipeline only yesterday. We acquired an exclusive license for BHV-8000, an oral, brain-penetrant, dual TYK2/JAK1 inhibitor offering a unique and exquisite therapeutic approach to addressing brain disorders. There are currently no brain-penetrant, selective, dual TYK2/JAK1 inhibitors approved for brain disorders and we look forward to exploring the vast potential afforded by this compound’s unique therapeutic profile. TYK2/JAK inhibition is a validated mechanism that has led to the approval of peripheral acting agents and our dual TYK2/JAK1 asset will bring one of the most exciting immunoscience targets to the potential treatment of brain disorders. In other pipeline developments, we continue to advance our Phase 3 study evaluating taldefgrobep alfa in patients with spinal muscular atrophy, with 22 sites now activated and enrollment ongoing in the US and EU, and remain on track to complete enrollment in our pivotal Phase 3 study evaluating troriluzole in patients with OCD by year-end 2023. In discovery efforts, we have taken encouraging strides with our burgeoning bispecific platform and were thrilled to share exciting non-human primate data with our IgG degrader, BHV-1300; we expect to submit an IND for BHV-1300 in the second half of 2023. I could not be more enthusiastic about the opportunities ahead for Biohaven – with a world-class, diverse portfolio of assets addressing some of the most critical life-threatening illnesses impacting patients, a plethora of upcoming milestones and multiple INDs supporting continued pipeline development, our highly experienced drug development team, and strengthened capital position – we are well positioned to continue delivering the same impressive results that patients, shareholders, and other key stakeholders have come to expect from our team," Dr. Coric concluded.

Bruce Car, PhD, Chief Scientific Officer of Biohaven added, "We are excited about the promise of our bispecific platform which is advancing multiple compounds including degraders for IgG and IgA, our CD38 targeting therapy for multiple myeloma, and a next generation ADC technology. First, we were thrilled to report data with our first ‘MoDE,’ or molecular degrader of extracellular proteins, where we demonstrated in cynomolgus monkeys that a single dose of our IgG degrader, BHV-1300, reduced IgG levels by 75% from baseline in three days, in comparison to efgartigimod which took 5 to 7 days to achieve a 50% reduction. We separately reported preclinical data from our second MoDE designed to target galactose deficient IgA (Gd-IgA), which is thought to play a pathogenic role in IgA Nephropathy. These early preclinical studies showed the chimeric antibody-ASGPR ligand conjugate specifically mediated endocytosis of Gd-IgA, as opposed to normal IgA. Our team is also advancing next-generation antigen specific degraders that will allow for even more targeted approaches to treat disorders of extracellular proteins. With our antibody recruiting molecule program (ARM), a CD38 targeted cell therapy for multiple myeloma, we have now treated three patients in a Phase 1 trial at Dana-Farber Cancer Institute. The first patient treated has survived to one year, which is encouraging given historic survival rates in this aggressive disease. Taken together, these datasets provide early validation for the power of our bispecific platform and broader discovery efforts."

Full Year and Recent Business Highlights

Ion Channel Platforms – Milestones and Next Steps

Acquired Kv7 channel platform for treatment of epilepsy and other neurologic disorders – In April 2022, the Company closed its acquisition of Channel Biosciences, LLC to acquire a Kv7 channel targeting platform, adding the latest advances in ion-channel modulation to Biohaven’s growing neuroscience portfolio. BHV-7000 (formerly known as KB-3061) is the lead asset from the Kv7 platform and is a potassium channel activator with a profile suggestive of a wide therapeutic index, high selectivity, and significantly reduced GABA-ergic activity. As reported in the second quarter of 2022, the Clinical Trial Application for BHV-7000 was approved by Health Canada and Biohaven subsequently began clinical development.
Reported preliminary Phase 1 results with BHV-7000 – In January 2023, the Company reported preliminary safety, tolerability and pharmacokinetic (PK) data from the Phase 1 SAD/MAD study with BHV-7000. In the study, single doses up to 100 mg and multiple doses up to 40 mg daily for 15 days were safe and well-tolerated, with low rates of adverse events. Most adverse events were mild and resolved spontaneously. No serious or severe adverse events and/or dose limiting toxicities were reported. Importantly, CNS adverse events typically associated with other anti-seizure medications were not reported with BHV-7000; in unblinded data from the MAD cohorts, mild headache was the most common adverse event reported across all dose groups. Drug-related signal for AEs of somnolence, dizziness, fatigue, and ataxia were not observed. With respect to preliminary PK results, the Company exceeded target concentrations for efficacy based on the preclinical maximal electroshock (MES) model, which is clinically validated and predictive of target concentration ranges in humans.
Upcoming studies with BHV-7000 – The Company expects to initiate an EEG study in the first half of 2023 and expects to initiate Phase 2/3 studies in focal epilepsy patients and bipolar disorder patients in the second half of 2023.
Upcoming studies with BHV-7010 – The Company expects to submit an IND with BHV-7010, a next generation Kv7 ion channel activator, in the second half of 2023; the Company intends to investigate its potential in epilepsy and mood disorders.
Additional ion channel development expectations – The Company also intends to submit an IND in the second half of 2023 for BHV-2100, a TRPM3 ion channel antagonist targeting chronic pain.
TYK2/JAK1 Inhibition Platform – Milestones and Next Steps

