On June 19, 2015 Bristol-Myers Squibb reported that the European Commission has approved Opdivo, a PD-1 immune checkpoint inhibitor, for the treatment of advanced (unresectable or metastatic) melanoma in adults, regardless of BRAF status (Press release, Bristol-Myers Squibb, JUN 19, 2015, View Source [SID:1234505464]). Schedule your 30 min Free 1stOncology Demo! Today’s approval allows for the marketing of Opdivo in all 28 Member States of the EU. It follows an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP), which was announced on April 24, 2015. This accelerated assessment was given because Opdivo qualified for the designation as a "medicinal product of major interest from the point of view of public health and in particular from the view point of therapeutic innovation." Opdivo is the only PD-1 immune checkpoint inhibitor to receive an accelerated assessment in Europe, and is the first approval given by the European Commission for a PD-1 inhibitor in any cancer. Know more, wherever you are: The incidence of melanoma has continued to increase in almost all European countries, with an estimated one in five patients expected to develop metastatic, or advanced, disease. Historically, prognosis for late-stage metastatic melanoma has been poor: the average survival rate for stage IV is just six months with a one-year mortality rate of 75%.
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"At Bristol-Myers Squibb, we are continually focused on developing new ways to transform the outlook for patients with some of the hardest-to-treat and deadliest cancers," said Emmanuel Blin, senior vice president, head of commercialization, policy and operations, Bristol-Myers Squibb. "We are pleased to bring the first PD-1 immune checkpoint inhibitor to the European Union for the treatment of advanced melanoma. We are working relentlessly and at record-breaking speed to build upon our Immuno-Oncology science to deliver new treatment options, with the goal of improving long-term survival for patients."
About CheckMate -066, -037
The European Commission’s approval is based on data from two Phase 3 studies (CheckMate -066, -037). Together, the trials investigated Opdivo across treatment lines and mutational status with a consistent dose of 3 mg/kg every two weeks that has been well-established across the Phase 3 clinical development program for Opdivo.
"The Phase 3 data supporting the approval of Opdivo demonstrates both superior overall survival and response rate for treatment-naïve patients with advanced melanoma, against the standard of care," said Dirk Schadendorf, M.D., professor, director and chair, Clinic for Dermatology, University Hospital, Essen, Germany. "It is an important step forward in offering a new option for advanced melanoma patients in the European Union, especially considering that long-term benefits have largely been elusive in this treatment category."
CheckMate -066 is a Phase 3 randomized, double-blind study comparing Opdivo (n=210) to the chemotherapy dacarbazine (DTIC) (n=208) in patients with treatment-naïve advanced melanoma. It is the first Phase 3 trial of a PD-1 immune checkpoint inhibitor to demonstrate superior overall survival (OS) in advanced melanoma, demonstrating a one-year survival rate of 73% for Opdivo versus 42% for DTIC, and there was a 58% decrease in the risk of death for patients treated with Opdivo based on a hazard ratio of 0.42 (99.79% CI, 0.25-0.73; P<0.0001). Objective response rate (ORR) also was significantly higher for Opdivo than DTIC (40% vs. 14%, P<0.0001). The primary endpoint of this trial was OS. Secondary endpoints included progression-free survival (PFS) and ORR by RECIST v1.1 criteria.
Safety was reported in all patients treated in the Opdivo and DTIC arms. Fewer discontinuations were observed with Opdivo than DTIC (6.8% vs. 11.7%) as well as for treatment-related Grade 3/4 adverse events (AEs) (11.7% vs. 17.6%), which were managed using established safety algorithms. The most common Opdivo treatment-related AEs were fatigue (20%), pruritus (17%), and nausea (16.5%). Common adverse events in the DTIC arm were consistent with those in previous reports and included nausea (41.5%), vomiting (21%), fatigue (15%), diarrhea (15%) and hematological toxicities. No deaths were attributed to study drug toxicity in either arm.
