On November 2, 2023 Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported financial results for the quarter ended September 30, 2023, and highlighted select corporate milestones and progress on its key clinical development programs (Press release, Karyopharm, NOV 2, 2023, View Source [SID1234636772]).

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"We are strongly positioned for our next stage of growth driven by our focused and rapidly advancing late-stage pipeline with evolving data including impressive durability data observed with selinexor 60mg in combination with ruxolitinib in patients with myelofibrosis as well as the substantial progression-free survival observed in patients with TP53 wild-type endometrial cancer," said Richard Paulson, President and Chief Executive Officer of Karyopharm. "Our commercial organization continues to perform with resilience amidst an increasingly competitive multiple myeloma landscape, focusing on fueling growth in the community and expanding use of selinexor in the earlier lines."

Third Quarter 2023 and Recent Highlights

XPOVIO Commercial Performance

Achieved U.S. net product revenue of $30.2 million for the third quarter of 2023, compared to $32.0 million U.S. net product revenue in the third quarter of 2022.
Net XPOVIO revenue continued to be adversely impacted year over year by increased utilization of the KaryForward Patient Assistance Program (PAP), resulting from multiple myeloma foundation closures2 and higher gross-to-net driven by increased 340B discounts and Medicaid rebates, as compared to the third quarter of 2022. During the third quarter of 2023, new patient starts within the PAP normalized, although the impact from refills remained.
Total demand for XPOVIO was adversely impacted by 3% year over year, largely due to increasing competitive pressures seen in the later lines in the academic setting.
Continued shift in earlier lines with more than 60%3 of all XPOVIO new starts in the second to fourth line, representing approximately 20% year over year growth.
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines elevated XPOVIO in combination with bortezomib (Velcade) and dexamethasone (XVd) to a preferred and category 1 regimen for lenalidomide refractory patients with relapsed or refractory multiple myeloma who have received one-to-three prior lines of therapy in the September 2023 Clinical Practice Guidelines in Oncology.
R&D Highlights

Myelofibrosis

Data from the Phase 1 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with JAKi-naïve myelofibrosis (NCT04562389) on durability of response is being presented today at the 15th International Congress on Myeloproliferative Neoplasms. As of the August 1, 2023 data cut-off date, all patients treated with 60mg selinexor and who achieved ≥35% reduction in spleen volume (SVR35) at week 24 (n=11), continued to remain in radiographic response1. In addition, all of the 7 patients who achieved TSS50 at Week 24 remained in response as of the data cut-off1. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.
Endometrial Cancer

The Phase 3 SIENDO study (NCT03555422) manuscript was published in the Journal of Clinical Oncology.
Long term exploratory subgroup analysis of the pre-specified subgroup of patients with advanced or recurrent TP53 wild-type endometrial cancer from the SIENDO study was presented as an encore oral presentation at the 24th European Gynaecological Oncology Congress (ESGO) in September.
Presented pre-clinical data from patient derived cancer models at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) that suggest TP53 wild-type status may predict sensitivity to exportin 1 (XPO1) inhibitors selinexor and eltanexor in multiple cancer types, including endometrial, ovarian, kidney, liver, esophageal, lung, pancreatic and bladder, and that sensitivity was similar for both eltanexor and selinexor. These data support the importance of TP53 wild-type status with XPO1 inhibition in endometrial cancer.
Multiple Myeloma

The Company entered into a clinical trial collaboration and supply agreement with Bristol Myers Squibb (BMS) to evaluate BMS’ proprietary investigational cereblon E3 ligase modulator (CELMoD) agent mezigdomide in combination with selinexor in patients with relapsed/refractory multiple myeloma progressing after T-cell immunotherapies. This trial will evaluate mezigdomide in combination with selinexor doses of either 40mg or 60mg plus dexamethasone in patients who have prior exposure to immunomodulatory drug agent, proteasome inhibitors, and anti-CD38 monoclonal antibody treatment. All patients must have received at least two prior lines of therapy, and either have progressed after or are not eligible to receive CAR-T or bispecific antibody treatment. Under the terms of the agreement with BMS, Karyopharm will sponsor the trial as a new arm of its Phase 1b/2 STOMP trial and BMS will supply the study’s clinical drug mezigdomide.
Third Quarter 2023 Financial Results

Total Revenues: Total revenue for the third quarter of 2023 was $36.0 million, compared to $36.1 million for the third quarter of 2022.

