Opko Health Inc (OPK)

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OPKO / Tesaro’s Rolapitant: Competition for Emend or New Drug of Choice?

Medscape Medical News > Conference News
Roxanne Nelson
September 27, 2014

Rolapitant Reduces Chemo-Induced Nausea and Vomiting

MADRID — A new neurokinin receptor (NK)-1 antagonist, rolapitant (under development by Tesaro), could soon be available for the prevention of chemotherapy-induced nausea and vomiting (CINV).

Rolapitant was significantly better than placebo in a study reported here at the European Society for Medical Oncology Congress 2014.

A complete response was achieved by more of the rolapitant group than of the placebo group for patients in the delayed phase of CINV (72.7% vs 58.4%; P < .001), the acute phase (83.7% vs 73.7%; P = .005), and the overall phase (70.1% vs 56.5%; P = .001).

The manufacturer has submitted the data for approval in the United States.

But the unanswered question is how rolapitant compares with aprepitant (Emend, Merck & Co.), the first and so far only NK-1 antagonist on the market, which is used in conjunction with 5-HT3 antagonists such as ondansetron. These highly effective drugs "have together dramatically changed the experience of cancer treatment, bringing unprecedented improvements to patients' quality of life," the American Society of Clinical Oncology noted when the agents were recently voted to be among the top 10 clinical cancer advances in the past 50 years. These drugs are all highly active against CINV.

"Nausea and vomiting is the most feared side effect of chemotherapy," said Bernardo L. Rapoport, MD, chief medical oncologist at The Medical Oncology Center of Rosebank in Johannesburg, who presented the rolapitant findings during a press briefing. "It dramatically affects quality of life."

Severe nausea and vomiting is frequently experienced by patients undergoing treatment with cisplatin-based chemotherapy, and can lead to dose reductions and treatment discontinuation.

End Points Met

Rolapitant appears to be different from other agents in this class, in that it does not interact with any other drugs and has a long half-life, Dr. Rapoport noted.

He presented results from a phase 3 multicenter trial that involved 532 patients receiving cisplatin chemotherapy. All received granisetron and dexamethasone. In addition, half received rolapitant and half received placebo.

The primary end point was a complete response (no emesis/no rescue medicines) in the delayed phase (from 24 to 120 hours after chemotherapy). The demographic characteristics of both groups were well balanced, and the median age was 57.3 years (range, 20 to 90).

As well as meeting the primary end point, the secondary end points of a complete response in the acute and overall phases were significantly better with rolapitant. In addition, more patients in the rolapitant group than in the placebo group reported no effect of quality of life (72.8% vs 67.8%; P = .231). Treatment-emergent adverse events were consistent in both groups.

"The majority of adverse events were considered by the investigators to be related to chemotherapy or the underlying cancer, not the drug," said Dr. Rapoport.

Effects were also seen in different geographic regions, he added.

Table. Regional Comparison of Complete Responses

http://opkodd.files.wordpress.com/2014/10/rolapitant_table.png&h=255

"This agent makes a significant difference in the way people tolerate their chemotherapy," said lead study investigator Martin Chasen, MD, medical director of palliative care at the Ottawa Hospital Cancer Centre in Ontario, Canada.

"Patients experienced no loss in quality of life and, in fact, many saw meaningful improvements. One of the patients in the rolapitant cohort reported that he finished 18 holes of golf 1 week after receiving chemotherapy. This is in sharp contrast to many patients on current standard antiemetics who are too ill to get out of bed the week after each cycle of cisplatin," Dr. Chasen explained.

"We must treat nausea and vomiting, not just the cancer," ha added, emphasizing that some patients are extremely sensitive to cisplatin effects. He recalled that he had 1 or 2 patients with curable cancers who refused treatment after 1 round of cisplatin. "They preferred to die," he said.

"Rolapitant demonstrated a significant effect in both the acute and delayed phases. Our primary end point was achieved in the delayed phase — an incredible result," Dr. Chasen reported.

"We know that the NK-1 receptor in the brain must be blocked to control nausea and vomiting, and there are other agents that block this for a short time. But rolapitant is an exceptionally long-term receptor blocker that binds to the receptor and remains in place for up to 120 hours, not allowing the chemotherapy to induce nausea and vomiting," he explained.

He pointed out that rolapitant might also save money. For example, in Ottawa, after chemotherapy, patients can be visited by a nurse who will administer intravascular hydration and nutrients. "Patients receiving rolapitant may not require this service. They are able to eat and drink as they should," he explained.

During a discussion of the study, Jørn Herrstedt, MD, DMSci, from the Institute of Clinical Research at the University of Southern Denmark in Odense and the Department of Oncology at the Odense University Hospital, agreed with most of the conclusions of the study.

"There was an improvement in quality to life," he noted " but I don't think it's really clinically relevant, as the differences were very small."

The study will probably have an impact on future antiemetic therapy, he added.

The study was sponsored by Tesaro. Some of the study investigators are employees of Tesaro.

European Society for Medical Oncology (ESMO) Congress 201: Abstract LBA47 PR. Presented September 27, 2014.

