On March 12, 2019 Verastem, Inc. (Nasdaq:VSTM), operating as Verastem Oncology, (or "the Company"), focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported financial results for the three and twelve months ended December 31, 2018, including revenue from its first commercial product, COPIKTRA (duvelisib), which was approved by the U.S. Food and Drug Administration (FDA) on September 24, 2018 (Press release, Verastem, MAR 12, 2019, View Source [SID1234534239]).

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"This year is poised to be an exciting one as we continue to drive awareness of COPIKTRA and work to expand upon the potential of PI3K inhibition through the investigation of duvelisib, initially as a monotherapy, and through novel combinations, in additional hematologic malignancies like peripheral T-cell lymphoma (PTCL)."

"Following FDA approval, COPIKTRA was quickly added to the National Comprehensive Cancer Network (NCCN) guidelines, and as of December 31, 2018, we had secured formulary listing and reimbursement for approximately 75% of targeted health plans. As of March 11, 2019, that number increased to 90%, underscoring our efforts to provide access to treatment for appropriate patients," said Joseph Lobacki, Executive Vice President and Chief Commercial Officer of Verastem Oncology. "Looking ahead to 2019, we are focused on further identifying appropriate patients for treatment with COPIKTRA, and we intend to continue to work with the leukemia and lymphoma community to increase awareness and help ensure physicians and patients are able to get the support they need."

Key 2018 Accomplishments:

Launched COPIKTRA in the United States – Verastem Oncology launched COPIKTRA, an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, in the United States following FDA approval for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies. COPIKTRA also received accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. Accelerated approval in FL was based on overall response rate and continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, the first of which is expected to start in 2019.
Use of COPIKTRA is associated with a BOXED WARNING for four fatal and/or serious toxicities: infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem Oncology has implemented a Risk Evaluation and Mitigation Strategy to provide appropriate dosing and safety information to better support physicians in managing their patients on COPIKTRA.

Additionally, use of COPIKTRA is associated with additional adverse reactions which may also require dose reduction, treatment delay or discontinuation of COPIKTRA.

Please see www.COPIKTRAHCP.com/prescribinginformation for full Prescribing Information including BOXED WARNING and Medication Guide in addition to the Important Safety Information provided below.