Net product revenue: Net product revenue for the third quarter of 2023 was $30.2 million, compared to $32.0 million for the third quarter of 2022.

License and other revenue: License and other revenue for the third quarter of 2023 was $5.8 million, compared to $4.1 million for the third quarter of 2022. The increase was primarily due to an increase in revenue for the reimbursement of development-related expenses from the Menarini Group.

Cost of sales: Cost of sales for the third quarter of 2023 was $0.9 million, compared to $1.0 million for the third quarter of 2022. Cost of sales reflects the costs of XPOVIO units sold and third-party royalties on net product revenue.

Research and development (R&D) expenses: R&D expenses for the third quarter of 2023 were $35.6 million, compared to $31.4 million for the third quarter of 2022. The increase was primarily due to higher clinical trial costs related to the advancement of our three pivotal Phase 3 programs.

Selling, general and administrative (SG&A) expenses: SG&A expenses for the third quarter of 2023 were $30.8 million, compared to $34.6 million for the third quarter of 2022. The decrease was primarily due to a decrease in consulting, professional and other costs as a result of more focused commercial-related activities due to lower headcount.

Interest income: Interest income for the third quarter of 2023 was $2.8 million, compared to $0.7 million for the third quarter of 2022, due to higher average interest rates on investments.

Interest expense: Interest expense for the third quarters of both 2023 and 2022 was $6.1 million.

Net loss: Karyopharm reported a net loss of $34.5 million, or $0.30 per share, for the third quarter of 2023, compared to a net loss of $36.3 million, or $0.45 per share, for the third quarter of 2022.

Cash position: Cash, cash equivalents, restricted cash and investments as of September 30, 2023 totaled $209.2 million, compared to $279.7 million as of December 31, 2022.

2023 Financial Outlook

Based on its current operating plans, Karyopharm reiterates its guidance for full year 2023 as follows:

Total revenue expected to be in the range of $145 million to $160 million. Total revenue consists of U.S. XPOVIO net product revenue and license, royalty and milestone revenue earned from partners.
U.S. XPOVIO net product revenue expected to be in the range of $110 million to $125 million.
Non-GAAP R&D and SG&A expenses*, which exclude stock-based compensation expense, expected to be in the range of $240 million to $255 million.
The Company continues to expect that its existing cash, cash equivalents and investments, and the revenue it expects to generate from XPOVIO net product sales, as well as revenue generated from its license agreements, will be sufficient to fund its planned operations into late 2025.
* Karyopharm has not reconciled the full year 2023 outlook for non-GAAP R&D and SG&A expenses to full year 2023 outlook for GAAP R&D and SG&A expenses because Karyopharm cannot reliably predict without unreasonable efforts the timing or amount of the factors that substantially contribute to the projection of stock compensation expense, which is excluded from the full year 2023 outlook for non-GAAP R&D and SG&A expenses.

Non-GAAP Financial Information

Karyopharm uses a non-GAAP financial measure, non-GAAP R&D and SG&A expenses, to provide operating expense guidance. Non-GAAP R&D and SG&A expenses exclude stock-based compensation expense. Karyopharm believes this non-GAAP financial measure is useful to investors because it provides greater transparency regarding Karyopharm’s operating performance as it excludes non-cash stock compensation expense. This non-GAAP financial measure should not be considered a substitute or an alternative to GAAP R&D and SG&A expenses and should not be considered a measure of Karyopharm’s liquidity. Instead, non-GAAP R&D and SG&A expenses should only be used to supplement an understanding of Karyopharm’s operating results as reported under GAAP.

Conference Call Information

Karyopharm will host a conference call today, November 2, 2023, at 8:00 a.m. Eastern Time, to discuss the third quarter 2023 financial results and financial outlook for 2023 and to provide other business highlights. To access the conference call, please dial (888) 349-0102 (local) or (412) 902-4299 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with accompanying slides, will be available under "Events & Presentations" in the Investor section of the Company’s website, View Source An archived webcast will be available on the Company’s website approximately two hours after the event.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with VELCADE (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO in certain countries) has received regulatory approvals in a growing number of ex-U.S. territories and countries, including Europe, the United Kingdom, China, South Korea and Israel, and is marketed in those areas by Karyopharm’s global partners. Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:
Tel: +1 (888) 209-9326; Email: [email protected]

XPOVIO (selinexor) is a prescription medicine approved:

In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (XVd).
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti–CD38 monoclonal antibody (Xd).
For the treatment of adult patients with relapsed or refractory diffuse large B–cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
SELECT IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care.
Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony–stimulating factors.
Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care.
Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care.
Serious Infection: Monitor for infection and treat promptly.
Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes.
Embryo–Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception.
Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract.
Adverse Reactions

The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3–4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%.
The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.
The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3–4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients.
Use In Specific Populations
Lactation: Advise not to breastfeed.

