On August 12, 2015 Juno Therapeutics, Inc. (NASDAQ:JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported business highlights and financial results for the second quarter of 2015 (Press release, Juno, AUG 12, 2015, View Source;p=RssLanding&cat=news&id=2079196 [SID:1234507230]).

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"I am pleased by the progress we have made over the last quarter. Data we presented on JCAR014, JCAR015, and JCAR017 demonstrate the progress we are making in the clinic. The FDA clearance of the IND for JCAR015 was also an important milestone, and we are now well placed to start our first pivotal clinical trial," stated Hans Bishop, Juno’s CEO. "We also completed a number of strategic transactions that significantly improve our capabilities, access to transformative technologies, and balance sheet."
Concurrent with the Celgene partnership, the company announced that Thomas O. Daniel, M.D., President, Celgene Research and Early Development, has been appointed to the Juno Board of Directors. Dr. Daniel has extensive experience in oncology and immunology coupled with a proven track record of building and leading research and development teams.

"Tom has a tremendous track record of strategic leadership in building a world-class pipeline and successfully translating discovery research into new clinical candidates. We look forward to Tom’s contributions and insights as a member of the Juno Board," said Hans Bishop.

Second Quarter 2015 and Recent Corporate Highlights

Clinical Progress:

The U.S. Food and Drug Administration (FDA) cleared investigational new drug (IND) applications for JCAR015 and JCAR017 for the treatment of adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL), and r/r B cell non-Hodgkin lymphoma (NHL), respectively. The JCAR015 Phase 2 study will serve as Juno’s U.S. registration trial in adult r/r ALL, and the Phase 1 JCAR017 trial is the backbone component of Juno’s multi-pronged strategy in NHL. Juno expects both of these studies to begin this quarter.

Translational insights from ongoing trials across Juno’s CD19 portfolio were presented at various medical meetings and highlight several important areas of progress, including:

Early data of improved response rates in r/r NHL (6/7 or 86%) with greater cell expansion and persistence as presented in data for JCAR014 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting in May.

Emerging clinical data that corroborate pre-clinical evidence of the potential benefits of defined cell products in creating deeper remissions, with 91% complete molecular remission rates as measured by flow cytometry for both JCAR017 (20/22 evaluable patients) in r/r pediatric ALL and JCAR014 (21/23 evaluable patients) in r/r adult ALL, presented at ASCO (Free ASCO Whitepaper) and the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

JCAR015 data continue to be encouraging, demonstrating complete remission (CR) in 87% of evaluable patients with ALL, and minimal residual disease (MRD) negative CR was reported in 81% of patients who achieved a CR. Median overall survival (OS) for all efficacy-evaluable patients was 8.5 months, and the six month OS rate was 59 percent (95 percent CI: 39-74), presented at ASCO (Free ASCO Whitepaper).

Safety profile across the CD19 portfolio remains consistent with what has been previously reported.

Corporate News:
Entered into a ten-year collaboration with Celgene to leverage T cell therapeutic strategies with an initial focus on CAR T and TCR therapies. Celgene gained the option to commercialize Juno programs outside North America and co-promote certain programs globally. Celgene also purchased 9.1 million of Juno shares. Juno has gained the option to co-develop, co-promote and share profits with respect to select Celgene programs. Juno also received $1 billion in total payments. The collaboration became effective on July 31 after an early termination of the Hart-Scott-Rodino Antitrust waiting period.

Acquired Stage Cell Therapeutics GmbH (Stage), bringing access to transformative cell selection and activation capabilities, next-generation manufacturing automation technologies, enhanced supply chain control, and lower expected long-term cost of goods.
Acquired X-Body, Inc., bringing in-house an innovative discovery platform that interrogates the human antibody repertoire, rapidly selecting fully-human antibodies and single-chain variable fragments with desired characteristics, even against difficult targets.
Entered into an exclusive collaboration with Editas to conduct trials using Editas’ genome editing technologies, including CRISPR/Cas9, in creating improved, next-generation CAR T and TCR products.

Entered into a collaboration with Fate Therapeutics to identify and utilize small molecules to modulate cell signaling pathways in creating improved, next-generation CAR T and TCR products.

Entered into a collaboration with MedImmune to conduct combination clinical trials in immuno-oncology with one of Juno’s CD19-directed CAR T cell candidates and MedImmune’s investigational programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitor, MEDI4736.