Acquired BHV-8000, a brain-penetrant inhibitor of TYK2/JAK1, from Highlightll – In March 2023, the Company acquired exclusive rights (ex-China) to a novel, oral, first-in-class, brain-penetrant, dual inhibitor of TYK2/JAK1 offering wide therapeutic index with TYK2 inhibition and high selectivity for JAK1 inhibition without the severely limiting adverse class effects of JAK2/JAK3 inhibitors.
Upcoming studies with BHV-8000 – The Company expects to commence Phase 1 development in 2023.
Myostatin Targeting Taldefgrobep Alfa License – Milestones and Next Steps

Fast Track Designation and Orphan Drug Designation Granted – In February 2023, Taldefgrobep alfa was granted Fast Track designation by the U.S. Food and Drug Administration (FDA). The Company had previously received Orphan Drug Designation in December 2022.
Commenced enrollment in a Phase 3 study with taldefgrobep alfa, an anti-myostatin adnectin for SMA – In July 2022, the Company commenced enrollment in a Phase 3 clinical trial assessing the efficacy and safety of taldefgrobep in SMA. Taldefgrobep targets myostatin, a natural protein that limits skeletal muscle growth, through two mechanisms: lowering myostatin directly and blocking key downstream signaling mechanisms. The Company expects to enroll approximately 180 patients in this randomized, double-blind, placebo-controlled global trial.
Glutamate Modulation Platform – Milestones and Next Steps:

Pivotal Phase 3 trial ongoing with troriluzole in OCD – The Company continues accelerating Phase 3 clinical studies assessing the efficacy and safety of troriluzole in patients with Obsessive Compulsive Disorder (OCD). Biohaven is advancing a 280 mg once daily dose of troriluzole into two double-blind, placebo-controlled Phase 3 clinical trials with identical study designs and plans to enroll up to 700 patients in each of these adjunctive treatment trials across study sites in the United States, Canada and Europe. The Company made several enhancements to the trial to adequately power for previously observed treatment effect, including increasing the sample size in the trial, including a higher dose, and optimizing clinical trial design to minimize placebo effect. The Company expects to complete enrollment by the end of 2023.
Regulatory engagement planned for first half of 2023 in SCA – In May 2022, the Company reported top-line results from a Phase 3 clinical trial evaluating the efficacy and safety of its investigational therapy, troriluzole, in patients with spinocerebellar ataxia (SCA). While the primary endpoint, did not reach statistical significance in the overall SCA population as there was less than expected disease progression over the course of the study, post hoc analysis of efficacy measures by genotype suggested a treatment effect in patients with the SCA Type 3 (SCA3) genotype. SCA3 represents the most common form of SCA and accounted for 41 percent of the study population. The Company intends to interact with the FDA and/or EMA in the first half of 2023. We could seek advice through various formal or informal interactions with regulatory agencies or we could choose to submit a New Drug Application (NDA) if we believe that is warranted from the results of our ongoing post-hoc analyses.
Global Coalition for Adaptive Research (GCAR) commenced enrollment in Glioblastoma Adaptive Global Innovative Learning Environment (GBM Agile) Phase 2-3 adaptive platform trial for patients with glioblastoma – In July 2022, GCAR announced the activation of Biohaven’s troriluzole in GBM AGILE, a patient-centered, adaptive platform trial for registration that tests multiple therapies for patients with newly-diagnosed and recurrent glioblastoma (GBM). GBM AGILE is an international, innovative platform trial designed to more rapidly identify and confirm effective therapies for patients with glioblastoma through response adaptive randomization.
Bispecific Molecule Platform – Milestones and Next Steps:

