On December 6, 2018 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported an expansion of its existing cell therapy collaboration with Novartis, to include the ex vivo development of innovative cell therapies using certain ocular stem cells (Press release, Intellia Therapeutics, DEC 6, 2018, View Source [SID1234531945]). As part of the updated collaboration terms, Novartis will have the right to develop CRISPR/Cas9-based products for one or more targets using these stem cells. Intellia will receive a one-time $10 million cash payment and, consistent with the original collaboration agreement, Intellia also is eligible to receive downstream success-based milestones and royalties.

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With the collaboration expansion announced today, Intellia will gain expanded rights to Novartis’ lipid nanoparticle (LNP) technology for all genome editing applications in both in vivo and ex vivo settings. This licensed LNP technology is the foundation of Intellia’s proprietary modular delivery system of CRISPR/Cas9 for its in vivo product pipeline. Intellia retains rights to all other in vivo and ex vivo applications of CRISPR/Cas9, including for eye disorders, subject to certain in vivo target selection options by Novartis set forth in the original agreement.

"Genome editing enhancements made by CRISPR/Cas9 will enable the next generation of cell therapies. With our collaborator, Novartis, we are broadening the ex vivo application of our CRISPR/Cas9 technology from hematopoietic stem cells, or HSCs, to ocular stem cells. We are pleased to expand our relationship with Novartis, and to continue to work together to develop cell therapies," said Intellia President and Chief Executive Officer John Leonard, M.D. "Broader rights to Novartis’ LNP technology will assist our efforts to apply this technology in ex vivo settings for the development of proprietary cell therapies, just as we have done to develop our proprietary modular delivery system for in vivo products in the liver and other organs."

On December 6, 2018 Novartis reported additional analysis from the global Phase III SOLAR-1 trial investigating the alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant in men and postmenopausal women with PIK3CA mutated hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer (Press release, Novartis, DEC 6, 2018, https://www.novartis.com/news/media-releases/novartis-investigational-byl719-alpelisib-plus-fulvestrant-consistently-improved-pfs-patients-pik3ca-mutated-hrher2-advanced-breast-cancer-new-solar-1-analyses [SID1234531929]).

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In SOLAR-1, the addition of BYL719 to fulvestrant nearly doubled median progression-free survival (PFS) in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who progressed on or after an aromatase inhibitor (AI) compared to fulvestrant alone. In this analysis, BYL719 plus fulvestrant also showed consistent clinically meaningful treatment benefit after progression on an AI or after receiving up to one additional line of therapy for advanced breast cancer[1]. These data will be presented today during an oral presentation at the 2018 San Antonio Breast Cancer Symposium (SABCS) (Abstract #GS3-08).

Approximately 40% of patients living with HR+ advanced breast cancer have a PIK3CA mutation, which over activates the PI3K pathway[2]. When activated, the PI3K pathway is associated with tumor growth, resistance to endocrine treatment and a poor overall prognosis[3],[4]. Currently there are no approved treatments for breast cancer that specifically target this mutation.

"PIK3CA mutation is the most common actionable alteration in ER+ breast cancer, so it is encouraging to see a meaningfully prolonged PFS with BYL719 combination therapy in patients with PIK3CA mutated breast cancer who progressed on an aromatase inhibitor and who received up to one additional line of therapy prior to treatment with BYL719 plus fulvestrant," said Dejan Juric, MD, Director, Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center. "With the SOLAR-1 trial results, we can confidently say that identifying and targeting PIK3CA mutations is clinically important as we apply the precision oncology paradigm to breast cancer and continuously look for new treatment solutions to extend the lives of patients with this disease."

BYL719 in combination with fulvestrant consistently improved median PFS in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who progressed within 12 months of AI treatment (mPFS: 11.0 months vs 6.8 months for fulvestrant alone) or received up to one additional line of therapy for advanced breast cancer (mPFS: 10.9 months vs 3.7 months, respectively).

