On May 15, 2020 Bristol Myers Squibb (NYSE: BMY) reported that Pomalyst (pomalidomide) was approved by the U.S. Food and Drug Administration (FDA) for patients with AIDS-related Kaposi sarcoma whose disease has become resistant to highly active antiretroviral therapy (HAART), or in patients with Kaposi sarcoma who are HIV-negative.3 Patients with AIDS-related Kaposi sarcoma should continue HAART for their HIV as recommended by their physician (Press release, Bristol-Myers Squibb, MAY 15, 2020, View Source [SID1234558145]). Pomalyst was granted accelerated approval, Breakthrough Therapy designation and Orphan Drug designation in these indications based on overall response rates observed in a Phase 1/2 open label, single-arm clinical trial (12-C-0047). Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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Kaposi sarcoma is a rare form of cancer that usually presents as skin lesions, but can also develop in several other areas of the body including the lungs, lymph nodes and digestive system. The disease occurs at a rate of about 6 cases per million people each year in the United States, and mostly affects people who are immunocompromised.1,4,5 This oral therapy is the first new treatment option available for those with Kaposi sarcoma in more than 20 years.1,2

"Patients with Kaposi sarcoma have had few options to manage their disease for two decades," said Diane McDowell, M.D., vice president, Hematology Global Medical Affairs, Bristol Myers Squibb. "We’re excited that the additional research into Pomalyst in this rare disease area has resulted in our ability to provide a much-needed oral treatment option for patients."

As described in the Boxed Warnings of the prescribing information, Pomalyst can cause fetal harm and is contraindicated in females who are pregnant. Pomalyst is only available through a restricted distribution program, Pomalyst REMS. Deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke can occur in patients treated with Pomalyst and thromboprophylaxis is recommended. See additional Important Safety Information below.

"Pomalyst has shown positive results in Kaposi sarcoma patients, regardless of their HIV status," said Robert Yarchoan, M.D., Chief of the HIV and AIDS Malignancy Branch within the Center for Cancer Research of the National Cancer Institute (NCI). "Also, it provides a therapy that is taken orally and works by a different mechanism of action than the cytotoxic chemotherapy drugs generally used to treat Kaposi sarcoma."

About 12-C-0047

The approval of Pomalyst was based on the findings of a Phase 1/2 open-label, single-arm study conducted evaluating the safety, pharmacokinetics and efficacy of Pomalyst in patients with HIV-positive and HIV-negative symptomatic Kaposi sarcoma, the majority of whom had advanced disease.3 The study was performed under a Cooperative Research and Development Agreement (CRADA) by a team led by Dr. Robert Yarchoan of the HIV and AIDS Malignancy Branch within the Center for Cancer Research of the National Cancer Institute (NCI).6

A total of 28 patients (18 HIV-positive, 10 HIV-negative) received 5 mg of Pomalyst, once daily for 21 of 28-day cycles, until disease progression or unacceptable toxicity. All HIV-positive patients continued concomitant highly active antiretroviral therapy (HAART). The trial excluded patients with symptomatic pulmonary or visceral Kaposi sarcoma, history of venous or arterial thromboembolism, or procoagulant disorders. Patients received thromboprophylaxis with aspirin 81 mg once daily throughout therapy. The median time to first response was 1.8 months (0.9 to 7.6).3

The primary endpoint of the study was overall response rate (ORR), which included complete response (CR), clinical complete response (cCR) and partial response (PR), as assessed by investigators according to the AIDS Clinical Trial Group (ACTG) Oncology Committee response criteria for Kaposi sarcoma. For all patients, the ORR was 71% (95% CI: 51, 87) with 14% (4/28) of patients achieving CR and 57% (16/28) of patients achieving a PR, respectively. The median duration of response for all patients was 12.1 months (95% CI: 7.6, 16.8). Additionally, half (50%) of patients who responded maintained a response at more than 12 months with Pomalyst.3

The most common adverse reactions including laboratory abnormalities (≥30%) are decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea and diarrhea.

Adverse reactions were evaluated in 28 patients who received treatment with Pomalyst. Adverse reactions (≥20%) included maculopapular rash (71%), constipation (71%), fatigue (68%), nausea (36%), diarrhea (32%), cough (29%), dyspnea (29%), peripheral edema (29%), upper respiratory tract infection (29%), muscle spasms (25%), hypothyroidism (21%), dry skin (21%) and chills (21%). Grade 3 or 4 adverse reactions included maculopapular rash (3.6%), diarrhea (3.6%) and peripheral edema (3.6%). Grade 3 or 4 laboratory abnormalities (≥5%) worsening from baseline included decreased absolute neutrophil count (50%), decreased phosphate (25%), elevated glucose (7%) and elevated creatine kinase (7%).

