On January 7, 2019 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported its key 2019 initiatives in conjunction with its presentation at the 37th Annual J.P. Morgan Healthcare Conference in San Francisco (Press release, Agios Pharmaceuticals, JAN 7, 2019, View Source [SID1234532553]). The company will webcast its presentation today at 9:30 a.m. PT (12:30 p.m. ET) at investor.agios.com.

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"During 2018, just 10 years after the founding of Agios, we achieved approval of our second internally discovered oncology medicine, launched a robust registrational program in PK deficiency and successfully opened the company’s seventh IND," said David Schenkein, M.D., chief executive officer at Agios. "Our validated research platform and proven drug development strategy are poised to help drive future growth across our oncology and rare genetic disease portfolios. Our priorities for 2019 include expanding the reach of our IDH inhibitors into the frontline AML and solid tumor settings, completing enrollment in two pivotal studies of mitapivat, exploring the utility of PKR activators in other hemolytic anemias, and furthering clinical development for AG-270 in MTAP deleted tumors and AG-636 in lymphoma."

The company plans to achieve the following milestones in 2019.

Cancer:

Potential FDA approval of the supplemental new drug application (sNDA) for single agent TIBSOVO (ivosidenib) for the treatment of patients with newly diagnosed AML with an IDH1 mutation who are not eligible for standard therapy.
Submit a sNDA to the FDA for TIBSOVO for second line or later IDH1m cholangiocarcinoma by year-end.
Initiate a registration-enabling Phase 3 study of vorasidenib (AG-881) in low-grade glioma with an IDH1 mutation by year-end.
Determine recommended dose of AG-270, a first-in-class methionine adenosyltransferase 2a (MAT2A) inhibitor, in methylthioadenosine phosphorylase (MTAP)-deleted tumors and initiate expansion arms, including a single-agent arm in a variety of MTAP-deleted cancers and a combination arm in a solid tumor in the first half of 2019.
Initiate a Phase 1 dose-escalation trial of AG-636, an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase (DHODH), in lymphoma in the first half of 2019.
Rare Genetic Diseases:

Complete enrollment in two global pivotal trials for mitapivat in adults with pyruvate kinase (PK) deficiency by year-end 2019:

ACTIVATE-T: A single-arm trial of approximately 20 regularly transfused patients
ACTIVATE: A 1:1 randomized, placebo-controlled trial of 80 patients who do not receive regular transfusions
Achieve proof-of-concept for mitapivat in thalassemia in the second half of 2019.
The company highlighted key data presentations expected in 2019.

Updated data from the ongoing Phase 1 combination trial of TIBSOVO with azacitidine in patients with newly diagnosed AML with an IDH1 mutation in the first half of 2019.
Data from the perioperative ‘window’ trial with TIBSOVO and vorasidenib in IDHm low-grade glioma in the first half of 2019.
Topline data from the Phase 3 ClarIDHy study of TIBSOVO in IDH1m advanced cholangiocarcinoma to be reported in the first half and full data to be presented in the second half of 2019.
Data from the dose-escalation portion of the ongoing Phase 1 study of AG-270 in patients with MTAP-deleted tumors in the second half of 2019.
The company also provided an update on the following 2018 milestones achieved in December.

Submitted an sNDA to the FDA for TIBSOVO for the treatment of patients with newly diagnosed AML with an IDH1 mutation who are not eligible for standard therapy.
Submitted a Marketing Authorization Application to the European Medicines Agency for TIBSOVO for the treatment of adult patients with R/R AML with an IDH1 mutation.
Initiated a Phase 2 proof-of-concept trial of mitapivat in thalassemia.
2018 Year-End Cash and Guidance
Agios ended 2018 with approximately $805 million of cash, cash equivalents and marketable securities. The company expects that its cash, cash equivalents and marketable securities as of December 31, 2018, together with anticipated product and royalty revenue, anticipated interest income, and anticipated expense reimbursements under our collaboration agreements, but excluding any additional program-specific milestone payments, will enable the company to fund its anticipated operating expenses and capital expenditure requirements through at least the end of 2020.

Presentation at 37th Annual J.P. Morgan Healthcare Conference
Agios will webcast its corporate presentation from the 37th Annual J.P. Morgan Healthcare Conference in San Francisco on Monday, January 7, 2019 at 9:30 a.m. PT (12:30 p.m. ET). A live webcast of the presentation can be accessed under "Events & Presentations" in the Investors section of the company’s website at agios.com. A replay of the webcast will be archived on the Agios website for at least two weeks following the presentation.