COPIKTRA Added to NCCN Guidelines for CLL/SLL, FL and Marginal Zone Lymphoma (MZL) – The NCCN added COPIKTRA to the Clinical Practice Guidelines in Oncology (NCCN Guidelines), the standard physician resource for determining the appropriate course of treatment for patients. The Company believes these updated guidelines will increase awareness for COPIKTRA and help health care providers make informed decisions for patients battling these difficult to treat advanced cancers. COPIKTRA is not approved for use in MZL.
Presented COPIKTRA Data at the 23rd Annual International Congress on Hematologic Malignancies (ICHM) – The Company presented four COPIKTRA abstracts at ICHM 2019, including an abstract highlighting Phase 3 DUO data in patients with relapsed or refractory CLL/SLL who have progressed following two prior lines of the therapy. This is the same indication for which COPIKTRA received approval from the FDA in September 2018. In this analysis, COPIKTRA demonstrated progression-free survival (PFS) of 16.4 months and an ORR of 78%, with a manageable safety profile. The remaining three abstracts featured data from a long-term (>2 years) efficacy and safety analysis, the Phase 3 DUO crossover extension study, and prognostic and immune-related factors associated with response to duvelisib from the Phase 2 DYNAMO study in indolent non-Hodgkin’s lymphoma (iNHL). Collectively, the data presented at ICHM 2019 continue to support the use of COPIKTRA in its approved indications of relapsed or refractory CLL/SLL after at least two prior therapies and FL after at least two prior systemic therapies. PDF copies of all of the ICHM 2019 poster presentations are available here.
Presented Updated Duvelisib Combination Data in PTCL at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting (ASH 2018) – The oral presentation highlighted updated data from an investigator-sponsored Phase 1 study evaluating duvelisib in combination with romidepsin in relapsed or refractory T-cell lymphomas, including PTCL and cutaneous T-cell lymphoma (CTCL). Of the 27 patients with PTCL evaluable for efficacy, 16 responded (9 complete responses (CRs) and 7 partial responses (PRs)) for an overall response rate (ORR) of 59%. Importantly, of the 27 patients with PTCL treated with the combination of duvelisib and romidepsin, 6 (22%) responded deeply enough to allow them to bridge to potentially curative stem cell transplant (SCT). Median progression-free survival (PFS) for patients with PTCL was 6.72 months, which was confounded by 6 subjects that proceeded to SCT. Among the 31 patients at the maximum tolerated dose who were evaluable for safety, the most common Grade ≥3 adverse events occurring in ≥10% of patients were neutropenia (32%), diarrhea (19%), increased transaminase (23%; alanine aminotransferase 16% and aspartate aminotransferase 6%), hyponatremia (13%) and platelet count decrease (10%).
Presented Frontline Duvelisib Combination Data in Younger CLL Patients at European Hematology Association (EHA) (Free EHA Whitepaper) 2018 Annual Meeting (EHA 2018) – Dr. Matthew Davids, M.D., MMSc, Assistant Professor of Medicine, Harvard Medical School, and Associate Director, Center for Chronic Lymphocytic Leukemia at the Dana-Farber Cancer Institute, presented Phase 1b/2 clinical data from 31 patients who received duvelisib in combination with fludarabine (F), cyclophosphamide (C), and rituximab (R) (dFCR) as frontline therapy. The ORR was 94%, with 26% (n=8) of patients achieving a CR or CRi, and 68% achieving a PR. The best rate of minimum residual disease (MRD) negativity in the bone marrow (BM) in patients with at least one evaluation was 76% (22 of 29 patients). The two-year progression-free survival and overall survival rates for patients in the study were both 97%. The recommended Phase 2 dose for duvelisib in combination with FCR was established as 25mg twice daily. The most common all grade non-hematologic adverse events (AEs) were nausea (72%, all Grade 1/2), fatigue (69%, 3% Grade 3), fever (53%, all Grade 1/2), diarrhea (47%, 3% Grade 3), transaminitis (34%, 28% Grade 3/4), anorexia (34%, all Grade 1/2), vomiting (28%, all Grade 1/2), pruritus (16%, 3% Grade 3), arthritis (9%, all Grade 2) and Cytomegalovirus (CMV) reactivation (6%, both Grade 2). The most common all grade hematologic adverse events were thrombocytopenia (65%; 34% Grade 3/4), neutropenia (59%; 50% Grade 3/4), and anemia (38%, 16% Grade 3/4). Serious AEs included febrile neutropenia (n=6, all Grade 3) and pneumonia (n=6, including 3 cases of PJP despite planned prophylaxis).
Investigator-Sponsored Study Initiated Evaluating COPIKTRA in Combination with Venetoclax – In early September 2018, the first patient was dosed in a multicenter Phase 1/2 clinical trial investigating COPIKTRA in combination with venetoclax, an oral selective inhibitor of BCL-2, in patients with relapsed or refractory CLL/SLL. Preclinical data support this combination, as COPIKTRA has been shown to upregulate BCL-2 transcript and protein expression levels and potentially enhance the ability of venetoclax to induce apoptosis in ex vivo human CLL cells. The primary objectives of the Phase 1 portion of the trial are to determine the maximum tolerated dose and the recommended Phase 2 dose of venetoclax for this combination regimen. The trial is being led by Dr. Matthew Davids.
Signed Exclusive License Agreements in China and Japan – Verastem Oncology entered into exclusive license agreements with CSPC Pharmaceutical Group Limited (CSPC) to develop and commercialize COPIKTRA in China, Hong Kong, Macau and Taiwan (collectively, the CSPC Territory), and Yakult Honsha Co., Ltd. (Yakult) to develop and commercialize COPIKTRA in Japan. Both agreements are for the treatment, prevention or diagnosis of all oncology indications.
Under the terms of the agreement with CSPC, Verastem Oncology received an upfront payment of $15.0 million and is entitled to receive aggregate payments of up to $160.0 million if certain development, regulatory and commercial milestones are successfully achieved, plus double-digit royalties on net sales of products containing duvelisib in the CSPC Territory. CSPC is a leading pharmaceutical group in China.
The transaction with Yakult carries a total deal value of up to $100.0 million, includes a one-time upfront payment of $10.0 million and up to an additional $90.0 million if certain development, regulatory and commercial milestones are successfully achieved by Yakult. In addition, Verastem Oncology is also eligible to receive double-digit royalties based on future net sales of products containing duvelisib in Japan. Yakult has a strong presence in development and commercialization of therapeutic products in the field of oncology and markets several branded anti-cancer therapies, including Elplat and Campto.
Collaboration with The Leukemia & Lymphoma Society for Development of Duvelisib in PTCL – Duvelisib was selected for The Leukemia & Lymphoma Society’s (LLS) Therapy Acceleration Program (TAP) which provides additional resources to support the development of therapies for patients with blood cancers. The Company plans to use the TAP funds to conduct certain translational and clinical activities relating to the development of duvelisib for the treatment of PTCL. LLS and Verastem Oncology will share the cost of the PTCL development program, portions of which will be conducted in collaboration with Memorial Sloan Kettering Cancer Center, The Dana-Farber Cancer Institute, The Washington University in St. Louis and Stanford University.
Phase 3 DUO Study Results Published in the Journal BLOOD – The results of the randomized, multicenter, open-label Phase 3 DUO study (NCT02004522), which evaluated COPIKTRA versus ofatumumab in patients with relapsed or refractory CLL/SLL, were published in the peer-reviewed journal Blood (Flinn et al). The publication was accompanied by a review article by Jennifer R. Brown, M.D., Ph.D., Director of the Center for Chronic Lymphocytic Leukemia at the Dana-Farber Cancer Institute, discussing the role of PI3K inhibitors and duvelisib in current CLL therapy. The full manuscript titled "The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL," is available at www.bloodjournal.org.
Entering 2019 with Cash, Cash Equivalents and Short-Term Investments of $249.7 Million – During 2018, Verastem Oncology successfully completed multiple fundraising transactions, including an underwritten registered offering in May 2018, a registered offering in June 2018, and a registered direct offering of 5.00% Convertible Senior Notes in October 2018 (Convertible Senior Notes). The Company also raised funds through the sale of shares of common stock under its at-the-market equity offering program. These fundraising transactions helped to provide the Company with a strong cash, cash equivalents and short-term investments balance of $249.7 million as of December 31, 2018.
Key Commercial, Clinical and Investor Relations Team Additions – In February 2019, the Company expanded its commercial and clinical teams through the appointment of several new employees, including Amy Cavers as Senior Vice President, Strategic Engagement and Alignment, Robert Morgan as Senior Vice President, Development Operations, and Erin Cox, Senior Director, Investor Relations and Corporate Communications.
Selected posters and presentations are available within the "Media" section of the Company’s website at www.verastem.com.

Fourth Quarter 2018 Financial Results

Net loss for the three months ended December 31, 2018 (2018 Quarter) was $11.3 million, or $0.15 per share (basic), as compared to $18.2 million, or $0.43 per share (basic), for the three months ended December 31, 2017 (2017 Quarter). Net loss for the 2018 Quarter includes a non-cash gain of $25.6 million, or $0.35 per share (basic), relating to the accounting impact of a financial derivative related to our Convertible Senior Notes. In addition, net loss includes non-cash stock-based compensation expense of $1.8 million and $1.0 million for the 2018 and 2017 Quarters, respectively.

Net product revenue for the 2018 Quarter was $1.2 million which reflects the first full quarter of recorded sales for COPIKTRA. The Company did not have any product revenue for the 2017 Quarter as the FDA approved COPIKTRA on September 24, 2018.

