On May 19, 2016 Oncolytics Biotech Inc. ("Oncolytics" or the "Company") (TSX: ONC) (OTCQX: ONCYF) (FRA: ONY) reported preliminary data from a randomized Phase II clinical trial of its lead product, REOLYSIN, in combination with FOLFOX-6 and bevacizumab (Avastin) in patients with advanced or metastatic colorectal cancer (IND 210) (Press release, Oncolytics Biotech, MAY 19, 2016, View Source [SID:1234512601]). The study is being sponsored by the National Cancer Institute of Canada ("NCIC") Clinical Trials Group ("CTG") at Queen’s University in Kingston, Ontario. The preliminary analysis includes data from an NCIC study summary report, and follows the release of an abstract to be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Annual Meeting, which will run from June 3-7, 2016 in Chicago, IL.

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Highlights


Objective Response Rate

(%)

Progression Free Survival
(months)

Median Overall Survival
(months)1

Test

Control

Test

Control

Test

Control

Female
Patients

63.2 (n=19)

23.8 (n=21)

7.43 (n=19)

8.08 (n=21)

19.3 (n=19)

14.5 (n=21)

Male
Patients

46.9 (n=32)

41.9 (n=31)

7.33 (n=32)

9.26 (n=31)

15.4 (n=32)

15.7 (n=31)

Overall



52.9 (n=51)

34.6 (n=52)

7.33 (n=51)

9.13 (n=52)

15.57 (n=51)

15.21(n=52)

Source: Report of Statistical Analysis for NCIC CTG Protocol Number IND.210

1 This was an interim analysis, as 62 (60.2%) patients out of a total of 103 patients were alive at the time of data cut-off. All of the median survivals noted could change at final analysis.


The abstract reported that the overall test arm had an objective response rate of 52.9% (n=51) versus 34.6% (n=52) in the control arm (p=0.06). The Company conducted a pre-planned analysis of patient responses by gender, as specified in the study protocol. The male patients in the test arm had an objective response rate of 46.9% (n=32) versus 41.9% (n=31) in the control arm (p=0.6747). The female patients in the test arm had an objective response rate of 63.2% (n=19) versus 23.8% (n=21) in the control arm (p=0.0054).

"We are encouraged by these preliminary data from the NCIC study suggesting that the inclusion of REOLYSIN in the treatment combination may have a profound impact on response rates for women with colorectal cancer," said Dr. Brad Thompson, President and CEO of Oncolytics Biotech Inc. "Various immune-based therapies have demonstrated a profile where patients derive tumour response and overall survival benefit with limited or no impact on progression free survival. REOLYSIN, as an oncolytic virotherapy, appears to be demonstrating a similar profile in female patients with advanced or metatstatic colorectal cancer. This is a further example of our sponsored randomized Phase II program identifying specific indications, patient populations and endpoints for examination in future trials to be conducted by Oncolytics. Building on these findings, we intend to conduct a study in female metastatic colorectal cancer patients using this treatment regimen combined with a checkpoint inhibitor."

Analysis of Patients with Liver Metastases
The Company conducted an additional analysis of all those patients (both male and female) with liver metastases, with or without metastases to other sites. For patients who had metastases to the liver, those treated with REOLYSIN had objective tumour response rates of 55% (n=40), versus 28.6% (n=42) for those who did not receive REOLYSIN (p=0.0077). For the patients who did not have liver metastases (21 of the 103 patients), there was no statistically significant difference in response rate (five of 11 in the test arm, versus 6 of 10 in the control arm).

"When cancer spreads to the liver, treatment becomes more difficult, leading to a drop in response and survival rates," said Dr. Thompson. "Based on these randomized data, we believe that REOLYSIN may have particular utility in those patients who have late-stage colorectal cancer with liver metastases."