For additional product information, including full prescribing information, please visit www.XPOVIO.com.

To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1–888–209–9326 or FDA at 1–800–FDA–1088 or www.fda.gov/medwatch.

On November 2, 2023 Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, reported that several abstracts that include selinexor data in myelofibrosis (MF) have been selected for presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, being held December 9-12, 2023, in San Diego, CA (Press release, Karyopharm, NOV 2, 2023, View Source [SID1234636771]). The data include an oral presentation featuring long-term efficacy results from the Phase 1 open-label, dose-escalation study of selinexor in combination with ruxolitinib in patients with treatment-naïve MF.

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"We are pleased to have a number of MF presentations at ASH (Free ASH Whitepaper), which underscore the potential of selinexor to deliver meaningful benefit for patients with this disease," said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. "These presentations demonstrate our commitment and substantial progress toward our goal of improving long-term outcomes for patients and addressing important areas of unmet need."

Details for the ASH (Free ASH Whitepaper) 2023 abstracts are as follows:

Abstract Title

Presentation Type

Abstract #

Session Date/Time

Selinexor Plus Ruxolitinib in JAK
Inhibitor (JAKi)-Naïve Patients with
Myelofibrosis: Long Term Follow up
from XPORT-MF-034 Suggestive of
Disease Modification

Oral

622

Sunday, December 10th,
2023 5:15 pm

A Global, Phase 3, Randomized,
Double-Blind Study to Evaluate Safety
and Efficacy of Selinexor, an XPO-1
Inhibitor in Combination with
Ruxolitinib in JAK Inhibitor-Naïve
Myelofibrosis (XPORT-MF-034)

Poster

3209

Sunday December 10th,
2023 6:00-8:00 pm

A Phase 2 Study to Evaluate the
Efficacy and Safety of Selinexor
Monotherapy in Patients with JAK
Inhibitor-Naïve Myelofibrosis and
Moderate Thrombocytopenia (XPORT-
MF-044)

Poster

3211

Sunday December 10th,
2023 6:00-8:00 pm

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:

Tel: +1 (888) 209-9326
Email: [email protected]

SELECT IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Thrombocytopenia: Monitor platelet counts throughout treatment. Manage with dose interruption and/or reduction and supportive care.

Neutropenia: Monitor neutrophil counts throughout treatment. Manage with dose interruption and/or reduction and granulocyte colony‐stimulating factors.

Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care.

Hyponatremia: Monitor serum sodium levels throughout treatment. Correct for concurrent hyperglycemia and high serum paraprotein levels. Manage with dose interruption, reduction, or discontinuation, and supportive care.

Serious Infection: Monitor for infection and treat promptly.

Neurological Toxicity: Advise patients to refrain from driving and engaging in hazardous occupations or activities until neurological toxicity resolves. Optimize hydration status and concomitant medications to avoid dizziness or mental status changes.

Embryo‐Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception.

Cataract: Cataracts may develop or progress. Treatment of cataracts usually requires surgical removal of the cataract.
Adverse Reactions

The most common adverse reactions (≥20%) in patients with multiple myeloma who receive XVd are fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract and vomiting. Grade 3‐4 laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON trial, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients. Treatment discontinuation rate due to adverse reactions was 19%.

The most common adverse reactions (≥20%) in patients with multiple myeloma who receive Xd are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea and upper respiratory tract infection. In the STORM trial, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.

The most common adverse reactions (incidence ≥20%) in patients with DLBCL, excluding laboratory abnormalities, are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3‐4 laboratory abnormalities (≥15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL trial, fatal adverse reactions occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal adverse reactions was infection (4.5% of patients). Serious adverse reactions occurred in 46% of patients; the most frequent serious adverse reaction was infection (21% of patients). Discontinuation due to adverse reactions occurred in 17% of patients.
Use In Specific Populations
Lactation: Advise not to breastfeed.