Reached a favorable settlement that resolved litigation with the University of Pennsylvania and Novartis Pharmaceuticals Corporation and included an initial payment as well as potential future milestone and royalty payments to Juno.
Appointed Hyam I. Levitsky, M.D. as executive vice president, research and chief scientific officer. Dr. Levitsky is responsible for developing a comprehensive immunotherapy program focused on advancing chimeric antigen receptor and T-cell receptor technologies.

Second Quarter 2015 Financial Results

Cash Position: Cash, cash equivalents, and marketable securities as of June 30, 2015 were $313.4 million compared to $474.1 million as of December 31, 2014. After giving effect to the effectiveness of the Celgene collaboration on July 31, 2015, including the initial purchase of Juno stock by Celgene, the pro forma cash is $1.31 billion.

Cash Burn: Cash burn in the three months ended June 30, 2015 was $134.2 million. This included net cash paid of $77.7 million related to the Stage and X-Body acquisitions and $38.0 million in upfront fees to acquire technology. The additional burn of $18.5 million was primarily due to cash used in operations of $24.0 million related to the overall growth of Juno’s business, including the hiring of key talent, litigation costs, and increased purchases of property and equipment of $6.8 million, offset by cash received in the second quarter of 2015 of $12.25 million in connection with the Novartis sublicense agreement. Cash burn in the six months ended June 30, 2015 was $160.6 million.

Revenue: Revenue was $12.5 million in the three and six months ended June 30, 2015, which consisted primarily of $12.25 million received in connection with the Novartis sublicense agreement.

R&D Expenses: Research and development expenses in the three and six months ended June 30, 2015, inclusive of non-cash expenses and computed in accordance with GAAP, were $60.2 million and $118.0 million, respectively, compared to $6.5 million and $9.4 million in the three and six months ended June 30, 2014, respectively. The increase of $53.7 million and $108.6 million in the three and six months ended June 30, 2015, respectively, was primarily due to increased costs related to acquiring technology, expanding the company’s overall research and development capabilities, hiring key talent, advancing programs at Juno’s founding institutions, non-cash stock-based compensation expense, and expenses related to the change in estimated value and elapsed accrual period for Juno’s potential success payments to the Fred Hutchinson Cancer Research Center (FHCRC) and Memorial Sloan Kettering Cancer Center (MSK).

Non-GAAP R&D Expenses: Non-GAAP research and development expenses in the three and six months ended June 30, 2015 were $23.8 million and $40.8 million, respectively. Non-GAAP research and development expenses in 2015 exclude the following:
Success payment expense of $4.0 million and $42.9 million for the three and six months ended June 30, 2015, respectively, associated with the change in estimated value and elapsed accrual period for Juno’s potential success payment liabilities to FHCRC and MSK.

Upfront payments related to license agreements of $30.8 million for the three and six months ended June 30, 2015 associated with the Editas and Fate Therapeutics collaborations.

Non-cash stock-based compensation expense of $1.7 million and $3.6 million for the three and six months ended June 30, 2015, respectively, related to a 2013 restricted stock award to a co-founding director that became a consultant upon his departure from Juno’s board of directors in 2014.

Non-GAAP research and development expenses in the three and six months ended June 30, 2014 were $6.3 million and $9.0 million, respectively, and exclude success payment expense of $0.2 million and $0.4 million, respectively.
G&A Expenses: General and administrative expenses in the three and six months ended June 30, 2015, inclusive of non-cash expenses and computed in accordance with GAAP, were $14.9 million and $21.5 million, respectively, compared with $4.6 million and $8.0 million in the three and six months ended June 30, 2014, respectively. The increase of $10.3 million and $13.5 million in the three and six months ended June 30, 2015, respectively, was primarily due to increased personnel expense, including non-cash stock-based compensation expense, transaction costs associated with the Stage and X-Body acquisitions as well as the Celgene, Fate, and Editas collaborations, and an increase in patent and corporate legal fees.

