On January 8, 2019 Ono Pharmaceutical Co., Ltd. (Osaka, Japan; President, Representative Director, Gyo Sagara; "ONO") reported that it received a manufacturing and marketing approval of Demser (metyrosine) Capsule 250 mg ("Demser"), a tyrosine hydroxylase inhibitor, in Japan for the improvement of status of catecholamine excess secretion in patients with pheochromocytoma (Press release, Ono, JAN 8, 2019, View Source [SID1234605553]). Pheochromocytoma (PC) is a neuroendocrine tumor deriving from the adrenal medulla or the extraadrenal gland ganglion with 2,920 patients estimated in Japan*. Catecholamine excessively secreted from PC causes various symptoms, such as tachycardia, headache, palpitation, sweating, constipation, including hypertension. Sympatholytic drugs, α-blocker and β-blocker, for control of blood pressure and heart rate have been usually used to improve these symptoms. As there are many cases where surgical removal of tumors is not applicable in patients with locally invasive or metastatic malignant PC, a long-term therapy, such as radiotherapy and chemotherapy is required. The chronic continuation of catecholamine excess secretion may increase a risk of causing cardiovascular-related adverse events such as heart failure or fatal arrhythmia. Demser inhibits tyrosine hydroxylase related to the production of catecholamine, reduces catecholamine extremely secreted from PC, and alleviates symptoms due to catecholamine excess secretion. Demser is a promising drug with an efficacy in the improvement of the symptoms in patients who are not able to sufficiently control the symptoms with sympatholytic drugs. Demser is a product for which development companies were recruited in Japan at the "Review Committee on Unapproved or Off-label Drugs with High Medical Needs", established by the Ministry of Health, Labour and Welfare (MHLW), and ONO has been developing this product. In May 2015, the product was designated for the orphan drug by the MHLW. ONO obtained exclusive rights to develop and commercialize metyrosine in Japan for the treatment of PC (and conditions and symptoms related thereto), in accordance with the license agreement concluded in October 2013 with Valeant Pharmaceuticals North America LLC, an affiliate of Valeant Pharmaceuticals International, Inc. (In July 2018, the company name was changed to Bausch Health Companies Inc., "Bausch Health"). In the US, Bausch Health markets the product under the tradename of "Demser" in the indication of PC. *: "Actual condition survey and preparation of medical guideline of pheochromocytoma" Research Report 2009, Research Project on Overcoming Intractable Diseases Project being conducted by the Ministry of Health, Labour and Welfare Overview of Demser Capsule 250 mg Product Name Demser Capsule 250 mg Generic name (JAN) Metyrosine Indication Improvement of status of catecholamine excess secretion in patients with pheochromocytoma Dosage and administration Usually, for adults and children 12 years of age and older, start to administer 500 mg of metyrosine orally daily. When the effect is insufficient, titrate the dose by 250 mg or 500 mg daily at intervals of 3 days or more by monitoring the clinical course closely, and dosage should be adjusted under adequate observation of urinary catecholamine amount and symptoms of the patient. However, the maximum daily dose is 4,000 mg with the highest dose of 1,000 mg per dose at intervals of 4 hours or longer. The daily dose of 500 mg is divided twice a day, 750 mg three times a day and 1,000 mg four times a day. Manufacturer/distributor Ono Pharmaceutical Co., Ltd. Approval date January 8, 2019 Conditions for approval 1. Risk Management Plan should be designed appropriately implemented. 2. Because of the very limited number of patients treated with the product in Japanese clinical trials, a post-marketing use-results survey covering all cases should be performed until data on a certain minimum number of patients have been accumulated. Through these activities, actions necessary to ensure the proper use of the product should be taken by identifying the characteristics of patients to be treated with the product and collecting safety and efficacy data as soon as possible.

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On January 7, 2019 Aduro Biotech, Inc presented the corporate presentation (Presentation, Aduro Biotech, JAN 7, 2019, View Source [SID1234532498]).

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On January 7, 2019, 2019 Mirati Therapeutics, Inc. (NASDAQ: MRTX) a clinical-stage targeted oncology company, reported a clinical collaboration with Bristol-Myers Squibb Company to evaluate the combination of sitravatinib and nivolumab (OPDIVO), in Mirati’s planned Phase 3 trial in second line non-small cell lung cancer (NSCLC) patients who have progressed following treatment with a platinum-based regimen and a checkpoint inhibitor (Press release, Mirati, JAN 7, 2019, View Source [SID1234532531]).

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The Phase 3 pivotal trial is expected to start in the first half of 2019 and will randomize patients to either the combination of sitravatinib with nivolumab or single-agent docetaxel. The trial will include an interim analysis of overall response rate (ORR) as the basis for potential accelerated approval. This interim analysis and the use of a docetaxel control arm follows guidance from Mirati’s FDA end of phase 2 meeting. The primary endpoint of the final analysis for the Phase 3 clinical trial will be overall survival.