Permanent discontinuation due to an adverse reaction occurred in 11% (3/28) of patients who received Pomalyst. No new safety signals were identified, and the safety of Pomalyst in Kaposi sarcoma was consistent with the known safety profile of Pomalyst in approved indications.3

About Kaposi sarcoma

Kaposi sarcoma is a rare form of cancer that usually presents as skin lesions, but can also develop in several other areas of the body including the lungs, lymph nodes and digestive system. Kaposi sarcoma is caused by Kaposi sarcoma-associated herpesvirus, also called human herpesvirus-8, and most commonly arises in persons infected with HIV who are immunocompromised. Although the use of combination anti-retroviral treatments (cART or HAART) has reduced the incidence of Kaposi sarcoma in the United States, it still occurs at a rate of approximately 6 cases per million people each year.5 The disease is more prevalent in areas of the world where HIV treatments are less available, and where more persons are infected with Kaposi sarcoma-associated herpesvirus, such as sub-Saharan Africa, and in some countries is the most common tumor in men overall.5

About Pomalyst (pomalidomide)

Indications

Pomalyst is a thalidomide analogue indicated for the treatment of adult patients:

• in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

• with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV-negative. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Pomalyst is contraindicated in pregnancy. Pomalyst is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting Pomalyst treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping Pomalyst treatment.
Pomalyst is only available through a restricted distribution program called Pomalyst REMS.

Venous and Arterial Thromboembolism

Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with Pomalyst. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
CONTRAINDICATIONS

Pregnancy: Pomalyst can cause fetal harm and is contraindicated in females who are pregnant. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
Hypersensitivity: Pomalyst is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients.
WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS
– Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Pomalyst and for up to 4 weeks after discontinuing Pomalyst, even if they have undergone a successful vasectomy. Males must not donate sperm.

– Blood Donation: Patients must not donate blood during treatment with Pomalyst and for 4 weeks following discontinuation of Pomalyst therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to Pomalyst.

Pomalyst REMS Program: See Boxed WARNINGS
– Prescribers and pharmacies must be certified with the Pomalyst REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive Pomalyst. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.

– Further information about the Pomalyst REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.

Venous and Arterial Thromboembolism: See Boxed WARNINGS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hematologic Toxicity: In the Pomalyst multiple myeloma (MM) trials, neutropenia (46%) was the most frequently reported Grade 3 or 4 adverse reaction, followed by anemia and thrombocytopenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification. In the Kaposi sarcoma (KS) trial, hematologic toxicities were the most common all Grades and Grade 3 or 4 adverse reactions. Fifty percent of patients had Grade 3 or 4 neutropenia. Monitor complete blood counts every 2 weeks for the first 12 weeks and monthly thereafter. Withhold, reduce the dose or permanently discontinue Pomalyst based on the severity of the reaction.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with Pomalyst. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with Pomalyst. Monitor liver function tests monthly. Stop Pomalyst upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Severe Cutaneous Reactions: Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These reactions can be fatal. Consider Pomalyst interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue Pomalyst for Grade 4 rash, exfoliative or bullous rash, or any other severe cutaneous reactions such as SJS, TEN or DRESS.
Dizziness and Confusional State: In patients taking Pomalyst in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy: In patients taking Pomalyst in the MM clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving Pomalyst as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with Pomalyst. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Hypersensitivity: Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to Pomalyst have been reported. Permanently discontinue Pomalyst for angioedema or anaphylaxis.
ADVERSE REACTIONS

Multiple Myeloma:

The most common adverse reactions for Pomalyst (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.

In the phase III trial, nearly all patients treated with Pomalyst + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the Pomalyst + low-dose dex arm and ≥2% higher than control) included neutropenia (51%), fatigue and asthenia (47%), upper respiratory tract infection (31%), thrombocytopenia (30%), pyrexia (27%), dyspnea (25%), diarrhea (22%), constipation (22%), back pain (20%), cough (20%), pneumonia (19%), bone pain (18%), edema peripheral (17%), peripheral neuropathy (17%), muscle spasms (15%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the Pomalyst + low-dose dex arm and ≥1% higher than control) included neutropenia (48%), thrombocytopenia (22%), and pneumonia (16%).

