On June 6, 2016 Takeda Pharmaceutical Company Limited (TSE: 4502) and Roivant Sciences Ltd. reported the formation of Myovant Sciences Ltd. ("Myovant"), a biopharmaceutical company focused on delivering innovative women’s health and prostate cancer solutions by efficiently advancing new medicines to market that have the potential to improve the lives of millions of patients (Press release, Takeda, JUN 6, 2016, View Source [SID:1234513109]). In addition, Lynn Seely, MD, an endocrinologist who led the development of XTANDI (enzalutamide) for the treatment of prostate cancer as the Chief Medical Officer of Medivation from 2005 to 2015, was named the President & Chief Executive Officer of Myovant Sciences, Inc.

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Myovant Partnership Summary
Takeda has granted Myovant an exclusive, worldwide license (excluding Japan and certain other Asian countries) to relugolix (TAK-385), a phase 3 drug candidate that has been evaluated in over 1,300 patients to date. Relugolix has successfully demonstrated significant clinical benefit and was generally well-tolerated across multiple, large, randomized phase 2 clinical trials in three different indications. Relugolix is being developed as an oral, once-daily, potential best-in-class gonadotropin-releasing hormone (GnRH) receptor antagonist for uterine fibroids, endometriosis and prostate cancer. Takeda will retain commercial rights for relugolix in Asian countries, including Japan, where Takeda is actively conducting two phase 3 registration studies for the treatment of uterine fibroids. Takeda has also granted Myovant an exclusive, worldwide license to RVT-602 (TAK-448), a novel, oligopeptide kisspeptin receptor agonist as a product candidate for the treatment of infertility in females. Financial terms of the partnership were not disclosed.

"With Takeda strengthening its focus around the core therapeutic areas of oncology, gastroenterology and central nervous system diseases, as well as establishing a strategy that embraces innovative partnerships, it is important that we seek alternatives to further develop and create value around promising assets that are either outside these areas of focus or where strategic partnership makes more sense for our business," said Andrew Plump, M.D., Ph.D., Chief Medical and Scientific Officer of Takeda. "The formation of Myovant Sciences represents such an innovative partnership arrangement to further advance relugolix by relying on Roivant’s and Myovant’s in-house development capabilities in the major markets where they are building deep expertise, while leveraging Takeda’s commercial presence in certain Asian territories."

"We are very pleased to partner with Takeda to meet the needs of patients suffering from hormone-driven diseases and disorders," said Vivek Ramaswamy, CEO of Roivant Sciences, Inc. "The creation of Myovant enables a ‘win-win’ outcome for both our partner and for patients by launching a company to address major unmet medical needs in women’s health, prostate cancer and beyond."

Appointment of Dr. Lynn Seely as President & Chief Executive Officer
Lynn Seely, MD, brings over 20 years of drug development and biopharmaceutical company leadership to her role as the President & Chief Executive Officer of Myovant Sciences, Inc. Most recently, Dr. Seely served as Chief Medical Officer of Medivation, Inc. from its early stages in March 2005 through October 2015. She served on the Executive Committee and led the development of XTANDI for the treatment of metastatic castration-resistant prostate cancer from IND-enabling studies through to NDA approval and post-approval clinical studies. Dr. Seely was responsible for building the clinical organization at Medivation, as well as the regulatory, quality, project management, medical affairs and biologics manufacturing functions. Dr. Seely currently serves on the board of directors of Blueprint Medicines Corporation, and she previously served as Vice President of Clinical Development at Anesiva, Inc. (formerly Corgentech) and at Cytyc Health Corporation. Dr. Seely received a medical degree from the University of Oklahoma College of Medicine and completed her residency in internal medicine at Yale-New Haven Hospital. After serving as Chief Resident in Internal Medicine at Yale University School of Medicine, she completed her basic science and clinical fellowship in endocrinology and metabolism at the University of California, San Diego.
"I look forward to delivering on Myovant’s mission to bring innovative new treatments to women suffering from diseases such as uterine fibroids and endometriosis and to men with prostate cancer," stated Dr. Lynn Seely, President & CEO of Myovant Sciences, Inc. "Relugolix and our partnership with Takeda represent an exceptional foundation on which to build this exciting new company."

