On December 17, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the expanded approval of Sprycel (dasatinib), in combination with chemotherapy, to include the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (Press release, Bristol-Myers Squibb, DEC 17, 2018, View Source [SID1234532093]). The positive opinion includes the tablet form of Sprycel and the powder for oral suspension formulation, which was first approved by the European Commission (EC) in July 2018, making Sprycel the only tyrosine kinase inhibitor with a formulation developed for administration in pediatric patients and patients who cannot swallow tablets. The CHMP recommendation will now be reviewed by the EC, which has the authority to approve medicines for the European Union (EU).

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"We are pleased with today’s CHMP recommendation for Sprycel in pediatric patients with Ph+ ALL, and look forward to the possibility of expanding Sprycel’s pediatric indications in the EU to include young patients with this particularly high-risk leukemia," said Fouad Namouni, M.D., head, oncology development, Bristol-Myers Squibb.

The application is based on data from CA180-372 (NCT01460160), an ongoing Phase 2 trial evaluating the addition of Sprycel to a chemotherapy regimen modeled on a Berlin-Frankfurt-Munster high-risk backbone in pediatric patients with newly diagnosed Ph+ ALL.

About Sprycel

Sprycel first received FDA approval in 2006 for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) who are resistant or intolerant to prior therapy including imatinib. At that time, Sprycel also received FDA approval for adults with Ph+ acute lymphoblastic leukemia (ALL) who are resistant or intolerant to prior therapy. Sprycel is approved and marketed for these indications in more than 60 countries.

Sprycel is also an FDA-approved treatment for adults with newly diagnosed Ph+ CML-CP and is approved for this indication in more than 50 countries.

Both the FDA and the European Commission approved the expansion of Sprycel’s indication to include pediatric patients with Ph+ CML-CP in November 2017 and July 2018.

U.S. FDA-APPROVED INDICATIONS FOR SPRYCEL

SPRYCEL (dasatinib) is indicated for the treatment of adults with:

Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
SPRYCEL is indicated for the treatment of pediatric patients with:

Ph+ CML in chronic phase
IMPORTANT SAFETY INFORMATION

Myelosuppression

Treatment with SPRYCEL is associated with severe (NCI CTCAE Grade 3/4) thrombocytopenia, neutropenia, and anemia, which occur earlier and more frequently in patients with advanced phase CML or Ph+ ALL than in patients with chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients with chronic phase CML, perform complete blood counts (CBCs) every 2 weeks for 12 weeks, then every 3 months thereafter, or as clinically indicated
In patients with advanced phase CML or Ph+ ALL, perform CBCs weekly for the first 2 months and then monthly thereafter, or as clinically indicated
Myelosuppression is generally reversible and usually managed by withholding SPRYCEL temporarily and/or dose reduction
In clinical studies, myelosuppression may have also been managed by discontinuation of study therapy
Hematopoietic growth factor has been used in patients with resistant myelosuppression
Bleeding-Related Events

SPRYCEL can cause serious and fatal bleeding. In all CML or Ph+ ALL clinical studies, Grade ≥3 central nervous system (CNS) hemorrhages, including fatalities, occurred in <1% of patients receiving SPRYCEL. The incidence of Grade 3/4 hemorrhage, occurred in 5.8% of adult patients and generally required treatment interruptions and transfusions. The incidence of Grade 5 hemorrhage occurred in 0.4% of adult patients. The most frequent site of hemorrhage was gastrointestinal.

Most bleeding events in clinical studies were associated with severe thrombocytopenia
In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro
Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of hemorrhage
Fluid Retention

SPRYCEL may cause fluid retention. After 5 years of follow-up in the adult randomized newly diagnosed chronic phase CML study (n=258), grade 3/4 fluid retention was reported in 5% of patients, including 3% of patients with grade 3/4 pleural effusion. In adult patients with newly diagnosed or imatinib resistant or intolerant chronic phase CML, grade 3/4 fluid retention occurred in 6% of patients treated with SPRYCEL at the recommended dose (n=548). In adult patients with advanced phase CML or Ph+ ALL treated with SPRYCEL at the recommended dose (n=304), grade 3/4 fluid retention was reported in 8% of patients, including grade 3/4 pleural effusion reported in 7% of patients. In pediatric patients with chronic phase CML cases of Grade 1 or 2 fluid retention were reported in 10.3% of patients.