Kaposi Sarcoma:

The most common adverse reactions including laboratory abnormalities (≥30%) were decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea, and diarrhea.

In the KS trial, adverse reactions were evaluated in 28 patients who received treatment with Pomalyst. Adverse reactions (N=28) ≥ 20% included maculopapular rash (71%), constipation (71%), fatigue (68%), nausea (36%), diarrhea (32%), cough (29%), dyspnea (29%), peripheral edema (29%), upper respiratory tract infection (29%), muscle spasms (25%), hypothyroidism (21%), dry skin (21%), and chills (21%). Grade 3 or 4 adverse reactions included maculopapular rash (3.6%), diarrhea (3.6%) and peripheral edema (3.6%). Grade 3 or 4 laboratory abnormalities ≥ 5% worsening from baseline included decreased absolute neutrophil (50%), elevated glucose (7%), decreased phosphate (25%) and elevated creatine kinase (7%).

DRUG INTERACTIONS

Avoid concomitant use of Pomalyst with strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce Pomalyst dose to 2 mg.

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a Pomalyst pregnancy exposure registry that monitors pregnancy outcomes in females exposed to Pomalyst during pregnancy as well as female partners of male patients who are exposed to Pomalyst. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to Pomalyst to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Lactation: There is no information regarding the presence of pomalidomide in human milk, the effects of Pomalyst on the breastfed child, or the effects of Pomalyst on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from Pomalyst, advise women not to breastfeed during treatment with Pomalyst.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Geriatric Use:
– Multiple Myeloma (MM): No dosage adjustment is required for Pomalyst based on age. Patients >65 years of age were more likely than patients ≤65 years of age to experience pneumonia.

– Kaposi sarcoma (KS): The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Renal Impairment: For MM patients with severe renal impairment requiring dialysis, reduce Pomalyst dosage to 3 mg orally daily or for KS, reduce Pomalyst dosage to 4 mg orally daily. Take dose of Pomalyst following hemodialysis on hemodialysis days.
Hepatic Impairment: For MM patients with mild to moderate hepatic impairment, reduce Pomalyst dosage to 3 mg orally daily and to 2 mg orally daily in patients with severe hepatic impairment. For KS in patients with mild, moderate, or severe hepatic impairment, reduce Pomalyst dosage to 3 mg orally daily.
Smoking Tobacco: Advise patients that smoking may reduce the efficacy of Pomalyst. Cigarette smoking reduces pomalidomide AUC due to CYP1A2 induction.
Please see full Prescribing Information, including Boxed WARNINGS.

Bristol Myers Squibb: Advancing Cancer Research

At Bristol Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase quality, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational chimeric antigen receptor (CAR) T-cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering potential new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

On May 15, 2020 Celsion Corporation (NASDAQ: CLSN), an oncology drug development company, reported financial results for the three months ended March 31, 2020, and provided an update on clinical development programs with ThermoDox, its proprietary heat-activated liposomal encapsulation of doxorubicin currently in Phase III development for the treatment of hepatocellular carcinoma (HCC), or primary liver cancer, and GEN-1, its DNA-mediated IL-12 immunotherapy, currently in Phase I/II development for the treatment of advanced stage ovarian cancer (Press release, Celsion, MAY 15, 2020, View Source [SID1234558144]).

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"During the first quarter and recent weeks, Celsion continued to make substantial progress with our ongoing development programs with ThermoDox and GEN-1, while maintaining a strong balance sheet," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "With our pivotal 556-patient Phase III OPTIMA Study in HCC fully enrolled, we now look forward to the preplanned interim efficacy analysis in July 2020."

"Our GEN-1 immunotherapy product continued to show encouraging results at the 100 mg/m² dose cohort in the OVATION 2 Study, which is consistent with the results reported from our earlier Phase Ib trial (the OVATION 1 Study) in advanced stage ovarian cancer. These findings were reinforced by strong progression-free survival when comparing study patients to a statistically validated synthetic control arm of matched patients from prior studies. This unique means of evaluating efficacy holds great potential for clinical research, and we plan to use it in upcoming discussions with the U.S. Food and Drug Administration as part of our goal to accelerate GEN-1 clinical development. In addition, GEN-1 received Orphan Drug Designation from the European Medicines Agency in April 2020." Mr. Tardugno added, "Our fundamentals are strong, and we are well positioned with a capital structure sufficient to see our clinical programs through transformative milestones in 2020."

Recent Developments

ThermoDox

Sufficient Number of Patient Deaths Were Reached for the Second Interim Analysis of the Phase III OPTIMA Study of ThermoDox in Primary Liver Cancer. In April 2020 the Company announced that the prescribed minimum number of events (158 patient deaths) was reached for the second pre-specified interim analysis of the OPTIMA Phase III Study with ThermoDox plus RFA (radiofrequency ablation) in patients with HCC. Following preparation of the data, the Independent Data Monitoring Committee (iDMC) is expected to meet in July to conduct the second interim analysis. Celsion expects to announce iDMC recommendations as soon as possible after the meeting. The hazard ratio (HR) and p-value necessary for success at 158 deaths are 0.70 and 0.022, respectively, which compare favorably with the hazard ratio and p-value observed in the prospective HEAT Study subgroup upon which the OPTIMA Study is based.

The OPTIMA Study was fully enrolled in August 2018 with 556 subjects from 65 clinical sites in 14 countries. The study design is based on the Company’s HEAT Study, in which a prospective subgroup analysis of 285 subjects with a single lesion of 3-7 cm in size received a single ThermoDox administration in combination with a 45 minute or longer RFA procedure. Followed prospectively for 3 years, those patients demonstrated a median survival of more than 7 ½ years and a survival benefit of more than 2 years over the control group. These data were published in the October 2017 issue of the peer-reviewed journal Clinical Cancer Research, and are available here.

GEN-1 Immunotherapy

GEN-1 Showed Strong Progression-Free Survival Treatment Effect Utilizing Medidata’s Synthetic Control Arm. In March 2020 the Company announced that Medidata-matched patient data from a synthetic control arm (SCA) compared with results from the Company’s completed Phase Ib dose-escalating OVATION 1 Study with GEN-1 in Stage III/IV ovarian cancer patients showed positive results in progression-free survival (PFS). The HR was 0.53 in the intent-to-treat group, showing strong signals of efficacy. Medidata is a globally recognized leader in clinical data management.

Celsion believes these data may warrant consideration of strategies to accelerate the clinical development for GEN-1 in newly diagnosed, advanced ovarian cancer patients by the U.S. Food and Drug Administration (FDA). In its March 2019 discussion with Celsion, the FDA noted that preliminary findings from the Phase Ib OVATION 1 Study were exciting but lacked a control group to evaluate GEN-1’s independent impact on impressive tumor response, surgical results and PFS. The FDA encouraged Celsion to continue its GEN-1 development program and consult with FDA with new findings that may have a bearing on designations such as Fast Track and Breakthrough Therapy.

GEN-1’s strong and encouraging treatment effect, evidenced by the synthetic control arm, suggests a potentially remarkable improvement in PFS, an FDA-recognized surrogate for overall survival, and appears to confirm the science behind IL-12’s ability to recruit the innate and adaptive elements of the immune system to fight malignancies. The strong PFS trend is supported by previously published translational data that clearly demonstrate the pro-immune changes in the tumor micro-environment associated with loco-regional GEN-1 therapy. Celsion’s randomized Phase II OVATION 2 Study in advanced ovarian cancer patients is expected to commence in the fourth quarter of 2020 and is designed to demonstrate a 33% improvement in PFS (HR = 0.75) over current standard of care. PFS is the primary endpoint for this study.

SCAs have the potential to revolutionize clinical trials in certain oncology indications and some other diseases where a randomized control is not ethical or practical. SCAs are formed by carefully selecting control patients from historical clinical trials to match the demographic and disease characteristics of the patients treated with the new investigational product. SCAs have been shown to mimic the results of traditional randomized controls so that the treatment effects of an investigational product can be visible by comparison to the SCA. SCAs can help advance the scientific validity of single-arm trials, and in certain indications, reduce time and cost, and expose fewer patients to placebos or existing standard-of-care treatments that might not be effective for them. Medidata is in a unique position to create fit-for-purpose synthetic controls because of access to a pool of more than six million anonymized patients from nearly 20,000 previous clinical trials.

Highly Encouraging Initial Clinical Results from the Phase I Portion of the Phase I/II OVATION 2 Study with GEN-1 in Patients with Advanced Ovarian Cancer. In March 2020 the Company announced highly encouraging initial clinical data from the first 15 patients enrolled in the ongoing Phase I/II OVATION 2 Study for patients newly diagnosed with Stage III and IV ovarian cancer. The OVATION 2 Study combines GEN-1, the Company’s IL-12 gene-mediated immunotherapy, with standard-of-care neoadjuvant chemotherapy (NACT). Following NACT, patients undergo interval debulking surgery (IDS), followed by three additional cycles of chemotherapy.

GEN-1 plus standard NACT produced positive dose-dependent efficacy results, with no dose-limiting toxicities, which correlates well with successful surgical outcomes as summarized below:

●Of the 15 patients treated in the Phase I portion of the OVATION 2 Study, nine were treated with GEN-1 at a dose of 100 mg/m² plus NACT and six were treated with NACT only. All 15 had successful resections of their tumors, with seven out of nine patients (78%) in the GEN-1 treatment arm having an R0 resection, which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed. Only three out of six patients (50%) in the NACT only treatment arm had an R0 resection.

●When combining these results with the surgical resection rates observed in the Company’s prior Phase Ib dose-escalation trial (the OVATION 1 Study), a population of patients with inclusion criteria identical to the OVATION 2 Study, the data reflect the strong dose-dependent efficacy of adding GEN-1 to the current standard of care NACT:

●The objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for the 0, 36, 47 mg/m² dose GEN-1 patients were comparable, as expected, to the higher (61, 79, 100 mg/m²) dose GEN-1 patients, with both groups demonstrating an approximate 80% ORR.

GEN-1 Received Orphan Drug Designation from the European Medicines Agency. In March 2020 the Company announced the European Medicines Agency (EMA) Committee for Orphan Medicinal Products recommended that GEN-1 be designated as an orphan medicinal product for the treatment of ovarian cancer. As established by the EMA, this designation provides for scientific advice and certain regulatory assistance during the product development phase, direct access to centralized marketing authorization and certain financial incentives for companies developing new therapies intended for the treatment of a life-threatening or chronically debilitating condition that affects no more than five in 10,000 people in the European Union (EU).

Benefits of the designation include:

●10 years of market exclusivity (in which other industry sponsors are prevented from entering the market with a similar product for the same therapeutic indication);
●EMA protocol assistance for sponsors on the conduct of the tests and trials necessary to demonstrate their quality, safety and efficacy, or regulatory assistance;
●EMA advice will be free or given in return for reduced fees;
●Access to a centralized procedure allowing immediate marketing authorization in all Member States and facilitating the availability of medicines to all patients in the EU;
●Eligibility for a reduction of regulatory fees associated with pre-authorization inspections, as well as marketing authorization application fees and certain other fees for qualifying companies.

GEN-1 previously received orphan drug designation from the FDA.

Corporate Developments

Received $1.8 Million in Non-Dilutive Funding from the Sale of Its New Jersey State Net Operating Losses. In April 2020 the Company announced it received $1.82 million of net cash proceeds from the sale of approximately $1.9 million of its unused New Jersey net operating losses (NOLs). The NOL sales cover the tax years 2017 and 2018 and are administered through the New Jersey Economic Development Authority’s (NJEDA) Technology Business Tax Certificate Transfer (NOL) Program. With this new non-dilutive funding, coupled with the $4.4 million in net proceeds from the recent registered direct equity offer completed on March 3, 2020, the Company strengthened its balance sheet at a time of capital markets uncertainty. An additional sale of $2.0 million of unused New Jersey NOLs anticipated in the second half of 2020 will further increase Celsion’s cash reserves on a non-dilutive basis. In addition, the Company initiated several cost containment measures to ensure that it has sufficient cash to fund operations and clinical development programs through the second quarter of 2021, which includes all major Phase III OPTIMA Study readouts.

On April 21, 2020, we entered into a loan agreement with Silicon Valley Bank (the "PPP Loan"), pursuant to the Paycheck Protection Program of the Coronavirus Aid, Relief, and Economic Security Act. We thereafter received proceeds of $632,220 under the PPP Loan. The PPP Loan application required Celsion to certify that there was economic uncertainty surrounding the Company and that, as such, the PPP Loan was necessary to support our ongoing operations. Celsion made this certification in good faith after analyzing, among other things, its financial situation and access to alternative forms of capital, and believes that the Company satisfied all eligibility criteria for the PPP Loan, and that our receipt of the PPP Loan proceeds was consistent with the broad objectives of the PPP of the CARES Act. The certification given with respect to the PPP Loan does not contain any objective criteria and is subject to interpretation. In light of subsequent guidance issued by the U.S. Small Business Administration in consultation with the U.S. Department of the Treasury, out of an abundance of caution, we returned the proceeds of the PPP Loan in full on May 13, 2020. Celsion may choose to reapply for the loan if the SBA provides future applicable guidance.

