On March 22, 2021 iCo Therapeutics Inc. (TSXV: ICO) (OTCQB: ICOTF) ("iCo") and Satellos Bioscience Inc. ("Satellos"), a private Canadian corporation, reported to announce the execution of a definitive agreement, dated March 21, 2021 (the "Arrangement Agreement"), providing for the business combination of iCo and Satellos by way of a plan of arrangement (the "Arrangement") in accordance with Section 192 of the Canada Business Corporations Act (the "CBCA") (Press release, iCo Therapeutics, MAR 22, 2021, View Source [SID1234576951]). Pursuant to the Arrangement, Satellos will become a wholly-owned subsidiary of iCo, and the parties expect to complete an amalgamation of iCo and Satellos, with the resulting entity named "Satellos Bioscience Inc." (the "Resulting Issuer"), operating in the life sciences industry. Following the Arrangement, and the Concurrent Financing (described below) shareholders of iCo will hold an approximately 27.7% ownership interest, and the shareholders of Satellos will hold approximately 58.8.% of the outstanding common shares of the Resulting Issuer (the "Resulting Issuer Common Shares"). Prior to completion of the Arrangement, iCo, which is formed under the Business Corporations Act (British Columbia) is expected to continue under the CBCA and the Resulting Issuer will exist as a CBCA corporation. The completion of the Arrangement will result in a reverse takeover of iCo as defined in the policies of the TSX Venture Exchange (the "Exchange"). Completion of the Arrangement is subject to, among other things, the approval of the Exchange and approval from iCo and Satellos’ shareholders.

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Recommendation of the Board of Directors and Support Agreements

The board of directors of each of iCo and Satellos have: (a) determined that the Arrangement is in the best interests of iCo and Satellos, respectively; (b) recommended that its respective shareholders vote in favour of the resolutions approving the Arrangement; and (c) authorized the execution of the Arrangement Agreement and the performance of iCo’s and Satellos’ respective obligations under the Arrangement Agreement.

The directors and officers of iCo and Satellos, and certain other shareholders of iCo and Satellos representing an aggregate of 1,692,756 (0.9%) iCo common shares ("iCo Shares") and 8,138,400 (66.7%) Satellos common shares ("Satellos Shares"), respectively, in each case on a non-diluted basis, entered into voting support agreements pursuant to which they agreed to vote their eligible securities in favour of the Arrangement.

Bloom Burton & Co. Inc. ("Bloom Burton") is acting as exclusive financial advisor to iCo on the Arrangement. Bloom Burton, through Bloom Burton Development Corp., owns approximately 31.4% of the outstanding Satellos Shares on a fully diluted basis and certain Bloom Burton employees are directors of Satellos. For the purposes of considering and approving the Arrangement, such Bloom Burton directors have declared their conflict and recused themselves from the activities of the Satellos board in accordance with the requirements of the CBCA.

In coming to its recommendation with respect to the Arrangement, the board of directors of iCo reviewed and considered a fairness opinion from Evans & Evans, Inc., financial advisors to the board of directors of iCo in connection with the Arrangement, which report provides that, as of the date of such opinion, and subject to the assumptions, limitations and qualifications set forth therein, the consideration to be received by the iCo shareholders pursuant to the Arrangement is fair from a financial point of view.

In addition, in coming to its recommendation with respect to the Arrangement, the board of directors of Satellos also reviewed and considered a fairness opinion from Leede Jones Gable, financial advisors to the board of directors of Satellos in connection with the Arrangement, which report provides that, as of the date of such opinion, and subject to the assumptions, limitations and qualifications set forth therein, the consideration to be received by the Satellos shareholders pursuant to the Arrangement is fair from a financial point of view.

On March 22, 2021 Aura Biosciences, a clinical-stage oncology company developing a novel class of virus-like drug conjugate (VDC) therapies for multiple oncology indications, reported the closing of an oversubscribed $80 million financing (Press release, Aura Biosciences, MAR 22, 2021, View Source [SID1234576969]). The financing was led by Matrix Capital Management and Surveyor Capital (a Citadel company) with participation from new investors, including Rock Springs Capital, Adage Capital Management LP and Velosity Capital. Existing investors Medicxi, Advent Life Sciences, Lundbeckfonden Ventures, Arix Bioscience, Chiesi Ventures, Ysios Capital and Columbus Venture Partners also participated in the round.