Litigation Expense: Litigation expense in the three and six months ended June 30, 2015 was $5.3 million and $6.0 million, respectively, compared with $1.6 million and $3.6 million in the three and six months ended June 30, 2014, respectively. All litigation expense in those periods were comprised of costs Juno incurred with respect to Trustees of the University of Pennsylvania v. St. Jude Children’s Research Hospital, Civil Action No. 2:13-cv-01502-SD (E.D. Penn.), as well as expenses Juno was required to reimburse to St. Jude Children’s Research Hospital with respect to such litigation. In April 2015 this litigation was settled favorably, and Novartis agreed to execute a sublicense agreement with Juno, in connection with which Novartis paid Juno $12.25 million.

GAAP Net Loss Attributable to Common Stockholders: Net loss attributable to common stockholders for the three and six months ended June 30, 2015 was $66.0 million, or $0.79 per share and $130.9 million, or $1.58 per share, respectively. This compares to $38.1 million, or $5.80 per share, and $47.1 million, or $7.06 per share, respectively, for the same periods in 2014.

Non-GAAP Net Loss Attributable to Common Stockholders: Non-GAAP net loss attributable to common stockholders, which incorporates the non-GAAP R&D expense, for the three and six months ended June 30, 2015 was $29.5 million, or $0.35 per share, and $53.7 million, or $0.65 per share, respectively.

For the three and six months ended June 30, 2014, non-GAAP net loss attributable to common stockholders, which incorporates the non-GAAP R&D expense, was $12.5 million, or $1.90 per share and $20.6 million, or $3.09 per share, respectively. Non-GAAP net loss attributable to common stockholders for the three and six months ended June 30, 2014 exclude the following:

Success payment expense of $0.2 million and $0.4 million for the three and six months ended June 30, 2014, respectively, associated with the change in estimated value and elapsed accrual period for Juno’s potential success payment liabilities to FHCRC and MSK.

Non-cash convertible preferred stock option expense of $10.1 million and $10.7 million in the three and six months ended June 30, 2014, respectively.

A non-cash charge of $15.4 million for the three and six months ended June 30, 2014 related to deemed dividends upon issuance of convertible preferred stock.

A reconciliation of GAAP net loss to non-GAAP net loss is presented below under "Non-GAAP Financial Measures."

2015 Financial Guidance
Juno expects 2015 cash burn, excluding cash inflows or outflows from business development activities and the now-settled litigation, to be at the higher end of its guidance of between $125 million and $150 million.

On August 12, 2015 DARA BioSciences, Inc. (NASDAQ: DARA), an oncology supportive care pharmaceutical company dedicated to providing health care professionals a synergistic portfolio of medicines to help cancer patients adhere to their therapy and manage side effects arising from their cancer treatment, reported its second quarter 2015 results (Press release, Dara Biosciences, AUG 12, 2015, View Source [SID:1234507228]).

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Second Quarter 2015 Financial Snapshot

DARA reported net revenues of $990.8 thousand for the second quarter ended June 30, 2015 based on gross product sales in excess of $1.4 million, as compared to net revenues of $409.4 thousand for the second quarter ended June 30, 2014, a year over year increase of 142%. The increase in revenues was primarily attributable to the expanded commercial sales organization and ongoing success in generating interest and prescriptions across DARA’s oncology supportive care product portfolio.

DARA reported a loss attributable to controlling interest of approximately $2.7 million or ($0.14) per share for the second quarter ended June 30, 2015 as compared to a loss attributable to controlling interest of approximately $2.6 million, or ($0.24) per share for the second quarter ended June 30, 2014. The loss attributable to controlling interest for the current quarter was $101.0 thousand more than the same period last year. Sales and marketing costs for the quarter increased $130.8 thousand over the same period last year, primarily as a result of increased personnel costs, including an increase in incentive based field sales compensation driven by higher sales achievement. An increase in general and administrative expenses of $268.5 thousand was primarily driven by increased professional services costs related to DARA’s proposed merger with Midatech Pharma PLC. Research and development expenses increased by $58.7 thousand primarily as a result of increased consulting and professional service expenses, partially offset by decreased personnel costs. As of June 30, 2015, cash and cash equivalents totaled approximately $7.0 million.

"Our second quarter results illustrate continued growth from our commercial efforts, as our product portfolio continues to be accepted and utilized to support oncology patients and oncology health care providers nationwide," stated Christopher G. Clement, President and CEO of DARA BioSciences. "In combination with our national field sales team’s efforts, DARA’s unique service offerings for our products continue to result in positive sales trends across our product portfolio. Our continued momentum in the business and prescription increases for our key products Gelclair and Soltamox on a year to date basis support our full year estimates of net revenues for these two products to reach $3.7 million for 2015, excluding any net revenue contribution from the launch of Oravig later in the year."