Research and development expense for the 2018 Quarter was $8.8 million compared to $11.3 million for the 2017 Quarter, a decrease of $2.5 million or 22%, primarily related to lower R&D costs associated with the development of COPIKTRA.

Selling, general and administrative expense for the 2018 Quarter was $26.2 million compared to $6.8 million for the 2017 Quarter. The increase of $19.4 million, or 285%, from the 2017 Quarter to the 2018 Quarter was due to higher personnel and related costs, as well as promotional and consulting costs in support of the commercial launch of COPIKTRA.

Other income of $25.6 million for the 2018 Quarter relates entirely to a non-cash gain for the accounting impact of a financial derivative related to our Convertible Senior Notes.

Full-Year 2018 Financial Results

Net loss for the year ended December 31, 2018 (2018 Period) was $72.4 million, or $1.12 per share (basic), as compared to $67.8 million, or $1.76 per share (basic), for the year ended December 31, 2017 (2017 Period). Net loss for the 2018 Period includes a non-cash gain of $25.6 million, or $0.39 per share (basic), relating to the accounting impact of a financial derivative related to our Convertible Senior Notes. In addition, net loss includes non-cash stock-based compensation expense of $6.7 million and $5.0 million for the 2018 and 2017 Periods, respectively.

Total revenue for the 2018 Period was $26.7 million which reflects net product revenue of $1.7 million for sales of COPIKTRA and license revenue of $25.0 million relating to our license agreements with Yakult and CSPC. The Company did not have any product revenue for the 2017 Period as the FDA approved COPIKTRA on September 24, 2018. The Company did not have any license revenue for the 2017 Period.

Research and development expense for the 2018 Period was $43.6 million compared to $46.4 million for the 2017 Period. The decrease of $2.8 million, or 6%, from the 2017 Period to the 2018 Period was primarily related to a decrease of $6.0 million in license fees related to a one-time milestone earned pursuant to our Infinity license agreement which was recognized in the 2017 Period, offset, in part, by a net increase of $3.2 million in personnel related costs, including non-cash stock-based compensation, clinical trial costs and consulting fees for COPIKTRA.

Selling, general and administrative expense for the 2018 Period was $77.3 million compared to $21.4 million for the 2017 Period. The increase of $55.9 million, or 261%, from the 2017 Period to the 2018 Period primarily resulted from higher personnel and related costs, promotional and consulting costs in support of the commercial launch of COPIKTRA.

Other income of $25.6 million for the 2018 Period relates entirely to a non-cash gain for the accounting impact of a financial derivative related to our Convertible Senior Notes.

In October 2018, the Company completed an offering of 5.00% Convertible Senior Notes due 2048 through a registered direct offering. The Company received net proceeds of $145.3 million, after transaction fees and expenses. Verastem Oncology ended 2018 with cash, cash equivalents and short-term investments of $249.7 million.

For more information about Verastem Oncology, including its leadership, product and pipeline, please visit verastem.com

Important Safety Information

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.
Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.
Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.
Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS

Infections: Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving COPIKTRA 25 mg BID (N=442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold COPIKTRA until infection has resolved. Resume COPIKTRA at the same or reduced dose.

Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with COPIKTRA and following completion of treatment with COPIKTRA until the absolute CD4+ T cell count is greater than 200 cells/μL. Withhold COPIKTRA in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.

Cytomegalovirus (CMV) reactivation/infection occurred in 1% of patients taking COPIKTRA. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold COPIKTRA until infection or viremia resolves. If COPIKTRA is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.

Diarrhea or Colitis: Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month).

Advise patients to report any new or worsening diarrhea. For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e., up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents, continue COPIKTRA at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting COPIKTRA at a reduced dose.

For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e., > 6 stools per day over baseline), withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart COPIKTRA at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue COPIKTRA. Discontinue COPIKTRA for life-threatening diarrhea or colitis.

Cutaneous Reactions: Serious, including fatal (2/442; <1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months) with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).

Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue COPIKTRA at the current dose, initiate supportive care with emollients, antihistamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold COPIKTRA for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or antihistamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart COPIKTRA at a reduced dose. Discontinue COPIKTRA if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue COPIKTRA. In patients with SJS, TEN, or DRESS of any grade, discontinue COPIKTRA.

Pneumonitis: Serious, including fatal (1/442; <1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months. The median event duration was 1 month, with 75% of cases resolving by 2 months.

Withhold COPIKTRA in patients with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation, and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on COPIKTRA at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids and resume COPIKTRA at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue COPIKTRA. For severe or life-threatening non-infectious pneumonitis, discontinue COPIKTRA and treat with systemic steroids.

Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, of patients receiving COPIKTRA 25 mg BID (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).

Monitor hepatic function during treatment with COPIKTRA. For Grade 2 ALT/AST elevation (> 3 to 5 X ULN), maintain COPIKTRA dose and monitor at least weekly until return to < 3 X ULN. For Grade 3 ALT/AST elevation (> 5 to 20 X ULN), withhold COPIKTRA and monitor at least weekly until return to < 3 X ULN. Resume COPIKTRA at the same dose (first occurrence) or at a reduced dose for subsequent occurrences. For grade 4 ALT/AST elevation (> 20 X ULN), discontinue COPIKTRA.

Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA 25 mg BID (N=442), with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.

Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L, then resume COPIKTRA at same dose for the first occurrence or at a reduced dose for subsequent occurrences.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

ADVERSE REACTIONS

B-cell Malignancies Summary

Fatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).

Adverse reactions resulted in treatment discontinuation in 156 patients (35%) most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.

CLL/SLL: Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). COPIKTRA was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash. The most common adverse reactions with COPIKTRA (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

FL: Serious adverse reactions were reported in 58% of patients and most often involved diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis. The most common adverse reactions (≥20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia. Adverse reactions resulted in COPIKTRA discontinuation in 29% of patients, most often due to diarrhea or colitis and rash. COPIKTRA was dose reduced in 23% due to adverse reactions, most often due to transaminase elevation, diarrhea or colitis, lipase increased and infection.