About Relugolix
Relugolix is a once-daily, orally administered, potential best-in-class gonadotropin-releasing hormone (GnRH) receptor antagonist for the treatment of uterine fibroids and endometriosis, and a potential best- and first-in-class treatment for hormone-sensitive prostate cancer (HSPC). Relugolix has been evaluated in over 1,300 patients to date, and has successfully demonstrated significant clinical benefit and was generally well-tolerated across multiple, large, randomized phase 2 clinical trials in three different indications. Takeda is currently enrolling two phase 3 clinical trials of relugolix for registration in Japan for the treatment of uterine fibroids.

By inhibiting GnRH receptors in the pituitary gland, relugolix rapidly reduces circulating sex hormone levels leading to suppression of estrogen and testosterone. Suppression of these sex hormones improves the symptoms of women with uterine fibroids and endometriosis, and decreases prostate-specific antigen (PSA) levels in men with HSPC.

In a 216-patient phase 2 study for the treatment of uterine fibroids, women who received relugolix had a significant reduction in menorrhagia, or abnormally heavy bleeding during menstruation. In a 487-patient phase 2 study for the treatment of endometriosis, women who received relugolix had a significant reduction in both non-menstrual and menstrual pelvic pain. Based on these results, two phase 3 registration studies in women with uterine fibroids are underway in Japan (NCT02655237, NCT02655224). In two phase 2 studies in approximately 225 men with HSPC, which included control arms of either an injectable GnRH agonist (leuprolide acetate) or a GnRH antagonist (degarelix), respectively, oral once-daily relugolix suppressed serum testosterone to castrate levels and decreased PSA. The safety of relugolix across all phase 2 studies was generally well-tolerated, consistent with the mechanism of action.

The clinical experience to date, supported by an extensive preclinical development program, suggests that oral relugolix, administered once-daily, could be an important advancement in the treatment options available for women suffering from endometriosis and uterine fibroids. In addition, relugolix could provide men with HSPC an important new treatment option as the first oral GnRH receptor antagonist that offers an alternative to injectable therapies.

About RVT-602
RVT-602 (TAK-448) is a kisspeptin analog that acts to stimulate the physiologic release of GnRH and downstream hormones important in fertility such as luteinizing hormone. Recent evidence from trials performed in women undergoing In-vitro Fertilization (IVF) revealed that the native kisspeptin peptide has the potential to act as an alternative to human chorionic gonadotropin (hCG) or GnRH agonists in triggering egg maturation, an essential step in every IVF cycle.

About Myovant Sciences
Myovant Sciences is focused on innovative treatments for women’s health conditions and prostate cancer. The company’s lead program is relugolix, a phase 3 drug candidate for multiple indications, including uterine fibroids, endometriosis and prostate cancer. Myovant was formed through a strategic partnership between Roivant Sciences and Takeda. Additional information about Myovant Sciences is available through its website, www.myovant.com

OnJune 7, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA:CTIC) reported long-term safety and efficacy results from the pivotal Phase 3 PERSIST-1 trial evaluating pacritinib versus best available therapy, excluding treatment with JAK2 inhibitors (BAT), in patients with myelofibrosis (Press release, CTI BioPharma, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175567 [SID:1234513106]). As previously reported, the PERSIST-1 trial met its primary endpoint in the intent-to-treat population with statistically significant reduction in spleen volume when compared to patients receiving BAT. The results represent an update on the efficacy and safety for all patients regardless of their initial platelet count, including patients with very low platelet counts at study entry, a condition known as severe or life-threatening thrombocytopenia. The most frequently occurring adverse events with pacritinib were gastrointestinal events and incidence decreased over time. For patients crossing over to receive pacritinib treatment (84 percent of BAT patients), less than 5 percent of patients had diarrhea with only one patient experiencing grade 3. Patients in the BAT arm that crossed over to receive pacritinib treatment had a similar rate of events as patients initially randomized to BAT or pacritinib. A planned analysis of the study up to 72 weeks demonstrated treatment with pacritinib led to durable reductions in spleen volume and symptom burden, two key measures of disease control, in patients with myelofibrosis, including patients with low platelets at baseline (less than 50,000 per microliter and less than 100,000 per microliter). Patients who crossed over to pacritinib from BAT experienced similar reductions in spleen volume and symptom burden as patients initially randomized to pacritinib, including patients with low platelets. Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R, which are kinases found to be involved in the growth and spread of myelofibrosis and other blood-related cancers.

