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%).

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

(Filing, 10-Q, Soligenix, AUG 12, 2015, View Source [SID:1234507216])

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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 11, 2015 Genmab reported Financial Results for the First Half of 2015 (Press release, Genmab, AUG 11, 2015, View Source [SID:1234507199]).

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Interim Report First Half 2015

Rolling submission of BLA to U.S. FDA for daratumumab in double refractory multiple myeloma completed by Janssen, triggering a USD 15 million milestone payment

Regulatory submissions for ofatumumab (Arzerra) as maintenance therapy for relapsed chronic lymphocytic leukemia (CLL) submitted by Novartis to the EMA and FDA

Achieved USD 10 million milestone payment under daratumumab collaboration with Janssen for progress in Phase III study ("Alcyone" MMY3007)

Positive top-line results from the Phase III COMPLEMENT 2 study of ofatumumab plus fludarabine and cyclophosphamide in relapsed CLL

Entered commercial agreement for DuoBody platform with BioNTech in the field of immuno-oncology

Improved operating result by DKK 147 million over the first half of 2014

"During the second quarter we continued to see steady advances in our two most advanced programs, daratumumab and ofatumumab. The daratumumab program continues to progress very rapidly with the first regulatory application submitted in the U.S. by Janssen Biotech, Inc. under our collaboration. Together with Novartis, we reported positive top-line results in a pivotal study of ofatumumab in combination with fludarabine and cyclophosphamide in relapsed CLL; the data will be shared with the regulatory authorities to determine the potential for regulatory filings. Regulatory submissions for ofatumumab as maintenance therapy in relapsed CLL were submitted by Novartis to the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) in July. We also continue to focus on our technologies and effectively progress a robust early stage pipeline, having entered an agreement with BioNTech for the DuoBody platform in the field of immuno-oncology and obtaining a license from Bristol-Myers Squibb for antibodies targeting CD19," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Financial Performance First Half
Revenue was DKK 281 million in the first half of 2015 compared to DKK 363 million in the first half of 2014. The decrease of DKK 82 million or 23% was mainly driven by lower milestone revenue under our daratumumab collaboration with Janssen.

Operating expenses were DKK 244 million in the first half of 2015 compared to DKK 298 million in the first half of 2014. The decrease of DKK 54 million or 18% was primarily related to a decrease in costs associated with the ofatumumab and daratumumab programs, which was partly offset by increased investment in our research and technology platforms.

Operating income was DKK 212 million in the first half of 2015 compared to DKK 65 million in the first half of 2014. The improvement of DKK 147 million was driven by the income from reversal of the ofatumumab funding liability of DKK 176 million combined with lower expenses, which were partly offset by decreased revenue.

On June 30, 2015, Genmab had a cash position of DKK 2,958 million. This represented a net increase of DKK 297 million from December 31, 2014, which was driven primarily by the proceeds from exercise of warrants of DKK 478 million partly offset by the increased investment in our research and development activities to advance our pipeline of products.

Business Progress Second Quarter to Present
July: The rolling submission of a Biologics License Application (BLA) to the U.S. FDA for daratumumab was completed by Janssen, triggering a USD 15 million milestone payment to Genmab. The initiation of the rolling submission was announced in June. (Genmab granted Janssen an exclusive worldwide license to develop, manufacture and commercialize daratumumab in 2012.)

July: Announced that regulatory applications were submitted to the EMA and FDA for the use of ofatumumab as maintenance therapy of patients with relapsed CLL by Novartis.

June: Entered an agreement for an exclusive license from Bristol-Myers Squibb to a panel of human antibodies targeting CD19.
May: Entered an agreement with BioNTech AG to jointly research, develop and commercialize bispecific antibody products within the field of immuno-oncology using the DuoBody technology platform.

May: Presented first preliminary clinical data from the ongoing Phase I study of HuMax-TF-ADC in solid tumors, showing that HuMax-TF-ADC can be dosed safely in therapeutically meaningful doses and with encouraging early signs of efficacy.

April: Announced positive top-line results from the Phase III COMPLEMENT 2 study which showed that treatment with Arzerra plus fludarabine and cyclophosphamide met the primary endpoint of improved progression-free survival (PFS) in patients with relapsed CLL (HR 0.67, p = 0.0032) compared to those given fludarabine and cyclophosphamide alone. The data will be shared with the US and EU regulatory agencies to evaluate the potential for future regulatory filings.

April: Achieved a USD 10 million milestone payment in the daratumumab collaboration with Janssen for progress in the ongoing Phase III study ("Alcyone" MMY3007) which compares daratumumab in combination with bortezomib, melphalan and prednisone (VMP) to VMP alone as front line treatment for multiple myeloma patients who are not considered candidates for stem cell transplantation.

Outlook
Genmab is maintaining its updated 2015 financial guidance published on May 20, 2015.