Reported preclinical data with extracellular target degrader platform technology (MoDE), a pan-IgG degrader – In January 2023, the Company evaluated the effect of a single dose of immunoglobulin gamma (IgG) degrader, BHV-1300, in cynomolgus monkeys. The Company reported 75% reduction of IgG levels from baseline and noted the observation occurred in three days; the data in this pre-clinical study compares favorably to standard of care therapy efgartigimod, where reduction of IgG levels with efgartigimod was observed to be 50% and had taken 5-7 days. The Company expects BHV-1300 will be ready for IND submission in the second half of 2023. In October 2022, the Company had announced advancements in the development of its MoDE extracellular target degrader platform technology licensed from Yale University for various disease indications, including, but not limited to, neurological disorders, cancer, infectious and autoimmune diseases. Biohaven made further innovations in this ground-breaking technology with new patent applications covering additional targets and functionality.
Reported preclinical data with second MoDE in bispecific platform targeting IgA Nephropathy – In January 2023, the Company reported preclinical data with a second MoDE targeting galactose deficient IgA (Gd-IgA), which is believed to play a pathogenic role in IgA Nephropathy. Specific removal of pathogenic Gd-IgA with preservation of normal IgA potentially permits disease remission without incurring an infection risk. The Company shared preliminary data demonstrating the chimeric antibody-ASGPR ligand conjugate specifically mediated endocytosis of Gd-IgA, as opposed to normal IgA, in an endocytosis assay with HepG2 cells.
Provided update on ongoing Phase 1 trial with BHV-1100 in MRD + post-transplant multiple myeloma patients – In an ongoing Phase 1 study at Dana-Farber Cancer Institute, the first patient treated has survived to one year. Additional patients have been enrolled and recruitment for the study is ongoing.
Corporate Updates:

Company launch – On October 3, 2022, Biohaven Ltd. began operating as a separate independent entity in connection with the merger agreement entered into with Pfizer Inc. in May 2022. As of October 4, 2022, Biohaven Ltd. commenced regular way trading under the symbol "BHVN" on the New York Stock Exchange as an independent, publicly traded company focused on delivering innovative life-changing treatments for neurological and neuropsychiatric diseases, including rare disorders, and leveraging its proven drug development capabilities and proprietary technology platforms to advance a pipeline of therapies. The Company, led by Vlad Coric, M.D. as Chairman and Chief Executive Officer, launched with approximately $257.8 million in cash and no debt.
Public offering – On October 25, 2022, the Company closed its previously announced underwritten public offering of 28,750,000 of its common shares, which includes the full exercise of the underwriters’ option to purchase 3,750,000 additional shares, at the public offering price of $10.50 per share. The gross proceeds raised in the offering, before deducting underwriting discounts and estimated expenses of the offering payable by the Company, were approximately $301.9 million.
Retains Board and key management team and appoints leading industry executives – In connection with the Company launch, Biohaven announced the appointment of Bruce Car, Ph.D. as Chief Scientific Officer; Irfan Qureshi, M.D. as Chief Medical Officer; and Tanya Fischer, M.D., Ph.D. as Chief Development Officer and Head of Translational Medicine.
Operationalized efficient laboratory capabilities to advance the degrader and ion channel programs – The Company’s laboratory capabilities now include space in Cambridge, Massachusetts to enhance the accelerated development of its early assets.
Matthew Buten, Chief Financial Officer, commented, "As we continue efficiently accelerating clinical development and exploring the vast life cycle potential across each of our platforms, we uphold the same judicious strategy that has driven outsized results in years past: ensuring capital access by tactically evaluating opportunities for portfolio rationalization and optimization and continuously assessing partnering, out-licensing, and other creative, non-dilutive financing opportunities. We also periodically review bolt-on acquisition opportunities like BHV-8000, preferentially pursuing clinically validated mechanisms with fast follower potential in large markets and select rare disease opportunities. Biohaven is well capitalized to fund our current programs and we have demonstrated the ability to prioritize near-term value generating inflection points over longer term discovery efforts."