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"From the time a patient is diagnosed with myelofibrosis, the incidence of disease-related thrombocytopenia increases with time," stated Claire Harrison, M.D., Consultant Hematologist, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom and one of the principal investigators for PERSIST-1. "Patients with thrombocytopenia have significantly greater symptom burden, distinct clinical characteristics and shorter overall survival. There is currently a significant unmet need for patients with myelofibrosis who are unable to tolerate or control their disease on other treatments due to low platelet counts.

Dr. Harrison added, "It is encouraging to see that patients with baseline thrombocytopenia who were treated with pacritinib, had stable mean platelet counts and hemoglobin levels through the end of treatment, and that some patients with very low platelets increased their platelet counts while receiving pacritinib treatment. In this intermediate- to high-risk patient group, pacritinib was generally well tolerated."

Myelofibrosis is a rare, but serious and life-threatening chronic leukemia that disrupts the normal production of blood cells and results in scarring of the bone marrow, limiting the ability to produce new blood cells and prompting the spleen and other organs to take over this function. The disease often leads to an enlarged spleen and lower than normal counts of blood cells – including red blood cells and platelets, which are essential for blood clotting. Frequent causes of death among patients with myelofibrosis include leukemic transformation (31 percent), disease progression (18 percent), and thrombosis and cardiovascular complications (13 percent) 1.

Below are highlights presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held June 3–June 7, 2016 in Chicago, Ill. The poster presentations are available at www.ctibiopharma.com.

Highlights of Data Presented

Mesa, R, et al. Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): 72 week follow-up of the phase III PERSIST-1 trial. Abstract #7065
In this poster, an update on efficacy and safety of the PERSIST-1 clinical trial up to Week 72 is provided for all patients in the study (pacritinib n=220; BAT n=107), regardless of platelet count. Ninety patients (84 percent) randomized to BAT crossed over to receive pacritinib at a median of 27.2 weeks.

Responses to pacritinib were durable and rates of 35 percent or greater spleen volume reduction (SVR) were maintained from Weeks 24 to 72 (25 percent vs. 24 percent). Patients who crossed over to receive pacritinib achieved similar responses to those receiving initial treatment with pacritinib. Overall survival, although not a primary or secondary endpoint of the trial, did not show a statistically significant difference between the pacritinib and BAT arms. This was primarily due to an imbalance between the two arms, with higher risk patients in the pacritinib arm vs. BAT. The result was potentially confounded by a high percentage of patients who crossed over at Week 24 to receive pacritinib therapy. Pacritinib-treated patients who achieved SVR greater or equal to 20 percent had statistically significant longer overall survival vs. patients who did not achieve SVR at this level.

The most frequently occurring adverse events with pacritinib were gastrointestinal events and the incidence decreased over time. Incidence of grade 3/4 treatment-emergent diarrhea with initial pacritinib treatment was highest in Weeks 1-8 (3 percent) and decreased in Weeks 8-16 (1.4 percent), Weeks 16-24 (1.5 percent) and in the final period analyzed, Weeks 64-72 (0.9 percent). Up to 24 weeks, prior to the majority of patients in the BAT arm crossing over, there was no statistically significant difference in the incidence of cardiac and bleeding adverse events between the pacritinib and BAT arms; following crossover to pacritinib, BAT patients had a similar rate of all grades of adverse events. The incidence of all grade cardiac AEs was similar between pacritinib and BAT arms between Weeks 1 and 24; incidence of cardiac AEs was greater for pacritinib between Weeks 24 and 72 vs. BAT, but was low overall (5 percent or less at any time). Among all patients, incidence of grade 3/4 bleeding events was 3 percent or less during any 8-week time interval.