Patients who develop symptoms of pleural effusion or other fluid retention, such as new or worsened dyspnea on exertion or at rest, pleuritic chest pain, or dry cough should be evaluated promptly with a chest x-ray or additional diagnostic imaging as appropriate
Fluid retention events were typically managed by supportive care measures that may include diuretics or short courses of steroids
Severe pleural effusion may require thoracentesis and oxygen therapy
Consider dose reduction or treatment interruption
Cardiovascular Events

SPRYCEL can cause cardiac dysfunction. After 5 years of follow-up in the randomized newly diagnosed chronic phase CML trial in adults (n=258), the following cardiac adverse reactions occurred:

Cardiac ischemic events (3.9% dasatinib vs 1.6% imatinib), cardiac related fluid retention (8.5% dasatinib vs 3.9% imatinib), and conduction system abnormalities, most commonly arrhythmia and palpitations (7.0% dasatinib vs 5.0% imatinib). Two cases (0.8%) of peripheral arterial occlusive disease occurred with imatinib and 2 (0.8%) transient ischemic attacks occurred with dasatinib
Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pulmonary Arterial Hypertension (PAH)

SPRYCEL may increase the risk of developing PAH in adult and pediatric patients, which may occur any time after initiation, including after more than 1 year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL.

Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued
QT Prolongation

SPRYCEL may increase the risk of prolongation of QTc in patients including those with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy

Correct hypokalemia or hypomagnesemia prior to and during SPRYCEL administration
Severe Dermatologic Reactions

Cases of severe mucocutaneous dermatologic reactions, including Stevens-Johnson syndrome and erythema multiforme, have been reported in patients treated with SPRYCEL.

Discontinue permanently in patients who experience a severe mucocutaneous reaction during treatment if no other etiology can be identified
Tumor Lysis Syndrome (TLS)

TLS has been reported in patients with resistance to prior imatinib therapy, primarily in advanced phase disease.

Due to potential for TLS, maintain adequate hydration, correct uric acid levels prior to initiating therapy with SPRYCEL, and monitor electrolyte levels
Patients with advanced stage disease and/or high tumor burden may be at increased risk and should be monitored more frequently
Embryo-Fetal Toxicity

Based on limited human data, SPRYCEL can cause fetal harm when administered to a pregnant woman. Hydrops fetalis, fetal leukopenia and fetal thrombocytopenia have been reported with maternal exposure to SPRYCEL. Transplacental transfer of dasatinib has been measured in fetal plasma and amniotic fluid at concentrations comparable to those in maternal plasma.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception, during treatment with SPRYCEL and for 30 days after the final dose
Effects on Growth and Development in Pediatric Patients

In pediatric trials of SPRYCEL in chronic phase CML after at least 2 years of treatment, adverse reactions associated with bone growth and development were reported in 5 (5.2%) patients, one of which was severe in intensity (Growth Retardation Grade 3). These 5 cases included cases of epiphyses delayed fusion, osteopenia, growth retardation, and gynecomastia. Of these 5 cases, 1 case of osteopenia and 1 case of gynecomastia resolved during treatment.

Lactation

No data are available regarding the presence of dasatinib in human milk, the effects of the drug on the breastfed child or the effects of the drug on milk production. However, dasatinib is present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing children from SPRYCEL, breastfeeding is not recommended during treatment with SPRYCEL and for 2 weeks after the final dose
Drug Interactions

Strong CYP3A4 inhibitors: The coadministration with strong CYP3A inhibitors may increase dasatinib concentrations. Increased dasatinib concentrations may increase the risk of toxicity. Avoid concomitant use of strong CYP3A4 inhibitors. If concomitant administration of a strong CYP3A4 inhibitor cannot be avoided, consider a SPRYCEL dose reduction
Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided
Strong CYP3A4 inducers: The coadministration of SPRYCEL with strong CYP3A inducers may decrease dasatinib concentrations. Decreased dasatinib concentrations may reduce efficacy. Consider alternative drugs with less enzyme induction potential. If concomitant administration of a strong CYP3A4 inducer cannot be avoided, consider a SPRYCEL dose increase
St. John’s wort may decrease plasma concentrations of SPRYCEL and should be avoided
Gastric Acid Reducing Agents: The coadministration of SPRYCEL with a gastric acid reducing agent may decrease the concentrations of dasatinib. Decreased dasatinib concentrations may reduce efficacy.