Most adverse events were mild to moderate in severity and generally manageable through dose interruption, dose reductions and medical management. Treatment discontinuation rate due to adverse events in those with a PIK3CA mutation receiving BYL719 plus fulvestrant was 3% compared to 2% for fulvestrant alone. The most frequent all-grade adverse events (>=40%) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%) and rash (40% vs 6%). The most common grade 3/4 events (>=10%) were hyperglycemia (37% vs <1%) and rash (13% vs <1%)[1].

Mutation status of participants in SOLAR-1 was identified by a clinical trial assay developed by Qiagen*. A significant PFS benefit was observed for BYL719 plus fulvestrant in patients with a PIK3CA mutation regardless of whether the mutation was identified by a tumor tissue test or ctDNA test, suggesting the potential viability of using liquid biopsies to identify PIK3CA mutation status (tissue positive HR=0.65; mPFS 11.0 months; plasma positive HR=0.56; mPFS 10.9 months)[1].

Novartis has entered into agreements with both Qiagen and Foundation Medicine** to develop flexible companion diagnostic solutions for BYL719 that utilize both tumor tissue and plasma sample types.

"Our work to develop an effective PI3K inhibitor started more than two decades ago, and learning from multiple clinical trial experiences, we have been able to advance an investigational targeted therapy for patients with this specific breast cancer," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "SOLAR-1 is the first breast cancer trial to show potential utility of liquid biopsies. We are excited to collaborate with Qiagen and Foundation Medicine on tissue and plasma tests that, if approved, may help oncologists identify patients who could benefit from BYL719 plus fulvestrant."

The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival and will be presented and discussed in the future. Overall survival (OS) results were immature at the time of data cut-off after 52% of events (HR=0.73; 95% CI 0.48-1.10; p=0.06; median not estimable vs 26.9 months). The prespecified O’Brien-Fleming stopping boundary was not crossed. Discussions with health authorities regarding the SOLAR-1 data have begun.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor[1].

The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment[1].

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with a PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability[1].

For the primary SOLAR-1 analysis, mutation status was determined by tumor tissue via polymerase chain reaction (PCR) analysis. Plasma ctDNA samples were also collected at baseline as a secondary endpoint. Plasma ctDNA mutation status of participants in SOLAR-1 was identified by an assay developed by Qiagen.

About BYL719 (alpelisib)
BYL719 is an investigational, orally bioavailable, alpha-specific PI3K inhibitor. In breast cancer cell lines harboring PIK3CA mutations, BYL719 has been shown to potentially inhibit the PI3K pathway and have antiproliferative effects. In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers[5].

On December 5, 2018 Janssen pharmaceutical companies at Johnson & Johnson reported the results of the MAIA phase 3 study, which shows that the addition of daratumumab to lenalidomide and dexamethasone (Rd) significantly reduced the risk of progression of the disease or death in patients with recently diagnosed multiple myeloma who are not suitable for autologous stem cell transplantation (ASCT) ( abstract # LBA-2 ) (Press release, Johnson & Johnson, DEC 5, 2018, View Source [SID1234531914]). 1 These data were presented during the oral session of last-minute last-minute summaries at the 60th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California.

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"The Phase 3 MAIA study reinforces the clinical profile of daratumumab in combination with a standard treatment regimen for newly diagnosed patients with multiple myeloma who are not eligible for transplantation," states Thierry Facon, MD, Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France and principal investigator. "The positive data show the potential role of daratumumab in combination with lenalidomide and dexamethasone as a new important therapeutic approach for this patient population."

At a mean follow-up of 28 months, data from the phase 3 MAIA study showed that daratumumab in combination with Rd significantly reduced the risk of progression or death of the disease by 44 percent in newly diagnosed multiple myeloma patients who are not fit for transplantation, compared to treatment with Rd alone (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.43-0.73, p <0.0001). 1 The median progression free survival (PFS) for daratumumab-Rd has not yet been achieved, compared to 31.9 months for patients who received Rd alone. oneThe incorporation of daratumumab resulted in deeper responses with respect to Rd alone, including increased rates of complete response (CR) or higher (48 percent vs. 25 percent) and improved rates of very good partial response (VGPR) or better (79 percent, versus 53 percent). 1 Daratumumab-Rd induced a 3-fold higher rate of negativity to minimal residual disease (MRD) compared to those who received Rd alone (24 percent vs. 7 percent). one