Strengthened Balance Sheet Through a $4.8 Million Registered Direct Offering. In February 2020 the Company entered into securities purchase agreements with several institutional investors for the purchase and sale of 4,571,428 shares of the Company’s common stock pursuant to a registered direct offering. Celsion also agreed to issue to such investors, in a concurrent private placement, warrants to purchase approximately 3.2 million shares of the Company’s common stock. The warrants are exercisable on the six-month anniversary of the issuance date, will expire on the five-year anniversary of the initial exercise date and have an exercise price of $1.24 per share. Gross proceeds of the offering were $4.8 million before deducting placement agent fees and other estimated offering expenses.

First Quarter Financial Results

Celsion reported a net loss for the first quarter of 2020 of $5.1 million ($0.20 per share) compared with a net loss of $2.4 million ($0.12 per share) for the first quarter of 2019. Operating expenses were $4.9 million for the first quarter of 2020, which represented a $0.1 million (2%) decrease from $5.0 million in the same period of 2019. During the first quarter of 2020, the Company incurred $0.5 million in non-cash stock option expense compared with $0.7 million in the comparable prior-year period.

Cash, cash equivalents, short-term investments, interest receivable and receivable on sale of deferred tax asset as of March 31, 2020 was $17.5 million. In the second quarter of 2020, the Company received $1.8 million in net proceeds from the sale of its New Jersey net operating losses. The Company has approximately $2.0 million in future tax benefits remaining under the NJEDA Technology Business Tax Certificate Transfer program for future years. Cash provided by financing activities was $5.8 million and net cash used for operating activities was $5.0 million for the first quarter of 2020, compared with $5.5 million for the comparable prior-year period.

Research and development costs for the first quarter of 2020 were $3.1 million compared with $2.8 million for the first quarter of 2019. Clinical development costs for the Phase III OPTIMA Study were $0.7 million for the first quarter of 2020 compared with $0.9 million for the same period of 2019. These costs have decreased as the trial has moved into the follow-up phase after full patient enrollment in August 2018. Costs associated with the OVATION 2 Study increased to $0.3 million for the first quarter of 2020 compared with $0.1 million for the same period in 2019. The Company announced the initiation of the follow-on Phase I/II OVATION 2 Study in September 2018 with full enrollment of the Phase I portion of the trial completed in the first half of 2020. Costs associated with Celsion’s wholly-owned subsidiary CLSN Laboratories, Inc. (which includes research and development activities for GEN-1, TheraPlas and TheraSilence) increased to $0.9 million in the first quarter of 2020 compared with $0.6 million in the first quarter of 2019 as the Company continued to expand its manufacturing capabilities and implemented programs to reduce manufacturing costs for GEN-1.

General and administrative expenses were $1.8 million for the first quarter of 2020 compared with $2.2 million for the first quarter of 2019. The $0.4 million decrease was primarily attributable to a decrease in personnel costs and lower compensation expenses related to non-cash stock option compensation expense, partially offset by an increase in premiums for directors’ and officers’ insurance for 2020.

Other expenses during the first quarter of 2020 included a non-cash charge of $41,000 for the change in valuation of the earn-out milestone liability for the GEN-1 ovarian product candidate compared with a non-cash gain of $2.7 million, net of charge of $0.4 million for the 200,000 warrant issuance related to an amendment for the potential milestone payments for the GEN-1 ovarian product candidate during the first quarter of 2019. The Company realized $0.1 million of interest income from its short-term investments during both the first quarter of 2020 and 2019. In connection with the Company’s new venture debt facility with Horizon in June 2018, the Company incurred interest expense of $0.3 million during both the first quarter of 2020 and 2019.

First Quarter Conference Call

The Company will host a conference call to provide a business update and discuss its first quarter 2020 financial results at 11:00 a.m. EDT today. To participate in the call, interested parties may dial 1-800-367-2403 (Toll-Free/North America) or 1-334-777-6978 (International/Toll) 10 minutes before the call is scheduled to begin, and ask for the Celsion Corporation First Quarter 2020 Earnings Call (Conference Code: 6901311). The call will also be broadcast live on the internet at www.celsion.com. The call will be archived for replay through May 29, 2020. The replay can be accessed at 1-719-457-0820 or 1-888-203-1112 using Conference ID: 6901311. An audio replay of the call will also be available on the Company’s website, www.celsion.com, for 90 days after 2:00 p.m. EDT Friday, May 15, 2020.

