On January 13, 2020 Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of immune reset to more patients, reported that recent progress across several programs and outlined goals for 2020 (Press release, Magenta Therapeutics, JAN 13, 2020, View Source [SID1234553070]). These updates will be discussed during a webcast presentation at the 38th annual J.P. Morgan Healthcare Conference on Wednesday, January 15th at 11:30 a.m. PT (2:30 p.m. ET).

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"In 2019 we generated landmark data from our ADC-based targeted patient preparation platform, which is delivering a new class of antibody-drug conjugates (ADCs) that have the power to bring one-time treatment to more patients with autoimmune diseases, blood cancers and genetic diseases. We also presented clinical data for our first-line stem cell mobilization program, MGTA-145, which we are developing as the new standard of care for stem cell mobilization with the potential to benefit all of the transplant-eligible patients each year," said Jason Gardner, D. Phil., President and Chief Executive Officer, Magenta. "As we begin 2020, we are particularly excited to unveil our MGTA-117 clinical candidate for targeted patient preparation for stem cell transplant or gene therapy. New results announced today highlight the potency, safety and broad therapeutic index of MGTA-117, well above that of currently approved ADCs. We believe that MGTA-117 is the optimal agent for depleting stem cells to enable safe immune reset. We look forward to moving this program into the clinic with initial clinical data expected in 2021."

Targeted Patient Preparation Programs

Current methods to condition patients before transplant and gene therapy are dependent on toxic, non-specific chemotherapy or radiation. These pre-transplant treatments are associated with significant side effects, including infertility, cancer, organ damage and death. Magenta is developing targeted, disease-modifying ADCs that are designed to precisely and rapidly remove the disease-causing cells in the body and enable immune system reset without the need for chemotherapy or radiation.

CD117-ADC Recent Progress

Data presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in December 2019, showed the first-ever successful transplant of gene-modified cells in non-human primates using a CD117-targeted, single-agent ADC from Magenta, without the use of chemotherapy or radiation. These unprecedented results validate and advance Magenta’s conditioning platform.

Building on this work, Magenta’s new clinical candidate, MGTA-117, is a CD117 antibody conjugated to amanitin. Results published today in an abstract for the Transplant and Cellular Therapy annual meeting show that MGTA-117 potently depleted stem and progenitor cells and demonstrated a wide tolerability: potency ratio of 30 fold (therapeutic index; typical range for approved ADCs at this stage is two to six fold). This program is advancing to the clinic and further validates Magenta’s antibody drug conjugate-based conditioning platform. MGTA-117 was developed under a partnership with Heidelberg Pharma that grants Magenta exclusive worldwide development and marketing rights for ADCs using an amanitin payload and targeting CD117.

MGTA-117 in 2020

Magenta is scaling up manufacturing of MGTA-117 and completing IND-enabling studies in 2020. The Company intends to move this new product candidate into the clinic with initial clinical data expected in 2021.

CD45-ADC Recent Progress

Current standard treatment for patients with multiple sclerosis involves years of chronic dosing of medications that do not halt the progression of the disease. For patients with systemic sclerosis, a potentially fatal autoimmune disease, there are no approved therapies. Immune reset through stem cell transplant has demonstrated durable remissions in thousands of patients with autoimmune diseases such as multiple sclerosis and systemic sclerosis, and it is recommended by the European League Against Rheumatism (EULAR) in treatment guidelines for systemic sclerosis. The immune reset process involves two main steps: removing the disease-causing cells and replacing them with healthy cells to rebuild the immune system to a healthy state.

Magenta is developing targeted ADCs designed to precisely remove the disease-causing cells in the body without the need for chemotherapy or radiation. Magenta’s CD45-ADC program targets CD45, a protein expressed on immune cells and stem cells and is designed to remove the cells that cause autoimmune diseases in order to enable curative immune reset.