Colorectal Cancer Clinical Program: Next Steps
Based on these results, Oncolytics has filed for a U.S. Phase II run–in study examining the treatment of female patients with metastatic colorectal cancer with FOLFOX-6, bevacizumab, REOLYSIN, and the checkpoint inhibitor pembrolizumab (KEYTRUDA). Subject to confirmation of overall responses, liver metastases-specific responses, and immune marker analyses, the Company intends to conduct a registration study using the modified therapeutic regime including pembrolizumab. This will be the second clinical study that Oncolytics is conducting with the addition of a checkpoint inhibitor. Oncolytics is currently conducting a standard of care, REOLYSIN, and pembrolizumab combination clinical study in patients with advanced pancreatic cancer.

Safety
The abstract also noted that, of grade 3 or higher adverse events, there was less abdominal pain (3.5% versus 17.3%, p=0.02), more hypertension (26.3% versus 3.8%, p=0.001) and more proteinuria (22.8% versus 1.9%, p=0.001) in the test arm than the control arm.

About IND 210
The study is an open-label, multi-institution, randomized, non-blinded, Phase 2 clinical study of patients with advanced or metastatic colorectal cancer. Patients were randomized to receive either REOLYSIN FOLFOX-6, bevacizumab and REOLYSIN (test arm) or FOLFOX-6 and bevacizumab alone (control arm). Patients in both arms received FOLFOX-6 and bevacizumab every 14 days, with either REOLYSIN (test arm) or placebo (control arm) administered on days one through five of cycles 1, 2, 4, 6, 8 and alternate cycles thereafter. Approximately 50 response-evaluable patients were enrolled in each arm, after a six- to nine-patient safety run-in.

The primary endpoint of the trial is progression free survival. Secondary endpoints include changes in CEA levels, objective response rate, overall survival, quality of life, and the tolerability and toxicity of the treatment combination. Other objectives include the measurement of molecular factors which may be prognostic or predictive of response.

On May 19, 2016 Merck, a leading science and technology company, reported significant increases in sales and earnings for the first quarter of 2016. While the acquisition of Sigma-Aldrich played a major role, the business also grew organically (Press release, Merck KGaA, MAY 19, 2016, View Source [SID:1234512594]).

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"We started off 2016 well and have grown profitably. The integration of Sigma-Aldrich is progressing quickly and we are also right on target with our debt reduction," said Stefan Oschmann, Chairman of the Executive Board, in his presentation of the quarterly figures for the first time as Merck CEO. "For 2016 we continue to expect slight organic growth for the Merck Group," said Oschmann.
Group net sales increased in the first quarter of 2016 by 20.5% to € 3.7 billion (Q1 2015: € 3.0 billion). Organically, Group sales rose by 4.7% thanks to the strong operating performance of the Healthcare and Life Science business sectors. Sales increased by 19.8% due to acquisitions, which was primarily attributable to the purchase of Sigma-Aldrich. The acquisition closed in November 2015 and the business has now been consolidated for a full quarter for the first time. Merck experienced currency headwinds of -4.0%, which were mainly due to Latin American currencies. In the first quarter, Merck grew organically in all reporting regions, especially in North America and Latin America. Due to the acquisition of Sigma-Aldrich, the share of sales attributable to North America rose considerably to 26% (Q1 2015: 20%). Accounting for 33% of Group sales, Europe was our largest region.

EBITDA pre exceptionals, the key earnings indicator of the Group, rose by 27.0% to € 1.1 billion (Q1 2015: € 853 million) thanks to the good operational performance of Healthcare and Life Science as well as the Sigma-Aldrich acquisition. Group EBIT rose by 76.8% to € 849 million (Q1 2015: € 480 million). This includes the one-time effect of the gain of around € 325 million from the sale of Kuvan, which was announced in October 2015. Merck’s net income more than doubled in the first three months of the year to € 591 million (Q1 2015: € 282 million). Earnings per share pre exceptionals rose in the first quarter of 2016 by 37.5% to € 1.54 (Q1 2015: € 1.12).

Merck has started deleveraging and reduced its net financial debt in the first quarter by € 581 million to € 12.1 billion. This follows the strong increase in debt at the end of 2015 due to the acquisition of Sigma-Aldrich. As with major acquisitions in the past, Merck is aiming to rapidly and extensively reduce its debt. Merck had 50,259employees worldwide on March 31, 2016.