Upcoming Milestones:

Biohaven is progressing its product candidates through clinical programs in a number of common and rare disorders. The Company expects to reach significant pipeline milestones in the coming periods. Biohaven expects to:

Initiate EEG study with BHV-7000 in the first half of 2023: Following Phase 1 study completion, Biohaven expects to initiate pivotal trials in patients with epilepsy and patients with bipolar disorder in the second half of 2023.
Submit IND with BHV-7010 in epilepsy and mood disorders: The Company expects to submit an IND with next-generation Kv7 activator BHV-7010 in epilepsy in the second half of 2023.
Submit IND with BHV-2100 in chronic pain: The Company expects to submit an IND with BHV-2100, a TRPM3 antagonist in the Company’s ion channel platform targeting a pain disorder in 2023.
Commence Phase 1 studies with BHV-8000: The Company expects to commence Phase 1 studies with BHV-8000, an oral, brain-penetrant, dual TYK2/JAK1 inhibitor for immune-mediated brain disorders in 2023.
Complete enrollment in Phase 3 study of troriluzole in OCD in 2023: Two Phase 3 randomized, double-blind, placebo-controlled studies are expected to enroll up to 700 patients (in each trial) across nearly 200 global study sites. The Company anticipates completing enrollment in 2023.
Provide an update on troriluzole in SCA: The Company intends to interact with the FDA and/or EMA in the first half of 2023 on next steps.
Continue advancing Phase 3 clinical studies of taldefgrobep alfa in SMA: The Company expects to enroll approximately 180 patients in the study through the expansion of approximately 40 additional sites.
Continue advancements across multiple neuroscience and immunoscience indications: The Company’s preclinical pipeline includes molecular degraders of extracellular proteins, CD38 targeting antibody recruiting molecules (ARMs), TRP channels, and other undisclosed targets, including those with disease-modifying potential. The Company expects to submit an IND with pan-IgG degrader BHV-1300 in the second half of 2023.
Capital Position:

Cash, cash equivalents and marketable securities as of December 31, 2022 was $465.3 million, excluding $37.7 million of restricted cash, compared to $76.1 million as of December 31, 2021. As of December 31, 2022, restricted cash primarily consisted of restricted cash held by the Company on behalf of the Former Parent of $35.2 million related to the execution of the United States Distribution Services Agreement for which the Company recorded a related liability of $35.2 million as Due to Former Parent on the consolidated balance sheet. On October 3, 2022, in connection with the closing of the acquisition of Biohaven Pharmaceutical Holding Company Ltd. by Pfizer, Biohaven Ltd. launched with a cash balance of approximately $257.8 million. On October 25, 2022, the Company closed a public offering of its common shares, which resulted in net proceeds to the Company of approximately $282.8 million.

Fourth Quarter 2022 Financial Highlights:

Research and Development (R&D) Expenses: R&D expenses, including non-cash share-based compensation costs, were $137.0 million for the three months ended December 31, 2022, compared to $41.8 million for the three months ended December 31, 2021. The increase of $95.2 million was primarily due to an increase of $62.1 million in non-cash share-based compensation, late-stage clinical program spend, and one-time employee costs related to the Pfizer acquisition of the Former Parent in the fourth quarter of 2022. Non-cash share-based compensation expense was $69.4 million for the three months ended December 31, 2022, which included $61.7 million of expense allocated from the Former Parent recognized in connection with the settlement of outstanding Former Parent stock options and RSUs upon the effectiveness of the Separation.

General and Administrative (G&A) Expenses: G&A expenses, including non-cash share-based compensation costs, were $76.4 million for the three months ended December 31, 2022, compared to $9.1 million for the three months ended December 31, 2021. The increase of $67.3 million was primarily due to an increase of $40.6 million in non-cash share-based compensation, and $8.2 million of transaction-related expenses and $8.9 million of one-time employee costs related to the Pfizer acquisition of the Former Parent in the fourth quarter of 2022. Non-cash share-based compensation expense was $46.2 million for the three months ended December 31, 2022, which included $39.7 million of expense allocated from the Former Parent recognized in connection with the settlement of outstanding Former Parent stock options and RSUs upon the effectiveness of the Separation.

