On October 29, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported that it has issued an additional $22.5 million aggregate principal amount of its 3.00% convertible senior notes due 2025 (the "notes") pursuant to the exercise in full of the option to purchase additional notes granted to the initial purchasers in Karyopharm’s previously announced private offering of $150 million aggregate principal amount of notes to qualified institutional buyers in reliance on Rule 144A under the Securities Act of 1933, as amended (the "Securities Act") (Press release, Karyopharm, OCT 29, 2018, View Source [SID1234530309]). The additional notes were sold on the same terms in all respects as the notes previously issued on October 16, 2018, and the terms of the additional notes are identical to those previously issued. The closing of the sale of the additional notes occurred on October 26, 2018. Following such closing, Karyopharm has issued a total of $172.5 million aggregate principal amount of notes.

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The notes were offered and sold to qualified institutional buyers pursuant to Rule 144A under the Securities Act. The offer and sale of the notes and the shares of common stock issuable upon conversion of the notes, if any, have not been and will not be registered under the Securities Act or the securities laws of any other jurisdiction, and the notes and any such shares may not be offered or sold in the United States absent registration or an applicable exemption from such registration requirements. Any offer of the notes was made only by means of a private offering memorandum.

This press release does not constitute an offer to sell or the solicitation of an offer to buy the notes or any other securities, nor shall there be any offer, solicitation or sale of the notes or any other securities (including the shares of Karyopharm’s common stock issuable upon conversion of the notes, if any) in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful.

On October 29, 2018 Dynavax Technologies Corporation (NASDAQ: DVAX) reported that it will report financial results for the third quarter ended September 30, 2018 after market close on Monday, November 5, 2018, and host a conference call that day to review the results and provide an update on the launch of HEPLISAV-B [Hepatitis B Vaccine, (Recombinant) Adjuvanted] and its SD-101 immuno-oncology program at 4:30pm ET/1:30pm PT (Press release, Dynavax Technologies, OCT 29, 2018, View Source [SID1234530326]).

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To access the call, participants must dial (866) 420-4066 in the U.S. or (409) 217-8237 internationally, and use the conference ID 5179228. The live call will be webcast and can be accessed in the "Investors and Media" section of the company’s website at www.dynavax.com. A replay of the webcast will be available for 30 days following the live event.

On October 29, 2018 Genmab A/S (Nasdaq Copenhagen: GEN) reported topline results from the Phase III MAIA study (MMY3008) of daratumumab in combination with lenalidomide and dexamethasone (DRd) versus Rd alone as treatment for newly diagnosed patients who are not candidates for high dose chemotherapy and autologous stem cell transplant (ASCT) (Press release, Genmab, OCT 29, 2018, View Source [SID1234530362]). The study met the primary endpoint of improving progression free survival (PFS) at a pre-planned interim analysis (Hazard Ratio (HR) = 0.55 (95% CI 0.43 – 0.72), p < 0.0001) resulting in a 45% reduction in the risk of progression or death in patients treated with DRd. The median PFS for patients treated with daratumumab in combination with Rd has not been reached, compared to an estimated median PFS of 31.9 months for patients who received Rd alone.

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Overall, the safety profile of daratumumab in combination with Rd is consistent with both the known safety profiles of the Rd regimen and daratumumab.

Based on the results at the pre-planned interim analysis conducted by an Independent Data Monitoring Committee (IDMC), it was recommended releasing the interim analysis results. Further analysis of the safety and efficacy data is ongoing and Janssen Biotech, Inc., which licensed daratumumab from Genmab in 2012, will discuss the potential for a regulatory submission for this indication with health authorities, and plans to submit the data to an upcoming medical conference and for publication in a peer-reviewed journal.

"We are highly encouraged by this data as this is the fifth randomized study showing a profound benefit when adding daratumumab to standard of care treatments in multiple myeloma, and the second showing efficacy for patients with newly diagnosed multiple myeloma who are not eligible for ASCT. As such this data increases our hope that daratumumab may one day help even more patients at the outset of treatment of this disease," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Today’s news does not impact Genmab’s 2018 financial guidance.

About the MAIA (MMY3008) study
The Phase III study (NCT02252172) is a randomized, open-label, multicenter study that includes 737 newly diagnosed patients with multiple myeloma who are not candidates for high dose chemotherapy and ASCT. Patients were randomized to receive either daratumumab in combination with lenalidomide (an immunomodulatory drug) and dexamethasone (a corticosteroid) or lenalidomide and dexamethasone alone. In the daratumumab treatment arm, patients received 16 milligrams per kilogram (mg/kg) weekly for first 8 weeks (Cycles 1 and 2), every other week for 16 weeks (Cycles 3 to 6) and then every 4 weeks (Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide is administered at 25 mg orally on days 1 through 21 of each 28-day cycle, and dexamethasone was administered at 40 mg once a week for both treatment arms. Participants in both treatment arms will continue Rd until disease progression or unacceptable toxicity. The primary endpoint of the study is PFS.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 30,770 new patients are expected to be diagnosed with multiple myeloma and approximately 12,770 people are expected to die from the disease in the U.S. in 2018.3 Globally, it was estimated that 124,225 people would be diagnosed and 87,084 would die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.6 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (U.S. FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy; and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. In Japan, DARZALEX is approved in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for treatment of adults with relapsed or refractory multiple myeloma. DARZALEX is the first human CD38 monoclonal antibody to reach the market. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).6,7,8,9,10