"Estos datos subrayan el perfil clínico estable observado en los pacientes recién diagnosticados con mieloma múltiple que reciben terapia con daratumumab, incluso para aquellos que no son aptos para el trasplante", comenta la Dra. Catherine Taylor, directora del área de terapia hematológica para Europa, Oriente Medio y África (EMEA) de Janssen-Cilag Limited. "Es el tercer estudio en pacientes recientemente diagnosticados que ha alcanzado su principal criterio de evaluación y esperamos continuar proporcionando avances innovadores a pacientes con mieloma múltiple a través de nuestro robusto programa de investigación clínica, que cuenta con el potencial de revolucionar el tratamiento del cáncer atacando a la enfermedad en sus etapas más tempranas", añade Taylor.

The most common grade 3/4 adverse events arising from treatment (TEAE) for daratumumab-Rd (≥ 10 percent) included neutropenia (50 percent), lymphopenia (15 percent), pneumonia (14 percent), and anemia (12 percent). 1 Infusion-related reactions (RRI) occurred in 41 percent of patients, of whom only 3 percent were grade 3/4. 1 The incidence of invasive secondary neoplasms was 3 percent in the daratumumab-Rd group, compared to 4 percent with Rd alone. 1 TEAEs with a death result were 7 percent in the daratumumab group, compared to 6 percent in the Rd group.1 The safety profile of daratumumab was in line with that of previous studies. one

These data will support a future marketing authorization request for daratumumab in combination with Rd for this patient population.

#FINISH#

About the MAIA 1 trial

The randomized, open-label, multi-center phase 3 study included 737 newly diagnosed patients with multiple myeloma unsuitable for high-dose chemotherapy and ASCT between 45 and 90 years (mean age 73). Patients were randomly assigned to receive daratumumab-Rd or Rd only in cycles of 28 days. In the daratumumab-Rd treatment group, patients received IV daratumumab 16 milligrams per kilogram (mg / kg) weekly for cycles 1 – 2, every two weeks for cycles 3-6 and every 4 weeks for cycle 7 and later. Patients in the daratumumab-Rd and Rd treatment group received 25 mg of lenalidomide on days 1 – 21 of each 28-day cycle and dexamethasone at 40 mg once per week for each cycle.

About daratumumab

Daratumumab is a first-generation biologic drug against the CD38 antigen, a protein that is expressed at high levels on the surface of multiple myeloma tumor cells, regardless of the stage of the disease. 2 Daratumumab induces rapid death of cancer cells through multiple immunologically mediated mechanisms of action, including complementary cytotoxicity (CDC), cellular cytotoxicity by antibody dependence (ADCC), cellular phagocytosis by antibody dependence (ADCP) and apoptosis , in which a series of molecular steps in a cell leads to its death. 3 Daratumumab also reduced a subset of suppressor cells of myeloid origin (CD38 + MDSCs), CD38 + T regulatory cells (Tregs) and CD38 + B (Bregs). 3 Currently daratumumab is under study through a comprehensive clinical development program on different treatments for multiple myeloma, including parameters such as first-line treatment and relapse. 4,5,6,7,8,9,10,11 Likewise, there are additional studies in progress or planned in order to study their potential in malignant or premalignant hematological diseases in which the CD38 protein is expressed, such as latent myeloma. . 12-13 For more information, see www.clinicaltrials.gov.

In Europe, daratumumab is currently indicated for use in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for an autologous stem cell transplant, whose previous treatment included an inhibitor of the proteasome and an immunomodulatory agent, and that they would have demonstrated a progression of the disease in the last treatment and 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 previous therapy 3 . For more information on daratumumab, see the Summary of Product Characteristics inView Source .