CheckMate -037 is a Phase 3 randomized, controlled open-label study of Opdivo (n=272) versus investigator’s choice chemotherapy (ICC) (n=133) — either single-agent dacarbazine or carboplatin plus paclitaxel — in patients with advanced melanoma who were previously treated with Yervoy (ipilimumab), and, if BRAF mutation positive, a BRAF inhibitor. Co-primary endpoints of the study are ORR and OS. In a planned interim analysis of ORR, an improvement in ORR of 32% was seen in the Opdivo arm (95% CI, 23.5%-40.8%) versus 11% in the investigator’s choice chemotherapy arm (95% CI, 3.5%-23.1%). A majority of responses (87%) were ongoing in those patients administered Opdivo. Responses to Opdivo were demonstrated in both patients with or without BRAF mutuation and regardless of PD-L1 expression.
Safety was reported on all patients treated in the Opdivo (n=268) and ICC (n=102) arms. The majority of Opdivo treatment-related adverse events (AEs) were Grade 1/2 and managed using recommended treatment algorithms. Grade 3/4 drug-related AEs were less frequent for the Opdivo arm (9% vs. 31% of patients treated with chemotherapy). Discontinuations due to drug-related AEs of any grade occurred in 3% of Opdivo-treated patients and 7% of patients administered ICC. There were no deaths related to study drug toxicity.
The approval also was based on data from a Phase 1b study (Study -003) in relapsed advanced or metastatic melanoma, which demonstrated the first characterization of Opdivo benefit/risk in advanced melanoma. Of the 306 previously-treated patients enrolled in the study, 107 had melanoma and received Opdivo at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg every two weeks for a maximum of two years. In this patient population, objective response was reported in 33 patients (31%) with a median duration of response of 22.9 months (95% CI: 17.0, NR). The median PFS was 3.7 months (95% CI: 1.9, 9.3). The median OS was 17.3 months (95% CI: 12.5, 36.7), and the estimated OS rates were 63% (95% CI: 53, 71) at one year, 48% (95% CI: 38, 57) at two years, and 41% (95% CI: 31, 51) at three years.
About Opdivo
Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.
Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. On December 22, 2014, the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.
IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis
Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.
Immune-Mediated Colitis
In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.
Immune-Mediated Hepatitis
In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.
Immune-Mediated Nephritis and Renal Dysfunction
In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism
In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions
In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.
Embryofetal Toxicity
Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions
In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
Common Adverse Reactions
The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).
Author: [email protected]
CYRAMZA® (ramucirumab) Hepatocellular Carcinoma Data Published by The Lancet Oncology
On June 19, 2015 Eli Lilly reported that The Lancet Oncology has published results of the Phase III REACH trial that evaluated CYRAMZA (ramucirumab) as a second-line treatment for people with hepatocellular carcinoma (HCC), also known as liver cancer (Press release, Eli Lilly, JUN 19, 2015, View Source [SID:1234505463]). Schedule your 30 min Free 1stOncology Demo! While the REACH trial’s primary endpoint of overall survival favored the CYRAMZA arm, it was not statistically significant. However, encouraging single-agent CYRAMZA activity was observed, with meaningful improvements in key secondary endpoints as well as within certain patient subgroups.
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The global, randomized, double-blind REACH trial compared ramucirumab plus best supportive care to placebo plus best supportive care as a second-line treatment in patients with HCC after being treated with sorafenib in the first-line setting. Median overall survival (OS) was 9.2 months on the ramucirumab arm compared to 7.6 months on the placebo arm (HR 0.866; 95% CI: 0.717-1.046; p=0.1391). While the median OS was not statistically significant, a prespecified subgroup of patients with an elevated baseline of alpha-fetoprotein (AFP) ≥400 ng/mL showed a greater survival improvement with ramucirumab treatment. Median OS in this subgroup of patients was 7.8 months in the ramucirumab arm compared to 4.2 months in the placebo arm (HR 0.674; 95% CI 0.508-0.895; p=0.0059).