Net Loss: Biohaven reported a net loss for the three months ended December 31, 2022, of $201.1 million, or $3.32 per share, compared to $51.9 million, or $1.32 per share, for the same period in 2021. Non-GAAP adjusted net loss for the three months ended December 31, 2022 was $77.3 million, or $1.27 per share, compared to $38.9 million, or $0.99 per share for the same period in 2021. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges, and transaction-related costs incurred relating to the Company’s spin-off from Biohaven Pharmaceutical Holding Company Ltd. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below. Net loss per share and Non-GAAP adjusted net loss per share for periods prior to the October 3, 2022 spin-off were calculated based on the 39,375,944 common shares of Biohaven Ltd. common stock distributed to Biohaven Pharmaceutical Holding Company Ltd. shareholders at the time of the Distribution, including common shares issued in connection with Biohaven Pharmaceutical Holding Company Ltd. stock options that were settled on October 3, 2022 and common shares issued in connection with Biohaven Pharmaceutical Holding Company Ltd. restricted stock units that vested on October 3, 2022. The same number of shares is being utilized for the calculation of basic and diluted earnings per share for all periods presented prior to the Spin-Off.

Full Year 2022 Financial Highlights

Note: As described in our Annual Report on Form 10-K, full year results include direct and allocated expenses on a carve-out basis of accounting for the period prior to October 3, 2022, when the Company became a standalone public company.

R&D Expenses: R&D expenses, including non-cash share-based compensation, were $437.1 million for the year ended December 31, 2022, compared to $181.5 million for the year ended December 31, 2021. The increase of $255.6 million was primarily due to an increase in Kv7 platform expense in 2022 related to the $93.7 million acquisition and a $25.0 million milestone, $77.0 million increase in non-cash share-based compensation, and $5.2 million of one-time employee costs related to the Pfizer acquisition of the Former Parent in the fourth quarter of 2022. Non-cash share-based compensation expense was $116.4 million for the year ended December 31, 2022, which included $108.7 million of expense allocated from the Former Parent, including $61.7 million of expense allocated from the Former Parent recognized in connection with the settlement of outstanding Former Parent stock options and RSUs upon the effectiveness of the Separation.

G&A Expenses: G&A expenses, including non-cash share-based compensation costs, were $130.9 million for the year ended December 31, 2022, compared to $37.4 million for the year ended December 31, 2021. The increase of $93.4 million was primarily due to increases of $50.9 million in non-cash share-based compensation expense, and $14.1 million of transaction expenses and $8.9 million of one-time personnel expenses related to related to the Pfizer acquisition of the Former Parent and spin-off of Biohaven Ltd. as an independent, publicly traded company in 2022. Non-cash share-based compensation expense was $71.5 million for the year ended December 31, 2022, which included $70.6 million of expense allocated from the Former Parent, including $39.7 million of expense allocated from the Former Parent recognized in connection with the settlement of outstanding Former Parent stock options and RSUs upon the effectiveness of the Separation.

Net Loss: The Company reported a net loss attributable to common shareholders for the year ended December 31, 2022 of $570.3 million, or $12.75 per share, compared to $213.8 million, or $5.43 per share for the same period in 2021. Non-GAAP adjusted net loss for the year ended December 31, 2022 was $362.7 million, or $8.11 per share, compared to $153.4 million, or $3.90 per share for the same period in 2021. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges, gains or losses from equity method investment and transaction-related costs incurred relating to the Company’s spin-off from Biohaven Pharmaceutical Holding Company Ltd. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below.

Non-GAAP Financial Measures
This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP), and also certain non-GAAP financial measures. In particular, Biohaven has provided non-GAAP adjusted net loss and adjusted net loss per share, adjusted to exclude the items below. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, Biohaven believes the presentation of non-GAAP adjusted net loss, when viewed in conjunction with GAAP results, provides investors with a more meaningful understanding of ongoing operating performance. These measures exclude (i) non-cash share-based compensation, which is substantially dependent on changes in the market price of common shares, (ii) gains or losses from equity method investment, which are non-cash and based on the financial results and valuation of another company that we did not manage or control, and (iii) transaction-related costs incurred relating to the Company’s spin-off from Biohaven Pharmaceutical Holding Company Ltd., which are limited to a specific period of time and related to Biohaven Ltd. being established as a standalone public company.

Biohaven believes the presentation of these non-GAAP financial measures provides useful information to management and investors regarding Biohaven’s results of operations. When GAAP financial measures are viewed in conjunction with these non-GAAP financial measures, investors are provided with a more meaningful understanding of Biohaven’s ongoing operating performance and are better able to compare Biohaven’s performance between periods. In addition, these non-GAAP financial measures are among those indicators Biohaven uses as a basis for evaluating performance, and planning and forecasting future periods. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between these non-GAAP measures and the most directly comparable GAAP measures is provided later in this press release.