Do not administer H2 antagonists or proton pump inhibitors with SPRYCEL. Consider the use of antacids in place of H2 antagonists or proton pump inhibitors. Administer the antacid at least 2 hours prior to or 2 hours after the dose of SPRYCEL. Avoid simultaneous administration of SPRYCEL with antacids.
Adverse Reactions

The safety data reflects exposure to SPRYCEL at all doses tested in clinical studies (n=2809) including 324 adult patients with newly diagnosed chronic phase CML, 2388 adult patients with imatinib resistant or intolerant chronic or advanced phase CML or Ph+ ALL, and 97 pediatric patients with chronic phase CML.

The median duration of therapy in a total of 2712 SPRYCEL-treated adult patients was 19.2 months (range 0–93.2 months). Median duration of therapy in:

1618 adult patients with chronic phase CML was 29 months (range 0–92.9 months)
Median duration for 324 adult patients in the newly diagnosed chronic phase CML trial was approximately 60 months
1094 adult patients with advanced phase CML or Ph+ ALL was 6.2 months (range 0–93.2 months)
In two non-randomized trials in 97 pediatric patients with chronic phase CML (51 patients newly diagnosed and 46 patients resistant or intolerant to previous treatment with imatinib), the median duration of therapy was 51.1 months (range 1.9 to 99.6 months).

In the newly diagnosed adult chronic phase CML trial, after a minimum of 60 months of follow-up, the cumulative discontinuation rate for 258 patients was 39%.

In the overall population of 2712 adult SPRYCEL-treated patients, 88% of patients experienced adverse reactions at some time and 19% experienced adverse reactions leading to treatment discontinuation.

Among the 1618 adult SPRYCEL-treated patients with chronic phase CML, drug-related adverse reactions leading to discontinuation were reported in 329 (20.3%) patients.

In the adult newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 16% of SPRYCEL-treated patients with a minimum of 60 months of follow-up
Among the 1094 SPRYCEL-treated patients with advanced phase CML or Ph+ ALL, drug-related adverse reactions leading to discontinuation were reported in 191 (17.5%) patients.

Among the 97 pediatric subjects, drug-related adverse reactions leading to discontinuation were reported in 1 patient (1%).

Patients ≥65 years are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema and weight decrease, and should be monitored closely.

In adult newly diagnosed chronic phase CML patients:
Drug-related serious adverse reactions (SARs) were reported for 16.7% of patients. Serious adverse reactions reported in ≥5% of patients included pleural effusion (5%)
Grade 3/4 laboratory abnormalities included neutropenia (29%), thrombocytopenia (22%), anemia (13%), hypophosphatemia (7%), hypocalcemia (4%), elevated bilirubin (1%), and elevated creatinine (1%)
In adult patients resistant or intolerant to prior imatinib therapy:
Drug-related SARs were reported for 26.1% of SPRYCEL-treated patients treated at the recommended dose of 100 mg once daily in the randomized dose-optimization trial of patients with chronic phase CML resistant or intolerant to prior imatinib therapy. Serious adverse reactions reported in ≥5% of patients included pleural effusion (10%)
Grade 3/4 hematologic laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily with a minimum follow up of 60 months included neutropenia (36%), thrombocytopenia (24%), and anemia (13%). Other grade 3/4 laboratory abnormalities included: hypophosphatemia (10%), and hypokalemia (2%)
Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative grade 3/4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%), and anemia (13% vs 13%)
Grade 3/4 elevations of transaminases or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML
Elevations in transaminases or bilirubin were usually managed with dose reduction or interruption
Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation
In pediatric subjects with Ph+ CML in chronic phase
Drug-related SARs were reported for 14.4% of pediatric patients
In the pediatric studies, the rates of laboratory abnormalities were consistent with the known profile for laboratory parameters in adults
Most common adverse reactions (≥15%) in patients included myelosuppression, fluid retention events, diarrhea, headache, skin rash, hemorrhage, dyspnea, fatigue, nausea, and musculoskeletal pain

On December 17, 2018 Horizon Pharma plc (Nasdaq: HZNP) reported that the company will participate in the 37th Annual J.P. Morgan Healthcare Conference (Press release, Horizon Pharma, DEC 17, 2018, View Source [SID1234532092]). Timothy P. Walbert, chairman, president and chief executive officer, will present at 4:30 p.m. PT on Jan. 8, 2019.