DRUG INTERACTIONS

CYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.
CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.
CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
See full Prescribing Information, including Boxed Warning, at www.COPIKTRA.com

About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes and are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. The symptoms of CLL/SLL include a tender, swollen abdomen and feeling full even after eating only a small amount. Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. In 2018, there were approximately 200,000 patients in the United States affected by CLL/SLL with nearly 20,000 new diagnoses. While there are therapies currently available, real-world data reveals that a significant number of patients either relapse following treatment, become refractory to current agents, or are unable to tolerate treatment, representing a significant medical need. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with CLL/SLL.

About Follicular Lymphoma

Follicular lymphoma (FL) is typically a slow-growing or indolent form of non-Hodgkin lymphoma (NHL) that arises from B-lymphocytes, making it a B-cell lymphoma. In 2018, this lymphoma subtype accounted for 20 to 30 percent of all NHL cases, with more than 140,000 people in the United States with FL and more than 13,000 newly diagnosed patients. Common symptoms of FL include enlargement of the lymph nodes in the neck, underarms, abdomen, or groin, as well as fatigue, shortness of breath, night sweats, and weight loss. Often, patients with FL have no obvious symptoms of the disease at diagnosis. Follicular lymphoma is usually not considered to be curable, but more of a chronic disease, with patients living for many years with this form of lymphoma. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with FL.

About Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a rare, aggressive type of non-Hodgkin lymphoma (NHL) that develops in mature white blood cells called "T cells" and "natural killer (NK) cells"1 which circulate with the lymphatic system.2 PTCL accounts for between 10-15% of all non-Hodgkin lymphomas (NHLs) and generally affects people aged 60 years and older.1 Although there are many different subtypes of peripheral T-cell lymphoma, they often present in a similar way, with widespread, enlarged, painless lymph nodes in the neck, armpit or groin.2 There is currently no established standard of care for patients with relapsed or refractory disease.1

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.3,4,5 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.6 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On March 12, 2019 Inovio Pharmaceuticals, Inc. (NASDAQ:INO), a late-stage biotechnology company focused on the development and commercialization of DNA immunotherapies targeted against cancers and infectious diseases, reported financial results for the fourth quarter and year ended December 31, 2018 (Press release, Inovio, MAR 12, 2019, View Source [SID1234534260]). Inovio’s management will host a live conference call and webcast at 4:30 p.m. Eastern Time today to discuss financial results and provide a general business update.

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Inovio Pharmaceuticals. (PRNewsFoto/Inovio Pharmaceuticals, Inc.)
Inovio Highlights

MEDI0457 (formerly INO-3112, licensed to AstraZeneca)
Between October 2018 and January 2019, Inovio announced two patients with human papilloma virus (HPV)-related head and neck cancer that were treated with INO-3112 (now called MEDI0457) in a Phase 1 trial achieved a sustained complete response (full remission) following subsequent treatment with a PD-1 checkpoint inhibitor. Both patients who achieved full cancer remission were treated with four doses of synthetic DNA vaccine as part of a Phase 1 monotherapy trial of 22 patients with HPV-related head and neck squamous cell carcinoma in which 91% of patients (20/22) showed T cell activity in the blood or tissue. The administration of synthetic DNA vaccine in the trial generated robust HPV16/18 specific CD8+ T cell responses in peripheral blood and increased CD8+ T cell infiltration in resected tumor tissue samples. Complete response in 2 out of 4 (50%) progressors is encouraging, as to Inovio’s knowledge, the best complete response rate by PD-1 inhibitors as a monotherapy in metastatic head and neck cancer is approximately 4% (8/192 with KEYTRUDA alone and 6/240 with OPDIVO alone).