Uncle’s DD Note#

Ref: Opko / Tesaro License Agreement

CINV Rolapitant

Tesaro 10-K Annual Report ( http://ir.tesarobio.com/secfiling.cfm?filingID=1104659-14-19488&CIK=1491576 )
Licensing with (Opko) Mar 14, 2014

Licensing Agreements

License for Rolapitant

In December 2010, we entered into a license agreement with OPKO to obtain an exclusive, royalty bearing, sublicensable worldwide license, to research, develop, manufacture, market and sell rolapitant. The license agreement also extends to an additional, backup compound, SCH900978, to which we have the same rights and obligations as rolapitant, but which we are not currently advancing. Under the OPKO license we are obligated to use commercially reasonable efforts to conduct all preclinical, clinical, regulatory and other activities necessary to develop and commercialize rolapitant.

Rolapitant In-License

In December 2010, the Company entered into a license agreement with OPKO Health, Inc., or OPKO, to obtain an exclusive, royalty-bearing, sublicensable worldwide license to research, develop, manufacture, market and sell rolapitant. The license agreement also extended to an additional, backup compound, SCH900978, to which the Company has the same rights and obligations as rolapitant, but which the Company is not currently advancing. Under the OPKO license the Company is obligated to use commercially reasonable efforts to conduct all preclinical, clinical, regulatory and other activities necessary to develop and commercialize rolapitant. Under the terms of the OPKO license, the Company paid OPKO $6.0 million upon signing the agreement and issued 1,500,000 shares of its Junior Preferred Stock. At the time of the license transaction, the fair value of Junior Preferred Stock was determined to be $630,000. The Company is also required to make development milestone payments to OPKO of up to an aggregate of $30.0 million if specified regulatory and initial commercial sales milestones are achieved. In addition, the Company is required to make additional milestone payments to OPKO of up to an aggregate of $85.0 million if specified levels of annual net sales of rolapitant are achieved. If commercial sales of rolapitant commence, the Company is required to pay OPKO tiered royalties on the amount of annual net sales achieved in the United States and Europe at percentage rates that range from the low teens to the low twenties, which the Company expects will result in an effective royalty rate in the low teens. The royalty rate on annual net sales outside of the United States and Europe is slightly above the single digits. If the Company elects to develop and commercialize rolapitant in Japan through a third-party licensee the Company will share equally with OPKO all amounts received by it in connection with such activities under the Company’s agreement with such third party, subject to certain exceptions and deductions. OPKO also retains an option to become the exclusive distributor of such products in Latin America, provided that OPKO exercises that option within a defined period following specified regulatory approvals in the United States. The Company is responsible for all preclinical, clinical, regulatory and other activities necessary to develop and commercialize rolapitant. There were no ongoing clinical trials for rolapitant at the time of its acquisition. As of the date of acquisition, none of the assets acquired had alternative future uses, nor had they reached a stage of technological feasibility. As no processes or activities that would constitute a “business” were acquired along with the license, the transaction was accounted for as an asset acquisition by recording the entire purchase price as acquired in-process research and development expense of $6.6 million. As of December 31, 2013, the Company has not made any additional milestone payments under this license agreement.

The license with OPKO will remain in force until the expiration of the royalty term in each country, unless OPKO has cause to terminate the license earlier for our material breach of the license or bankruptcy. We have a right to terminate the license at any time during the term for any reason on three months’ written notice to OPKO.

OPKO 10-K Filed 3/3/2014 ( http://investor.opko.com/secfiling.cfm?filingID=944809-14-3&CIK=944809 )
NK-1 Program

In November 2009, we acquired rolapitant and other neurokinin-1 (“NK-1”) assets from Schering Plough Corporation. In December 2010, we exclusively out-licensed the development, manufacture and commercialization of our lead NK-1 candidate, rolapitant, to TESARO, Inc. (“TESARO”). Rolapitant, a potent and selective competitive antagonist of the NK-1 receptor, has successfully completed phase 2 clinical testing for prevention of chemotherapy induced nausea and vomiting, or CINV, and post-operative induced nausea and vomiting (“PONV”). In December 2013, TESARO announced successful achievement of the primary endpoint in each of two phase 3 trials of Rolapitant for prevention of chemotherapy-induced nausea and vomiting. Under the terms of the license, we are eligible to receive up-front and milestone payments of up to $121 million, double digit tiered royalties on sales of licensed product, as well as a share of future profits from the commercialization of licensed products in Japan, and an option to market the products in Latin America. In addition, we acquired an equity position in TESARO.

TESARO

In December 2010, we entered into a license agreement with TESARO, Inc. (“TESARO”) granting TESARO exclusive rights to the development, manufacture, commercialization and distribution of rolapitant and a related compound (the “TESARO License”). Under the terms of the TESARO License, we are eligible for payments of up to $121.0 million, including an up-front payment of $6.0 million, which has been received, and additional payments based upon achievement of specified regulatory and commercialization milestones. In addition, TESARO will pay us double digit tiered royalties on sales of licensed products. We will share future profits from the commercialization of licensed products in Japan with TESARO and we will have an option to market the products in Latin America. In connection with the TESARO License, we also acquired an equity position in TESARO. We recorded the equity position at $0.7 million, the estimated fair value based on a discounted cash flow model.

Neither we nor our related parties have the ability to significantly influence TESARO and as such, we accounted for our investment in TESARO under the cost method until June 2012 on which date, TESARO had an initial public offering. As a result of the initial public offering, we determined TESARO had a readily determinable fair value and we changed the accounting for our investment in TESARO from a cost method investment to an investment, available for sale. We record changes in the fair value as an unrealized gain or loss in Other comprehensive loss and determine the cost using the specific identification method. Refer to Note 18.