On January 7, 2019 Adagene, Inc., an innovative antibody discovery and engineering company, reported a collaboration with Dr. Richard Childs, Chief of the Laboratory of Transplantation Immunotherapy at the National, Heart, Lung, and Blood Institute, part of the National Institutes of Health, to discover antibodies targeting a novel antigen expressed on the surface of tumor cells (Press release, US NIH, JAN 7, 2019, View Source [SID1234553809]). Dr. Childs’s laboratory will convert these antibodies into a CAR-T, as they work to develop a non-major histocompatibility complex (MHC) restricted immunotherapy approach to targeting an endogenous retrovirus with tumor-restricted expression.

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"We are very pleased to be collaborating with such an expert in the field of clinical cancer biology," said Peter Luo, CEO of Adagene. "At Adagene, our goal is to translate innovation and scientific research into life-saving medications. It is incredibly rewarding to have the opportunity to leverage our proprietary Dynamic Precision Library to develop antibodies against a disease with such highly unmet medical need."

"Adagene has gone to great lengths to develop our leading antigen display technology," said Felix Du, Head of Technology Development at Adagene. "With our unique combination of antigen presentation technologies and having a very large, diverse and fully human antibody discovery library we were able to find the first antibodies targeting non-MHC restricted surface-expressed antigens against this class of challenging cancer targets."

On January 7, 2019 Cellectar Biosciences (Nasdaq: CLRB), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of drugs for the treatment of cancer, reported median overall survival (mOS) in Cohorts 1-4 of the company’s ongoing Phase 1 clinical trial evaluating CLR 131 for the treatment of relapsed/refractory (R/R) multiple myeloma (MM) (Press release, Cellectar Biosciences, JAN 7, 2019, View Source [SID1234532506]). The results showed mOS of 22.0 months among 15 patients, all of whom were heavily pretreated, averaging five prior lines of systemic therapy. Each patient in Cohorts 1-4 of this dose-escalation study received a single 30-minute infusion of CLR 131.

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All patients enrolled in Cohorts 1 through 4 were previously treated with both proteasome inhibitors and immunomodulatory drugs, and experienced disease progression with greater than one-third dual refractory. While no head-to-head studies have been conducted between CLR 131 and other therapies in this heavily pretreated population, for background purposes, a 2016 article published in the journal Bone Marrow Transplantation refractory to both proteasome inhibitors and immunomodulatory drugs achieve mOS of 9 months.1 Additionally, mOS for R/R MM patients receiving treatment in third line averages approximately 12 months of survival, including several recently approved drugs.2,3

"The median overall survival of 22 months in this heavily pretreated patient population is very encouraging. These are patients with limited therapeutic options and, unfortunately, face poor prognoses," said James Caruso, president and chief executive officer of Cellectar Biosciences. "The convenience afforded by CLR 131 delivered in only one or two doses as currently administered in our ongoing hematology studies makes it a far less intrusive regimen than other treatments that must be administered at regular dosing intervals. We believe extending mOS with a more patient-friendly dosing regimen provides both a distinctive product profile and the potential to provide beneficial patient outcomes even in later lines of therapy."

1. R.F Cornell and A.A. Kassim (2016). Evolving paradigms in the treatment of relapsed/refractory multiple myeloma: increased options and increased complexity. Journal of Bone Marrow Transplantation

2. Jurczyszyn et al (2014). New drugs in multiple myeloma – role of carfilzomib and pomalidomide. Contemporary Oncology

3. Dimopolous et al (2016). Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood Review

About the Phase 1 R/R MM Trial

The objective of this multicenter, open-label, Phase 1 dose-escalation study is the characterization of safety and tolerability of CLR 131 administered either as a single-dose or split-dose, 30-minute infusion(s) in patients with R/R MM. In Cohorts 1-4, patients received doses of 12.5 mCi/m2 up to 31.25 mCi/m2. All doses were deemed safe and well tolerated by an independent Data Monitoring Committee (DMC). All 15 patients were heavily pretreated, receiving an average of five previous lines of multidrug therapy including anti-CD38, immunomodulating drugs and proteasome inhibitors. All patients were relapsed or refractory to at least one proteasome inhibitor and IMiD. Most patients presented with advanced stage 2 or 3 disease and 67% had previously received at least one stem cell transplant.

Data from Cohort 5, released in August 2018, evaluated a split or fractionated dose of 31.25 mCi/m2 for tolerability and safety. The dosing schedule provided higher average drug exposure but lower peak serum levels than non-fractionated dosing, potentially reducing adverse events and improving efficacy. The DMC determined the fractionated dose used in Cohort 5 to be safe and well tolerated, and recommended advancement to a higher dose cohort.

In December 2018, Cohort 6 was initiated. Cohort 6 will evaluate up to four patients with each receiving two doses of 18.75 mCi/m2 of CLR 131 administered one week apart. This fractionated dosing regimen will result in each patient being treated with a total of approximately 75.0 mCi of CLR 131, representing an increase in average total exposure of greater than 15% over Cohort 5.