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies in smoldering, relapsed and frontline multiple myeloma settings and in amyloidosis. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases, such as NKT-cell lymphoma, myelodysplastic syndromes, B and T-ALL. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA, for multiple myeloma, as both a monotherapy and in combination with other therapies.

On October 29, 2018 Kazia Therapeutics Limited (ASX: KZA;NASDAQ: KZIA), an Australian oncology-focused biotechnology company, is reported to shareholders regarding progress with GDC-0084, which is currently in human trials for glioblastoma and several other forms of brain cancer (Press release, Kazia Therapeutics, OCT 29, 2018, View Source [SID1234530440]).

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Key Points

Phase II clinical trial of GDC-0084 in glioblastoma is progressing well, with all sites open to recruitment and the first cohort of patients fully enrolled and undergoing treatment
Investigator-initiated clinical collaborations launched with St Jude Children’s Research Hospital in diffuse intrinsic pontine glioma (DIPG), and with Dana-Farber Cancer Institute in breast cancer brain metastases (BCBM)
Poster on the Kazia glioblastoma study to be presented at upcoming Society for Neuro-Oncology meeting in New Orleans, LA on 16 November 2018
Manufacture of an additional batch of GDC-0084 capsules for clinical trial use has commenced
Kazia CEO, Dr James Garner, commented, "We are delighted with progress across the GDC-0084 program. Our own study in glioblastoma is off to an excellent start, and we are very pleased to now also be working with two top-tier research hospitals to explore additional uses of the drug in other forms of brain cancer. The hard work that has been undertaken over the past twelve to eighteen months is now paying off, which sets the company up for several important and value-driving data read-outs from the GDC-0084 program during calendar 2019."

He added, "The PI3K inhibitor class has seen some dramatic developments in the past six months. We were excited to see FDA approve Copiktra (duvelisib) from Verastem in October 2018, bringing the number of FDA-approved PI3K inhibitors to three. The recent European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) meeting also saw promising data presented from Novartis for their PI3K inhibitor, alpelisib, in certain forms of breast cancer. It is clear that this class of drugs is well-established and well-proven. However, GDC-0084 remains the only PI3K inhibitor in mainstream development that is able to cross the blood-brain barrier, and this gives it a unique advantage in brain cancer."

Phase II Clinical Trial in Glioblastoma

All seven participating centres are fully open to recruitment. To date, the first cohort of three patients has been enrolled and are currently receiving treatment. If the first cohort is able to complete treatment without experiencing significant toxicity, a second cohort will be enrolled at a higher dose. A number of potential patients have already been identified for the second cohort and are undergoing pre-screening. Once the maximum tolerated dose (MTD) has been established in this first part of the trial, the remainder of the study will proceed at that dose.

Recruitment to date has exceeded expectations, and the study remains on track to report initial data early in calendar 2019. It is listed on clinicaltrials.gov as NCT03522298. The study is also listed in the clinical trial finder section of the US National Brain Tumor Society website.

Investigator-Initiated Collaborations

As previously announced, Kazia is supporting two leading US hospitals to explore the potential use of GDC-0084 in other forms of brain cancer.

St Jude Children’s Research Hospital in Memphis, TN has commenced a phase I human trial of GDC-0084 in children with diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas. This study is currently recruiting and is listed on clinicaltrials.gov as NCT03696355.

Dana-Farber Cancer Institute (DFCI) in Boston, MA is establishing a phase II human trial of GDC-0084 in women with breast cancer brain metastases (BCBM), which is breast cancer that has spread to the brain. This study is expected to commence recruitment in early calendar 2019, pending approval by the Institutional Review Board at DFCI, and is not yet listed on clinicaltrials.gov.

Kazia has been pleased to observe very strong interest from clinicians and scientists in a range of other potential exploratory studies of GDC-0084 and remains in discussion regarding several other potential clinical collaborations.

Publications

Kazia is gratified to have been accepted for a ‘trials in progress’ poster presentation at the upcoming 23rd Annual Scientific Meeting of the Society for Neuro-Oncology (SNO), which will be held in New Orleans, LA on 16-18 November 2018.

The Company will make the poster presentation available to all shareholders at approximately the same time it is presented at conference. The poster is expected to focus primarily on the design of the company-sponsored ongoing phase II study in glioblastoma, and the rationale for GDC-0084 in this group of patients, and it is not anticipated that meaningful clinical data will be available at this early stage.