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The conference presentation will be webcast live and may be accessed by visiting Horizon’s website at View Source A replay of the webcast will be available for the event.

On December 17, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that the first patients have been enrolled in two global Phase 3 clinical trials of its investigational anti-PD-1 antibody, tislelizumab (Press release, BeiGene, DEC 17, 2018, View Source;p=irol-newsArticle&ID=2380809 [SID1234532091]). These trials are evaluating tislelizumab combined with chemotherapy as potential first-line treatments in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, and in patients with unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

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"Available data have shown promise for anti-PD-1 antibodies in patients with advanced gastric or gastroesophageal adenocarcinoma and in patients with advanced esophageal carcinoma. We are looking forward to investigating tislelizumab globally in these Phase 3 trials," said Amy Peterson, M.D., Chief Medical Officer, Immuno-Oncology, at BeiGene. "Gastric and esophageal cancers are among the most common malignancies in Asia and collectively are responsible for over 800,000 deaths annually in China1 alone. We are hopeful that these global studies of tislelizumab may ultimately lead to improved treatment options for patients diagnosed with these malignancies."

Global Phase 3 Trial in Advanced Gastric or Gastroesophageal Adenocarcinoma

The global, randomized, double-blind, placebo-controlled Phase 3 trial is designed to enroll 720 patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients will either receive 200 mg of tislelizumab or placebo combined with platinum- and fluoropyrimidine-based chemotherapy, the standard chemotherapy treatment, intravenously once every three weeks.

The co-primary endpoints will be progression-free survival (PFS) and overall survival (OS). Secondary endpoints include overall response rate (ORR), duration of response (DOR) and quality of life (QoL), as well as safety and tolerability.

Global Phase 3 Trial in Advanced ESCC

The global, randomized, double-blind, placebo-controlled Phase 3 trial is designed to enroll 480 patients with unresectable, locally advanced recurrent, or metastatic ESCC. Patients will either receive 200 mg of tislelizumab or placebo combined with platinum- and fluoropyrimidine-based chemotherapy, intravenously once every three weeks.

The co-primary endpoints will be PFS and OS. Secondary endpoints include ORR, DOR, and QoL, as well as safety and tolerability.

For more information about these trials, patients and physicians should email BeiGene at [email protected].

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Discovered by BeiGene scientists, tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. The new drug application (NDA) for tislelizumab in China for patients with R/R cHL has been accepted by the China National Medical Products Administration (NMPA, formerly known as CFDA) and granted priority review status. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumors in the United States, Europe, Japan, and the rest of world outside Asia.

On December 17, 2018 Ayala Pharmaceuticals, Inc., a clinical-stage company developing medicines for cancers that are genetically identified, reported that the first patient has been enrolled in its Phase 2 ACCURACY study, to evaluate lead investigational candidate AL101 in patients with adenoid cystic carcinoma (ACC) bearing Notch activated mutations (Press release, Ayala Pharmaceuticals, DEC 17, 2018, View Source [SID1234532090]).

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AL101 is a small-molecule that inhibits gamma secretase, an enzyme which plays a key role in the activation of the Notch signaling pathway by releasing the Notch intracellular domain (NICD) which migrates to the nucleus initiating a complex transcription program. In a Phase 1b study (n=94), the recommended Phase 2 dose of 4 mg IV weekly administered every 7 days was established, which was well tolerated in patients with locally advanced or metastatic solid tumors, including ACC.

In prior research, sequencing of ACC tumor samples revealed genomic alterations in the Notch pathway in a subset of patients with a distinct ACC phenotype. ACC patients with Notch1 mutations have an aggressive course of disease with a distinct pattern of metastasis and worse prognosis than their wild type counterparts. In addition to Notch1 mutations, mutations in Notch 2 and 4 were reported in ACC. There is a pressing unmet need as currently there are no available therapies for these patients.

"Based on the promising preclinical and clinical data generated to date, we strongly believe AL101 has potential as a targeted therapy for adenoid cystic carcinoma with notch activated mutations," said Roni Mamluk, PhD, chief executive officer at Ayala. "The advancement of AL101 into a Phase 2 study is an important milestone in the development of this clinical candidate, as well as for patients suffering from ACC, a rare cancer with high unmet medical need."