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Aura intends to use the proceeds from this financing to advance the clinical development of its VDC technology platform, including the pivotal Phase 3 program for AU-011, the Company’s lead candidate in development for the first line treatment of choroidal melanoma, and ongoing research for additional programs in ocular oncology, as well as expanding the VDC technology into bladder cancer, the first non-ophthalmic solid tumor indication.

"Aura is pioneering the development of a new class of targeted therapies for life-threatening cancers with our novel VDC technology platform. This funding from a syndicate of distinguished investors enables us to advance AU-011 into a pivotal Phase 3 program for the first line treatment of choroidal melanoma, a rare, life- and vision-threatening form of cancer with no drugs approved. It also allows us to continue to expand the reach of our VDC technology in additional ocular oncology indications and in the treatment of solid tumors like bladder cancer where there is a high unmet medical need for better targeted therapies to treat early and reduce the incidence of metastasis," said Elisabet de los Pinos, Ph.D., Chief Executive Officer of Aura.

In connection with this financing, Karan Takhar, Senior Managing Director of Matrix Capital Management, will join Aura’s Board of Directors.

Mr. Takhar said, "Matrix believes in the long-term potential of Aura’s VDC technology to further strengthen the Company’s position as a leader in ocular oncology and beyond within other types of cancers in need of better treatment options. We look forward to supporting Aura’s leadership team through this next stage of pipeline growth and transition into late-stage development with the commencement of the AU-011 pivotal program."

About AU-011 (belzupacap sarotalocan)

AU-011 is a first-in-class virus-like drug conjugate (VDC) therapy in development for the first line treatment of choroidal melanoma. The virus-like component of the VDC selectively binds unique heparan sulphate proteoglycans (HSPGs) that are modified and overexpressed on the tumor cell surface of choroidal melanoma cells (and other tumors) and delivers a potent cytotoxic drug that is activated with infrared light. Upon activation with an ophthalmic laser, the cytotoxic drug rapidly and specifically disrupts the cell membrane of malignant melanoma cells with a pro-immunogenic cell death that is believed to activate the immune system generating long term anti-tumor immunity. The unique specificity of tumor binding by the VDC enables the preservation of key eye structures, which may allow for the potential of preserving patients’ vision and reducing other long-term complications of radiation treatment. The possibility of early treatment intervention and the activation of the immune system could lead to a reduction in the metastatic rate for patients with this life-threatening disease. AU-011 can be delivered using equipment commonly found in an ophthalmologist’s office and does not require a surgical procedure, pointing to a potentially less invasive, more convenient therapy for patients and physicians. AU-011 for the treatment of choroidal melanoma has been granted Orphan Drug and Fast Track designations by the U.S. Food and Drug Administration and is currently in Phase 2 clinical development.

On March 22, 2021 Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for rare endocrine diseases and endocrine-related tumors, reported details of four presentations that were made at the Endocrine Society’s annual ENDO 2021 congress on the company’s product pipeline (Press release, Crinetics Pharmaceuticals, MAR 22, 2021, View Source [SID1234576990]). A late-breaking e-poster and oral presentation provided details of the preclinical findings supporting the company’s development of CRN04894 and CRN04777. In addition, a summary of the previously announced ACROBAT Edge Phase 2 results as well as details of an improved tablet formulation of paltusotine were presented:

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Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion from Isolated Human Islets
Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess
Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Nonpeptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly
Safety and Efficacy of Switching Injected Peptide Long-Acting Somatostatin Receptor Ligands to Once Daily Oral Paltusotine: ACROBAT Edge Phase 2 Study
"I have never been more excited to share our data with the audience at ENDO. We believe CRN04894, which is now in Phase 1 development, represents an important advancement in the field of the endocrine stress axis. We also presented encouraging findings from our SST5 agonist program, from which we developed CRN04777. I am especially excited about this candidate, which I believe , if successfully developed and approved, has the potential to offer real benefit to kids with congenital HI and their families," stated Scott Struthers, Ph.D., president and CEO of Crinetics. "In addition to our early-stage pipeline programs, we presented information from the Phase 2 ACROBAT Edge study and the new formulation of paltusotine to be used in our Phase 3 acromegaly program."