On May 15, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported that the U.S. Food and Drug Administration (FDA) has issued a complete response letter (CRL) for the new drug application of avapritinib for the treatment of adults with unresectable or metastatic fourth-line gastrointestinal stromal tumor (GIST) (Press release, Blueprint Medicines, MAY 15, 2020, View Source [SID1234558143]). The CRL states that the FDA cannot approve the application.

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As previously announced, Blueprint Medicines plans to continue to commercialize AYVAKIT (avapritinib) in the United States for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations, and seek marketing approval for avapritinib for the treatment of this patient population in additional geographies, including the European Union. In addition, Blueprint Medicines continues to advance development of avapritinib for the treatment of systemic mastocytosis (SM). Based on top-line results reported in April 2020 for Blueprint Medicines’ Phase 3 VOYAGER trial, the company previously announced plans to discontinue further development of avapritinib in GIST indications other than PDGFRA exon 18 mutant GIST.

About AYVAKIT (avapritinib)

AYVAKIT (avapritinib) is a kinase inhibitor approved by the FDA for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. AYVAKIT is the first precision therapy approved to treat a genomically defined population of patients with GIST and the only highly active treatment for PDGFRA exon 18 mutant GIST. The FDA granted Breakthrough Therapy Designation to avapritinib for the treatment of unresectable or metastatic GIST harboring the PDGFRA D842V mutation. For more information, visit AYVAKIT.com.

Avapritinib is not approved for the treatment of any other indication in the U.S. or any other jurisdiction by the FDA or any other health authority.

Blueprint Medicines is developing avapritinib globally for the treatment of advanced, smoldering and indolent SM. The FDA granted Breakthrough Therapy Designation to avapritinib for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of avapritinib and certain other drug candidates in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for avapritinib in the rest of the world.

On May 15, 2020 Ribon Therapeutics, a clinical stage oncology company developing first-in-class therapeutics targeting stress response pathways, reported the presentation of new data at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II, taking place from June 22-24, 2020 (Press release, Ribon Therapeutics, MAY 15, 2020, View Source [SID1234558132]).

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Ribon will present findings from its development program, which includes the following:

Title: PARP7 negatively regulates the Type I interferon response in cancer cells and its inhibition leads to tumor regression
Abstract ID: 3405
Session Type: Minisymposium (oral presentation)
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Mechanisms Enabled by Tool Molecules
Date/Time: June 23, 2020, 9:00 – 11:00 a.m. EDT
Presenter: Joseph Gozgit, PhD
Title: A bespoke screening platform to study mono(ADP-ribosylation)
Abstract ID: 506 / 2
Session Type: Poster Session
Session Title: Screening, Lead Identification, and Optimization
Date/Time: June 22, 2020, 9:00 a.m. – 6:00 p.m. EDT
Presenter: Tim J. Wigle, PhD
Title: A multi-omic characterization of PARP enzymes in cancer to identify novel monoPARP drug targets
Abstract ID: 4381
Session Type: Poster Session
Session Title: Knowledge, Networks, Graphs, and Models for Discovery
Date/Time: June 22, 2020, 9:00 a.m. – 6:00 p.m. EDT
Presenter: Ryan Abo, PhD
AACR Virtual Meeting II the second of two virtual meetings being held by AACR (Free AACR Whitepaper); the first, AACR (Free AACR Whitepaper) Virtual Meeting I, took place April 27-28, 2020. Presentations from Virtual Meeting I can be accessed at View Source

On May 15, 2020 HiFiBiO Therapeutics reported that have generated preclinical data packages for novel monoclonal antibodies that demonstrate favorable clinical development profiles as new cancer immunotherapeutic options (Press release, HiFiBiO Therapeutics, MAY 15, 2020, View Source [SID1234558131]). The team will present highlights in three poster sessions at the forthcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, June 22-24, 2020. Taken together, these three programs from the HiFiBiO Therapeutics pipeline are evidence of the maturation of the company’s unique and comprehensive capabilities to uncover disease mechanisms and indications at the single-cell level; apply a deep understanding of immune system biology to select antibodies that present the best prospects for clinical development; and match these high-quality antibodies to the patients who are most likely to derive benefit.

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"We are pleased to have the opportunity to present our work to the oncology research community at AACR (Free AACR Whitepaper) and to share our innovative approach to transform the drug discovery and development paradigm by combining a deep understanding of immune-modulation with a world-leading single-cell platform and integrated analytics. By applying this approach over the past two and a half years, we have built a sustainable pipeline with high-quality candidates moving rapidly towards clinical studies," said Liang Schweizer, PhD, President and CEO of HiFiBiO Therapeutics.

The three HiFiBiO Therapeutics pipeline programs being presented at the AACR (Free AACR Whitepaper) meeting are:

HFB3010 (OX40)

HFB301001 is a novel, fully human IgG1 class OX-40 agonistic antibody with an optimized pharmacological profile. In contrast to previous anti-OX-40 antibodies, the agonistic activity of HFB301001 is further enhanced in the presence of the endogenous ligand OX-40L, does not result in reduced expression of OX-40 on T cells, and leads to superior anti-tumor activity in a human OX-40 knock-in mouse model compared to a benchmark antibody. Applying innovative biomarker strategy by leveraging its cutting-edge single-cell platform, HiFiBiO Therapeutics is developing the HFB301001 clinical candidate targeting certain patient populations which confer sensitivity towards treatment.

HFB2003 (TNFR2)

HiFiBiO Therapeutics has discovered and is pursuing the development of a first-in-class anti-TNFR2 monoclonal antibody capable of co-stimulating T cell proliferation and inducing strong in vivo anti-tumor immunity. In tumors, TNFR2 is expressed on activated and exhausted T cells. Targeting TNFR2 has the potential to enhance anti-tumor immunity by stimulating T-cell activation and proliferation in the tumor microenvironment. HiFiBiO’s CelliGO platform enabled the identification of diverse anti-TNFR2 antibodies that target different epitopes of the receptor. The candidate HFB200301 preferentially binds to TCR-activated primary CD8 and CD4 T cells as compared to unstimulated T cells and enhances CD3/CD28-induced activation and proliferation. Single agent anti-tumor activity comparable to anti-PD-1 was observed in several mouse tumor models at well-tolerated doses. An acute NHP exploratory study revealed no safety concerns for this novel mechanism. The clinical candidate HFB200301 has favorable developability and PK profiles and is currently at CMC development stage.

HFB2009 (Gal-9)

Galactoside-binding lectin Galectin 9 (Gal-9) is a key pleiotropic immunosuppressive modulator present in the tumor microenvironment. High Gal-9 expression has been reported in several cancer types including hematological malignancies such as AML and ALL, as well as in multiple solid tumors. Neutralization of Gal-9 has the potential to enhance anti-tumor immune response in the tumor micro-environment. HiFiBiO Therapeutics has discovered and is pursuing the development of HFB200902, an anti-Gal-9 neutralizing antibody with first-in-class potential in AML and solid tumors. HFB200902 blocks the interaction of Gal-9 with TIM3 and CD44, two receptors that have been described to mediate Gal-9-immunosuppressive signals in effector and regulatory T cells. As a result, HFB200902 inhibits Gal-9 induced Th1 cell apoptosis and Treg expansion. Anti-tumor activity and increased survival were observed as single agent and in combination with anti-PD1 in a syngeneic tumor model.

HiFiBiO Therapeutics will take innovative approaches to clinical development of these and other candidates in its pipeline, by pairing these novel antibody candidates with patient stratification biomarkers identified using the company’s proprietary DIS approach. This enables the company’s scientists to analyze individual patient cell samples to understand the complex functions and heterogeneity in immune system characteristics and responses among different patient groups, and to define predictive biomarkers that can be used to match the therapeutics to those patients who will most likely benefit from them.

"The challenges of achieving clinical success for immunotherapies are often related to the complex biology of the tumor microenvironment. Our pipeline focuses on targets with roles on multiple immune cell types, and our development strategy hinges on combining candidates with novel biomarkers to ensure a higher probability of clinical success," commented Francisco Adrian, Senior Vice President of Global Research, HiFiBiO Therapeutics.

"Our single-cell technology paired with our unique data analysis capability enables us to identify novel biomarkers derived from particular immune cell types and mechanisms. Using this approach, we should be able to stratify patients using their profiled genotype and phenotype, which predict sensitivity or resistance to treatment with our antibody candidates," said Andreas Raue, Senior Director of Drug Intelligent Science, HiFiBiO Therapeutics.

Registration for the virtual meeting is being offered by AACR (Free AACR Whitepaper) free of charge; more information is available at AACR (Free AACR Whitepaper) Virtual Annual Meeting II.