Data presented at the American College of Rheumatology (ACR) meeting in November 2019 showed that a single dose of CD45-ADC removed disease-causing reactive T cells, enabled successful immune reset and rebuild of the immune system and was well tolerated in three models of autoimmune disease, including the EAE model, the most reliable murine model of multiple sclerosis. Further, a single dose of CD45-ADC significantly reduced disease incidence and delayed disease onset in this model that has successfully provided preclinical proof of concept for many clinically validated standard-of-care therapies.

CD45-ADC in 2020

Magenta has identified a lead antibody and has progressed this program into IND-enabling studies, which the Company plans to further advance in 2020.

MGTA-145 First-Line Stem Cell Mobilization Therapy

MGTA-145 Recent Progress

Magenta is developing MGTA-145 as the new first-line standard of care for stem cell mobilization in a broad range of diseases, including autoimmune diseases, blood cancers and genetic diseases. MGTA-145, a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to harness the physiological mechanism of stem cell mobilization.

Magenta is currently studying MGTA-145 and plerixafor in a Phase 1 study in healthy volunteers. Data from the Phase 1 study presented at the ASH (Free ASH Whitepaper) annual meeting in December 2019 showed that MGTA-145 in combination with plerixafor successfully enables safe, same-day dosing, mobilization and collection of sufficient high-quality hematopoietic stem cells for transplant. Further, when cells collected from the first two apheresis subjects were transplanted into humanized mice, the cells engrafted more rapidly and at a five-fold higher level than cells from G-CSF-mobilized peripheral blood.

MGTA-145 in 2020

Magenta intends to complete the Phase 1 study and move this program into multiple Phase 2 studies in patients in 2020. The Phase 2 studies will include both allogeneic and autologous transplant settings and will evaluate mobilization and collection of high-quality cells and engraftment of the cells after transplant.

MGTA-456 Cell Therapy

MGTA-456 Recent Progress

MGTA-456 is a cell therapy designed to provide a high dose of stem cells that are well matched to the patient to enable safe immune and blood system rebuild and durable remissions in patients with blood cancers. In September, the U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation for MGTA-456 for the treatment of multiple inherited metabolic disorders.

Magenta is currently studying MGTA-456 in a Phase 2 study in patients with inherited metabolic disorders, including cerebral adrenoleukodystrophy (cALD) and Hurler syndrome. These are rare, rapidly progressive neurologic disorders that are fatal when left untreated. Results in the first two evaluable patients with cALD updated in December 2019 showed early and durable resolution of the disease at 12 months’ follow-up. The Loes score and NFS score, which measure progress of the disease, remained stable, suggesting that progress of the disease has been halted in these patients. The early and durable resolution of disease with MGTA-456 is not consistently seen with other therapies, including standard stem cell transplant, gene therapy or enzyme replacement therapy.

MGTA-456 in 2020

Magenta intends to complete enrollment in the Phase 2 in 2020 and continue dialogue with the FDA under the RMAT designation, and to discuss with the European Medicines Agency (EMA) for development in Europe

On January 13, 2020 Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, and Kyowa Kirin Co., Ltd., (Kyowa Kirin, TYO: 4151) reported that they submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) on December 18, 2019, for Crysvita (burosumab) for the treatment of FGF23-related hypophosphatemia associated with phosphaturic mesenchymal tumors (tumor-induced osteomalacia; TIO) that cannot be curatively resected or localized (Press release, Ultragenyx Pharmaceutical, JAN 13, 2020, View Source [SID1234553069]). The companies expect to hear back from FDA on submission acceptance and review designation in February 2020.

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"Approximately half of patients with TIO have tumors that cannot be surgically removed, leaving them with no other current treatment options," said Camille L. Bedrosian, M.D., Chief Medical Officer of Ultragenyx. "We look forward to continuing to work closely with the FDA during the review process, with the goal of bringing Crysvita to patients with TIO in the U.S."