Crinetics presented a late-breaking e-poster describing the potential of SST5 receptor agonists to regulate glucose-stimulated insulin secretion from human islet cells. One of somatostatin’s roles in maintaining blood glucose concentrations is to regulate insulin secretion, yet the lack of highly selective agonists has previously hampered efforts to identify the role of the individual somatostatin receptor subtypes in this process. In its preclinical efforts, Crinetics observed that SST5 receptor agonists were potent inhibitors of insulin secretion in the healthy pancreas and under conditions that stimulate excess insulin secretion. Based on these results, the company believes that a selective SST5 agonist may have therapeutic value in the treatment of congenital HI, which is a condition associated with dysregulated insulin secretion. Based on these preclinical findings, Crinetics advanced CRN04777, an experimental oral nonpeptide SST5 agonist, into a clinical program for congenital HI. CRN04777 is currently being evaluated in a Phase 1 trial designed to evaluate safety, pharmacokinetics, and clinical proof-of-concept by employing well-established methods for evaluating insulin secretion.

Crinetics also discussed preclinical results related to CRN04894, an oral nonpeptide ACTH antagonist, during a live oral presentation at ENDO 2021. CRN04894 recently advanced into a Phase 1 clinical program in healthy volunteers that is designed to evaluate safety, pharmacokinetics, and clinical proof-of-concept by measuring the ability of CRN04894 to suppress cortisol, cortisol precursors and adrenal androgens following exogenous ACTH stimulation. Preclinical data featured in the oral presentation showed that repeat dosing of CRN04894 suppressed plasma corticosterone levels in a robust and dose-dependent manner in animal models of ACTH excess. Results also showed that after seven days, the weight gain and adrenal gland hypertrophy caused by excess ACTH were reduced. This evidence supports the further evaluation of CRN04894 in conditions such as Cushing’s disease and congenital adrenal hyperplasia (CAH), which are associated with excessive ACTH.

"ENDO 2021 was our first opportunity to present the entirety of our growing clinical-stage pipeline, including the supportive evidence for our emerging programs in congenital HI and diseases of ACTH excess like Cushing’s disease and CAH," added Alan S. Krasner, M.D., Crinetics’ chief medical officer. "We are extremely excited to expand our development efforts to three clinical programs with more expected from our experienced in-house discovery team."

In addition to the company’s pipeline programs, Crinetics presented two posters on paltusotine, (formerly CRN00808) for the treatment of acromegaly, including results from the Phase 2 ACROBAT Edge study. Edge was a single-arm study designed to evaluate the impact of switching patients with acromegaly from monthly injected somatostatin receptor ligands (SRLs) to paltusotine, an experimental oral, once-daily, nonpeptide SST2 receptor agonist. Edge enrolled individuals who had not achieved normal insulin-like growth factor-1 (IGF-1) levels despite receiving long-acting octreotide or lanreotide. As previously reported, after 13 weeks of treatment 20 of 23 participants who completed the dosing period maintained their IGF-1 to levels within 20% of their baseline or lower. The most common treatment-emergent adverse events (>10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis. There were no discontinuations due to adverse events and no treatment-related serious adverse events.

Crinetics plans to advance paltusotine into a Phase 3 clinical program in acromegaly in the first half of 2021 using a new tablet formulation. Results of a Phase 1 pharmacokinetic study reported at ENDO 2021 demonstrated that this new once-daily tablet formulation of paltusotine had a fasting requirement of only 0.5-1 hour, compared to the 2-hour requirement of the prior capsule formulation. The tablet formulation also showed improved dose-proportional exposure up to 80 mg, which offers the potential for greater dosing flexibility compared to the prior formulation. In addition, the new tablet formulation was observed to be less sensitive to effects of acid lowering drugs, such as proton pump inhibitors (PPIs). In planned Phase 3 studies of paltusotine, the new tablet formulation will be administered with a 1-hour post-dose fast without the exclusion of acid lowering drugs.

All presentations made at the annual ENDO 2021 congress may be accessed in the virtual conference environment through April 30, 2021. In addition, they will be available on the Crinetics website.

ABOUT PALTUSOTINE
Paltusotine (formerly CRN00808) is an investigational, orally available nonpeptide agonist that is designed to be highly selective for the somatostatin receptor type 2 (SST2). It was designed by the Crinetics discovery team to provide a once-daily option for patients with acromegaly and neuroendocrine tumors, which are currently treated by injected therapies that have approximately $3.2 billion in revenues annually. A previously completed Phase 1 trial of paltusotine showed clinical proof of concept by providing evidence of potent suppression of the growth hormone (GH) axis in healthy volunteers. In Phase 2 trials, paltusotine maintained insulin-like growth factor-1 (IGF-1) levels in acromegaly patients who switched from injectable depot medications to once-daily oral paltusotine. IGF-1 is the primary biomarker endocrinologists use to manage their acromegaly patients. Based on these findings, Crinetics plans to advance paltusotine into a Phase 3 program for acromegaly in the first half of 2021.