"Our Phase 2 clinical trial of sitravatinib plus nivolumab in patients with checkpoint refractory NSCLC has shown promising activity and a well-tolerated safety profile," said Charles Baum, M.D., Ph.D., President and Chief Executive Officer of Mirati. "The trial is expected to result in a new drug application (NDA) for sitravatinib for the treatment of NSCLC patients whose tumors have progressed following treatment with a platinum containing regimen and a checkpoint inhibitor. This collaboration further validates the potential of sitravatinib and allows Mirati to invest in and expand the development of our clinical and pre-clinical programs."

Under the terms of the collaboration, Mirati will sponsor and fund the clinical trial and Bristol-Myers Squibb will provide nivolumab at no cost. Mirati maintains global development and commercial rights to sitravatinib outside of certain Asian territories, where it is partnered with BeiGene, and is free to develop the program in combination with other agents.

About Sitravatinib

Sitravatinib is a spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including TAM family receptors (TYRO3, Axl, Mer), split family receptors (VEGFR2, KIT) and RET. As an immuno-oncology agent, sitravatinib is being evaluated in combination with nivolumab (OPDIVO), an anti-PD-1 checkpoint inhibitor, in patients who have experienced documented disease progression following treatment with a checkpoint inhibitor. Sitravatinib’s potent inhibition of TAM and split family RTKs may overcome resistance to checkpoint inhibitor therapy through targeted reversal of an immunosuppressive tumor microenvironment, enhancing antigen-specific T cell response and expanding dendritic cell-dependent antigen presentation.

Sitravatinib is also being evaluated as a single agent in a Phase 1b expansion clinical trial emphasizing enrollment of patients whose tumors harbor specific mutations in the CBL protein. When CBL is inactivated by mutation, multiple RTKs, including TAM, VEGFR2 and KIT, are dysregulated and may act as oncogenic tumor drivers in NSCLC and melanoma. Sitravatinib potently inhibits these RTKs and is being investigated as a treatment option for cancer patients with CBL mutations

On January 7, 2019 Forbius, a clinical-stage company developing biologics for the treatment of cancer and fibrosis, reported that the first patient was dosed in a Phase 1 clinical trial with AVID200 (Press release, Forbius, JAN 7, 2019, View Source [SID1234532547]). The trial will evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor effects of escalating doses of AVID200 in patients with solid tumors.

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"Our goal is to significantly expand the number of cancer patients who benefit from checkpoint blockade and other immunotherapies. AVID200 was designed to have the potency and isoform selectivity to effectively counteract the highly immunosuppressive effects of TGF-beta in the tumor microenvironment and reverse resistance to immunotherapy," commented Dr. Maureen O’Connor-McCourt, CSO of Forbius.

AVID200 selectively neutralizes TGF-beta 1 & 3 with best-in-class pM potency, thus neutralizing the principal immunosuppressive TGF-beta isoforms. AVID200’s optimal selectivity was also designed to circumvent cardiac and other safety issues that have limited the applicability of older-generation, non-selective TGF-beta inhibitors.

TGF-beta 1 & 3 are the main oncogenic TGF-beta isoforms expressed by many solid tumors. They are believed to play a major role in T-cell suppression, fibrosis, and resistance to immunotherapeutics such as nivolumab (Opdivo) and pembrolizumab (Keytruda) (Chakravarthy et al., Nature Comm., 2018; Tauriello et al., Nature, 2018; Mariathasan et al., Nature, 2018).

AVID200’s immuno-oncology mode of action focuses on the reversal of both immunosuppression and fibrosis in the tumor stroma. In syngeneic mouse tumor models, AVID200 treatment led to T-cell activation, increased immune cell infiltration, and increased efficacy of immune checkpoint agents.

On January 7, 2019 AMAG Pharmaceuticals, Inc. (NASDAQ: AMAG) reported preliminary unaudited fourth quarter and full year 2018 financial results and provided 2019 financial guidance (Press release, AMAG Pharmaceuticals, JAN 7, 2019, View Source [SID1234532499]).

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The company will provide a portfolio update at the 37th Annual J.P. Morgan Healthcare Conference in San Francisco on Wednesday, January 9, 2019 at 7:30 a.m. PT (10:30 a.m. ET). A live audio webcast of the presentation and following breakout session will be accessible through the Investors section of AMAG’s website at www.amagpharma.com.

"In 2018, we achieved several key milestones including receiving two approvals from the U.S. Food and Drug Administration (FDA), launching both the Makena subcutaneous auto-injector and Feraheme broad label, and receiving FDA acceptance of our new drug application for VyleesiTM (bremelanotide). In addition, we bolstered our pipeline by adding two promising late-stage development assets, AMAG-423 and ciraparantag, targeting orphan patient populations," said William Heiden, AMAG’s president and chief executive officer.

"As we enter 2019, AMAG is in a unique position with a number of growing commercial products that together generate significant cash flows, allowing us to invest in the development and launch of our new pharmaceutical products. We have built an innovative and diversified portfolio that I believe positions us well for long-term growth and will deliver significant shareholder value," added Mr. Heiden.