For additional product information, including full prescribing information, please visit www.XPOVIO.com.

To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1‐888‐209‐9326 or FDA at 1‐800‐FDA‐1088 or www.fda.gov/medwatch.

On November 2, 2023 Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), reported financial results for the third quarter of 2023 (Press release, Ionis Pharmaceuticals, NOV 2, 2023, View Source [SID1234636770]).

"We continue to successfully execute on our strategy to deliver a steady cadence of potentially transformational medicines to patients," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "Eplontersen is on track for its first potential approval in the U.S. and is under regulatory review in the EU and Canada. We believe the positive efficacy and safety data coupled with an attractive self-administration dosing profile positions eplontersen to be the preferred therapy in the largely underserved hereditary ATTR polyneuropathy population. We reported positive data from the olezarsen Phase 3 Balance study in patients with familial chylomicronemia syndrome, showing statistically significant triglyceride lowering, substantial reductions in acute pancreatitis attacks and favorable safety and tolerability, positioning olezarsen to be our first independent commercial launch. We also made additional progress across our wholly owned and partnered pipeline, and further expanded our rich Phase 3 pipeline with the advance of zilganersen for patients with Alexander disease into Phase 3 development. Looking ahead, we expect to continue our positive momentum with the potential approval and launch of eplontersen and the Phase 3 data readout of donidalorsen in hereditary angioedema."

Third Quarter 2023 Summary Financial Results:

Three months ended
September 30,

Nine months ended
September 30,

2023

2022

2023

2022

(amounts in millions)

Total revenue

$
144

$
160

$
463

$
435

Operating expenses

$
287

$
219

$
811

$
637

Operating expenses on a non-GAAP basis

$
261

$
195

$
732

$
562

Loss from operations

$
(143
)

$
(59
)

$
(348
)

$
(202
)
Loss from operations on a non-GAAP basis

$
(117
)

$
(35
)

$
(269
)

$
(127
)

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1
Financial Highlights

•
Revenue continued to be substantial and sustained, with revenues of $144 million and $463 million in the three and nine months ended September 30, 2023, reflecting a 10% decrease and 6% increase compared to the same periods last year, respectively, driven by the timing of certain partner payments

•
Operating expenses increased in the three and nine months ended September 30, 2023 compared to the same periods last year, primarily due to strategic investments to bring eplontersen, olezarsen and donidalorsen to patients

•
Cash and short-term investments of $2.2 billion as of September 30, 2023 enables continued investments to drive increasing value

•
Reaffirmed 2023 financial guidance

Near-Term Commercial Opportunities and Late-Stage Pipeline Highlights

•
Achieved multiple milestones with eplontersen:

o
Eplontersen is under regulatory review by the European Medicines Agency (EMA) and Health Canada for the treatment of hereditary ATTR polyneuropathy (ATTRv-PN)

o
The EMA granted orphan drug designation to eplontersen for the treatment of ATTR in the EU

o
Published positive data from the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN in the Journal of the American Medical Association (JAMA) showing eplontersen halted measures of disease progression and continuously improved quality of life at 35-, 66- and 85-weeks

o
Presented positive new data showing continued benefit in secondary endpoints from the Phase 3 NEURO-TTRansform study in patients with ATTRv-PN at the European ATTR Amyloidosis (EU-ATTR) meeting

o
Presented positive exploratory data from a pre-defined cardiac sub-population of patients in NEURO-TTRansform showing improvement in cardiac function and structure compared to external placebo at the Heart Failure Society of America (HFSA) Annual Scientific Meeting

o
Completed enrollment of the Phase 3 CARDIO-TTRansform study of eplontersen in patients with ATTR cardiomyopathy (ATTR-CM), the largest study ever conducted in ATTR-CM; on track for data readout as early as H1:2025

•
Reported positive data from the Phase 3 Balance study of olezarsen in patients with familial chylomicronemia syndrome (FCS)

o
Olezarsen demonstrated robust, dose-dependent reductions in APOCIII, statistically significant reductions in triglycerides, substantial reductions in acute pancreatitis attacks and a favorable safety and tolerability profile

o
On track to file for regulatory approval in the U.S. and EU in early 2024

•
The FDA granted orphan drug designation to donidalorsen for the treatment of patients with hereditary angioedema (HAE); on track for data readout in the Phase 3 OASIS-HAE study in H1:2024