Harrison, C, et al. Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): Outcomes in patients (pts) with baseline (BL) thrombocytopenia. Abstract #7011
This analysis examines outcomes up to 72 weeks among patients in the PERSIST-1 trial with baseline platelets less than 100,000 per microliter treated with pacritinib vs. BAT (pacritinib, n=72; BAT, n=34). For patients receiving pacritinib, a median duration of spleen volume reduction (SVR) of 35 percent or greater was 48 weeks for patients with baseline platelets less than 50,000 per microliter and 57 weeks for patients with baseline platelets less than 100,000 per microliter. For BAT-treated patients who crossed over to receive pacritinib before or after Week 24, duration of SVR was 73 weeks for patients with baseline platelets less than 50,000 per microliter and 46 weeks for patients with baseline platelets less than 100,000 per microliter. At Week 36, 46 percent (6/13) of evaluable pacritinib-treated patients with baseline platelets less than 50,000 per microliter and 48 percent (12/28) of evaluable pacritinib-treated patients with baseline platelets less than 100,000 per microliter achieved 50 percent or greater reduction in Total Symptom Score (TSS). This is an increase from 32 percent and 42 percent, respectively, at Week 24.

Patients treated with pacritinib had stable mean platelet counts and hemoglobin levels through Week 72 and increased platelet counts in patients with platelets less than 50,000 per microliter. At 24 weeks, bleeding events occurred at a similar rate in pacritinib-and BAT-treated patients; following crossover to pacritinib, BAT patients had a similar rate of events. Among patients with baseline thrombocytopenia treated with pacritinib, mean hemoglobin levels remained stable through Week 72. Due to BAT crossover to pacritinib at Week 24, there were no evaluable patients with baseline thrombocytopenia in the BAT arm beyond Week 36. These data suggest pacritinib treatment led to durable reductions in spleen volume and symptom burden.

Harrison, C, et al. Outcomes in patients with myelofibrosis and RBC-transfusion dependence in the phase III PERSIST-1 study of pacritinib vs. best available therapy. Abstract #7066
In this poster, pacritinib-treated patients demonstrated clinically meaningful reductions in spleen volume independent of RBC-transfusion independence (RBC-TI). Among pacritinib-treated patients, 16 percent (36/220) were RBC-transfusion dependent (RBC-TD) at baseline. Eighteen (18) patients were RBC-TD at the time of crossover.

Twenty-two percent (12/54) of RBC-TD patients treated with pacritinib either from study start or after crossover achieved RBC-TI during the course of the study. During the course of the study, 25 percent (9/36) of RBC-TD patients treated with pacritinib at the start of the study achieved RBC-TI vs. 0 percent (0/16) patients treated with BAT (p=0.043). Seventeen percent (3/18 patients) of RBC-TD patients at the time of crossover achieved RBC-TI during the crossover period. Pacritinib treatment was associated with improved patient outcomes for those with baseline RBC-TD.

Mesa, R, et al. Pacritinib (PAC) vs. best available therapy (BAT) in myelofibrosis (MF): Long-term follow-up of patient-reported outcomes (PROs) in the phase III PERSIST-1 trial. Abstract #7067
Patient Reported Outcomes (PRO) data at 24 weeks was previously reported and the poster presented today provided an update at Week 48. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a PRO assessment tool designed to measure myelofibrosis-related symptom burden resulting in a TSS based on how the patient feels or functions in relation to six common symptoms. The proportion of patients achieving a TSS reduction of 50 percent or greater improved from Weeks 24 to 48 and was greater than observed with BAT showing that reduction in symptoms continued to increase over time. In patients who crossed over from BAT to pacritinib, reductions in TSS improved from Week 24 to Week 36. Mean percentage reductions in common symptoms measured in both MPN-SAF versions at Week 48 were greater than those observed at Week 24 among patients treated with pacritinib.