Preliminary Fourth Quarter and Full Year 2018 Financial Results (unaudited)
Fourth Quarter 2018
AMAG expects total revenues from continuing operations for the fourth quarter of 2018 to be between $85 million and $90 million. This includes Makena (hydroxyprogesterone caproate injection) net product sales of between $46 million and $48 million, Feraheme and MuGard net product sales of between $34 million and $36 million, and Intrarosa net product sales of between $5 million and $6 million. The Makena subcutaneous auto-injector maintained market share in the fourth quarter, as compared to the third quarter, despite the entry of generic competition to the intramuscular product. In addition, Makena ex-factory sales were impacted by a reduction in channel inventory levels in the fourth quarter, as compared to third quarter, due to temporary supply constraints, which are now resolved. Fourth quarter Feraheme revenues grew approximately 34% over prior year, driven by continuing success of the product’s expanded label. Intrarosa revenues were driven by strong prescription volume and market share growth in the quarter.

For the fourth quarter of 2018, AMAG expects an operating loss of between $17 million and $27 million. Adjusted EBITDA (earnings before interest, taxes, depreciation and amortization) for the fourth quarter of 2018 is expected to be within the company’s forecasted range of between a loss of $5 million and positive adjusted EBITDA of $5 million.

Full Year 2018
AMAG expects full year 2018 revenues and adjusted EBITDA to be within the company’s most recently issued financial guidance range. Total revenues from continuing operations are expected to be between $471 million and $476 million. This includes Makena net product sales of between $321 million and $323 million, Feraheme and MuGard net product sales of between $134 million and $136 million, and Intrarosa net product sales of between $15 million and $16 million. As a result of the sale of Cord Blood Registry (CBR), which closed on August 6, 2018, CBR’s results have been excluded from the financial results.

For the full year of 2018, AMAG expects an operating loss of between $45 million and $55 million and adjusted EBITDA of between $115 million and $125 million.2

The company ended 2018 with approximately $394 million in cash and investments, $21.4 million of short-term debt and $320 million of 2022 convertible notes (principal amount outstanding).

The company expects to report final financial results for the fourth quarter and audited results for the full year of 2018 in February.

2019 Overview
The company has a number of goals and key milestones upcoming in 2019:

Expand use of Makena subcutaneous auto-injector

Drive Feraheme growth

Continue successful Intrarosa direct-to-consumer campaign

Submit Vyleesi frequent-dosing study results prior to updated PDUFA date of June 23, 2019; prepare for commercial launch in 2H-2019

Target full enrollment in AMAG-423 Phase 2b/3a study by year end

Initiate ciraparantag Phase 3a clinical study

Pursue in/out-licensing opportunities

Meet/exceed financial guidance

The company is providing the following financial guidance for 2019:
$ in millions
2019 Financial Guidance
Total revenue
$365 – $415
Operating loss
($131) – ($101)
Adjusted EBITDA
($65) – ($35)

"During 2018, we increased our financial guidance three times and reported that we achieved our financial objectives for the full year of 2018," said Ted Myles, AMAG’s chief financial officer. "We also completed the transformation of our balance sheet, and with nearly $400 million of cash on hand and approximately $20 million in near-term debt, we are well positioned to advance our portfolio of novel products."

"2019 will be a year of investment and we are in the fortunate position that our cash flow generating products and our balance sheet can support the development of our future products; each of which has significant revenue and growth prospects because they provide innovative therapeutic solutions to patients with unmet medical needs," added Mr. Myles.

Webcast Information
A live audio webcast of the company’s presentation and the following breakout session, along with the accompanying slide presentation at the 37th Annual J.P. Morgan Healthcare Conference, will be accessible through the Investors section of the company’s website at www.amagpharma.com on January 9, 2019 at 7:30 a.m. PT (10:30 a.m. ET). Following the conference, the webcast will be archived on the company’s website until February 9, 2019.

Use of Non-GAAP Financial Measures
AMAG has presented certain non-GAAP financial measures, including non-GAAP adjusted EBITDA (earnings before income taxes, depreciation and amortization). These non-GAAP financial measures exclude certain amounts, expenses or income, from the corresponding financial measures determined in accordance with accounting principles generally accepted in the U.S. (GAAP). Management believes this non-GAAP information is useful for investors, taken in conjunction with AMAG’s GAAP financial statements, because it provides greater transparency regarding AMAG’s operating performance. Management uses these measures, among other factors, to assess and analyze operational results and trends and to make financial and operational decisions. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of AMAG’s operating results as reported under GAAP, not as a substitute for GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. The determination of the amounts that are excluded from non-GAAP financial measures is a matter of management judgment and depends upon, among other factors, the nature of the underlying expense or income amounts. Reconciliations between these non-GAAP financial measures and the most comparable GAAP financial measures are included in the tables accompanying this press release