On March 23, 2023 Celyad Oncology (Euronext & Nasdaq: CYAD) (the "Company"), a biotechnology company focused on innovative technologies for chimeric antigen receptor (CAR) T-cell therapies,reported its financial results for the fiscal year 2022 ended December 31, 2022 and provides a business update(Press release, Celyad, MAR 23, 2023, View Source [SID1234629258]).

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Michel Lussier, Interim Chief Executive Officer of Celyad Oncology, said: "2022 was a crossroad year for Celyad Oncology, with important changes and turning points. We strongly believe all those changes, together with our prior accomplishments, significantly strengthened our position. Having dealt with the 2022 challenges, Celyad has now positively reinvented itself as a leaner, more agile organization. We believe that Celyad is well prepared and has the relevant unique assets and know how to create significant shareholder value in the next few years."
Operational highlights
• Since late 2022, the Company has implemented a differentiated and innovative strategy, increasing its R&D efforts in areas of expertise where it believes it can leverage the differentiated nature of its platform technology and continue to bolster its intellectual property (IP) estate; and
• The Company will continue to explore options to tackle the major current limitations of CAR T-cell therapies through development of its dual targeting CARs with NKG2D capabilities, B7-H6 targeting immunotherapies and multiplexing approach of short hairpin RNAs (shRNAs).
Upcoming Anticipated Milestones
• The Company will provide an update on its shRNA multiplexing and dual CAR platforms and business development in the first half of 2023;
• The Company will take part in the World Oncology Cell Therapy Congress in Boston, US (25-26 April 2023), as well as in the Immuno-Oncology summit in London (20-22 June 2023);
• The Company anticipates the arrival of a new CEO in the first half of 2023; and
• We anticipate fundraising in the first half of 2023.
Full Year 2022 Financial Review
As of December 31, 2022, the Company had cash and cash equivalents of €12.4 million ($13.3 million).
The Company projects that its existing cash and cash equivalents should be sufficient to fund operating expenses and capital expenditure requirements into the fourth quarter of 2023.
After due consideration of detailed budgets and estimated cash flow forecasts for the years 2023 and 2024, the Company projects that its existing cash and cash equivalents will not be sufficient to fund its estimated operating and capital expenditures over at least the next 12 months from the date that the financial statements are issued.
The Company is currently evaluating different financing options to obtain the required funding to extend the Company’s cash runway beyond 12 months from the date the financial statements are issued.
Key financial figures for full-year 2022, compared with full-year 2021, are summarized below:
Selected key financial figures (€ millions) Full year 2022 Full year 2021 Revenue – - Research and development expenses (18.9) (20.8) General and administrative expenses (10.5) (9.9) Change in fair value of contingent consideration 14.7 0.8 Impairment of Oncology intangible assets (35.1) – Other income/(expenses) 9.0 3.4 Operating loss (40.9) (26.4) Loss for the period/year (40.9) (26.5) Net cash used in operations (28.0) (26.6) Treasury position(1) 12.4 30.0 (1) "Treasury position" is an alternative performance measure determined by adding Short-term investments and Cash and cash equivalents from the statement of financial position prepared in accordance with IFRS. The purpose of this measure by Management is to identify the level of cash available internally (excluding external sources of financing) within 12 months.
The Company’s license and collaboration agreements generated no revenue in 2022 and in 2021.
Research and Development (R&D) expenses were €18.9 million in 2022 as compared to €20.8 million in 2021, a year-over-year decrease of €1.8 million. The decrease in the Company’s R&D expenses is primarily driven by the Company’s decision to discontinue some of preclinical and in process development costs after the Company’s decision to adopt and implement a new business strategy over the last few months of 2022, as well as a decrease of the expenses associated with share-based payments (non-cash expenses) related to the warrant plan offered to our employees and directors.
General and Administrative (G&A) expenses were €10.5 million in 2022 as compared to €9.9 million in 2021, an increase of €0.6 million. This increase is primarily related to higher insurances costs and consulting fees partially compensated by the decrease of the expenses associated with the share-based payments (non-cash expenses) related to the warrants plan offered to our employees and directors.
The fair value adjustment (€14.7 million) relating to the contingent consideration and other financial liabilities as of December 31, 2022, is mainly driven by the full reversal of the liability. This liability is a result of business combination accounting (IFRS3) which requires the liability to be recorded unless the possibility of any outflow is remote.