The sBLA package includes data from two single-arm Phase 2 studies, a 144-week study in 14 adult patients conducted by Ultragenyx in the U.S. and an 88-week study in 13 adult patients conducted by Kyowa Kirin in Japan and South Korea. In both studies, Crysvita was associated with increases in serum phosphorus and serum 1,25-dihydroxyvitamin D levels. Increased phosphate levels led to improvements in osteomalacia, mobility and vitality. Bone scans also demonstrated an increase in healed fractures and a decrease in new fractures during Crysvita treatment. During the studies, adverse events generally reflected the patients’ underlying disease, and there were no serious treatment-related adverse events.

Crysvita is approved by the FDA for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients six months of age and older, and by Health Canada and Brazil’s National Health Surveillance Agency (ANVISA) for the treatment of XLH in adult and pediatric patients one year of age and older. It is approved by Japan’s Ministry of Health, Labor and Welfare (MHLW) for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. The medicine has received European conditional marketing authorization for the treatment of XLH with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons, and an application for the expanded use in adults with XLH is currently under review by the European Medicines Agency.

See below for Important Safety Information for Crysvita in X-linked hypophosphatemia.

About Tumor-Induced Osteomalacia (TIO)
TIO is caused by typically benign tumors that produce excess levels of fibroblast growth factor 23 (FGF23), causing phosphate wasting in the urine that leads to severe hypophosphatemia, osteomalacia, muscle weakness, fatigue, bone pain and fractures. The symptoms rapidly resolve if the causal tumors or lesion can be resected; however, there are cases in which resection is not feasible or recurrence of the tumor occurs after resection. In patients for whom the tumor or lesion is inoperable, the current treatment consists of oral phosphate and/or vitamin D replacement. Efficacy of this management is often limited, as it does not treat the underlying disease and its benefits must be balanced with monitoring for potential risks such as nephrocalcinosis, hypercalciuria and hyperparathyroidism. An estimated 500-1,000 people in the United States have TIO, and approximately half of all cases are inoperable.

About Crysvita
Crysvita (burosumab-twza) is a recombinant fully human monoclonal IgG1 antibody, discovered by Kyowa Kirin, against the phosphaturic hormone FGF23. FGF23 is a hormone that reduces serum levels of phosphorus and active vitamin D by regulating phosphate excretion and active vitamin D production by the kidney. Phosphate wasting in TIO and other hypophosphatemic conditions, including XLH, is caused by excessive levels and activity of FGF23. Crysvita is designed to bind to and thereby inhibit the biological activity of FGF23. By blocking excess FGF23 in patients with TIO and XLH, Crysvita is intended to increase phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium.

Kyowa Kirin and Ultragenyx have been collaborating in the development and commercialization of Crysvita globally based on the collaboration and license agreement between the parties.

INDICATION (IN THE U.S.)
Crysvita is indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 6 months of age and older.

IMPORTANT SAFETY INFORMATION
Crysvita should not be taken if:

An oral phosphate supplement and/or a specific form of vitamin D supplement are taken (such as calcitriol, paricalcitol, doxercalciferol, calcifediol).
Phosphorus levels from a blood sample are within or above the normal range for age.
Kidney problems are present.
What is the most important information to know about Crysvita?

Some patients developed allergic reactions (rash and hives) while taking Crysvita. Doctors will monitor for symptoms of an allergic reaction while Crysvita is taken.
High levels of phosphorus in the blood have been reported in some patients taking Crysvita. This may be related to a risk of high calcium levels in the kidneys. Doctors will collect samples to monitor levels.
Administration of Crysvita may result in reactions at the injection site, such as hives, reddening of the skin, rash, swelling, bruising, pain, severe itching of the skin, and collection of blood outside of a blood vessel (hematoma).
What are the possible side effects of Crysvita?