•
Advanced zilganersen (GFAP) into Phase 3 development for the treatment of patients with Alexander disease

2
•
The FDA granted orphan drug designation to ulefnersen (FUS) for the treatment of patients with FUS-ALS

Partnered Program Highlights

•
GSK reported positive data from the Phase 2b B-Together study of bepirovirsen followed by pegylated interferon in patients with chronic hepatitis B virus (HBV)

•
Reported positive interim data from the ongoing Phase 2 study of IONIS-FB-LRx in patients with immunoglobulin A nephropathy (IgAN)

•
Biogen reported positive data from the Phase 1/2 study of IONIS-MAPTRx (BIIB080) in patients with Alzheimer’s disease

•
Completed enrollment in the Phase 1/2 HALOS study of ION582 (BIIB121) in patients with Angelman syndrome

•
Entered a new agreement with Roche to advance two novel RNA-targeted programs for Alzheimer’s disease and Huntington’s disease

Third Quarter 2023 Financial Results

"Our year-to-date financial results keep us on track to achieve our 2023 guidance as we execute on a strategy to unlock next-level value," said Elizabeth L. Hougen, chief financial officer of Ionis. "Our strong financial foundation includes more than $2B in cash, significant royalty revenue with SPINRAZA, and substantial and sustained R&D revenue from multiple partners. We are well positioned to continue investing in our key priorities to drive future positive cash flow, including advancing our go-to-market activities, growing our wholly owned pipeline and optimizing new cutting-edge technologies for future medicines. We look forward to the potential U.S. eplontersen ATTRv-PN approval next month followed closely by launch. Together with our partner, AstraZeneca, we believe we are well positioned to identify new patients to further grow the market and become the treatment of choice for this population that remains largely underserved by current therapies."

Revenue

Ionis’ revenue was comprised of the following:

Three months ended
September 30,

Nine months ended
September 30,

2023

2022

2023

2022

Revenue:

(amounts in millions)

Commercial revenue:

SPINRAZA royalties

$
67

$
62

$
179

$
175

Other commercial revenue:

TEGSEDI and WAYLIVRA revenue, net

8

6

25

23

Licensing and royalty revenue

9

5

26

25

Total commercial revenue

84

73

230

223

Research and development revenue:

Amortization from upfront payments

18

18

47

54

Milestone payments

16

15

90

60

License fees

5

35

25

37

Other services

5

1

11

6

Collaborative agreement revenue

44

69

173

157

Eplontersen joint development revenue

16

18

60

55

Total research and development revenue

60

87

233

212

Total revenue

$
144

$
160

$
463

$
435

Commercial revenue for the three and nine months ended September 30, 2023 included $67 million and $179 million from SPINRAZA royalties, respectively, which were essentially flat compared to the same periods last year reflecting SPINRAZA’s resilience against emerging competition. Ionis’ commercial revenue in the three and nine months ended September 30, 2023 also included royalties from the U.S. launch of QALSODY.

R&D revenue decreased for the three months ended September 30, 2023 and increased for the nine months ended September 30, 2023 compared to the same periods last year due to the timing of certain partner payments, including the $35 million license fee for IONIS-FB-LRx that Ionis earned from Roche in the three months ended September 30, 2022.

Operating Expenses

Ionis’ operating expenses increased in the three and nine months ended September 30, 2023 compared to the same periods in 2022, consistent with expectations. As Ionis advanced its robust pipeline, study costs increased compared to the same periods in 2022 as most of the Company’s Phase 3 studies are either fully enrolled or approaching full enrollment, resulting in higher R&D expenses year over year. Ionis’ SG&A expenses also increased year over year primarily due to launch preparation activities for eplontersen, olezarsen and donidalorsen.

Balance Sheet

As of September 30, 2023, Ionis’ cash, cash equivalents and short-term investments increased to $2.2 billion compared to $2.0 billion at December 31, 2022 primarily due to the $500 million Ionis received from Royalty Pharma in January 2023. Ionis’ working capital also increased over the same period primarily due to the Company’s higher cash and short-term investments balance. In the first quarter of 2023, the Company recorded a long-term liability for future royalties due to Royalty Pharma. In June 2023, Ionis issued $575 million of senior convertible notes due in June 2028 with an interest rate of 1.75%. The Company used the majority of the proceeds to repurchase $504 million of its 0.125% convertible notes.