"Advanced liver cancer carries a poor prognosis with limited treatment options. Several phase III studies to date have not been able to demonstrate improved survival in the second-line setting following sorafenib failure," said Andrew X. Zhu, M.D., director of Liver Cancer Research at Massachusetts General Hospital Cancer Center and principal investigator of the REACH trial. "Further analyses from the REACH study have identified AFP as a potential marker for selecting patients with advanced hepatocellular carcinoma who may benefit from ramucirumab treatment."
The REACH study analyses presented at the Gastrointestinal Cancers Symposium earlier this year concluded that a greater reduction in the risk of death in patients with progressively higher baseline AFP values warrants further investigation. Based on these findings, Lilly will soon begin enrollment in REACH-2, a new Phase III trial to evaluate the benefit of ramucirumab treatment in advanced liver cancer patients with an elevated baseline AFP (ClinicalTrials.gov identifier: NCT02435433).
"Globally, a high unmet need exists in second-line hepatocellular carcinoma, and currently there are no therapies approved in the U.S., EU or Japan to treat patients in this setting," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "We are encouraged by the efficacy seen overall in the REACH study, especially in specific subpopulations, and we hope to confirm those results with the new CYRAMZA Phase III trial."
The safety data in the REACH study were consistent with results from previous single-agent ramucirumab studies and the safety information included in the U.S. Prescribing Information for ramucirumab. The most common (≥5% incidence) clinical grade ≥3 adverse events occurring more frequently in patients on the ramucirumab arm compared to the control arm were hypertension (12% vs. 4%), asthenia (fatigue) (5% vs. 2%), and malignant neoplasm progression (6% vs. 4%). The safety profile of ramucirumab in patients with elevated baseline AFP > 400 ng/mL was consistent with that observed in the overall safety population.
Ramucirumab has been granted Orphan Drug Designation for treatment of hepatocellular carcinoma in the U.S. and EU. Orphan drug status is given – in the U.S. by the FDA’s Office of Orphan Products Development (OOPD) and in the EU by the European Commission – to medicines that have demonstrated promise for the treatment of rare diseases.
About the REACH Trial
REACH is a global, randomized, double-blind Phase III study of ramucirumab plus best supportive care compared to placebo plus best supportive care as a second-line treatment in patients with hepatocellular carcinoma who have been previously treated with sorafenib in the first-line setting. Initiated in 2010, the study enrolled 565 patients across 27 countries; as defined in the trial protocol, the primary analyses are focused on patients with a Child-Pugh score of < 7 (Child-Pugh Class A only). The primary endpoint (also referred to as the major efficacy outcome measure) of the REACH trial was overall survival and key secondary endpoints (also referred to as the supportive efficacy outcome measures) include: progression-free survival; overall response rate; time to progression; and safety.
TFS to acquire US pharmaceutical partners to capture downstream revenues from product sales
On June 18, 2016 TFS Corporation Limited ("TFS", "Company", ASX: TFC), the world’s largest owner and manager of commercial Indian sandalwood plantations, reported it has entered into share purchase agreements to acquire US-based pharmaceutical partners ViroXis Corporation ("ViroXis") and Santalis Pharmaceuticals ("Santalis", together "the Acquisitions") (Press release, TFS, JUN 18, 2015, View Source [SID1234517229]).
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TFS Chief Executive Officer Frank Wilson said, "The Acquisitions will extend TFS’s soil to oil strategy by expanding the Company’s vertically integrated business model. TFS will benefit from direct ownership of the pharmaceutical companies which exclusively develop and sell products containing TFS-grown and processed Indian sandalwood oil to the high-value pharmaceutical sector."
"While TFS previously benefited from pharmaceutical product development through oil sales, with these Acquisitions we will also capture all of the future product earnings, including product royalties and licence fees, generated by ViroXis and Santalis, thereby significantly enhancing our own earnings," Mr Wilson said.