About PERSIST-1

PERSIST-1 is a randomized (2:1), controlled Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to BAT – which included a broad range of currently utilized treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis), regardless of the patients’ platelet counts. As previously reported, the trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan) in the intent-to-treat population (ITT). These results included patients with severe or life-threatening thrombocytopenia. At study entry, 62 percent of patients had primary myelofibrosis; 46 percent of patients were thrombocytopenic; 32 percent of patients had baseline platelet counts less than 100,000 per microliter; and 16 percent of patients had platelet counts less than 50,000 per microliter; normal platelet counts range from 150,000 to 450,000 per microliter. The design of PERSIST-1 allowed for patients on the BAT arm to crossover and receive treatment with pacritinib if their disease progresses or after they achieve the 24-week measurement endpoint. Although crossover design of clinical trials may confound evaluation of survival, which is a tertiary endpoint of PERSIST-1, such designs are frequently used in cancer studies. The median duration of treatment was 16.2 months in patients treated with pacritinib, compared to 5.9 months in patients treated with BAT. The majority of patients (84 percent) on the BAT arm eventually crossed over to receive pacritinib therapy.

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy. Clinical studies for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016. A second Phase 3 study, known as PERSIST-2, is evaluating pacritinib in a subset of patients with myelofibrosis whose platelet counts are 100,000 per microliter or less. Although not all patients enrolled reached the 24-week endpoint prior to the full clinical hold on pacritinib, approximately two thirds of the enrolled patients reached or exceeded the 24-week endpoint evaluation. Therefore, these patients will contribute to the evaluation of the study endpoints. Based on the assumptions of the design, CTI BioPharma believes there is sufficient power to reach statistical significance of the primary objectives. Top-line results from the PERSIST-2 Phase 3 trial of pacritinib are expected in the third quarter of 2016.

CTI BioPharma and Baxalta Incorporated (now part of Shire plc) are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S.

About Myelofibrosis and Myeloproliferative Neoplasms

Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers. The three main types of MPNs are myelofibrosis, polycethemia vera and essential thrombocythemia.2

Myelofibrosis is a serious and life-threatening bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain.

The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S., of which myelofibrosis accounts for approximately 18,000 patients.3 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis3 and is a progressive disease with approximately 20 percent of patients eventually developing AML.4 The median survival for high-risk myelofibrosis patients is less than one and a half years, while the median survival for patients with myelofibrosis overall is approximately six years.5

On June 6, 2016 GlycoMimetics, Inc. (NASDAQ:GLYC) reported dosing of the first patient with relapsed/refractory acute myeloid leukemia in the Phase 2 portion of its ongoing Phase 1/2 clinical trial evaluating its novel E-selectin antagonist, GMI-1271, combined with induction chemotherapy (Press release, GlycoMimetics, JUN 6, 2016, View Source [SID:1234513101]).

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For the study’s Phase 2 portion, the optimal dose has been determined, and clinical investigators will expand the number of patients receiving GMI-1271 to obtain additional safety and efficacy data. Study enrollment is limited to patients at least 18 years old with relapsed or refractory AML and who would be treated with mitoxantrone, etoposide, and cytarabine (‘MEC’). All patients must be eligible to receive this chemotherapy regimen, and will be given GMI-1271 in addition to this combination chemotherapy. During the Phase 1 portion of the study, patients received a single cycle of treatment including GMI-1271. During this Phase 2 portion, certain patients will be eligible to receive an additional cycle of treatment.

"The data from the first cohorts point to both the safety and potential efficacy of GMI-1271 as a treatment for AML," said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. "In the second half of this trial, we will further assess if patients with relapsed or refractory AML respond well to this combination approach while also including those who have been newly diagnosed with the disease in a separate arm of the study. If the second half confirms our earlier preclinical and clinical findings, we believe that GMI-1271 could well address the unmet needs of AML patients, beyond what can be done with currently available therapies."