In August 2012 , Janssen Biotech, Inc. and Genmab A / S signed a worldwide agreement that awarded Janssen an exclusive license to develop, manufacture and market daratumumab. 14

About multiple myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells. 15 In 2016, more than 45,000 new cases were diagnosed in Europe and more than 29,000 patients died 16 . Up to half of the patients with a recent diagnosis do not reach the five-year survival rate 17 and almost 29% of the patients with MM will die within one year of diagnosis. 18

Although treatment may result in remission, unfortunately, most patients will most likely relapse as there is currently no cure. 19 Refractory multiple myeloma occurs when the disease progresses within 60 days of the last therapy. 20,21 Recurrent cancer occurs when the disease returns after a period of initial, partial or complete remission. 22 While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that may include bone problems, low blood counts, elevated calcium, kidney problems, or infections. 2. 3 Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have a poor prognosis and few treatment options are available. 24

On December 5, 2018 iCell Gene Therapeutics, LLC reported results from a study ongoing at Chengdu Military General Hospital of ICG144, the first CLL1-CD33 Compound CAR T-cell (cCAR) in clinical study, in patients with particularly difficult to treat Acute Myeloid Leukemia (AML) (Press release, iCell Gene Therapeutics, DEC 5, 2018, View Source [SID1234531930]). Patients 1 and 2 both failed multiple previous cycles of therapy and presented with complex conditions limiting further options. Treatment with CLL1-CD33 cCAR led both patients to complete response and engraftment of haploidentical stem cell transplantation (allo-HSCT) without myeloablative conditioning.

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"Patient response seen to date is encouraging for refractory AML patients, and opens the potential of this novel therapy as bridge to transplant, a supplement to chemotherapy, or as a standalone therapy for patients with acute myeloid leukemia." stated Dr. Fang Liu, MD, PhD, the Principal Investigator of the study who presented the results at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego. Dr. Yupo Ma, MD, PhD, Chairman of iCell Gene Therapeutics added, "Initial patient experience highlights the potential importance of iCell’s proprietary multiple antigen targeting and enhancing technologies to overcome antigen escape and improve treatment outcomes."

Upon enrollment, patients receive a lymphodepletion regimen consisting of fludarabine and cyclophasphamide followed by 1×106 – 2×106 CAR T cells/kg, nonmyeloablative conditioning and Haplo-HSCT

Patient 1 is a 6-year-old originally diagnosed with Franconi anemia transformed JMML and eventually to AML-M5 with more than 90% blasts in the marrow, complex karyotype and FLT3-ITD mutation.
Patient 2 is a 23-year-old, failed to TKIs, AP-CML (basophils>20%, plt>1000X109/L), T315I mutation.
Complete response and Haplo-HSCT engraftment was observed in both patients.
Grade 1 CRS and pancytopenia was observed in both patients.
Grade 3 neurotoxicity was observed in Patient 1.
About CLL1-CD33 cCAR T cell therapy

CLL1-CD33 cCAR is a compound Chimeric Antigen Receptor (cCAR) immunotherapy with two distinct functional CAR molecules expressed on a T-cell, directed against the surface proteins CLL1 and CD33. The diseases treated by CLL1-CD33 cCAR could include acute myeloid leukemia, myelodysplastic syndromes, chronic myeloid leukemia and chronic myeloproliferative neoplasms. CLL1 is associated with leukemia stem cells and disease relapse, while CD33 is expressed on bulky AML disease. Treatment of AML is a challenge due to heterogeneity of AML bearing cells, which renders single antigen targeting CAR T-cell therapy ineffective. ICG144 cCAR is designed to target the mechanisms of single-CAR relapse, specifically antigen escape and leukemic stem cells.

About AML

Acute myeloid leukemia (AML) is the abnormal proliferation of immature myeloid cells and the most common leukemia in adults. Prognosis is dismal when AML relapses or is refractory to chemotherapy. Mortality associated with this disease is high, with approximately 10,000 deaths in 2018 in the US.

On December 5, 2018 Replimune Group Inc. (NASDAQ: REPL), a biotechnology company developing oncolytic immunotherapies derived from its Immulytic platform, reported that Robert Coffin, Ph.D., Chief Executive Officer and Director of Replimune, will present at the BMO Capital Markets 2018 Prescriptions for Success Healthcare Conference on Wednesday, December 12, 2018 at 2:40 PM ET at the Mandarin Oriental Hotel in New York, NY (Press release, Replimune, DEC 5, 2018, View Source [SID1234531896]).

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