"We have been directly involved over the last five years in successfully building the first mover advantage established by ViroXis and Santalis. These transactions will allow us to work even closer with the product development teams and accelerate the establishment of a range of sandalwood-based dermatological products. With increased control of the formulation we also expect to generate additional revenue from our oil sales."
Santalis has already licensed a range of dermatological products that contain TFS-grown Indian sandalwood oil to Nestle-owned Galderma, a global dermatological company. The acne product Benzac Acne Solutions, which is the first to have been commercialised by Santalis, successfully debuted on US shelves earlier this year and is already available in around 25,000 stores through major US retail chains. Following these Acquisitions, each sale of the Benzac Acne Solutions range will directly generate royalty revenues for TFS in addition to existing oil sales.
"Over time we expect a series of products containing TFS’s Indian sandalwood oil to be distributed by pharmaceutical companies to worldwide markets," Mr Wilson said.
Transaction summary
Subject to certain conditions to completion, TFS will pay minimum consideration of US$23.4 million for the issued shares in ViroXis and Santalis it does not already own (100% and 50% respectively), payable by US$1.5 million in cash and US$21.9 million in TFS shares.
The scrip component of the minimum consideration will involve the issuance of around 15.3 million TFS shares at a price of AU$1.85 per share. TFS anticipates issuing around 12.6 million shares in July 2015 and the remaining 2.7 million shares in the period between 10 September 2015 and 31 July 2016. Around 9.1 million of the 12.6 million shares expected to be issued in July 2015 will be subject to lock up provisions (which range between six and thirty months).
The shares issued pursuant to the Acquisitions will be made utilising the Company’s available placement capacity under ASX listing rule 7.1.
The total maximum consideration payable by TFS consists of fixed minimum payments of US$23.4 million and contingent payments over time of up to US$221.5 million. The contingent consideration only becomes payable when the acquired companies achieve significant operating and commercial milestones (from the launch or approval of new pharmaceutical products containing Indian sandalwood oil) and significant operating cash inflows.
The structure of the Acquisitions is designed to ensure that the founders of ViroXis and Santalis, who will continue to operate the businesses, are closely aligned to the ongoing and long-term success of the companies and their products. Both founders will sign new employment contracts on completion.
"Total consideration is directly linked to ViroXis and Santalis successfully developing and selling additional pharmaceutical products to the healthcare market, as has been achieved with the Benzac range. We have structured the transaction with minimal upfront cash outlay, flexibility with cash and scrip payments, incentives to generate additional revenue and profit, and lock-up provisions, to provide maximum value to TFS shareholders," Mr Wilson said.
Since 2010, ViroXis and Santalis have invested over US$17 million in the development and commercialisation of pharmaceutical products containing Indian sandalwood oil.
The Acquisitions do not impact TFS’s previous guidance for FY15 of NPAT of at least $90 million. After absorbing transaction costs, TFS continues to expect cash EBITDA to increase year-on-year by approximately 10%. On a stand-alone basis, and excluding any benefit from higher Indian sandalwood oil sales, the Acquisitions are expected to be EPS dilutive in FY16.
Further details on the key terms of the transactions are provided in Appendix One.
Background on ViroXis and Santalis
ViroXis is a bio-pharmaceutical company focused on developing and commercialising innovative, proprietary, botanical pharmaceuticals derived from sandalwood oil, exclusively for viral conditions. ViroXis was cofounded by its Chief Executive Officer Ian Clements, who has more than 20 years of experience in the pharmaceutical and biotechnology industries.
Santalis is focused on developing and commercialising sandalwood products targeting all possible conditions outside of viral skin diseases (dermatological conditions such as acne, eczema, psoriasis, redness and sensitive skin). Santalis was founded in 2010 and is a 50-50 joint venture with TFS. Santalis is led by Chief Executive Officer Paul Castella, who co-founded Santalis with Mr Clements and was also a co-founder of ViroXis. Dr Castella has a Ph.D. in molecular biology and has founded and managed numerous biotechnology companies with a successful record of product development, regulatory approval and commercialisation.