Other presentations and publications of GDC-0084 data are anticipated in the next six to twelve months, and the Kazia team will be discussing appropriate opportunities with investigators at the upcoming SNO meeting.

Manufacturing

Work has begun to manufacture a second batch of capsules for use across the GDC-0084 clinical program, under international Good Manufacturing Practice (GMP) conditions. The company obtained approximately 48kg of drug substance as part of its transaction with Genentech in October 2016, and this remains highly stable. Kazia has planned to periodically formulate a portion of this material into capsules for clinical trial use, according to progress with the studies. Given the pace of recruitment to date, it has been considered appropriate to accelerate manufacture of a second batch of capsules to ensure continuity of supply. Production of a second batch will also strengthen the data available regarding GDC-0084 manufacture for regulatory purposes, and will ultimately help to inform commercial supply.

Regulatory Affairs

In accordance with FDA requirements, Kazia has been undertaking a 13-week toxicology study of GDC-0084 in two animal species. This is a routine requirement to support long-term use of the drug in human patients. The study is progressing well according to plans, and is on track to conclude before the end of calendar 2018.

Kazia has applied to the World Health Organisation (WHO) for an International Non-proprietary Name (INN) for GDC-0084. It is common for drugs to be referred to by a code number during early development, but companies typically seek allocation of an INN around the initiation of phase II development. INNs are a necessary step for eventual regulatory approval and are determined centrally by WHO. Kazia expects to receive the INN for GDC-0084 in late calendar 2019.

Intellectual Property

Since assuming responsibility for GDC-0084 from Genentech in October 2016, Kazia has continued to pursue robust protection for the intellectual property associated with the drug. Of note, patents have been granted in Australia (July 2017), the People’s Republic of China (March 2018), Hong Kong SAR (March 2017), and the United States (January 2017), as well as in a number of other jurisdictions. In general, the patents relating to GDC-0084 provide comprehensive protection until at least 2031

On October 29, 2018 Novartis reported it was awarded the 2018 Prix Galien USA Award for Best Biotechnology Product for Kymriah (tisagenlecleucel) following its first-in-class approval by the US Food and Drug Administration (FDA) for the treatment of children and young adults with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Novartis, OCT 29, 2018, View Source [SID1234530441]). Kymriah is a ground-breaking one-time treatment that uses a patient’s own T cells to fight cancer, and the only chimeric antigen receptor T cell (CAR-T) therapy approved for two distinct B-cell malignancies1. The award, which recognizes excellence in scientific innovation that improves the state of human health, was presented at a ceremony in New York City.

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"It is a great honor to receive this prestigious award for Kymriah," said Liz Barrett, CEO, Novartis Oncology. "The impact for patients with aggressive blood cancers who previously had limited treatment options is our greatest reward and drives us to continue pioneering efforts to reimagine the way cancer is treated."

The historic approval of Kymriah was a result of collaboration with researchers at University of Pennsylvania (Penn) who demonstrated the first successful use of gene transfer therapy to use the body’s immune cells to fight cancer. Novartis further researched this emerging class of drug, initiating the first global CAR-T trials and in August 2017, became the first company to gain a regulatory approval of a CAR-T cell therapy. This year, Kymriah has also been approved in the United States for the treatment of adult patients with r/r diffuse large B-cell lymphoma (DLBCL); and for the treatment of pediatric and young adult patients with r/r ALL and adults with r/r DLBCL in the European Union, Canada and Switzerland. Of note, Kymriah is not approved for the treatment of patients with primary central nervous system lymphoma1.

Both B-cell ALL and DLBCL are aggressive malignancies, and for patients who relapse or don’t respond to therapy, there are limited treatment options2,3.

Novartis Prix Galien Awards
Considered "the pharmaceutical industry’s Nobel Prize," the Prix Galien recognizes excellence in scientific innovation that improves the state of human health, and acknowledges the technical, scientific and clinical research skills necessary to develop such innovative medicines. As a true testament to the company’s commitment to reimagine medicine, since 1970, Novartis has received more than 40 national Prix Galien awards in 15 countries for innovative therapies including Gleevec (imatinib mesylate), Kymriah (tisagenlecleucel), Parlodel (bromocriptine mesylate), Rimactane (rifampin), Sandimmune (cyclosporine), Sandostatin (octreotide acetate), Simulect (basiliximab) and Visudyne (verteporfin)4.

About Kymriah (tisagenlecleucel)
Kymriah is an innovative immunocellular therapy, manufactured individually for each patient by reprogramming the patient’s own immune system cells. Kymriah is the only approved CAR-T cell therapy manufactured using the 4-1BB costimulatory domain, which is critical for full activation of the therapy, enhancement of cellular expansion and durable persistence of the cancer-fighting cells. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

Kymriah (tisagenlecleucel) US Important Safety information
Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4◦F/38◦C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion.

Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their healthcare provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all of the possible side effects of Kymriah. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their healthcare provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.