AL101 Phase 2 Trial in Patients with ACC

ACCURACY is a Simon 2-Stage optimal design, non-comparative, open-label, single-arm, multi-center study in patients with ACC bearing activating Notch Mutations. Ayala plans to initially open eight clinical sites in North America, with the potential to expand into Europe and Australia.

AL101 is administered intravenously as a single agent at a dose of 4 mg every 7 days over 28-day cycles until disease progression, unacceptable toxicity or consent withdrawal. The study is designed to evaluate the objective response rate as outlined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Secondary endpoints include the frequency, duration and severity of adverse events and serious adverse events, overall survival, progression-free survival and duration of response. In order to meet the criteria for enrollment, patients must have confirmed ACC with known Notch 1/2/3/4 activating mutation that is recurrent or metastatic, not amenable to potentially curative surgery or radiotherapy.

On December 17, 2018 Sophiris Bio Inc. (NASDAQ: SPHS) (the "Company" or "Sophiris"), a biopharmaceutical company studying topsalysin (PRX302), a first-in-class, pore-forming protein, in late-stage clinical trials for the treatment of patients with urological diseases, reported its update from its Phase 2b study of topsalysin for localized prostate cancer, including top-line safety and biopsy results from the patients who received a second administration of study drug, which appeared to be safe and generally well-tolerated (Press release, Sophiris Bio, DEC 17, 2018, View Source [SID1234532089]). Additional benefit was not observed on targeted biopsy six months after re-treatment with a second administration of topsalysin.

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As previously stated, a total of 27% of patients (10/37) demonstrated a clinical response six months following a single administration of topsalysin. Six of the ten clinical responders experienced a complete ablation of their tumor. Based on these results, the Company is moving forward with its plans to propose a single Phase 3 registration trial design using a single administration of topsalysin, which it will discuss with regulatory agencies in the coming months.

"We remain encouraged by both the safety and biopsy data from the first administration of topsalysin and are working with Sophiris to design a protocol for a potential Phase 3 registration study using a single administration of topsalysin," stated Professor Mark Emberton, principal investigator in the Phase 2b trial and Dean of the University College London Faculty of Medical Sciences. "These data show that 27% of the patients who receive a single administration of topsalysin may avoid or delay the need for alternative treatment for their localized prostate cancer. Taking into account the observed efficacy and safety profile to date following a single administration, we believe urologists would welcome a treatment like topsalysin for men with clinically-significant localized prostate cancer."

Final Safety and Biopsy Results from a Single Administration of Topsalysin:

The primary objectives of the Phase 2b clinical study were to evaluate the safety, tolerability and efficacy, as assessed by targeted biopsy, of a single administration of topsalysin, when used to focally ablate a histologically-proven, clinically-significant lesion in patients with low-to-intermediate localized prostate cancer. In the trial, 38 patients received a single administration of topsalysin. Six months after administration, 37 of the 38 patients received a follow-up targeted biopsy of the treated lesion, with one patient having been lost to follow-up following re-location.

Based on the final results of the study, a single administration of topsalysin continues to appear safe and well-tolerated by patients. Adverse events considered related to topsalysin were typically mild and typically occurred and were resolved on the day of the administration. In addition, urine function was preserved, no sexual dysfunction, no hypersensitivity reactions or other serious systemic reactions to study medication were observed after a single administration.

The final six-month follow-up biopsy results demonstrated that 27% of patients (10/37) achieved a clinical response, defined in this study as no detectable tumor on targeted biopsy of the treated lesion or a sufficient reduction to deem the lesion clinically-insignificant (Gleason Score 6 (3+3) and a Maximum Cancer Core Length (MCCL) of less than 6 millimeters). Of the ten clinical responders in the Phase 2b study, six men experienced a complete ablation with no histological evidence of the tumor remaining.

Additionally, the final Phase 2b single administration follow-up biopsy data show that:

41% of patients (15/37) experienced a partial response, defined as a reduction in MCCL and/or Gleason pattern, but the targeted lesion was still deemed clinically-significant; and

32% (12/37) of patients did not respond to treatment, defined as no change in the targeted lesion or an increase in MCCL and/or Gleason pattern.