ViroXis CEO Ian Clements said: "I am delighted we have reached this agreement with TFS, with their ongoing support enabling us to extend and accelerate development of products using Indian sandalwood oil to treat viral skin infections, such as common skin warts and Molluscum contagiosum."
Santalis CEO Paul Castella added: "We have achieved great success to date through our landmark agreements with Galderma and we will be able to build on this by working even more closely with TFS in developing and marketing our pipeline of dermatological products containing Indian sandalwood oil. Santalis successfully developed the Benzac acne products, which have now launched across the US, and is well advanced with numerous other products, including for eczema."
Further details on ViroXis and Santalis are provided in Appendix Two.
APPENDIX ONE
TRANSACTION DETAILS
Transaction details The minimum purchase price is US$23.4 million (ViroXis: US$18.4 million, Santalis: US$5.0 million).
The maximum purchase price over time is US$244.9 million (ViroXis: US$154.9 million, Santalis: US$90.0 million) if all milestones, base earn out thresholds and incentive and final earn out thresholds are met through to the eight year anniversary of completion.
The contingent consideration has been structured as follows:
Minimum purchase price
The fixed minimum purchase price for ViroXis is US$18.4 million, comprising cash of US$1.5 million and stock of US$16.9 million.
The fixed minimum purchase price for Santalis is US$5.0 million comprised fully of stock.
The TFS shares will be issued at AU$1.85 per share, being the volume weighted average price for TFS shares for the 30 trading days to 17 June 2015.
In relation to the fixed minimum purchase price, a total of 15.3 million shares is expected to be issued within the following time-frames and be subject to the following lock up periods: Stock issued in July 2015 and subject to no lock up period: 3.5 million Stock issued in July 2015 and subject to lock up period of between 6 and 30 months: 9.1 million Stock issued between September 2015 and July 2016 and subject to no lock up period: 2.7 million
Milestone payments
The purchase price for ViroXis will increase by a maximum of US$26.0 million if the following milestones are achieved within certain periods in up to five years after completion:
1. US$2.0 million on the launch of an over-the-counter ("OTC") product
2. US$4.0 million on the enrolment of the first patient in a Phase 3 FDA trial for a skin indication
3. US$4.0 million on the enrolment of the first patient in a Phase 3 FDA trial for a second skin indication
4. US$8.0 million on FDA approval of a prescription product for a skin indication
5. US$8.0 million on FDA approval of a prescription product for a second skin indication
The purchase price for Santalis will increase by a maximum of US$20.0 million if the following milestones are achieved in the five years after completion:
1. US$5.0 million on the launch of a new OTC product
2. US$2.5 million on the enrolment of the first patient in a Phase 3 FDA trial for a skin indication
3. US$2.5 million on the enrolment of the first patient in a Phase 3 FDA trial for a second skin indication 4. US$5.0 million on FDA approval of a prescription product for a skin indication
5. US$5.0 million on FDA approval of a prescription product for a second skin indication
If FDA approval of a prescription product (milestones 4 and 5 above) is granted between five and eight years post completion, then 50% of the relevant milestone payment will be payable.
All milestone payments are payable in stock and/ or cash, at TFS’s election and in such proportions as TFS determines.