The most common adverse reactions that were seen in children with XLH are:
• Fever
• Injection site reaction
• Cough
• Vomiting
• Pain in arms and legs
• Headache
• Tooth infection
• Dental cavities
• Diarrhea
• Decreased vitamin D levels
• Toothache
• Constipation
• Muscle pain
• Rash
• Dizziness
• Nausea
The most common adverse reactions that were seen in adults with XLH are:
• Back pain
• Headache
• Tooth infection
• Restless leg syndrome
• Decreased vitamin D levels
• Dizziness
• Muscle spasms
• Constipation
• Phosphorus levels increased in the blood
Narrowing of the spaces within the spine is common in adults with XLH and pressure on the spinal cord has been reported in adults taking Crysvita. It is not known if taking Crysvita worsens the narrowing of the spaces within the spine or the pressure on the spinal cord.
Before taking Crysvita, doctors should be informed about all medications (including supplements) and medical conditions, including if:

One is taking oral phosphate and/or active vitamin D (such as calcitriol, paricalcitol, doxercalciferol, calcifediol).
One is pregnant, thinks she may be pregnant, or plans to become pregnant. There is not enough experience to know if Crysvita may harm an unborn baby. Report pregnancies to the Kyowa Kirin, Inc. Adverse Event reporting line at 1-888-756-8657.
One is breastfeeding or plans to breastfeed. There is not enough experience to know if Crysvita passes into breast milk. Women should talk with their doctors about the best way to feed their babies while taking Crysvita.
While taking Crysvita, doctors should be informed if one experiences:

An allergic reaction such as rash or hives
A rash, swelling, bruising or other reaction at the injection site
New or worsening restless leg syndrome
These are not all the possible side effects of Crysvita. Doctors should be contacted for medical advice about side effects.

Side effects may be reported to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. Side effects may also be reported to Kyowa Kirin, Inc. at 1-888-756-8657.

On January 13, 2020 Infinity Pharmaceuticals Inc. (NASDAQ: INFI) reported 2020 milestones for IPI-549, a first-in-class, oral, immuno-oncology product candidate targeting immune-suppressive tumor-associated myeloid cells through selective phosphoinositide-3-kinase-gamma (PI3K-gamma) inhibition and provided financial guidance for 2020 (Press release, Infinity Pharmaceuticals, JAN 13, 2020, View Source [SID1234553066]).

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"Our recently announced non-dilutive financing with BVF Partners has provided Infinity with the financial resources to fully fund all of our ongoing IPI-549 trials to key data readouts throughout 2020 and into 2H 2021," stated Adelene Perkins, Chief Executive Officer and Chair of Infinity Pharmaceuticals. "2020 will be a very exciting and important year for Infinity as we continue our efforts to expand the development of IPI-549 across earlier lines of therapy and broader indications, leveraging a safety profile that enables innovative combination therapy approaches. We continue to see growing recognition of the importance of MDSC-directed and tumor macrophage-directed immuno-oncology therapies among the medical and scientific communities, and we are well positioned to solidify our leadership in the field with expected clinical and translational data from IPI-549 studies in 2020 to mid-2021."

Infinity’s Chair and Chief Executive Officer, Adelene Perkins, will discuss the company’s continued execution on its corporate strategy and 2020 priorities as part of a podium presentation at the 38th Annual J.P. Morgan Healthcare Conference on January 16th, 2020 at 9 a.m. Pacific Time.

Recent Financial and Corporate Highlights

$20 million non-dilutive asset-backed financing with BVF Partners L.P. with sole recourse in potential royalty payments due on future sales of patidegib, a hedgehog pathway inhibitor discovered by Infinity and licensed to PellePharm in 2013. Infinity is eligible to receive from BVF an additional $5 million payment upon positive data from PellePharm’s Phase 3 trial in patients with Gorlin Syndrome.
Over $60 million cash on hand to fund all current IPI-549 trials to key data readouts throughout 2020 and into mid-2021.
Executive Leadership Promotions of Jeffery Kutok, M.D., Ph.D., Chief Scientific Officer, from Senior Vice President to Executive Vice President, and Seth Tasker, J.D. from General Counsel to Chief Business Officer.
2020 IPI-549 Development Guidance