ABOUT CRN04777
CRN04777 is an investigational, orally available selective nonpeptide somatostatin receptor type 5 (SST5) agonist designed to reduce insulin secretion and is intended to be a universal treatment for patients with congenital hyperinsulinism (HI). Congenital HI is a severe form of hyperinsulinism that, if not identified and treated early, can lead to life-threatening hypoglycemia, severe neurological sequelae and developmental delay. Congenital HI is driven by mutations in certain genes involved in regulating insulin secretion and occurs in approximately 1 in 30,000 to 50,000 new births in the United States. In 2020, the U.S. Food and Drug Administration granted rare pediatric disease designation for CRN04777 for the treatment of congenital HI. CRN04777 is being evaluated in a Phase 1 study in healthy volunteers to assess safety, tolerability, and clinical proof of concept.

ABOUT CRN04894
CRN04894 is an investigational, orally available, nonpeptide adrenocorticotropic hormone (ACTH) antagonist designed to selectively block the interaction of ACTH at the melanocortin type 2 receptor (MC2R), which is predominantly expressed in the adrenal gland. ACTH is synthesized and secreted by the pituitary gland and binds to MC2R to stimulate the production of cortisol, a stress hormone that is involved in the regulation of many systems. Cortisol is involved in the regulation of blood sugar levels, metabolism, inflammation, blood pressure, and memory formulation. Diseases associated with excess of ACTH, therefore, can have significant impact on physical and mental health. Crinetics’ ACTH antagonist, CRN04894, exhibited strong binding affinity for MC2R and demonstrated suppression of adrenally derived glucocorticoids that are under the control of ACTH, while maintaining mineralocorticoid production in preclinical models. CRN04894 is being evaluated in a Phase 1 study in healthy volunteers to assess safety, tolerability, and clinical proof of concept.

On March 22, 2021 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported the publication of results from its RUN-HN study, a Phase 2 open-label, single-arm trial of tipifarnib in patients with HRAS mutant head and neck squamous cell carcinoma (HNSCC) whose disease had progressed after prior therapy (Press release, Kura Oncology, MAR 22, 2021, View Source [SID1234576952]). The paper, titled "Tipifarnib in Head and Neck Squamous Cell Carcinoma with HRAS Mutations," was published online in the Journal of Clinical Oncology earlier today.

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As of the April 10, 2020 data cutoff, a total of 22 HNSCC patients with high HRAS mutant variant allele frequency1 were enrolled, of whom 20 were evaluable for response. Eleven of the 20 evaluable patients met RECIST v1.1 criteria for confirmed partial response (PR) and, for an objective response rate (ORR) of 55% (95% CI, 31.5 to 76.9).

Median progression-free survival (PFS) of 5.6 months (95% CI, 3.6 to 16.4) on tipifarnib was a statistically significant improvement over the median PFS of 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy (p=0.0012). The median overall survival (OS) was 15.4 months (95% CI, 7.0 to 29.7). Robust activity was seen despite resistance to chemotherapy, immunotherapy and/or cetuximab.

The ORR for three FDA-approved therapies for treatment of HNSCC in the second line range from 13-16%, with median PFS of 2-3 months and median OS of 5-8 months.

"We are encouraged by the compelling efficacy and safety profile of tipifarnib in patients with recurrent or metastatic HRAS mutant head and neck squamous cell carcinoma," said Alan Ho, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center and principal investigator of the trial. "Importantly, these patients experienced limited benefit on prior therapies, including immunotherapies, which demonstrates the high unmet need for this disease. These data also reinforce the relevance of genomic testing for HRAS mutations to identify patients who could potentially benefit from tipifarnib treatment."

Tipifarnib was generally well-tolerated in the trial. The most common grade 3 or 4 adverse events (AEs) seen in at least 10% of patients, were anemias and lymphopenias. Patients had received a median of two prior lines of systemic therapy (range 0-6; one patient received prior radiotherapy only), with 64% receiving prior immunotherapy, 50% receiving prior cetuximab, and 23% receiving both.