Base earn out payments
The purchase price for ViroXis will increase by a maximum of US$50.0 million based on the level of aggregate net cash flow ("NCF") generated by the business in the five years post completion. The base earn out payment thresholds are:
No earn out payment Less than US$4.3 million US$5.0 million NCF equal to or greater than US$4.3 million and less than US$8.6 million US$15.0 million NCF equal to or greater than US$8.6 million and less than US$12.8 million US$35.0 million NCF equal to or greater than US$12.8 million and less than US$17.1 million US$50.0 million NCF equal to or greater than US$17.1 million
The purchase price for Santalis will increase by a maximum of US$31.0 million based on the level of aggregate net cash flow ("NCF") generated by the business in the five years post completion. The base earn out payment thresholds are:
No earn out payment Less than US$2.5 million US$5.0 million NCF equal to or greater than US$2.5 million and less than US$5.0 million US$10.0 million NCF equal to or greater than US$5.0 million and less than US$7.4 million US$20.0 million NCF equal to or greater than US$7.4 million and less than US$9.9 million US$31.0 million NCF equal to or greater than US$9.9 million
All base earn out payments are payable in stock and/ or cash, at TFS’s election and in such proportions as TFS determines.
Incentive earn out payments
The purchase price for ViroXis will increase by an incentive earn out payment equal to 20% of the NCF in excess of US$10.0 million for each of the three years ending on the six, seven and eight year anniversaries of completion. The incentive earn out payment is capped at US$60.7 million.
The purchase price for Santalis will increase by an incentive earn out payment equal to 20% of the NCF in excess of US$10.0 million for each of the three years ending on the six, seven and eight year anniversaries of completion. The incentive earn out payment is capped at US$37.5 million.
All incentive earn out payments are payable in stock and/ or cash, at TFS’s election and in such proportions as TFS determines.
Final earn out payments
The purchase price for ViroXis will increase by a final earn out payment equal to 20% of the amount, if any, that aggregate NCF for the 8 year period after completion exceeds US$111.9 million, subject to the maximum purchase price cap for all purchase payments of US$154.9 million.
The purchase price for Santalis will increase by a final earn out payment equal to 20% of the amount, if any, that aggregate NCF for the 8 year period after completion exceeds US$111.7 million, subject to the maximum purchase price cap for all payments of US$90.0 million.
All final payments are payable in stock or cash, at TFS’s election and in such proportions as TFS determines.
Put and call mechanism: Santalis In accordance with the terms of the Santalis share purchase agreement, Mr Clements and Dr Castella will initially retain some of their Santalis shares following completion of the Acquisitions (which is expected to be in July 2015).
There are put and call options in place between TFS and Mr Clements and Dr Castella which are exercisable prior to 31 July 2016. These options require TFS to acquire the retained shares on the same terms as TFS acquired the balance of the shares at completion and TFS expects to exercise its call option within this timeframe.
Additional requirements
Further to the purchase prices, TFS will provide minimum funding support to ViroXis and Santalis for product development and other costs. The costs to TFS will be US$2.5 million per year for five years for each of ViroXis and Santalis (total of US$25 million over 5 years).
8-K – Current report
On June 18, 2015 TG Therapeutics reported updated clinical results from its Phase 2 study of TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, in combination with ibrutinib, the oral BTK inhibitor (Filing, 8-K, TG Therapeutics, JUN 18, 2015, View Source [SID:1234505460]). The updated results from the Phase 2 study were delivered in an oral presentation by Dr. John Burke, Rocky Mountain Cancer Associates/US Oncology, Aurora, CO during the 13th International Congress on Malignant Lymphoma (ICML), being held from June 17 – June 20, 2015 in Lugano, Switzerland.
OVERVIEW OF THE UPDATED RESULTS PRESENTED ON TG-1101 + IBRUTINIB
Today’s presentation included data from 44 patients with relapsed and/or refractory CLL treated with TG-1101 in combination with ibrutinib at the labeled dose of 420 mg. Forty patients were evaluable for efficacy, of which 50% (20 patients) were considered "High-Risk", defined as the presence of a 17p del, 11q del and/or p53 mutation, the same criteria which is being used for the current Phase 3 GENUINE study.
Dr. Jeff Sharman, Medical Director of Hematology Research for the US Oncology Network, and Study Chair for both the Phase 2 and the Phase 3 GENUINE Study stated: "The updated Phase 2 data continues to demonstrate that adding ublituximab to ibrutinib can induce not only significant response rates for high-risk CLL patients, but has the potential to impact depth of response, with higher CR and MRD negative rates observed compared to historical data with ibrutinib monotherapy. The Phase 3 study is now up and running, and we look forward to a strong collaboration with all investigators, as this is a very attractive protocol for patients with high-risk CLL."
Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commented on the data, "We continue to be pleased with the performance of the combination of TG-1101 plus ibrutinib and continue to believe the combination represents a best-in-class treatment for patients with relapsed/refractory CLL, especially in patients with high-risk disease, which is generally known to be chemotherapy resistant. We expect, if approved, TG-1101 will be the first chemo-free combination approved with ibrutinib for patients with relapsed/refractory CLL. The data presented today gives us additional confidence that the outcome of our Phase 3 GENUINE Study will be successful and we will be able to offer patients a novel chemo-free treatment option. We greatly appreciate the dedication to the program from our Study Chair Dr. Jeff Sharman and all the participating sites and physicians across the country that are participating in this important clinical trial."
Safety and Tolerability of TG-1101 + ibrutinib
TG-1101 in combination with ibrutinib was well tolerated in the 44 CLL patients evaluable for safety, with day 1 infusion related reactions (IRR) being the most frequently reported adverse event (regardless of causality), the majority of which were Grade 1 or 2 in severity. Only 3 Grade 3 or 4 adverse events were observed in > 5% of patients: neutropenia (11%), anemia (11%), and IRR (7%). Adverse events were manageable with only 7% of CLL patients (3/44) discontinuing from the study due to an adverse event: 1 diarrhea (attributed to ibrutinib) and 2 non-related adverse events. Overall, aside from day 1 IRR, the addition of TG-1101 to ibrutinib did not appear to alter the safety and tolerability profile of ibrutinib monotherapy.
Clinical Activity of TG-1101 + ibrutinib
Of the 44 CLL patients treated, 40 were evaluable for response. The 4 patients who were not evaluable included 2 who discontinued due to an adverse event and 2 who withdrew consent, in each case, prior to a first efficacy assessment. Of the 20 CLL patients with previously treated high-risk disease, the patient population we are currently studying in our Phase 3 GENUINE study, 95% (19/20) achieved an objective response with 20% achieving MRD negativity and/or a CR or an unconfirmed CR (pending bone marrow confirmation) as per the iwCLL (Hallek 2008). Additionally, disease response improved for the high-risk CLL patients from a median 64% nodal reduction by month 3 to a median 85% nodal reduction by month 6.
Amongst all 40 CLL patients evaluable for efficacy, 88% (35/40) achieved an objective response per the iwCLL (Hallek 2008) criteria and 4 patients, or an additional 10%, achieved nodal reductions ranging from 20%-55%, without disease progression.
TG-1101 also appeared to abrogate ibrutinib related lymphocytosis with patients experiencing a median 75% reduction in their absolute lymphocyte count (ALC) by the end of month 3 following initiation of combination therapy and 70% of patients achieving normal ALC ranges (< 4,000/uL) by month 6.
ADDITIONAL ICML MEETING PRESENTATIONS
In addition to the TG-1101 + ibrutinib data, the following data, which was presented previously at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper), was presented at the 13th International Congress on Malignant Lymphoma (ICML) meeting:
· Single agent TGR-1202 in patients with relapsed or refractory CLL, NHL or other B-cell Malignancies: Oral Presentation (Owen A. O’Connor, MD, PhD)
· Combination of TG-1101 + TGR-1202 (the Company’s "1303" combination) in patients with relapsed/refractory NHL and high-risk CLL: Poster Presentation (Matt Lunning, DO)
· Chemo-free triplet combination of TG-1101 + TGR-1202 + ibrutinib in patients with B-cell malignancies: Oral Presentation (Loretta Nastoupil, MD)
A copy of all data presentations from the ICML Lugano meeting can be found at View Source
ABOUT THE GENUINE PHASE 3 TRIAL (TG-1101 + IBRUTINIB)
The Phase 3 trial, the "GENUINE" trial, evaluating TG-1101 (ublituximab) in combination with ibrutinib compared to ibrutinib alone for the treatment of patients with previously treated high-risk CLL is now open in over 120 centers across the US and is actively enrolling patients. The trial is being conducted under Special Protocol Assessment (SPA) which provides agreement that the Phase 3 trial design adequately addresses objectives that would support the regulatory submission for drug approval.