Additionally, in December 2018, Inovio announced a second Phase 2 study in collaboration with AstraZeneca and the MD Anderson Cancer Center to evaluate MEDI0457 in combination with durvalumab targeting a broad array of cancers associated with HPV. The treatment of the first patient with cervical cancer in this trial resulted in a milestone payment from AstraZeneca to Inovio.
VGX-3100 – HPV-related Pre-cancers
VGX-3100, which is a sibling product candidate to MEDI0457, continues to be evaluated in the double-blind global Phase 3 study for the treatment of cervical dysplasia (CIN). The enrollment for primary study, REVEAL 1, is nearing completion; while the confirmatory study, REVEAL 2, is now open and recruiting. The company maintains the target objective on a BLA submission for VGX-3100 in 2021. In addition to VGX-3100 for the treatment of CIN, the company anticipates interim efficacy later this year from our 2 separate Phase 2 studies that are evaluating the efficacy of VGX-3100 in patients with precancerous lesions of the vulva, or vulvar dysplasia, as well as for anal dysplasia.
INO-5401 – Cancer Combination Trials
Inovio’s Phase 1/2 immuno-oncology trial evaluating INO-5401 plus INO-9012, in combination with Regeneron Pharmaceuticals’ cemiplimab (REGN2810) in patients with newly diagnosed glioblastoma currently has 20 sites open within the United States with the enrollment of 52 patients nearly completed. In Inovio’s other Phase 1/2a study of INO-5401 plus INO-9012, in combination with Genentech/Roche’s atezolizumab, for the treatment of advanced or metastatic bladder cancer, the company recently opened sites in Europe to further accelerate enrollment along with its 13 active sites in the United States. The company expects interim efficacy results from both programs in 2019.
Infectious Diseases
Inovio and its partner GeneOne Life Science, with a full funding from the International Vaccine Institute, are conducting a Phase 1/2a MERS vaccine study in South Korea, with data report expected in 2019. Inovio also plans to initiate a Phase 2 MERS vaccine field trial in the Middle East with full CEPI funding in 2H 2019.
Inovio received IND approval for another CEPI funded vaccine for combatting Lassa fever, which will advance into the first human trial in the second quarter.
All patient samples have been collected for Inovio’s Zika vaccine trial in Puerto Rico. Inovio’s partner GeneOne is analyzing all samples blindly and will report safety, immune responses and infection rate data from this study in 2019.
Inovio expects to have clinical data from several Phase 1 vaccine programs published multiple publications in 2019: Ebola vaccine; MERS vaccine; HIV; and ZIka vaccine study in Puerto Rico.
DNA-Encoded Monoclonal Antibody (dMAb)
In February 2019, the company dosed the first subject in the first-ever human study of Inovio’s DNA-encoded monoclonal antibody (dMAb) technology evaluating the dMAb’s (INO-A002) ability to prevent or treat Zika virus infection. This study is being fully funded by The Bill and Melinda Gates Foundation. While the trial’s focus is on evaluating the dMAb for Zika infection, the clinical results are intended to help advance Inovio’s dMAb programs in infectious diseases and cancer.
Geneos Therapeutics, Inc.
In February 2019, Inovio’s subsidiary Geneos, secured a Series A financing round with potential proceeds of up $10.5 million. This funding has launched Geneos’ operations as a standalone entity to develop the next generation of neoantigen-targeting cancer immunotherapies. Geneos has an exclusive license to Inovio’s DNA-based immunotherapy platform for personalized cancer immunotherapy; Inovio will continue to develop and potentially commercialize all global population-based (non-personalized) cancer immunotherapies and infectious disease vaccines based on its proprietary SynCon design.
Cash Position
As of December 31, 2018, cash and cash equivalents and short-term investments were $81.2 million compared to $85.5 million as of September 30, 2018. In February and March 2019, the Company completed a private placement of $78.5 million aggregate principal amount of 6.50% convertible senior notes due 2024, or the Notes. The Notes were sold in a private offering to qualified institutional buyers pursuant to Rule 144A under the Securities Act of 1933, as amended. Net proceeds from the offering were approximately $75.8 million, after deducting the initial purchasers’ discount and estimated offering expenses payable by the Company.
Dr. J. Joseph Kim, Inovio’s President & CEO said, "Our Phase 3 program for VGX-3100 is advancing with REVEAL 1 nearing complete enrollment and the opening of sites for REVEAL 2. Moreover, Inovio continues to generate impressive efficacy data for HPV-related head and neck cancers, further validating our objective to be the global leader in treating HPV-related diseases. The announcement of the second patient achieving full cancer remission in January provides additional corroboration for Inovio’s overall cancer combination strategy using a T cell activator combined with a checkpoint inhibitor against an array of cancers with big pharma partners providing various checkpoint inhibitors. With interim efficacy data expected later this year from our INO-5401 programs, we believe Inovio is well-positioned to continue to build upon its synthetic DNA immunotherapy approach, while continuing to leverage our current partnerships and seeking to form new ones."

Fourth Quarter 2018 Financial Results

Total revenue was $2.5 million and $30.5 million for the quarter and year ended December 31, 2018, respectively, compared to $8.8 million and $42.2 million for the same periods in 2017. Total operating expenses were $32.0 million and $124.6 million for the quarter and year ended December 31, 2018, respectively, compared to $31.7 million and $125.9 million for the same periods in 2017, respectively.

As a result of the adoption of Accounting Standards Update No. 2014-09, Revenue from Contracts with Customers, beginning on January 1, 2018, all contributions received from current grant agreements have been recorded as a contra-expense as opposed to revenue on the consolidated statement of operations. For the quarter and year ended December 31, 2018, $2.8 million and $9.5 million, respectively, was recorded as contra-research and development expense, which would have been classified as grant revenue in the prior year. Had this change in presentation not occurred, total revenue would have been $5.3 million and $40.0 million for the quarter and year ended December 31, 2018, respectively, compared to $8.8 million and $42.2 million for the same periods in 2017. Total operating expenses would have been $34.8 million and $134.1 million for the quarter and year ended December 31, 2018, respectively, compared to $31.7 million and $125.9 million for the same periods in 2017.

Inovio’s net loss for the quarter and year ended December 31, 2018 was $33.0 million, or $0.34 per basic and diluted share, and $97.0 million, or $1.05 per basic and diluted share, respectively, as compared to $21.5 million, or $0.24 per basic and diluted share, and $88.2 million, or $1.08 per basic and $1.09 per diluted share, for the same periods in 2017.

Revenue

The year over year decrease in comparable revenue and grant agreement recognition was primarily due to $15.4 million in lower revenues recognized under Inovio’s collaborative research and development agreement with AstraZeneca, as previously deferred revenue was recognized in June 2017 upon AstraZeneca’s selection of the first cancer research collaboration product candidate. There was also a decrease in grant funding recognized from Inovio’s DARPA Ebola grant of $8.8 million as well as no revenue recognized in 2018 from Roche compared to $6.1 million for 2017 due to the termination of the agreement in 2017. These decreases were partially offset by the recognition of the gross up-front payment from ApolloBio of $23.0 million during the year (approximately $19.4 million after payment of required taxes), as well as an increase in grant funding from the CEPI grant of $4.3 million, among other variances.

Operating Expenses

Research and development (R&D) expenses for the quarter and year ended December 31, 2018 were $26.4 million and $95.3 million, respectively, compared to $24.6 million and $98.6 million for the same periods in 2017. The year over year decrease in R&D expenses was primarily due to the $9.5 million contra-research and development expense recorded from grant agreements as discussed above, as well as a decrease in expenses related to Inovio’s DARPA Ebola grant. These decreases were offset by an increase in expenses for drug manufacturing related to Inovio’s collaboration with AstraZeneca, employee headcount to support clinical trials and partnerships, and expenses related to clinical trials, among other variances.

General and administrative expenses were $5.6 million and $29.3 million, respectively, for the quarter and year ended December 31, 2018 versus $8.0 million and $28.3 million, respectively, for the same periods in 2017.