Webcast

Management will host a conference call and webcast to discuss Ionis’ third quarter 2023 results at 11:30 a.m. Eastern time on Thursday, November 2, 2023. Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address. To access the Company’s third quarter 2023 earnings slides click here.

On November 2, 2023 Intra-Cellular Therapies, Inc. (Nasdaq: ITCI), a biopharmaceutical company focused on the development and commercialization of therapeutics for central nervous system (CNS) disorders, reported its financial results for the third quarter ended September 30, 2023 and provided a corporate update (Press release, Intra-Cellular Therapies, NOV 2, 2023, View Source [SID1234636769]).

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"Our third quarter results represent another period of significant CAPLYTA growth, and we are again increasing our revenue guidance for the full year 2023," said Dr. Sharon Mates, Chairman and CEO of Intra-Cellular Therapies. "We continue to solidify CAPLYTA’s position as an important option in the treatment of bipolar depression and schizophrenia and we remain focused on advancing our pipeline, including additional lumateperone development programs."

Third Quarter Financial Highlights:

Total revenues were $126.2 million for the third quarter of 2023, compared to $71.9 million for the same period in 2022. Net product sales of CAPLYTA were $125.8 million for the third quarter of 2023, compared to $71.9 million for the same period in 2022, representing a year-over-year increase of 75% and a 14% sequential increase over the second quarter of 2023.

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Net loss for the third quarter of 2023 was $24.3 million compared to a net loss of $53.5 million for the same period in 2022.

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Cost of product sales was $9.1 million in the third quarter of 2023 compared to $5.9 million for the same period in 2022.

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Selling, general and administrative (SG&A) expenses were $105.2 million for the third quarter of 2023, compared to $88.4 million for the same period in 2022.

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Research and development (R&D) expenses were $41.6 million for the third quarter of 2023, compared to $33.3 million for the same period in 2022.

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Cash, cash equivalents, restricted cash and investment securities totaled $494.8 million at September 30, 2023.

Fiscal 2023 Financial Outlook:

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Full year 2023 CAPLYTA net product sales guidance increased to $460 to $470 million from the previous range of $445 to $465 million.

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Full year 2023 SG&A expense guidance lowered to $405 to $420 million and R&D expense guidance lowered to $185 to $200 million.

CLINICAL HIGHLIGHTS

Lumateperone:

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Adjunctive Major Depressive Disorder (MDD) program: Studies 501, 502 and 505, our global Phase 3 clinical trials evaluating lumateperone 42 mg as an adjunctive therapy to antidepressants for the treatment of MDD are ongoing. We expect to report topline results from Study 501 and from Study 502 in the first and second quarters of 2024, respectively. Subject to the results of these studies, we anticipate filing a supplemental NDA in the second half of 2024.

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Mixed Features program: We presented results from Study 403 at the 2023 Psych Congress and at the European College of Neuropsychopharmacology Congress.

In this study, lumateperone 42mg was statistically significant on the primary endpoint of symptom reduction on the Montgomery Asberg Depression Rating Scale (MADRS) for the combined mixed features patient population of MDD and bipolar depression and the individual patient populations of MDD with mixed features and bipolar depression with mixed features. The robust effect sizes ranged from 0.64 to 0.67. Lumateperone was generally safe and well tolerated, with a side effect profile consistent with prior trials. There were no notable changes in weight, body mass index or waist circumference and no clinically relevant changes in metabolic parameters.

We plan to continue presenting analyses from Study 403 at upcoming medical conferences including a post-hoc analysis evaluating the antidepressant effects of lumateperone in a pre-specified patient population with mixed features exhibiting anxious distress, commonly known as anxious depression.

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Lumateperone Long Acting Injectable (LAI) formulation: We have completed the pre-clinical development of an LAI formulation, and we have conducted a Phase 1 single ascending dose study with this formulation. We expect to initiate a Phase 1 single ascending dose study with four additional formulations in the first half of 2024. The goal of the program is to develop LAI formulations that are effective, safe, and well-tolerated with treatment durations of one month or longer.