The GENUINE trial will enroll approximately 330 patients, with approximately the first two-thirds of the patients included in the ORR assessment. As per the SPA, the Company plans to use the ORR data from the trial as the basis for submission of a Biologics License Application (BLA) for accelerated approval for TG-1101. All patients will then be followed for progression free survival (PFS) assessment, which is designed to support full approval.
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Varian to Equip Inova With Integrated Technology for Radiotherapy, Radiosurgery, and Informatics
On June 18, 2015 Varian Medical Systems reported that it has entered into a multi-year agreement with Inova to be its exclusive supplier of advanced technology for image-guided, high-precision radiotherapy and radiosurgery (Press release, InfiMed, JUN 18, 2015, View Source [SID:1234505459]). Inova, a not-for-profit healthcare system operating five hospitals in Northern Virginia, will also install Varian software across its sites, as part of a long-term plan to create an integrated informatics system and to unify cancer care across its network.
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Under the agreement, Inova will acquire multiple Varian TrueBeam radiotherapy/ radiosurgery systems over nine years, with initial replacements at Inova’s Alexandria and Loudoun Hospitals. TrueBeam technology offers clinicians tremendous versatility in choosing and administering different types of radiation treatment for each patient as appropriate, from intensity-modulated radiotherapy to stereotactic radiosurgery. These treatments can be delivered with greater time efficiency—and hence cost effectiveness—than is possible with many other radiotherapy systems.
Inova will also expand its deployment of Varian’s ARIA information management and Eclipse treatment planning software, currently in use at two of the five sites, across the Inova network, and add Varian’s new InSightive software for data analytics.
"We have been managing radiation oncology departments at two of our sites using Varian software for some time," said says Gopal K. Bajaj, MD, Chairman and Medical Director of Radiation Oncology, Inova. "We will replace competitive solutions at the other sites in order to unify cancer care across the system. We like the fact that ARIA is a comprehensive system that consolidates all treatment data in a single database. It dovetails with our plans to integrate all of our cancer treatment services in support of better care coordination and closer collaboration among clinical team members."
Inova will also deploy Varian’s InSightive software for data analytics, which will enable clinicians and administrators to mine the enormous amount of data housed within the ARIA oncology information system database.
"ARIA is a robust practice management system and electronic medical record with a tremendous amount of information that Inova can mine and analyze to enhance the quality of care and the efficiency of its clinical operations," says Sukhveer Singh, vice president of Varian’s Oncology Continuum Solutions. "ARIA includes many interfaces for importing data from other hospital information systems, resulting in a very rich resource. InSightive Analytics provides access to this data, making it visible and useful."
"Our partnership with Varian will help as we create an integrated healthcare delivery system that uses knowledge-based approaches for the optimal benefit of patients," adds Donald Trump, MD, CEO of the Inova Dwight and Martha Schar Cancer Institute. "We will study the data from cancer patients across our network, including detailed information regarding patient characteristics as well from a detailed study of patients’ tumor tissue and their own genetic makeup, ultimately to analyze why different patients react differently to the same treatments. Varian’s ARIA and Insightive informatics will help us aggregate and analyze that data, and tease out actionable information for the benefit of our patients."
The total value of the multi-year agreement is estimated at $25 million inclusive of products and services, such as turnkey hardware and software support. Varian booked approximately $4 million of this amount during the third quarter of fiscal year 2015. The remainder of the order will be booked in accordance with the company’s policies over the term of the agreement.