Capital Resources

As of December 31, 2018, cash and cash equivalents and short-term investments were $81.2 million compared to $85.5 million as of September 30, 2018. As of December 31, 2018, the Company had 97.2 million common shares outstanding and 107.7 million common shares outstanding on a fully diluted basis, after giving effect to outstanding options, restricted stock units and convertible preferred stock.

During the year ended December 31, 2018, the Company sold 5,669,025 shares of common stock under its current and prior "at-the-market" (ATM) common stock sales agreements for aggregate net proceeds of $29.2 million.

During the year ended December 31, 2018, stock options and warrants to purchase an aggregate of 756,853 shares of common stock were exercised for aggregate net proceeds of $2.4 million.

In February and March 2019, the Company completed a private placement of $78.5 million aggregate principal amount of 6.50% convertible senior notes due 2024, or the Notes. The Notes were sold in a private offering to qualified institutional buyers pursuant to Rule 144A under the Securities Act of 1933, as amended. Net proceeds from the offering were approximately $75.8 million, after deducting the initial purchasers’ discount and estimated offering expenses payable by the Company.

On March 12, 2019 Scholar Rock Holding Corporation (NASDAQ:SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, reported that it has selected SRK‑181, a highly specific inhibitor of TGFβ1 activation, as the first product candidate in its TGFβ1 cancer immunotherapy program based on the strength of its preclinical data and human translational insights (Press release, Scholar Rock, MAR 12, 2019, View Source [SID1234537354]). Scholar Rock has initiated manufacturing and is progressing preclinical development efforts with plans to initiate a Phase 1 trial in patients with solid tumors in mid- 2020.

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"Given that a majority of cancer patients fail to respond to checkpoint blockade therapies, we are eager to advance the next product candidate from our pipeline of growth factor modulators to potentially address a key mechanism of pre-existing resistance," said Nagesh Mahanthappa, Ph.D., President and CEO of Scholar Rock. "A growing body of evidence strongly implicates elevated TGFβ1 activity as a cause of immunotherapy failure, and we see tremendous potential for SRK-181 to expand the number of patients who could benefit from checkpoint blockade therapies by potently and selectively inhibiting the activation of TGFβ1."

SRK-181 is a fully human antibody designed to bind to, and prevent the activation of, latent TGFβ1 with high affinity and high selectivity, as evidenced by minimal or no binding to latent TGFβ2 and latent TGFβ3 isoforms. Several important factors led to the decision to advance SRK-181 as a clinical development product candidate for the treatment of tumors resistant to checkpoint blockade therapies (CBTs), such as anti-PD1 antibodies. These factors include:

TGFβ signaling has been implicated as a culprit in primary resistance to CBTs in multiple peer-reviewed studies.
Translational data analyses by Scholar Rock highlight the prominent expression of TGFβ1 in many human tumor types, such as bladder cancer, non-small cell lung cancer and melanoma, for which CBTs have either been approved or demonstrated clinical activity in trials.
Clinical correlation and preclinical model data suggest that TGFβ1 excludes effector cell entry into the tumor, thereby limiting immune system access to tumor cells.
Preclinical studies in syngeneic mouse tumor models resistant to CBT show SRK-181-mIgG1 (the murine version of SRK-181), when combined with anti-PD1 antibodies, permitted effector T cell infiltration and expansion into the tumor microenvironment and led to tumor regression or control as well as significant survival benefit.
A 28-day pilot toxicology study of SRK-181 in adult rats showed no observed drug-related toxicity up to a weekly dose of 100 mg/kg for 4 weeks.
Detailed preclinical results for SRK-181-mIgG1 (formerly referred to as SRTβ1-Ab3) were presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting in November 2018. The poster presented at SITC (Free SITC Whitepaper) can be accessed by visiting the Scholar Rock website at View Source Additional preclinical data for SRK-181-mIgG1 will be presented at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting scheduled to take place March 29 to April 3, 2019 in Atlanta, GA.

About SRK-181
SRK-181 is a highly specific inhibitor of TGFβ1 activation being developed to overcome primary resistance to checkpoint blockade therapies (CBTs). TGFβ1 is the predominant TGFβ isoform expressed in many human tumors, particularly for those tumors where checkpoint therapies are currently approved. Based on analyses of human tumors that are resistant to CBT, TGFβ1 is implicated as a key contributor to exclude immune cell entry into the tumor microenvironment, thereby preventing normal immune function. By overcoming this immune cell exclusion, SRK-181 has the potential to induce tumor regression when administered in conjunction with CBT.

On March 12, 2019 Celgene Corporation (NASDAQ: CELG) reported two updates for ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) in the treatment of metastatic triple-negative breast cancer and early stage pancreatic cancer (Press release, Celgene, MAR 12, 2019, View Source [SID1234534240]).

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"ABRAXANE continues to be studied with immunotherapy agents as a combination partner across a range of solid tumors."

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Genentech, a member of the Roche Group, recently announced the accelerated approval of TECENTRIQ (atezolizumab) in combination with ABRAXANE for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). This combination is the first cancer immunotherapy regimen approved for breast cancer and is based on results from the Phase 3 IMpassion130 study, which demonstrated that the combination of TECENTRIQ plus ABRAXANE compared to ABRAXANE monotherapy, as an initial (first-line) treatment, significantly reduced the risk of disease worsening or death (progression-free survival) in patients with metastatic or unresectable locally advanced triple negative breast cancer (TNBC) in the PD-L1 positive populations who had not received chemotherapy for metastatic disease.

"This is the second approval from the U.S. Food and Drug Administration of a PD-1/PD-L1 antibody in combination with ABRAXANE," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "ABRAXANE continues to be studied with immunotherapy agents as a combination partner across a range of solid tumors."

In addition, the Celgene-sponsored, pivotal, Phase 3 apact study evaluating the investigational use of ABRAXANE in combination with gemcitabine following surgical resection (adjuvant treatment) in patients with pancreatic cancer did not achieve the primary endpoint of improvement in disease-free survival, as confirmed by independent radiological review, compared to gemcitabine alone. Overall survival, a secondary endpoint of the study, was improved, reaching nominal statistical significance, with ABRAXANE in combination with gemcitabine compared to gemcitabine alone. The safety profile observed in the apact study was consistent with previously reported studies of ABRAXANE. Data from apact will be submitted to a future medical meeting.

Currently, there are more than 130 studies evaluating the use of ABRAXANE in patients with pancreatic cancer in combination with more than 50 novel agents.

About apact

apact is an international, multicenter, randomized, open-label, controlled Phase 3 study (ClinicalTrials.gov, NCT01964430) to assess the efficacy of ABRAXANE in combination with gemcitabine versus gemcitabine alone as adjuvant therapy for patients with surgically resected pancreatic adenocarcinoma. The primary endpoint of the study was the independent assessment of disease-free survival (DFS); secondary endpoints included overall survival (OS) and safety. The study enrolled 866 patients randomized 1:1 to receive either ABRAXANE 125 mg/m2 followed by gemcitabine 1000 mg/m2, or gemcitabine 1000 mg/m2 monotherapy. Treatment was administered intravenously, weekly on Days 1, 8, and 15 of a 28-day cycle for a total of 6 cycles.

About Pancreatic Cancer

Each year, more than 350,000 people worldwide are diagnosed with pancreatic cancer – one of the deadliest cancers – with the majority of cases diagnosed in late stage. Despite advances in therapy over the past two decades that have led to doubled 5-year survival rates, pancreatic cancer 5-year survival is still only in the single digits – 8% – due to the complex nature of the disease and lack of symptoms until the disease has progressed.

Even among patients with localized pancreatic cancer, for whom surgery is potentially curative, survival remains poor and the rate of relapse is high. However, adjuvant chemotherapy has been proven to significantly improve survival compared with surgery alone. Despite the noted improvements with chemotherapy following surgery, recurrence rates of pancreatic cancer are still high with 69 to 75% of patients having a relapse within 2 years. There remains a high unmet medical need for more effective adjuvant therapies.

About Triple Negative Breast Cancer

Breast cancer is the second most common cancer among women in the United States. According to the American Cancer Society, it is estimated that about 266,000 American women will be diagnosed with invasive breast cancer in 2018, and nearly 41,000 will die from the disease. Approximately 10-20 percent of breast cancers are triple negative breast cancer (TNBC). TNBC is an aggressive form of the disease with a high unmet need. It can be more difficult to treat because it is not sensitive to hormone therapy or medicines that target HER2.

TECENTRIQ is a registered trademark of Genentech, a member of the Roche Group.

About ABRAXANE in Pancreatic Cancer

In September 2013, the U.S. Food and Drug Administration (FDA) approved ABRAXANE in combination with gemcitabine as first-line treatment of patients with metastatic pancreatic cancer. The current indication remains unchanged and clinical trials continue building on the foundation of ABRAXANE in combination with gemcitabine for a new wave of potential treatments, such as an ongoing Phase 2 cooperative group trial with SWOG S1505 (ClinicalTrials.gov, NCT02562716) investigating the safety and effectiveness of ABRAXANE in combination with gemcitabine as neoadjuvant treatment for localized pancreatic head adenocarcinoma.

ABRAXANE is not approved for the adjuvant treatment of pancreatic cancer.

About ABRAXANE

Indications

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC
In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3
In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Cross-hypersensitivity between ABRAXANE and other taxane products has been reported and may include severe reactions such as anaphylaxis. Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ABRAXANE therapy
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Embryo Fetal Toxicity

Based on mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman
Advise females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with ABRAXANE and for at least six months after the last dose of ABRAXANE
Advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE
ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively
Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported
Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported
Non–Small Cell Lung Cancer (NSCLC) Study

The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin–treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group
Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively
Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin
Pancreatic Adenocarcinoma Study

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. In postmarketing experience, cross-hypersensitivity between ABRAXANE and other taxanes has been reported
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Pregnancy

Based on the mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. Advise females of the potential risk to a fetus and to avoid becoming pregnant while receiving ABRAXANE
Lactation

Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Nursing must be discontinued when receiving treatment with ABRAXANE and for two weeks after the last dose
Females and Males of Reproductive Potential

Females of reproductive potential should have a pregnancy test prior to starting treatment with ABRAXANE
Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with and for at least six months after the last dose of ABRAXANE [see Warnings and Precautions]
Advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE [see Warnings and Precautions]
Based on findings in animals, ABRAXANE may impair fertility in females and males of reproductive potential
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

A higher incidence of epistaxis, diarrhea, dehydration, fatigue, and peripheral edema was found in patients 65 years or older who received ABRAXANE for MBC in a pooled analysis of clinical studies
Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC
Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
For MBC and NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment
For adenocarcinoma of the pancreas, do not administer ABRAXANE to patients who have moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely

On March 12, 2019 Protagonist Therapeutics, Inc. (Nasdaq: PTGX) reported its financial results for the fourth quarter and full year ended December 31, 2018, and provided a corporate update on its clinical development programs (Press release, Protagonist, MAR 12, 2019, View Source [SID1234534281]).

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"We continue to advance three different clinical development candidates discovered from our proprietary peptide engineering platform and have sufficient financial resources to support these programs and reach important milestones through the end of 2020," commented Dinesh V. Patel, Ph.D., Protagonist President and Chief Executive Officer. "We are pleased to have initiated a global Phase 2 trial of PTG-300 for the treatment of beta thalassemia and expect preliminary results in the second half of 2019. Based on the broad applicability of the mechanism of action of PTG-300, we see strong potential for its development in multiple indications, and plan to initiate a second indication for PTG-300 in the second half of the year. With our partner, Janssen Biotech, we are working towards filing a U.S. Investigational New Drug (IND) application in the first half of 2019 to support a global Phase 2 study of PTG-200 in Crohn’s patients. In addition, we are moving forward with the development of our oral, gut-restricted alpha-4-beta-7 integrin antagonist, PN-943, for the treatment of inflammatory bowel disease. Safety, pharmacokinetic, and pharmacodynamic results from the Phase 1 study of PN-943 in healthy volunteers are expected in the first half of 2019."