"We are pleased to see our data from the Phase 2 RUN-HN trial of tipifarnib published in the Journal of Clinical Oncology for review by the broader clinical community," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "The highlighted data from the RUN-HN trial comes on the heels of our Breakthrough Therapy Designation from the FDA and we continue to advance the ongoing AIM-HN registration-directed trial in patients with HRAS mutant HNSCC, for whom there is an urgent unmet need."

The AIM-HN registration-directed trial of tipifarnib, in patients with recurrent or metastatic HRAS mutant HNSCC, is currently recruiting at more than 100 clinical sites in the U.S., Europe, Russia/Ukraine and Asia/Pacific. Patients interested in participating in this trial may talk to their doctor to have their tumor tested for the HRAS mutation for eligibility to enroll in this trial. Further details regarding the trial are available at clinicaltrials.gov (NCT03719690).

HRAS mutations occur in 4%-8% of patients with recurrent and/or metastatic HNSCC. The HRAS biomarker can be found on most commercially available genomic panels. More information about HRAS and biomarker testing is available at uncoverhras.com

About HNSCC

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, accounting for more than 500,000 new cases each year. Despite advances in immunotherapy, the prognosis for advanced HNSCC patients remains poor, with an estimated median overall survival of 13-15 months in patients when stratified by PD-L1 expression. Although the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, was approved more than a decade ago, development of biomarker-directed therapies in HNSCC has been stymied by the limited number of druggable targets in the genomic landscape and the challenge of managing drug refractory recurrent/metastatic HNSCC.

About Tipifarnib

Tipifarnib, is a potent, selective and orally bioavailable inhibitor of farnesyl transferase in-licensed from Janssen. Previously, tipifarnib was studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets; however, no molecular mechanism of action had been determined that could explain its clinical activity across a range of solid tumor and hematologic indications. Leveraging advances in next generation sequencing as well as emerging information about cancer genetics and tumor biology, the Company is seeking to identify those patients most likely to benefit from tipifarnib. In addition to Breakthrough Therapy Designation, tipifarnib has been granted Fast Track designation by the FDA for the treatment of patients with HRAS mutant HNSCC. In addition to HNSCC, tipifarnib has demonstrated encouraging clinical activity in multiple additional genetically defined tumor types. Kura has received multiple issued patents for tipifarnib, providing patent exclusivity in the U.S. and foreign countries.

On March 22, 2021 Lantheus Holdings, Inc. (NASDAQ: LNTH) (Lantheus), an established leader and fully integrated provider of innovative imaging diagnostics, targeted therapeutics and artificial intelligence solutions to find, fight and follow serious medical conditions, reported that updated biochemical tumor marker data from its pivotal Phase 2 trial of AZEDRA (iobenguane I 131) were presented at the Endocrine Society’s 2021 Annual Meeting, ENDO 2021 (Press release, Lantheus Medical Imaging, MAR 22, 2021, View Source [SID1234576971]).

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Dr. Camilo Jimenez, Professor of Endocrine Neoplasia and Hormonal Disorders at the University of Texas MD Anderson Cancer Center, delivered an oral presentation entitled: "Biochemical Tumor Marker Status and Its Role in Treatment Response in Patients Who Received High-Specific-Activity I-131 MIBG in Advanced Pheochromocytoma and Paraganglioma (PPGL): Results from a Pivotal Phase 2 Clinical Trial" on Saturday, March 20, 2021.

"AZEDRA yielded reductions in hypersecreted tumor biomarkers in a majority of patients in this pivotal study of advanced pheochromocytoma and paraganglioma," said Dr. Jimenez. "In addition, the overall tumor biomarker response correlated significantly with both the primary and secondary endpoint responses in the study, underscoring the clinical utility and relevance of this important biochemical endpoint to the therapeutic benefit of AZEDRA in patients with these life-threatening tumors."

Tumor biomarkers were analyzed in patients with hypersecreting tumors (tumor biomarkers 1.5x above the upper limit of normal at baseline). The best biochemical responses (complete response (CR) or partial response (PR) at any time after treatment as evidenced by significant biomarker reductions) were observed in 80% (Chromogranin A), 70% (total metanephrines) and 64% (vanillylmandelic acid) of patients administered at least one therapeutic dose of AZEDRA. The overall tumor biomarker response correlated significantly with the best confirmed objective tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 (including PR and stable disease; r=0.35, p=0.006). Importantly, none of the responders with an overall biomarker response (CR or PR) had progressive disease as best response per RECIST.