Healthcare posts good organic growth
The Healthcare business sector achieved good organic sales growth of 5.4% in the first quarter of 2016, growing organically in all regions except for Europe. This was canceled out by negative foreign exchange effects of -6.8%. In addition, the return of the rights to Kuvan to BioMarin Pharmaceuticals lowered sales by -1.0%. Consequently, Healthcare net sales decreased by -2.4% in the first quarter of 2016 to € 1.6 billion (Q1 2015: € 1.7 billion).

Rebif, which is used to treat relapsing-remitting multiple sclerosis, sustained a slight organic sales decline of only -1.5% in the first quarter of 2016 despite increasing competitive pressure from oral formulations. Amid slightly negative currency effects of -0.2%, Rebif sales amounted to € 422 billion (Q1 2015: € 430 million). Sales of the oncology drug Erbitux grew organically by 3.8%. Including currency headwinds of -3.2%, Erbitux sales were stable at € 207 million (Q1 2015: € 205 million). With Gonal-f, the leading recombinant hormone used in the treatment of infertility, Merck achieved strong organic sales growth of 17.0% in the first quarter. Including negative exchange rate effects, sales rose to € 187 million (Q1 2015: € 164 million).

EBITDA pre exceptionals of the Healthcare business sector grew by 10.3% to € 508 million (Q1 2015: € 461 million) thanks to solid organic performance and the end of commission expenses stemming from the co-promotion of Rebif with Pfizer, despite increased R&D spending primarily for the avelumab program in immuno-oncology.

As part of the strategic transfer of products in the Healthcare business sector, as of January 1 we shifted vitamin preparations in India from the Biopharma business to Consumer Health, where they complement the existing business. The annual sales volume of the transferred business is around € 45 million.

Life Science increases profitability both organically and through acquisition
Sales increased in the Life Science business sector in the first quarter of 2016 by 89.3% to € 1.4 billion (Q1 2015: € 738 million). Apart from solid organic growth of 8.9% across all regions, the acquisition of Sigma-Aldrich fueled sales by 81.6% or € 602 million. By contrast, foreign exchange effects only had a minor impact of
-1.3% in the reporting period.

The Process Solutions business area, which markets products and services for the entire pharmaceutical production value chain, generated strong organic sales growth of 15.9%. Applied Solutions, which serves clinical and diagnostic testing laboratories as well as the food and environmental industries, posted an organic sales increase of 3.6%. The Research Solutions business area, which focuses on academia and pharmaceutical research institutions, generated organic sales growth of 2.0%

At € 393 million, EBITDA pre exceptionals of Life Science in the first quarter was more than two times higher than in the year-earlier quarter (Q1 2015: € 184 million). The EBITDA margin pre exceptionals rose to 28.1% (Q1 2015: 25.0%).

Merck is making good progress with the integration of Sigma-Aldrich. "Since completing the acquisition in November, we have added around half of the addressable legacy Merck Millipore portfolio to the industry-leading Sigma-Aldrich e-commerce platform in the United States and 30% in Europe," said Merck CEO Oschmann.

OLED business of Performance Materials is growing further
In the first quarter, net sales of the Performance Materials business sector grew by 0.9% to € 622 million (Q1 2015: € 617 million). This reflects acquisition-related sales increases of 2.7%, which were due to the consolidation of the SAFC Hitech business of Sigma-Aldrich. Organically, sales decreased by -2.4%. This decline in sales was primarily due to the expected destocking by display industry customers.

In the Display Materials business unit, the partly strong growth seen with the innovative liquid crystal technologies such as UB-FFS could not fully offset the volume decline of older liquid crystal technologies as well as destocking by customers. However, Display Materials maintained its market leadership position. The Pigments & Functional Materials business unit delivered moderate organic growth. The Integrated Circuit Materials business unit, which includes the business with materials used to manufacture integrated circuits as well as the SAFC Hitech business from Sigma-Aldrich, generated solid organic sales growth. Within the Performance Materials business sector, the highest growth rates were achieved by the Advanced Technologies business unit. This was primarily due to the expanding business with OLED materials. A new OLED materials production unit in Darmstadt involving an investment of around € 30 million is to be commissioned in the summer to manufacture materials for ultra-modern displays and lighting.

At € 273 million, EBITDA pre exceptionals of Performance Materials was at the previous year’s level (Q1 2015: € 277 million).

Merck confirms and specifies outlook for 2016
Merck has confirmed the qualitative forecast given with the publication of the 2015 Annual Report in March 2016 and specified it. Due to the good business performance in the first quarter, Merck assumes that Group net sales will increase to between € 14.8 billion and € 15.0 billion in 2016 and continues to expect slight organic sales growth. Owing to the acquisition of Sigma-Aldrich, Merck expects a portfolio-related increase in net sales in the low double-digit percentage range. This will be countered by negative foreign exchange effects predicted to range between –3% and –5%, due especially to the continued devaluations of Latin American currencies. The forecast for EBITDA pre exceptionals at Group level in 2016 is between € 4.1 billion and € 4.3 billion. Business free cash flow of the Merck Group is expected to be between € 3.1 billion and € 3.3 billion in 2016. Merck expects earnings per share pre exceptionals of € 5.65 to € 6.00.

Forecast for FY 2016

€ million
Net sales
EBITDA pre exceptionals
Earnings per share pre exceptionals

Merck Group
~14,800 – 15,000
~4,100 – 4,300
€ 5.65 – € 6.00

Healthcare
Slight organic growth, slightly negative portfolio effect due to the divestment of Kuvan
~ 1,800 – 1,900

Life Science
Organic growth in the mid-single-digit percentage range, high double-digit percentage portfolio effect due to the acquisition of Sigma-Aldrich
~1,620 – 1,670

Performance Materials
Organic stable
~ 1,100 – 1,150

Corporate and Other
-400 – -370

Merck Group – Key figures
€ million
Q1 2016
Q1 2015
Change

Net sales
3,665
3,041
20.5%

Operating result (EBIT)
849
480
76.8%

Margin (% of net sales)
23.2%
15.8%

EBITDA
1,282
805
59.1%

Margin (% of net sales)
35.0%
26.5%

EBITDA pre exceptionals
1,084
853
27.0%

Margin (% of net sales)
29.6%
28.0%

Earnings per share (€)
1.36
0.65
> 100.0%

Earnings per share pre exceptionals (€)
1.54
1.12
37.5%

Net income
591
282
>100,0 %

March 31,
2016
Dec. 31,
2015

Net financial debt
12,072
12,654
-4.6%

On May 19, 2016 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported the initiation of a biomarker-selected, multi-arm Phase 1 clinical study in metastatic colorectal, non-small cell lung, and head and neck cancers (Press release, Merrimack, MAY 19, 2016, View Source [SID:1234512581]).

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Merrimack’s first-of-its-kind basket study will use a combination of genetic and nongenetic biomarkers to match patients to appropriate novel combinations of investigational drug regimens based on their cancer’s molecular signature. This approach is expected to enable more than 95 percent of eligible patients to qualify for enrollment to one of the investigational arms of the study. Merrimack utilized its systems biology approach to identify the biomarkers and selection criteria of the study.

"This innovative trial design is a major step towards applying precision medicine in the earliest phases of clinical testing, while also ensuring that virtually every patient that enrolls in the study receives one of the investigational regimens," said Christopher Lieu, M.D., Investigator at the CU Cancer Center and Assistant Professor of Medical Oncology at the University of Colorado School of Medicine. "The difficulty with most basket studies is that they identify their patient population solely on genetic mutations, which often results in a very small percentage of patients qualifying for the investigational therapy. By targeting a combination of genetic markers and frequently activated resistance pathways, the vast majority of biopsied patients will be matched to a biomarker-selected study arm."

Merrimack’s approach to biomarker profiling and subsequent patient assignment builds on the foundation of previous basket studies. This study design has broadened its scope by also identifying molecular features in the tumor and its surrounding environment that are believed to indicate which signaling mechanisms are responsible for tumor growth and drug resistance. By exploring the dynamics of multiple molecular features, and by including multiple combinations of investigational therapies from its oncology pipeline, Merrimack expects to investigate a personalized drug regimen in almost all of the basket trial’s eligible patient population.

"We are committed to implementing precision medicine at every stage of clinical development," said Gavin MacBeath, Ph.D., Merrimack’s Senior Vice President of Translational Medicine. "At Merrimack, our research has shown that most cancers have multiple mechanisms supporting tumor growth and we are developing a number of investigational agents that are designed to block key drivers of tumor growth and resistance. We know enough about the biology of these pathways to prospectively assign patients to the investigational regimen that we believe most closely matches their specific disease. We believe this is the first trial to rationally combine novel regimens based upon specific multi-dimensional characteristics of the patient’s tumor. This unique approach is expected to provide a path forward in developing improved outcomes in difficult to treat patient populations."

All patients enrolling in the study will provide a core needle biopsy, which will be tested for KRAS and NRAS mutations and for expression of two resistance ligands – heregulin (HRG) and insulin-like growth factor 1 (IGF-1). Patients will receive Merrimack’s oligoclonal EGFR (epidermal growth factor receptor) inhibitor, MM-151, in combination with another agent that is intended to target their cancer’s mechanism of resistance to EGFR inhibition. Assignment to one of the four trial arms will be based on the following criteria:

Patients that test positive for HRG will be assigned to Group A and receive MM-151 in combination with seribantumab (MM-121), a fully human antibody designed to block heregulin-driven ErbB3 pro-survival signaling.
Patients that test negative for HRG and positive for activating mutations in either KRAS or NRAS will be assigned to Group B and receive MM-151 in combination with trametinib, a MEK inhibitor (Novartis). This regimen is designed to block signaling both upstream and downstream of RAS mutations.
Patients that test negative for HRG, wild-type for KRAS and NRAS, and positive for IGF-1 will be assigned to Group C and receive MM-151 in combination with istiratumab (MM-141), a bispecific antibody designed to block IGF-1R and ErbB3 pro-survival signaling.
Patients that test negative for both HRG and IGF-1 and wild-type for KRAS and NRAS will be assigned to Group D and receive MM-151 in combination with trametinib. This regimen is designed to block signaling from alternative receptors and to delay potential acquisition of KRAS and NRAS mutations.
MM-151, MM-121 and MM-141 are all wholly owned by Merrimack. Further information on the study will be available on clinicaltrials.gov in the coming weeks (Identifier: NCT02538627).

About MM-151

MM-151 is an oligoclonal therapeutic mixture consisting of three fully-human monoclonal antibodies designed to bind and inhibit signaling of the epidermal growth factor receptor (EGFR). EGFR-mediated signaling promotes the growth and survival of cancer cells and has long been recognized as an important drug target in several types of cancer, including colon, lung, breast, pancreatic, and head and neck cancers. MM-151 has previously been tested in a Phase 1 dose-escalation clinical trial in patients with advanced solid tumors.

About Istiratumab (MM-141)

Istiratumab is a tetravalent bispecific antibody designed to block tumor survival signals by inhibiting IGF-1R and ErbB3 (HER3) signaling. IGF-1R and ErbB3 complexes activate major signaling pathways that allow tumor cells to grow and develop resistance to chemotherapy. Currently, istiratumab is in Phase 2 testing in patients with metastatic pancreatic cancer that have a pre-defined IGF-1 biomarker profile. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation for istiratumab for the treatment of pancreatic cancer.

About Seribantumab (MM-121)

Seribantumab is Merrimack’s wholly owned, fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, seribantumab is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner. Seribantumab has been investigated in multiple Phase 2 and Phase 1 clinical trials covering a broad spectrum of patient populations and drug combinations.