This clinical trial is a multinational open-label study evaluating endpoints for safety, pharmacokinetics (PK) and efficacy of GMI-1271 in combination with induction chemotherapy in patients with high-risk AML. This trial is being conducted at a number of academic medical institutions in the United States, Ireland, and Australia. While the primary objective is to assess safety, additional endpoints include overall response rate, biomarkers of activity, durability of response and overall survival. This Phase 2 portion of the study is expected to include approximately 25 participants.

About GMI-1271

GMI-1271 is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with AML cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. Preclinical research points to the drug’s potential role in moving cancerous cells out of the protective environment of the bone marrow where they hide and escape the effects of chemotherapy. In preclinical studies using animal models of AML, the results of which were presented at meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper), GMI-1271 was also associated with a reduction of chemotherapy-induced neutropenia and chemotherapy-induced mucositis.

On June 6, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of clinical data related to KTN3379, the Company’s most advanced product candidate for the potential treatment of various solid tumors (Press release, Kolltan Pharmaceuticals, JUN 6, 2016, View Source [SID:1234513100]). These data were discussed in an oral presentation titled, "Safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity in a phase 1b study evaluating anti-ErbB3 antibody KTN3379 in adults with advanced tumors alone and with targeted therapies," at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting, which is taking place in Chicago, IL, June 3-7, 2016. KTN3379 is a novel antibody that blocks the activity of the ErbB3 (HER3) receptor by binding to a unique epitope and effectively locking the ErbB3 receptor in an inactive conformation. In addition, KTN3379 has been engineered to extend serum half-life. These features are believed to contribute to the favorable potency and pharmacology of KTN3379.

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"The data presented today are very encouraging and demonstrate that anti-tumor activity was observed in certain extensively pretreated patients when KTN3379 was administered in combination with other targeted therapeutics. The evidence from the Phase 1b clinical trial and several preclinical studies supports the initiation of a Phase 2 clinical trial in HNSCC, and we believe KTN3379 has the potential to provide clinical benefit across multiple tumor types where ErbB3 plays a role in tumor progression and therapeutic resistance. There exists an unmet medical need in cancer patients that have exhausted many or all treatment options, and we plan to advance the clinical development of KTN3379 to address this need," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

Study KTN3379-CL-001 (NCT02014909) has two parts. In Part 1, which was the subject of an oral presentation by Dr. Patricia LoRusso at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, KTN3379 was administered to patients with advanced solid tumors as a single agent. In this part of the study, a maximum tolerated dose was not reached and KTN3379 demonstrated favorable tolerability and pharmacology profiles. In Part 2 of the study, the focus of today’s oral presentation, KTN3379 was evaluated in combination with four different targeted therapies. KTN3379 was administered at 15 and 20 mg/kg every three weeks in combination with cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4), or trastuzumab (N=10). Safety monitoring and RECIST-based tumor assessments were conducted. Pharmacokinetic parameters and immunogenicity were evaluated. In addition, archival tumor tissue was tested for mRNA expression of neuregulin (NRG) in baseline tumor samples. Sixty percent of the patients had received at least four prior treatment regimens. Enrollment in the vemurafenib patient cohort is currently being expanded.

Joseph Paul Eder, M.D., Professor of Medicine (Medical Oncology) at the Yale Cancer Center, commented, "The ErbB family of receptors has been among the most successful targets in the treatment of cancer, resulting in therapies that are standard of care across a number of tumor types. The scientific rationale supporting the development of this anti-ErbB3 antibody, including its differentiated features and potency, together with durable responses observed in patients with resistant tumors, warrants the further development of KTN3379 in combination with targeted therapies."

Ronald Peck, M.D., Chief Medical Officer and Senior Vice President, Clinical Development at Kolltan added, "The responses reported in this trial were impressive, in particular the durable complete response in a HNSCC patient receiving the combination of KTN3379 and cetuximab after disease progression on single agent cetuximab and the durable partial response in a non-small cell lung cancer (NSCLC) patient receiving KTN3379 plus vemurafenib after progressing on another BRAF inhibitor and other prior therapy. These results, as well as extensive preclinical data, support the planned Phase 2 clinical trial of KTN3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma and the ongoing expansion of the Phase 1b BRAF-mutant tumor cohort receiving KTN3379 in combination with vemurafenib."