About CLR 131

CLR 131 is Cellectar’s investigational radioiodinated phospholipid ether-drug conjugate (PDC) therapy that exploits the tumor-targeting properties of the company’s proprietary phospholipid ether (PLE) and PLE analogs to selectively deliver radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. CLR 131 is in a Phase 2 clinical study in R/R MM and a range of B-cell malignancies, and a Phase 1 clinical study in patients with R/R MM exploring fractionated dosing.

The objective of the multicenter, open-label, Phase 1 dose-escalation study is the characterization of safety and tolerability of CLR 131 in patients with R/R MM. Patients in Cohorts 1-4 received single doses of CLR 131 ranging from 12.5 mCi/m2 to 31.25 mCi/m2, as well as a fractionated dose of 15.625 mCi/m2 given twice over seven days in Cohort 5. Cohort 6 will evaluate up to four patients with each receiving two doses of 18.75 mCi/m2 of CLR 131 administered one week apart. This fractionated dosing regimen will result in each patient being treated with a total of approximately 75.0 mCi of CLR 131, representing an increase in average total exposure of greater than 15% over Cohort 5. All study doses and regimens have been deemed safe and well tolerated by an independent DMC. The company plans to initiate a Phase 1 study with CLR 131 in pediatric solid tumors and lymphoma, as well as a second Phase 1 study in combination with external beam radiation for head and neck cancer.

About Phospholipid Drug Conjugates

Cellectar’s product candidates are built upon a patented delivery and retention platform that utilizes optimized PDCs to target cancer cells. The PDC platform selectively delivers diverse oncologic payloads to cancerous cells and cancer stem cells, including hematologic cancers and solid tumors. This selective delivery allows the payloads’ therapeutic window to be modified, which may maintain or enhance drug potency while reducing the number and severity of adverse events. This platform takes advantage of a metabolic pathway utilized by all tumor cell types in all cell cycle stages. Compared with other targeted delivery platforms, the PDC platform’s mechanism of entry does not rely upon specific cell surface epitopes or antigens. In addition, PDCs can be conjugated to molecules in numerous ways, thereby increasing the types of molecules selectively delivered. Cellectar believes the PDC platform holds potential for the discovery and development of the next generation of cancer-targeting agents.

On January 7, 2019 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that the Safety Review Committee (SRC) has endorsed dose escalation in the ongoing ADP-A2AFP (AFP) study in patients with hepatocellular carcinoma (liver cancer) to the second dose cohort (Press release, Adaptimmune, JAN 7, 2019, View Source;p=RssLanding&cat=news&id=2382311 [SID1234532522]). The SRC has also endorsed moving to the expansion phase of the ADP-A2M10 (MAGE-A10) lung cancer study.

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Across both studies, most adverse events have been consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies with no evidence of alloreactivity or toxicity related to off-target binding.

In the ADP-A2AFP study, two patients have received 100 million transduced SPEAR T-cells targeting AFP in the first dose cohort, and there was no evidence of hepatotoxicity. The SRC endorsed dose escalation after evaluating the first two patients and taking into consideration the benefit:risk profile observed across programs in Cohort 1.

In the ADP-A2M10 lung cancer study, ten patients have been treated in the first three cohorts (up to six billion transduced cells), and the expansion phase will allow for doses of up to ten billion transduced cells (range 1.2 to 10 billion).

"We are pleased that the SRC has endorsed moving to the expansion phase of the ADP-A2M10 lung cancer study. Additionally, our ADP-A2AFP study has progressed to the next dose level of 1 billion transduced cells. Importantly, we did not observe liver toxicity in the two patients treated at a dose of 100 million transduced cells. In our other studies, we continue to enroll in the expansion phases and, as we previously have said, we are on track to report our next clinical data by May this year," said Rafael Amado, Adaptimmune’s President of Research & Development.

Overview of ADP-A2AFP (AFP) Study Design

This is a first-in-human, open-label study utilizing a modified 3+3 design in up to 36 patients with escalating target doses of 100 million (Cohort 1), 1 billion (Cohort 2), and 1.2‑6 billion (Cohort 3) transduced SPEAR T-cells to evaluate safety, including dose limiting toxicities (DLTs) followed by an expansion phase with doses of up to 10 billion SPEAR T-cells
This trial is being conducted in patients with hepatocellular carcinoma
There was a 21-day stagger between patients in Cohort 1, with this stagger dropping to 7 days in Cohorts 2, and 3 in the absence of DLTs. There is no pre-determined stagger in the expansion phase
Cohorts 1-3 were intended to enroll 3 patients each with an expansion to 6 patients if DLTs were observed
The expansion phase can enroll up to 30 patients
The lymphodepletion regimen is fludarabine (flu) (20mg/m2/day) and cyclophosphamide (cy) (500 mg/m2/day) for 3 days
Efficacy is assessed by overall response rate, time to response, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 16, month 6, and then every 3 months until confirmation of disease progression
Overview of ADP-A2M10 (MAGE-A10) Lung Cancer Study Design