This impairment comes as a result of the Company’s strategic shift in focus away from clinical development and the early stage nature of the implementation of the Celyad 2.0 strategy, which involves shifting from an organization focused on clinical development to one prioritizing R&D discovery and the monetization of its intellectual property (IP) portfolio through partnerships, collaborations and license agreements. To date, no effective sublicence contract nor collaboration contract has been entered into, and as a result there is uncertainty as to the timing and amount of associated short, medium and long term revenues.
Given this uncertainty, and per accounting standards, the Company recognizes a full impairment loss on the remaining value of goodwill, In Process Research and Development, and Horizon Discovery’s shRNA platform, resulting in a non-cash impairment of €35.1 million on a consolidated basis for the financial year ended December 31, 2022.
This accounting conclusion, which reflects the Company’s financial situation as of December 31, 2022, does not affect Management’s commitment to continue in its efforts to pursue the potential monetization of the Company’s IP. If and when such a firm sublicense or collaboration contract occurs and hence increases the probability of revenue, the Management will estimate the reversal of the impairment which will be limited so that the carrying amount of the asset does not exceed its recoverable amount along with the remeasurement of the related contingent liability.
The Company’s other income is principally associated with grants received from the Walloon Region mainly in the form of recoverable cash advances (RCAs) and R&D tax credit income as well as the gain on sale of the CTMU activities:
• Grant income (RCAs): additional grant income has been recognized in 2022 on grants in the form of RCAs. According to IFRS standards, the Company has earned grants for the period amounting to €1.6 million, out of which €0.5 million is accounted for as a financial liability and the remaining €1.1 million as a grant income;
• Grant income (Others): additional grant income has been recognized in 2022 on grants received and from the regional government (for €0.9 million), not referring to RCAs and not subject to reimbursement;
• With respect to R&D tax credit, the current year income is €0.5 million; and
• Gain on sale of CTMU activities (for €5.2 million) results from the terms of the asset purchase agreement between Celyad Oncology and Cellistic under which Cellistic agreed to acquire Celyad Oncology’s Manufacturing Business Unit for a total consideration of €6.0 million.
Net loss for the year ended December 31, 2022 was €40.9 million, or €1.81 per share, compared to a net loss of €26.5 million, or €1.70 per share, for the same period in 2021. As noted above, the increase in net loss between periods was primarily due to the non-cash impairment adjustment on the Oncology intangible assets.
Net cash used in operations for the year ended December 31, 2022, which excludes non-cash effects, amounted to €28.0 million, which is in line with net cash used in operations of €26.6 million for the year ended December 31, 2021.
The net assets of the Company as of December 31, 2022, on a BE-GAAP non-consolidated basis, have fallen below half of the Company’s capital. As a result, in accordance with Article 7:228 of the Belgian Code for Companies and Associations, the Board of Directors plans to submit for a vote, at its May 5, 2023 shareholders’ meeting, its business plan including a proposal to continue the Company’s activities. The Board of Directors will publish a detailed report regarding this proposal on or around April 3, 2023, together with the convocation with proposed resolutions for the shareholders’ meeting.
Annual Report 2022
The Annual Report for the year ended December 31, 2022 will be published on March 23, 2023, and will be available on the Company’s website, www.celyad.com. The Company’s statutory auditor, EY Bedrijfsrevisoren/Réviseurs d’Entreprises BV/SRL (EY), has confirmed that the completed audit has not revealed any material misstatement in the consolidated financial statements. EY also confirmed that the accounting data reported in the press release are consistent, in all material respects, with the consolidated financial statements from which it has been derived.
Conference Call and Webcast Details
A conference call will be held on Friday, March 24th at 1:00 p.m. CET / 8:00 a.m. EDT to review the financial and operating results for full year 2022. Please dial into the call five to ten minutes prior to start time using the appropriate number below and ask to join the "Celyad Oncology SA call":
• United States / International: +1-877-407-9716 or +1-201-493-6779
• Belgium: +32 (0) 800-73-904 (Fixed) or +32 (0) 800-73-566 (Mobile)
Participants may also access to the live webcast link for instant telephone access to the event. Archived recording will be available in the "Events" section of the Celyad website after the event.
Financial Calendar 2023
• May 5th, 2023 First Quarter 2023 Business Update • May 5th, 2023 Annual shareholders meeting • August 3rd, 2023 First Half 2023 Interim Results • November 9th, 2023 Third Quarter 2023 Business Update The financial calendar is communicated on an indicative basis and may be subject to change.