The results were presented by Gerald Falchook, M.D., Director of Drug Development at Sarah Cannon Research Institute at HealthONE in Denver, Colorado. Following is a summary of the key results:

38 total patients were treated in four cohorts with KTN3379 in combination with the following targeted therapies: cetuximab (N=16), erlotinib (N=8), vemurafenib (N=4), or trastuzumab (N=10);

The patient population enrolled in Part 2 of Study KTN3379-CL-001 was generally heavily pretreated, with approximately 97% of patients having received at least one prior treatment regimen and 60% of patients having received at least four prior treatment regimens;

The safety profile of the combination therapies was consistent with the safety profiles of the individual agents. The most common treatment related adverse events included diarrhea and rash, which were resolved with medical therapy or dose reduction;

Pharmacokinetic data demonstrated that all patients achieved serum concentrations of KTN3379 required for maximal anti-tumor activity in animal tumor models; and

Showed a consistent trend towards slower clearance and longer terminal half-life of KTN3379 compared to published data for other anti-ErbB3 antibodies

Anti-tumor activity was achieved in several patients with resistant tumors treated with KTN3379 in combination with cetuximab or vemurafenib

Cetuximab combination arm:

Anti-tumor activity was observed in certain of the nine patients with HNSCC treated with KTN3379 in combination with cetuximab including a patient with a durable complete response (CR) who had undergone extensive prior therapy including chemotherapy, radiation, and multiple surgeries; and

The patient with a CR had previously progressed five months after initiating single agent cetuximab. The patient’s CR with KTN3379 in combination with cetuximab persisted for 10.5 months after starting study therapy. The patient’s tumor was found to express the ErbB3 ligand, neuregulin.

Vemurafenib combination arm:
In four patients with BRAF-mutant cancers that were treated with KTN3379 in combination with vemurafenib, stable disease was reported in one patient with colorectal cancer and durable partial responses (PRs) were reported in two patients with NSCLC; and
Notably, one of the two NSCLC PRs was in a patient who underwent extensive prior therapy, which included combination chemotherapy, another BRAF-inhibitor (dabrafenib), and combination immunotherapy (an investigational regimen of an anti-CTLA4 and an anti-PDL-1). Previously, the patient had disease progression within two months of initiating dabrafenib. The patient’s PR persisted for 12 months after starting study therapy. The patient’s tumor was found to express neuregulin.

About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, and gastric cancers, and melanoma. Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors (NCT02014909, NCT02456701, and NCT02473731).

On June 6, 2016 Principia Biopharma Inc., a private clinical-stage biopharmaceutical company, reported that initial Phase 1 clinical data for its fibroblast growth factor receptor (FGFR) 1-4 inhibitor, PRN1371, was presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Principia Biopharma, JUN 6, 2016, View Source [SID:1234513099]). PRN1371 is an oral, irreversible covalent FGFR 1-4 inhibitor currently being evaluated in a Phase 1 dose escalation trial in patients with solid tumors to be followed by a dose expansion phase.

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Clinical, pharmacokinetic and pharmacodynamic data from the ongoing international, multi-center trial were presented. The data demonstrated consistent pharmacokinetics with high apparent bioavailability, and robust pharmacodynamic impact on surrogate markers of serum phosphate and FGF23 levels. PRN1371 was well tolerated, with no dose limiting toxicities or any major off-target safety signals observed.

The presented poster will be available on the Scientific Publications section of Principia Biopharma’s website at View Source

About FGFR inhibition in cancer

FGFR genetic alterations occur in a wide range of cancers including lung, breast, stomach, liver and bladder. These alterations may be amenable to targeted therapy designed to inhibit the effects of the alteration in driving tumor growth. Highly selective and potent FGFR inhibitors, such as PRN1371, may be able to slow or reverse tumor growth with a lower rate of side effects compared with less selective drugs.