Other pipeline programs:

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ITI-1284-ODT-SL program: ITI-1284 is a deuterated form of lumateperone, a new chemical entity formulated as an oral disintegrating tablet for sublingual administration. We have initiated Phase 2 programs evaluating ITI-1284 in generalized anxiety disorder, psychosis in Alzheimer’s disease, and agitation in Alzheimer’s disease.

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Phosphodiesterase type I inhibitor (PDE1) program: We continue to develop our portfolio of PDE1 inhibitors:

Lenrispodun (ITI-214) Parkinson’s disease (PD) program: Patient enrollment in our Phase 2 clinical trial is ongoing. The objective of this study is to evaluate improvements in motor symptoms in patients with PD. Changes in cognition and inflammatory biomarkers are also being assessed.

ITI-1020 cancer immunotherapy program: Our Phase 1 single ascending dose study in healthy volunteers is ongoing. The objective of this study is to evaluate pharmacokinetics, safety, and tolerability of different doses of ITI-1020.

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ITI-333 program: ITI-333, a 5-HT2A receptor antagonist and µ-opioid receptor partial agonist, provides potential utility in the treatment of opioid use disorder and pain. A multiple ascending dose study and a positron emission tomography (PET) study are ongoing.

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ITI-1500 Non-Hallucinogenic Psychedelic Program: Our lead product candidate in this program, ITI-1549, continues to advance through IND enabling studies. This program is focused on the development of novel non-hallucinogenic psychedelics for the treatment of mood, anxiety and other neuropsychiatric disorders without the liabilities of known psychedelics, including the hallucinogenic potential and risk for cardiac valvular pathologies.

Conference Call and Webcast Details

The Company will host a live conference call and webcast today at 8:30 AM Eastern Time to discuss the Company’s financial results and provide a corporate update. To attend the live conference call by phone, please use this registration link (https://register.vevent.com/register/BI30bccb5ef41c4aa1b58d7db393a02621). All participants must use the link to complete the online registration process in advance of the conference call.

The live and archived webcast can be accessed under "Events & Presentations" in the Investors section of the Company’s website at www.intracellulartherapies.com. Please log in approximately 5-10 minutes prior to the event to register and to download and install any necessary software.

CAPLYTA (lumateperone) is indicated in adults for the treatment of schizophrenia and depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate.

Important Safety Information

Boxed Warnings:

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Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis.

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Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adults in short-term studies. All antidepressant-treated patients should be closely monitored for clinical worsening, and for emergence of suicidal thoughts and behaviors. The safety and effectiveness of CAPLYTA have not been established in pediatric patients.

Contraindications: CAPLYTA is contraindicated in patients with known hypersensitivity to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash (e.g., allergic dermatitis, papular rash, and generalized rash), and urticaria.

Warnings & Precautions: Antipsychotic drugs have been reported to cause:

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Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis, including stroke and transient ischemic attack. See Boxed Warning above.

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Neuroleptic Malignant Syndrome (NMS), which is a potentially fatal reaction. Signs and symptoms include: high fever, stiff muscles, confusion, changes in breathing, heart rate, and blood pressure, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Patients who experience signs and symptoms of NMS should immediately contact their doctor or go to the emergency room.

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Tardive Dyskinesia, a syndrome of uncontrolled body movements in the face, tongue, or other body parts, which may increase with duration of treatment and total cumulative dose. TD may not go away, even if CAPLYTA is discontinued. It can also occur after CAPLYTA is discontinued.

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Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. Measure weight and assess fasting plasma glucose and lipids when initiating CAPLYTA and monitor periodically during long-term treatment.

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Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases). Complete blood counts should be performed in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. CAPLYTA should be discontinued if clinically significant decline in WBC occurs in absence of other causative factors.

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Decreased Blood Pressure & Dizziness. Patients may feel lightheaded, dizzy or faint when they rise too quickly from a sitting or lying position (orthostatic hypotension). Heart rate and blood pressure should be monitored and patients should be warned with known cardiovascular or cerebrovascular disease. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension.

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Falls. CAPLYTA may cause sleepiness or dizziness and can slow thinking and motor skills, which may lead to falls and, consequently, fractures and other injuries. Patients should be assessed for risk when using CAPLYTA.

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Seizures. CAPLYTA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold.