Product Development Update:

PTG-300

The Company announced the initiation of dosing in the TRANSCEND study, a single-arm, open-label global Phase 2 study of PTG-300, an injectable hepcidin mimetic, in patients with transfusion-dependent or non-transfusion dependent beta thalassemia. Preliminary results from this Phase 2 trial are expected in the second half of 2019.
The Company expects to begin clinical development of PTG-300 in a second indication in the second half of 2019.
The Company received Orphan Drug Designation from the European Medicines Agency for PTG-300. PTG-300 had previously received Orphan Drug Designation and Fast Track Designation from the U.S. FDA.
PTG-200

Top-line results from a Phase 1 study of PTG-200, an oral peptide IL-23 receptor antagonist partnered with Janssen Biotech, demonstrated that the drug was well tolerated, with no serious adverse events or dose-limiting toxicities observed.
Protagonist and Janssen Biotech are working towards filing a U.S. IND application to support a global Phase 2 clinical study in patients with Crohn’s disease. This IND filing would trigger a milestone payment from Janssen Biotech of $25 million under the exclusive license and collaboration agreement between Janssen Biotech and Protagonist (Janssen License and Collaboration Agreement). The U.S. IND filing is expected in the first half of 2019.
PN-943

Protagonist announced initiation of dosing in a Phase 1 study of PN-943, which is being developed as a potential novel oral therapy for patients with inflammatory bowel disease. The study will evaluate safety, pharmacokinetics, and pharmacodynamic readouts of target engagement as measured by blood receptor occupancy in healthy volunteers. Top-line results from this Phase 1 study are expected in the first half of 2019.
The Phase 1 data will inform the design of a Phase 2 study of PN-943 in patients with ulcerative colitis, with an expected U.S. IND filing in late 2019.
Preclinical research findings of PN-943 have been accepted for oral presentation on Sunday, May 19, 2019, at the Digestive Diseases Week conference in San Diego.
Financial Results

Protagonist reported a net loss of $13.9 million and $38.9 million, respectively, for the fourth quarter and full year 2018, as compared to a net loss of $3.1 million and $37.0 million, respectively, for the same periods of 2017. The increase in net loss for the fourth quarter of 2018 as compared to the prior year period was driven primarily by numerous factors such as nearing the end of the revenue recognition phase of the $50.0 million upfront payment received from Janssen in 2017, a net decrease in license and collaboration revenue affected by an increase in variable consideration and the additional time required to deliver the services to Janssen, and increases in research and development (R&D) expenses. The increase in net loss for the full year 2018 as compared to the prior year was driven primarily by increases in R&D and general and administrative (G&A) expenses, partially offset by an increase in license and collaboration revenue and higher interest income. The net loss for the fourth quarter and full year 2018 included non-cash stock-based compensation of $2.1 million and $6.9 million, respectively, as compared to $1.2 million and $4.2 million, respectively, for the same periods of 2017.

License and collaboration revenue was $2.4 million and $30.9 million, respectively, for the fourth quarter and full year 2018, as compared to $11.3 million and $20.1 million, respectively, for the same periods of 2017. The decrease in license and collaboration revenue for the fourth quarter of 2018 as compared to the prior year period was primarily related to nearing the end of the revenue recognition phase of the $50.0 million upfront payment received from Janssen in 2017 coupled with the additional estimated time remaining to complete our increased compound supply services under the Janssen License and Collaboration Agreement. Protagonist estimates these services will be completed during the first half of 2019 compared to the previous estimate of end of 2018. The increase in license and collaboration revenue for the full year of 2018 as compared to the prior year was primarily driven by a full year of services performed under the Janssen License and Collaboration Agreement during 2018, compared to five months of revenue during 2017 following the signing of the agreement. The Company has determined that the transaction price of the Janssen License and Collaboration Agreement was $60.7 million at December 31, 2018, an increase in variable consideration of $6.8 million from the transaction price of $53.9 million at December 31, 2017.

R&D expenses were $14.2 million and $59.5 million, respectively, for the fourth quarter and full year 2018, as compared to $11.7 million and $46.2 million, respectively, for the same periods of 2017. The increases in R&D expenses were primarily due to costs related to contract manufacturing and the preparation for and conduct of clinical trials for our product candidates. R&D expenses for the fourth quarter and full year 2018 included increases in salaries and employee-related expenses due to an increase in R&D personnel.

G&A expenses for the fourth quarter and full year 2018 were $3.5 million and $13.7 million, respectively, as compared to $3.1 million and $11.8 million, respectively, for the same periods of 2017. The increases in G&A expenses were primarily due to increases in salaries and employee-related expenses to support the growth of our operations.

Interest income for the fourth quarter and full year 2018 was $0.7 million and $2.5 million, respectively, as compared to $0.5 million and $0.9 million, respectively, for the same periods of 2017. The increase in interest income is primary the result of the increasing interest rate environment during 2018.

Protagonist ended 2018 with $128.9 million in cash, cash equivalents and investments. Protagonist expects to have sufficient financial resources to fund operations to the end of 2020.

Conference Call and Webcast Information

Protagonist executives will host a conference call at 4:30 p.m. EDT today. To access the live call, dial 1-844-515-9178 (U.S./Canada) or 1-614-999-9313 (international) and refer to conference ID number 9688334. The call will also be webcast and will be accessible from "Events & Presentations" in the Investors section of the Company’s website at www.protagonist-inc.com. A replay will be available on the Company’s website approximately two hours after the call and will remain available for 60 days.