On March 23, 2023 Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZS) ("Aeterna" or the "Company"), a specialty biopharmaceutical company developing and commercializing a diversified portfolio of pharmaceutical and diagnostic products, reported its financial and operating results for the year ended December 31, 2022 (Press release, AEterna Zentaris, MAR 23, 2023, View Source;id=258662&p=2262532&I=1206939-c7Z3G6f3m8 [SID1234629257]).

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"Over the course of 2022 we made important pipeline progress and timely decisions through our pre-established go/no-go milestones related to the advancement of our development programs. Through this disciplined process, we have further prioritized our pipeline which enables us to focus our resources accordingly. Our active development programs continue to progress and we remain focused on driving enrollment in our ongoing DETECT trial and aim to continue exploring all strategic options for our Macrilen asset," commented Dr. Klaus Paulini, Chief Executive Officer of Aeterna.

Summary of Fourth Quarter and Full Year 2022 Financial Results

All amounts are in U.S. dollars

Cash and cash equivalents

The Company had $50.6 million in cash and cash equivalents at December 31, 2022.

Results of operations for the three-month period ended December 31, 2022

For the three-month period ended December 31, 2022, we reported a consolidated net loss of $12.5 million, or $2.56 loss per common share (basic and diluted), as compared with a consolidated net loss of $2.9 million, or $0.63 loss per common share (basic and diluted) for the three-month period ended December 31, 2021. The $9.6 million increase in net loss is primarily from a $2.5 million increase in total research and development expenses, a $8.3 million charge for the impairment of goodwill (non-cash), intangible assets and other assets, a $0.4 million decrease in net finance income, offset by a $1.5 million increase in revenues and a $0.1 million decrease in cost of sales and selling, office and general administration expenses.

Revenues

Our total revenue for the three-month period ended December 31, 2022 was $2.5 million as compared to $1.0 million for the same period in 2021, representing an increase of $1.5 million, primarily due to $0.5 million increase in License fees and $1.0 million increase in Development services relating to our DETECT trial.
Operating Expenses

Our total operating expenses for the three-month period ended December 31, 2022 was $14.8 million as compared with $4.1 million for the same period in 2021, representing an increase of $10.7 million. This increase arises primarily from a $2.5 million increase in research and development expenses, a $8.3 million charge for the impairment of goodwill (non-cash), intangible assets and other assets, offset by a $0.1 million reduction in cost of sales and selling, general and administrative expenses.
Net Finance Income

For the three-month period ended December 31, 2022, our net finance cost was $0.1 million as compared to $0.2 million net finance income for the three-month period ended December 31, 2021.
Results of operations for the year ended December 31, 2022

For the twelve-month period ended December 31, 2022, we reported a consolidated net loss of $22.7 million, or $4.68 loss per common share (basic and diluted), as compared with a consolidated net loss of $8.4 million, or $1.82 loss per common share (basic and diluted), for the year ended December 31, 2021. The $14.3 million increase in net loss is primarily from a $15.3 million increase in operating expenses offset by an increase of $0.3 million in total revenues and a $0.7 million increase in net finance income.

Revenues

Our total revenue for the twelve-month period ended December 31, 2022 was $5.6 million as compared to $5.3 million for the same period in 2021, representing an increase of $0.3 million, primarily due to $0.3 million increase in development services relating to our DETECT trial.
Operating Expenses

Our total operating expenses for the twelve-month period ended December 31, 2022 was $29.2 million as compared with $13.9 million for the same period in 2021, representing an increase of $15.3 million. This increase arises primarily from a $5.9 million increase in research and development expenses, a $8.3 million charge for the impairment of goodwill (non-cash), intangible assets and other assets, a $0.9 million increase in selling general and administration expenses and a $0.1 million increase in cost of sales.
Net Finance Income

Our net finance income for the twelve-month period ended December 31, 2022, was $0.9 million as compared with $0.2 million for the same period in 2021, representing a increase of $0.7 million. This is primarily due to a $0.7 increase in gains due to foreign currency exchange rates.
Consolidated Financial Statements and Management’s Discussion and Analysis

For reference, the Management’s Discussion and Analysis of Financial Condition and Results of Operations for the fourth quarter and full year 2022, as well as the Company’s consolidated financial statements as of December 31, 2022, will be available on the Company’s website (www.zentaris.com) in the Investors section or at the Company’s profile at www.sedar.com and www.sec.gov.