"AZEDRA is the first and only approved treatment option for patients with advanced or metastatic PPGL," said Istvan Molnar, M.D., Chief Medical Officer of Lantheus. "Elevated neuroendocrine markers are the hallmark of these diseases and are responsible for many of the signs and symptoms of PPGL. We believe these data support the established efficacy of AZEDRA in its approved indication by demonstrating that after treatment with AZEDRA, the majority of patients with elevated baseline neuroendocrine markers had a reduction of these markers."

Indication

AZEDRA (iobenguane I 131) is indicated for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.

Important Safety Information

Warnings and Precautions:

Risk from radiation exposure: AZEDRA contributes to a patient’s overall long-term radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of AZEDRA are greater in pediatric patients than in adults. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with AZEDRA consistent with institutional good radiation safety practices and patient management procedures.

Myelosuppression: Severe and prolonged myelosuppression occurred during treatment with AZEDRA. Among the 88 patients who received a therapeutic dose of AZEDRA, 33% experienced Grade 4 thrombocytopenia, 16% experienced Grade 4 neutropenia, and 7% experienced Grade 4 anemia. Five percent of patients experienced febrile neutropenia. Monitor blood cell counts weekly for up to 12 weeks or until levels return to baseline or the normal range. Withhold and dose reduce AZEDRA as recommended in the prescribing information based on severity of the cytopenia.

Secondary myelodysplastic syndrome, leukemia, and other malignancies: Myelodysplastic syndrome (MDS) and acute leukemias were reported in 6.8% of the 88 patients who received a therapeutic dose of AZEDRA. The time to development of MDS or acute leukemia ranged from 12 months to 7 years. Two of the 88 patients developed a non-hematological malignancy.

Hypothyroidism: Hypothyroidism was reported in 3.4% of the 88 patients who received a therapeutic dose of AZEDRA. Initiate thyroid-blocking medications starting at least 1 day before and continuing for 10 days after each AZEDRA dose to reduce the risk of hypothyroidism or thyroid neoplasia. Evaluate for clinical evidence of hypothyroidism and measure thyroid-stimulating hormone (TSH) levels prior to initiating AZEDRA and annually thereafter.

Elevations in blood pressure: Eleven percent of the 88 patients who received a therapeutic dose of AZEDRA experienced a worsening of pre-existing hypertension defined as an increase in systolic blood pressure to ≥160 mmHg with an increase of 20 mmHg or an increase in diastolic blood pressure to ≥100 mmHg with an increase of 10 mmHg. All changes in blood pressure occurred within the first 24 hours post infusion. Monitor blood pressure frequently during the first 24 hours after each therapeutic dose of AZEDRA.

Renal toxicity: Of the 88 patients who received a therapeutic dose of AZEDRA, 7% developed renal failure or acute kidney injury and 22% demonstrated a clinically significant decrease in glomerular filtration rate (GFR) measured at 6 or 12 months. Monitor renal function during and after treatment with AZEDRA. Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. AZEDRA has not been studied in patients with severe renal impairment.

Pneumonitis: Fatal pneumonitis occurred 9 weeks after a single dose in one patient in the expanded access program. Monitor patients for signs and symptoms of pneumonitis and treat appropriately.

Embryo-fetal toxicity: Based on its mechanism of action, AZEDRA can cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with AZEDRA and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose.

Risk of infertility: Radiation exposure associated with AZEDRA may cause infertility in males and females. Radiation absorbed by testes and ovaries from the recommended cumulative dose of AZEDRA is within the range where temporary or permanent infertility can be expected following external beam radiotherapy.

Adverse Reactions: The most common severe (Grade 3–4) adverse reactions observed in AZEDRA clinical trials (≥10%) were lymphopenia (78%), neutropenia (59%), thrombocytopenia (50%), fatigue (26%), anemia (24%), increased international normalized ratio (18%), nausea (16%), dizziness (13%), hypertension (11%), and vomiting (10%). Twelve percent of patients discontinued treatment due to adverse reactions (thrombocytopenia, anemia, lymphopenia, nausea and vomiting, multiple hematologic adverse reactions).

Drug Interactions: Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells and therefore interfere with dosimetry calculations or the efficacy of AZEDRA. These drugs were not permitted in clinical trials that assessed the safety and efficacy of AZEDRA. Discontinue the drugs listed in the prescribing information for at least 5 half-lives before administration of either the dosimetry dose or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 days after each AZEDRA dose.