Clement continued, "We are excited regarding the ongoing strong performance of our commercial business and look forward to sustained success as we continue towards the consummation of our merger agreement with Midatech PLC. As of today the timelines for the close of the transaction with Midatech remain on track and we believe that this will take place prior to the end of 2015. Midatech has completed the first significant goal in moving toward closing through the filing of their registration statement on Form F-4 with the Securities and Exchange Commission on August 11, 2015. Additionally, we are on schedule to launch Oravig back to the market in the fourth quarter of this year, providing an important product for both DARA’s oncology portfolio as well for Mission Pharmacal, DARA’s primary care partner for Oravig."

Dr. David J. Drutz, Executive Chairman of the Board and Chief Medical Officer of DARA BioSciences, commented, "We had several important developments during the quarter that we believe will enhance the attractiveness of KRN5500 to interested parties. On July 9, 2015 the FDA provided formal agreement with the Company’s full proposed development plan, beginning with design of the Phase 2b dose-escalation strategy in cancer patients with painful chronic chemotherapy-induced peripheral neuropathy, or CCIPN. The FDA also indicated agreement with proposed bridging studies for the new KRN5500 formulation. These are significant advances that clarify the steps needed to advance this product into further clinical development."

DARA believes that its currently available funds, together with projected sales of Gelclair, an FDA-approved bioadherent oral rinse gel for treating the painful symptoms of oral mucositis (OM), Soltamox, (tamoxifen citrate) oral liquid solution, Oravig, the first and only orally-dissolving buccal tablet approved for oral thrush, and the Mission Pharmacal products Ferralet 90 (for anemia) and Aquoral (for cancer-related dry mouth), will enable the Company to fund its current operations and to meet its obligations into the first quarter of 2016.

Second Quarter 2015 Operational Highlights and Recent Key Events

The Company made significant progress during the second quarter of 2015 in executing its strategy as well as expanding the commercial opportunity for its flagship oncology and oncology supportive care products, as follows:

Quarterly net revenues increased 142% from Q2 FY’14 to $990.8 thousand, based on continued increases in prescriptions for our oncology supportive care portfolio.

Signed merger agreement with Midatech Pharma PLC, a UK-Based Specialty Pharmaceutical Company with expected deal closing in the fourth quarter of 2015.

Planning for the Oravig Launch in Q4 of this year, into both the oncology and the primary care markets.
Gelclair continues to be the leading gel barrier prescribed in the U.S. retail market, per Symphony Prescription data, leading the nearest competitor by almost a 3 to 1 margin of prescriptions written in June and outperforming the overall gel barrier retail prescription market with an increase in retail prescriptions of 41% Q2 vs. Q1 of 2015 while the overall gel barrier retail was up less than 20% for the same time period.

Q2 showed a significant increase (over 300%) in Gelclair prescriptions through our HUB pharmacy vs Q1 of this year.
DARA has provided Gelclair to over 350 uninsured or underinsured patients, through our HUB program, providing health care providers a dependable option for prescribing Gelclair to all of their appropriate patients.

Soltamox has shown sequential quarterly growth both in the retail and wholesale sectors, with prescriptions rising on a quarter to quarter basis.

DARA initiated a patient- focused educational program with a leading provider of oncology patient portal services.
Ferralet and Aquoral demonstrated increased sales quarter over quarter.

Based upon continued strong sales performance of the oncology supportive care portfolio, DARA has initiated a tele sales program to bolster sales in white space areas across the country.

Key development asset KRN5500 obtained a Notice of Allowance for a new formulation, enhancing attractiveness of a partnership opportunity through improved clinical administration of the drug, as well as provision of IP protection through 2032, a period well beyond that afforded by its current orphan designations.

Based on our current trends and continued growth DARA continues to support our previous guidance of $3.7 million for Gelclair and Soltamox net sales for the full year 2015, excluding any net revenue contribution from the launch of Oravig later in the year.

On August 12, 2015 Argos Therapeutics, Inc. (Nasdaq:ARGS), an immuno-oncology company focused on the development and commercialization of fully individualized immunotherapies for the treatment of cancer based on the Arcelis technology platform, reported financial results for the second quarter ended June 30, 2015 and provided an update on the Company’s clinical programs (Press release, Argos Therapeutics, AUG 12, 2015, View Source [SID:1234507224]).

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"We have made important progress this quarter in our ongoing pivotal phase 3 ADAPT trial with AGS-003 for the treatment of metastatic renal cell carcinoma (mRCC)," said Jeff Abbey, president and chief executive officer. "We are pleased with the independent data monitoring committee’s (IDMC) recommendation to continue the trial following the first of three planned interim data analyses. We look forward to further IDMC reviews and interim data analyses as the trial advances. In parallel, we have continued the build-out of our centralized manufacturing facility to support anticipated commercialization efforts and we recently drew down the second and final tranche of $12.5 million under our debt facility with Horizon Technology Finance Corporation and Fortress Credit Co LLC which provides us with additional capital as we continue to progress our plan to becoming a fully-integrated commercial company."

Mr. Abbey continued, "Since the close of the second quarter, we also announced two significant and exciting accomplishments, including the completion of patient enrollment in the ADAPT trial and the formation of our first ever Scientific Advisory Board, which includes world renowned physicians and scientists. We look forward to the insight and guidance these experts will provide us on the many aspects of our development programs, most importantly the continued development of AGS-003. We believe that their input will be critical as we seek to initiate additional phase 2 trials with AGS-003 in other RCC settings and additional tumor types."

Recent Operational Highlights:

In April 2015, the Company entered into a license agreement with Lummy HK for the development of personalized immunotherapies to treat cancer in China.

Lummy HK licensed the rights to manufacture, develop and commercialize AGS-003 for the treatment of cancer in China, Hong Kong, Taiwan and Macau.

Lummy HK has agreed to pay Argos a royalty on net sales of AGS-003 at a rate in the teens and up to an aggregate of $20 million for regulatory and commercial milestones.

Argos sold $10 million of its common stock to an affiliate of Lummy and the China BioPharma Capital I Fund.
In June 2015, the IDMC recommended the continuation of the company’s pivotal phase 3 ADAPT clinical trial following the first of three planned interim data analyses. This data analysis took place at the point that the Company reached approximately 25% of events.

The Second interim data analysis by the IDMC at approximately 50% of events is expected during the first half of 2016.
In July 2015, the pivotal phase 3 ADAPT clinical trial of AGS-003 in combination with standard targeted therapy for the treatment of mRCC reached its enrollment goal of at least 450 randomized patients.

The breakdown of patients enrolled in the ADAPT study is approximately 75% intermediate risk patients, meaning they present with 1 or 2 risk factors at diagnosis, and approximately 25% poor risk patients, meaning they present with either 3 or 4 risk factors at diagnosis.

In July 2015, the Company established a Scientific Advisory Board (SAB).
Inaugural members include distinguished oncologists and immunologists to provide perspectives in further research and development of AGS-003.

In July 2015 the Company initiated an early stage RCC trial of AGS-003 at Roswell Park Cancer Institute in Buffalo, NY.
In August 2015, the Company received the second and final tranche of $12.5 million under its debt facility with Horizon Technology Finance Corporation and Fortress Credit Co LLC.

Selected Second Quarter 2015 Financial Results

Net loss attributable to common stockholders for the three months ended June 30, 2015 was $19.6 million, or $0.95 per share, compared to a net loss attributable to common stockholders of $12.0 million, or $0.61 per share, for the same period in 2014. Net loss attributable to common stockholders for the six months ended June 30, 2015 was $37.2 million, or $1.84 per share, compared to a net loss attributable to common stockholders of $22.8 million, or $1.52 per share, for the same period in 2014.

Revenue for the three months ended June 30, 2015 totaled $0.1 million compared to $0.5 million for the same period in 2014. Revenue for the six months ended June 30, 2015 totaled $0.3 million compared to $1.3 million for the same period in 2014.

Research and development expense for the three months ended June 30, 2015 totaled $16.1 million compared to $10.6 million for the same period in 2014. Research and development expense for the six months ended June 30, 2015 totaled $30.9 million compared to $19.0 million for the same period in 2014.