MARIO-275 enrollment completion. MARIO-275 is the company’s ongoing global, randomized, controlled Phase 2 study in collaboration with Bristol-Myers Squibb, to evaluate IPI-549 in combination with Opdivo in platinum-refractory, I/O naïve patients with advanced urothelial cancer. Data is expected in mid-2021.
MARIO-3 enrollment completion and initial data. MARIO-3 is the company’s ongoing Phase 2 study in collaboration with Roche/Genentech to evaluate IPI-549 in novel triple combination front-line therapies with Tecentriq and Abraxane in triple negative breast cancer (TNBC) and with Tecentriq and Avastin in renal cell cancer (RCC).
Arcus Biosciences Collaboration Study expansion cohort enrolling. This ongoing Phase 1/1b trial, being conducted by Arcus, is evaluating a checkpoint inhibitor-free, novel triple-combination regimen of IPI-549 + AB928 (dual adenosine receptor antagonist) + Doxil in advanced TNBC patients. The trial has been initiated with a goal of enrollment of up to 40 patients in an expansion cohort.
Additional MARIO-1 data. MARIO-1 is the company’s ongoing Phase 1/1b study of IPI-549 as a monotherapy and in combination with Opdivo in patients with advanced solid tumors.
2020 Financial Guidance

Infinity ended 2019 with approximately $42.4 million in cash and investments (unaudited) and plans to report its fourth quarter and full-year 2019 financial results in March. The company is providing the following financial guidance today:

Cash as of January 8, 2020: ~$62 million (including $20 million non-dilutive financing)
Net Loss: $40 million to $50 million
Year-end Cash: $15 million to $25 million
Cash Runway: Into 2H 2021
Infinity’s 2020 financial guidance is based on its current operating plans, excludes additional financing or business development activities, and excludes a potential $5 million milestone payment from BVF for positive Phase 3 patidegib data and any milestones from, or the sale of the company’s equity interest in, PellePharm.

On January 13, 2020 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical stage biotechnology company focused on discovering and developing novel small molecule drugs for the treatment of cancer and other life-threatening diseases, reported an overview of select expected fourth quarter 2019 financial results, initial 2020 financial guidance and upcoming corporate milestones (Press release, Calithera Biosciences, JAN 13, 2020, View Source [SID1234553065]).

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"We anticipate that 2020 will be an exciting year for Calithera, building on the substantial progress we made in 2019 and the potential for several significant clinical and regulatory milestones," said Susan Molineaux, PhD, president and chief executive officer of Calithera. "We remain in a strong financial position to advance our key clinical programs and robust pipeline this year, and we are pleased with our strong cash balance at the end of 2019."

2020 Milestones

Calithera expects to achieve the following milestones in 2020:

Announce topline data from randomized CANTATA trial of telaglenastat with cabozantinib in advanced renal cell carcinoma (RCC). The CANTATA trial is a global, randomized, double-blind clinical trial of telaglenastat combined with cabozantinib, in patients with advanced or metastatic RCC who have received one or two prior treatments. The CANTATA trial enrolled 445 patients at multiple centers globally. The primary endpoint is progression-free survival. Calithera plans to report top-line efficacy and safety data from the trial in the second half of 2020.

Initiate Phase 2 trial of telaglenastat in non-small cell lung cancer (NSCLC) patients with genetic mutation NRF2/KEAP1. The NRF2/KEAP1 pathway is known to drive the development of certain cancers, including a significant proportion of NSCLC through the regulation of reactive oxygen species in a manner that is dependent upon glutaminase activity. Recently presented clinical data demonstrate that activation of this pathway, either through the loss of KEAP1 function or activation of NRF2, results in very poor outcomes in NSCLC patients. The clear mechanistic rationale, strong preclinical data, and high unmet medical need in the NSCLC population have led Calithera to design a clinical study that will evaluate telaglenastat in combination with chemo-immunotherapy in first line NSCLC patients with tumors that harbor mutations in either KEAP1 or NRF2 that activate this pathway. This trial is expected to begin in the first half of 2020.