"Now that we have completed this Phase 2b study, we are focused on moving topsalysin into Phase 3 development," stated Randall E. Woods, President and CEO of Sophiris. "We are in the process of finalizing our proposed Phase 3 study design with our thought leaders, which will be submitted for discussion first to the European and then U.S. regulatory authorities to confirm the design of the Phase 3 study. We are equally focused on determining the best path forward for funding a potential Phase 3 study and continue to engage in business development discussions as part of this effort. We are also encouraged to see such strong interest from the medical community in the development of a focal treatment for clinically-significant localized prostate cancer."

Top-line Results from the Second Administration of Topsalysin

Another important objective for this Phase 2b study was to evaluate the safety of re-administering topsalysin, and to determine if additional clinical benefit could be observed following re-treatment of the targeted lesion six months after initial treatment, as assessed by targeted biopsy six months after re-administration. To be eligible to receive a second dose, patients must not have experienced a clinically-significant adverse event attributable to either topsalysin or the dosing procedure. Additionally, patients must have demonstrated evidence of a response to the first treatment with topsalysin, either through a reduction in lesion size, Gleason pattern, or MCCL. No patients who had a complete ablation following the first dose received a second administration.

A top-line review of the safety data from a total of ten patients who received a second administration indicates that a second dose appears to be both safe and well-tolerated by patients. There were no adverse events considered related to topsalysin that were experienced by more than one patient following the second administration. The adverse events that were considered related to topsalysin were typically mild and resolved within two days. Importantly, no hypersensitivity reaction or other serious systemic reactions to topsalysin were observed. Urine function was preserved and there were no reports of sexual dysfunction related to topsalysin. As previously reported, an eleventh patient received a second dose but unfortunately experienced a serious adverse event of sudden cardiac death which, following a thorough review of medical records, serology results and autopsy findings, was considered unlikely related to topsalysin by both the investigator and Company.

Based on the top-line review of the six-month biopsy results following the second administration of topsalysin, the Company has concluded that there appears to be no additional clinical benefit gained with a second administration. The decision to include a second administration of topsalysin in any future clinical studies is under review by the Company.

"While we are disappointed that no additional ablation occurred following a second administration of topsalysin, we had already planned the Phase 3 study around a single administration and will continue to move forward accordingly, while we continue to evaluate the potential benefit of a second dose separately," noted Professor Emberton. "The results from the second administration in no way impacts our excitement about topsalysin as a potential targeted focal therapy in localized prostate cancer.

Webcast scheduled for today at 9:00 a.m. Eastern Time

The Sophiris management team will host a conference call and webcast today, December 17, at 9:00 a.m. Eastern Time to review the topsalysin prostate cancer data, along with Professor Mark Emberton, Dean of University College London Faculty of Medical Sciences and Principal investigator for the Phase 2b clinical trial.

A live audio webcast will be accessible on the "Investor Relations" page of the Sophiris corporate website at www.sophirisbio.com. A replay will be available at the same location.

About Localized Prostate Cancer

Prostate cancer is the second most common form of cancer in men in the US with an estimated 161,000 new cases in 2017. Approximately 80 percent of patients in the US are diagnosed with localized disease. Research has shown that patients with early, localized disease have a low likelihood of the cancer spreading beyond the confines of the prostate; however, many men with clinically-significant localized disease choose to undergo radical treatment. Radical therapies include surgery to remove the entire prostate and/or radiation. Potential toxicities from radical treatments can be significant and permanent and include erectile dysfunction, urinary incontinence and rectal toxicity.

About Topsalysin

Topsalysin (PRX302), an innovative, "First-in-Class" transmembrane pore-forming protein, was genetically modified to be activated only by enzymatically-active PSA, which is produced in large quantities within the prostate of men with prostate cancer. The targeted focal treatment of prostate cancer is in line with current treatment trends for solid tumors such as breast and liver, where the goal is to remove the tumor and preserve as much of the organ and organ function as possible.

Topsalysin has the potential to provide a targeted focal therapy for the ablation of localized prostate cancer lesions while potentially avoiding many of the complications and side effects associated with whole gland radical treatments. The increasing use of multiparametric magnetic resonance imaging (mpMRI) and advances in software to co-register previously obtained mpMRI images with real-time three-dimensional ultrasound images enables urologists to more accurately locate tumors within the prostate when taking biopsies. This increases the accuracy with which men with clinically significant lesions are identified. It also enables the injection of an ablative agent, such as topsalysin, directly into previously identified clinically significant tumors located within the prostate.