General and administrative expense for the three months ended June 30, 2015 totaled $2.9 million compared to $1.9 million for the same period in 2014. General and administrative expense for the six months ended June 30, 2015 totaled $5.3 million compared to $3.8 million for the same period in 2014.

As of June 30, 2015, Argos’ cash, cash equivalents and short-term investments totaled $30.6 million compared to $56.2 million as of December 31, 2014.

On August 12, 2015 Endocyte, Inc. (NASDAQ:ECYT), a bio-pharmaceutical company and leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy in cancer and other serious diseases, reported that six posters will be presented by Endocyte scientists at the 250th American Chemical Society (ACS) National Meeting & Exposition being held in Boston, August 16-20, 2015 (Press release, Endocyte, AUG 12, 2015, View Source [SID:1234507221]).

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"Endocyte’s versatile technology platform for developing SMDCs toward folate-receptor-specific and prostate-specific-membrane-antigen-specific targeting will be highlighted at the national ACS meeting," said Iontcho Vlahov, Ph.D., vice president of discovery chemistry. "The focus of our presentations is centered on novel chemistries for targeted therapies of cancer, including cytotoxic GARFTase inhibitors, CCK2R-targeting conjugates, and our continued advancement in the design of super-potent analogs of the tubulysin. We will further discuss new folate conjugates and their properties."

Presentations are as follows:

Abstract #: MEDI 162
Title: "Novel strategies for targeted therapies of cancer: Solid-phase-based synthesis of CCK-2-receptor-targeting ligands and their tubulysin conjugates"
When: Sunday, August 16, 2015 from 7 – 9 p.m. EDT
Session ID: General Poster Session
Location: Westin Boston Waterfront, Galleria

Abstract #: MEDI 205
Title: "Design and regio-selective synthesis of folate-thapsigargin conjugates for cancer therapy"
When: Sunday, August 16, 2015 from 7 – 9 p.m. EDT
Session ID: General Poster Session
Location: Westin Boston Waterfront, Galleria

Abstract #: MEDI 497
Title: "Chemistry of folate-everolimus and folate-rapamycin conjugates: Avoiding side reactions and improving their physical properties"
When: Wednesday, August 19, 2015 from 7 – 9 p.m. EDT
Session ID: General Poster Session
Location: Boston Convention & Exhibition Center, Ballroom

Abstract #: MEDI 499
Title: "Novel strategies for targeted therapies of cancer: Double release mechanism for delivering cytotoxic GARFTase inhibitors and additional chemotherapeutic payloads to cancer cells"
When: Wednesday, August 19, 2015 from 7 – 9 p.m. EDT
Session ID: General Poster Session
Location: Boston Convention & Exhibition Center, Ballroom

Abstract #: MEDI 516
Title: "Design and synthesis of novel tubulysin analogs"
When: Wednesday, August 19, 2015 from 7 – 9 p.m. EDT
Session ID: General Poster Session
Location: Boston Convention & Exhibition Center, Ballroom

Abstract #: MEDI 517
Title: "Reducing off-target activity of folate-tubulysin conjugates by introducing unnatural amino acids and by increasing steric bulk within the peptidic spacer"
When: Wednesday, August 19, 2015 from 7 – 9 p.m. EDT
Session ID: General Poster Session
Location: Boston Convention & Exhibition Center, Ballroom

On August 12, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has extended the action date for the supplemental Biologics License Application (sBLA) for Opdivo for the treatment of patients with previously untreated advanced melanoma (Press release, Bristol-Myers Squibb, AUG 12, 2015, View Source [SID:1234507220]). The company has taken the opportunity to submit additional data from the Opdivo clinical trial program to ensure the broadest data set, irrespective of BRAF status, was available for review. This submission constitutes a major amendment that will require additional time for review and the new FDA action date is November 27, 2015.

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The sBLA was accepted by the FDA for filing and received priority review designation on April 29, 2015, and included data from the Phase 3 CheckMate -066 trial which evaluated Opdivo in treatment naïve patients with BRAF wild-type advanced melanoma as compared to dacarbazine chemotherapy (DTIC). The company will continue to work closely with the agency to support the review of this sBLA for Opdivo.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the FDA as a monotherapy in two cancer indications. On March 4, 2015, Opdivo received FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In the U.S., Opdivo is also indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).