Enroll telaglenastat (CB-839) combination trials in collaboration with Pfizer. Calithera and Pfizer have two clinical trial collaborations to evaluate Pfizer’s CDK4/6 inhibitor palbociclib, also known as IBRANCE, and the dual-mechanism poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib, also known as TALZENNA, each in combination with glutaminase inhibitor telaglenastat.

Continue enrollment of multiple clinical trials evaluating Calithera’s arginase inhibitor INCB001158. INCB001158 is a small-molecule immuno-oncology therapeutic being evaluated in multiple clinical trials as a single-agent and in combination with immunotherapies and chemotherapy for the treatment of patients with cancer. INCB001158 is being developed as part of a collaboration and license agreement with Incyte.

Enroll clinical dose escalation trial evaluating CB-280, an oral arginase inhibitor, in cystic fibrosis (CF). Arginase is believed to be critical in the pathology of cystic fibrosis. It impairs production of nitric oxide and generates metabolites of arginine that may impair lung function. A Phase 1b clinical study in people with CF, which is expected to start enrollment in the first half of 2020, will test multiple doses of CB-280 compared to placebo in approximately 30 adults with CF to determine a safe dose range, and pharmacodynamics effects of arginase inhibition in this population. Patients with any CF transmembrane conductance regulator mutational status will be eligible for the study.

Select Expected Fourth Quarter 2019 Financial Results and Financial Guidance for 2020

Based upon preliminary estimates, cash, cash equivalents and investments totaled $157.4 million at December 31, 2019. Calithera expects to utilize cash and investments between $75 and $85 million in 2020. The information relating to cash, cash equivalents and investments is preliminary, has not been audited and is subject to change upon completion of the audit of Calithera’s financial statements as of and for the year ended December 31, 2019.

On January 13, 2020 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported preliminary unaudited fourth quarter and full year 2019 net product sales for XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, and provided additional updates on the product’s commercial launch (Press release, Karyopharm, JAN 13, 2020, View Source [SID1234553064]).

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Strong XPOVIO Commercial Rollout Continues in the U.S.

Oral XPOVIO tablets became commercially available to patients in the U.S. on July 9, 2019. Based on preliminary unaudited financial information, Karyopharm expects net product sales of XPOVIO to be between $17 and $18 million during the fourth quarter and between $30 and $31 million for the full year 2019. As of December 31, 2019, approximately 1,400 XPOVIO prescriptions have been fulfilled, driven by strong demand from both academic and community-based oncologists. In less than 6 months on the market, XPOVIO has been prescribed by more than 550 unique physicians and healthcare accounts. These updates will be discussed during a webcast presentation at the 38th Annual J.P. Morgan Healthcare Conference in San Francisco on Tuesday, January 14, 2020 at 10:00 a.m. PT (1:00 p.m. ET). A live webcast of the presentation and Q&A session can be accessed through the investor section of the Company’s website at www.karyopharm.com. Following the live presentation, a replay of the webcast will be available on the Company’s website for 30 days.

"By all accounts, 2019 was a transformational year for Karyopharm with the accelerated approval and commercial launch of XPOVIO, the first and only oral nuclear export inhibitor approved in the U.S., indicated for patients with heavily pretreated multiple myeloma," said Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm. "We are extremely pleased with the commercial launch of XPOVIO thus far, including the breadth of prescribing physicians and early feedback from patients who have initiated therapy. We are proud to be making such an important impact for patients who are battling relapsed or refractory multiple myeloma."

The Company intends to provide 2020 financial guidance on non-GAAP R&D and SG&A expenses and year-end cash balance in connection with the final financial results for the fourth quarter and audited financial results for full year 2019 expected to be provided in February 2020.

The financial information presented in this press release may be adjusted as a result of the completion of customary quarterly review and audit procedures, and the Company’s actual financial results may differ materially from the preliminary estimated financial information set forth above.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. In addition to receiving accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) 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, Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. A New Drug Application was recently submitted to the FDA seeking accelerated approval for selinexor as a new treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Selinexor has received Fast Track and Orphan designation from the FDA for the patient population evaluated in the SADAL study. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.

Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.