This is a first-in-human, open-label study utilizing a modified 3+3 design in up to 28 patients with escalating target doses of 100 million (Cohort 1), 1 billion (Cohort 2), and 1.2‑6 billion (Cohort 3) transduced SPEAR T-cells to evaluate safety, including DLTs followed by an expansion phase with doses of up to 10 billion SPEAR T-cells
This trial is being conducted in patients with non-small cell lung cancer (NSCLC)
There was a 21-day stagger between patients in Cohort 1, with this stagger dropping to 7 days in Cohorts 2, and 3 in the absence of DLTs. There is no pre-determined stagger in the expansion phase
Cohorts 1-3 were intended to enroll 3 patients each with an expansion to 6 patients if DLTs were observed
The expansion phase can enroll up to 10 patients
The lymphodepletion regimen is cyclophosphamide (1800 mg/m2/day) for 2 days in Cohort 1, fludarabine (flu) (30mg/m2/day) and cyclophosphamide (cy) (600 mg/m2/day) for 3 days in Cohort 2, and Cy (600 mg/m2/d) x 3 days + Flu (30 mg/m2/d) X 4 days in Cohort 3
Efficacy is assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months (for 2 years) and then every 6 months until confirmation of disease progression

On January 7, 2019 OncoSec Medical Incorporated (OncoSec) (NASDAQ:ONCS), a company developing novel cancer immunotherapies, reported it has established a collaboration with the GOG Foundation, Inc., (GOG Foundation), to conduct a registration-enabled study of TAVO (tavokinogene telseplasmid) in women with recurrent/persistent cervical cancer (OMS-150) (Press release, OncoSec Medical, JAN 7, 2019, View Source [SID1234532538]).

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In June, 2018, KEYTRUDA (pembrolizumab) received accelerated approval from the FDA for the treatment of advanced cervical cancer with disease progression during or after chemotherapy based on data from a single-arm 98 patient study that showed a 14% overall response rate (ORR). Previous data in other advanced solid tumors demonstrate that TAVO combined with KEYTRUDA can induce objective responses in patients who do not respond to anti-PD-1 antibody monotherapy.

In this registration-directed clinical trial, OncoSec and GOG will evaluate the combination of TAVO and commercially available KEYTRUDA with the goal of achieving a clinically meaningful response rate greater than what has already been demonstrated with KEYTRUDA alone (14%). OncoSec and the GOG Foundation plan to enroll approximately 80 to 100 patients, who qualify for standard of care treatment with KEYTRUDA, in this single-arm study with TAVO. The trial will be open to patients with surface or subcutaneous lesions that are accessible via TAVO’s current delivery system. Patient enrollment is expected to begin in the first half of 2019. Importantly, should a clinically meaningful increase be observed in patients receiving the TAVO beyond that which they receive from KEYTRUDA alone, OncoSec plans to seek accelerated approval of TAVO in this patient population.

"KEYTRUDA is only the second drug in 30 years to be approved for the treatment of cervical cancer and, though it represents significant progress, the number of patients who can benefit is limited. Our goal is to improve upon the 14% KEYTRUDA response rate with the addition of TAVO," said Daniel J. O’Connor, President and Chief Executive Officer of OncoSec. "We believe that TAVO, our proprietary intratumoral plasmid-based IL-12, is an excellent complement for expanding the clinical benefit of anti-PD-1 therapies, especially for those patients that are resistant to anti-PD-1 therapies. Given that KEYTRUDA is already approved and reimbursed for this indication, this study fits perfectly with our strategy of identifying opportunities to conduct small, relatively low-cost single-arm clinical studies that have the potential to offer a rapid path to drug approval and commercialization."

The study will be conducted within GOG Foundation’s network under OncoSec’s investigational new drug (IND) application for TAVO. The GOG Foundation is a world-renowned non-profit organization with the purpose of conducting clinical research for the prevention and treatment of all gynecologic cancers, such as ovarian cancer, cervical cancer, endometrial cancer, vulvar cancer, and vaginal cancer. Its members make up a multi-disciplinary group, consisting of gynecologic oncologists, medical oncologists, pathologists, radiation oncologists, nurses, statisticians, and basic scientists.

"Conducting research that can lead to promising new therapies for women facing cervical cancer and other gynecological malignancies is central to our mission, and this collaboration is an exciting opportunity to bring our esteemed network and expertise in quality scientific research to the table," said Larry J. Copeland, MD, GOG Foundation President. "We’re grateful to play a role in this trial and look forward to advancing this therapy through the clinic."