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Potential for Cognitive and Motor Impairment. Patients should use caution when operating machinery or motor vehicles until they know how CAPLYTA affects them.

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Body Temperature Dysregulation. CAPLYTA should be used with caution in patients who may experience conditions that may increase core body temperature such as strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics.

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Dysphagia. CAPLYTA should be used with caution in patients at risk for aspiration.

Drug Interactions: CAPLYTA should not be used with CYP3A4 inducers. Dose reduction is recommended for concomitant use with strong CYP3A4 inhibitors or moderate CYP3A4 inhibitors.

Special Populations: Newborn infants exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Dose reduction is recommended for patients with moderate or severe hepatic impairment.

Adverse Reactions: The most common adverse reactions in clinical trials with CAPLYTA vs. placebo were somnolence/sedation, dizziness, nausea, and dry mouth.

CAPLYTA is available in 10.5 mg, 21 mg, and 42 mg capsules.

Please click here to see full Prescribing Information including Boxed Warning.

About CAPLYTA (lumateperone)

CAPLYTA 42 mg is an oral, once daily atypical antipsychotic approved in adults for the treatment of schizophrenia and depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. While the mechanism of action of CAPLYTA is unknown, the efficacy of CAPLYTA could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors.

Lumateperone is being studied for the treatment of major depressive disorder, and other neuropsychiatric and neurological disorders. Lumateperone is not FDA-approved for these disorders.

On November 2, 2023 Inhibrx, Inc. (Nasdaq: INBX), a clinical-stage biopharmaceutical company dedicated to the development of therapeutics for oncology and rare diseases, reported preliminary efficacy and safety data from the Phase 1 trial of INBRX-109 in combination with Irinotecan and Temozolomide (IRI/TMZ) for the treatment of advanced or metastatic, unresectable Ewing sarcoma (Press release, Inhibrx, NOV 2, 2023, View Source [SID1234636768]). Inhibrx presented this dataset as of the data cut of September 8th, 2023 at the Annual Connective Tissue Oncology Society (CTOS) Conference today.

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Among the 13 patients evaluable, which included 7 classical Ewing sarcoma patients (EWS) and 6 round cell sarcoma patients (RCS), the observed disease control rate was 76.9%, or 10 out of 13 patients as measured by RECISTv1.1. There were 7 patients who achieved partial responses (53.8%), 5 of which were observed in classical EWS patients (71.4%) and 2 of which were observed in RCS patients (33.3%). Durable clinical benefit was observed in 4 patients (30.8%) who achieved disease control lasting greater than 6 months. As of September 8, 2023, the longest duration of stable disease was over 10 months and ongoing and 7 of the 13 patients remained in the study.
Overall, INBRX-109 in combination with IRI/TMZ was well tolerated. The most common adverse events were diarrhea, nausea and fatigue, all consistent with the known safety profile of IRI/TMZ. No grade 3 or higher liver-related events occurred.

"I am encouraged by these initial data in relapsed/refractory Ewing sarcoma patients. This is a patient population with a high unmet need and limited effective treatment options," said Dr. Rashmi Chugh, MD, a Professor of Internal Medicine in the Division of Hematology/Oncology at University of Michigan Rogel Comprehensive Cancer Center. "I look forward to ongoing recruitment in this cohort of patients and seeing the results of the further expansion."

About Ewing Sarcoma

Ewing sarcoma, a round cell sarcoma, is a rare, aggressive tumor that occurs in children and adults. It is frequently metastatic at diagnosis with a poor prognosis and commonly relapses. Few effective treatments are available. IRI with TMZ is frequently used in the relapsed setting but response rates are low.

About INBRX-109

INBRX-109 is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to exploit the tumor-biased cell death induced by DR5 activation.

In January 2021, the FDA granted Fast Track designation to INBRX-109 for the treatment of patients with unresectable or metastatic conventional chondrosarcoma and orphan-drug designation to INBRX-109 for chondrosarcoma in the United States.

In June 2021, Inhibrx initiated a randomized, blinded, placebo-controlled, registration-enabling Phase 2 trial of INBRX-109 in conventional chondrosarcoma, which is currently ongoing. Additionally, in a Phase 1 trial, Inhibrx is currently investigating INBRX-109 in other indications in combination with certain chemotherapies, including Ewing sarcoma.