On September 15, 2016 PharmaCyte Biotech, Inc. (OTCQB:PMCB), a clinical stage biotechnology company focused on developing targeted treatments for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that they addressed shareholders on the development of PharmaCyte’s therapy for advanced pancreatic cancer today (Press release, PharmaCyte Biotech, SEP 15, 2016, View Source [SID:SID1234515154]).

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The Chief Executive Officer of PharmaCyte, Kenneth L. Waggoner, commented, "We understand that shareholders are frustrated with our current share price; however, the share price doesn’t reflect where PharmaCyte is today. In what has been a relatively short time for a biotech company, we have dramatically moved our Cell-in-a-Box technology forward along the path toward the clinic, we have surrounded our technology with some of the best minds in the industry and we have put together a team that is working diligently every single day to get PharmaCyte in front of the U.S. Food and Drug Administration (FDA) so that we can clear the final hurdles that will allow us to begin our clinical trial in advanced pancreatic cancer. There are numerous moving parts on many fronts. Just because our shareholders aren’t seeing news on a weekly basis, this does not mean there isn’t a flurry of work being done every single day.

"It is important for our shareholders to realize that PharmaCyte’s pancreatic cancer therapy is classified by drug regulatory authorities as a ‘biologic’ rather than a single molecule drug or a New Chemical Entity (NCE). This is because our therapy involves the use of living, genetically altered human cells. The overall development process is much more involved and more complex for a biologic than an NCE. Nevertheless, PharmaCyte’s therapy is moving forward at a realistic pace. Our partner Austrianova will be carrying out an engineering manufacturing ‘run’ in the near future of the production of the capsules that will be used with low dose ifosfamide as our pancreatic cancer therapy. If successful, not only will this run define the specifications of the capsules that will be use to encapsulate the living cells, it will also set the stage for cGMP production of the capsules for our planned clinical trial.

"An example of the different environment that we’re working in is that biologic products – particularly encapsulated living cell products like PharmaCyte’s and unlike most pharmaceutical products which can be simply ‘end-sterilized’ and delivered as sterile products – must be kept alive from the moment the cells are thawed from the frozen research cell bank and then encapsulated until they are implanted in a patient. At all times during these operations our product must be kept free of contamination by bacteria, yeast and fungi. Thus our biologic product is more akin to a live vaccine or to a stem cell therapy. The cell culture medium used to maintain the living cells within the capsules is also an excellent growth medium for all of those previously mentioned undesirable contaminants. Contaminant and other testing of our research cell bank is underway at ViruSure, one of PharmaCyte’s contractors, while Austrianova continues to make steady progress in order to manufacture cGMP clinical trial material that we will need to begin the trial.

"It goes without saying that great care has to be taken at every step to ensure the maintenance of aseptic conditions; this is one reason for carrying the production out in an ‘isolator’ that prevents actual contact between production staff and the product being manufactured. A living cell product also brings with it new regulatory challenges. PharmaCyte has been steadily working through these challenges with a number of regulatory advisors both in the United States and in the United Kingdom. These exciting new "Advanced Medicinal Products" are the future of treatment for serious diseases, and in many ways pioneering companies, like PharmaCyte, are working with the regulators to lay the ground work for tomorrow’s regulatory framework."

On September 15, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported several data presentations on Iclusig (ponatinib) that will take place at the 18th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy being held in Houston, September 15 to 18, 2016. A total of eight abstracts will be presented, including two oral presentations. The schedule and abstract information are listed below:

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Oral Presentations

Title:
Long-term Efficacy and Safety of Ponatinib in Heavily Pretreated Leukemia Patients: 4-Year Results from the Pivotal Phase 2 PACE Trial
Oral Session: Scientific Session 7: Therapeutic Interventions
Date & Time: Saturday, September 17, 2016, 4:25-5:45 p.m. CT, Presentation at
5:00 p.m. CT
Presenter: Jorge E. Cortes, M.D., (The University of Texas MD Anderson Cancer Center)

Title:
Impact of Early Responses on 3-Year Outcomes in Heavily Pretreated CP-CML Patients: Landmark Analyses in the Pivotal Ponatinib PACE Trial
Oral Session: Scientific Session 8: Predictors and Modeling Response
Date & Time: Sunday, September 18, 2016, 8:30-10:05 a.m. CT, Presentation at
8:50 a.m. CT
Presenter: Martin C. Müller, M.D. (Universitätsmedizin Mannheim, Mannheim)

Ponatinib Posters

Title:
A Superiority Trial of Two Lower Doses of Ponatinib Versus Standard Dose Nilotinib in Second-Line Chronic Phase CML, the OPTIC-2L Trial
Poster Session: Trials in Progress
Date: Thursday, September 15, 2016

Title:
A Evaluation of Three Doses of Ponatinib in a Multicenter, Randomized Phase 2 Trial with Response-Based Dose Reduction, the OPTIC Study
Poster Session: Trials in Progress
Date: Thursday, September 15, 2016

Title:
Ponatinib Therapy for Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Patients: Real-world Clinical Practice Versus the PACE Trial
Poster Session: Clinical Poster
Date: Thursday, September 15, 2016

Title:
Ponatinib Versus Bosutinib in 3rd-Line Chronic Phase-Chronic Myeloid Leukemia: Indirect Comparison of Efficacy Using Iterative Proportional Fitting
Poster Session: Clinical Poster
Date: Thursday, September 15, 2016

Title:
Preliminary Findings from a Chart Review of Lower Dosing of Ponatinib in Chronic Myeloid Leukemia (CML) Patients
Poster Session: Clinical Poster
Date: Thursday, September 15, 2016

Title:
The PACE Clinical Trial vs. the Real-world: Comparison of Ponatinib Prescribing and Duration of Therapy in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients
Poster Session: Clinical Poster
Date: Thursday, September 15, 2016

About Iclusig (ponatinib) tablets
Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs. Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada. In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Limitations of use: Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING
WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.
Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent Iclusig 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to singe agent imatinib 400 mg once-daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension and skin and subcutaneous tissue disorders. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP CML.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning.