Hepatitis C MK-5172:Merck Will Initiate all-oral, interferon-free combination

Merck Will Initiate Interferon-Free Phase II Clinical Trials for MK-5172, an Investigational, Once-Daily, Oral Treatment for Chronic Hepatitis C Virus

Friday, November 2, 2012 2:00 pm EDT

"For more than 30 years, Merck has been leading innovation in viral hepatitis. The science is advancing rapidly, and we recognize that future HCV treatment regimens will not include interferon,"

WHITEHOUSE STATION, N.J.--Today, Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced plans to initiate two new clinical trials with MK-5172, its investigational, once-daily, oral HCV NS3/4A protease inhibitor for the treatment of chronic hepatitis C (HCV) infection. The trials are designed to assess the efficacy and safety of MK-5172 in all-oral, interferon-free combination regimens in non-cirrhotic, treatment-naïve patients with chronic HCV genotype 1 infection.

“For more than 30 years, Merck has been leading innovation in viral hepatitis. The science is advancing rapidly, and we recognize that future HCV treatment regimens will not include interferon," said Roger Pomerantz, MD, FACP, senior vice president and Global Franchise Head for Infectious Diseases, Merck Research Laboratories. "The start of these new studies is the next step in our efforts to develop novel therapeutic regimens for the treatment of chronic hepatitis C. We look forward to evaluating the potential role of MK-5172 and our other earlier pipeline candidates for chronic HCV as part of our continuing commitment to improving patient care.”

The first clinical trial will evaluate a 12-week regimen containing MK-5172, MK-8742, an oral NS5A inhibitor in Phase I development, and ribavirin in non-cirrhotic treatment-naïve patients with HCV genotype 1 infection. The second clinical trial will evaluate 12- and 24-week regimens of MK-5172 in combination with ribavirin in non-cirrhotic treatment-naïve patients with HCV genotype 1 infection with an IL-28 CC genotype. More information is available at http://clinicaltrials.gov using identifiers, NCT01717326 and NCT01716156, respectively.

About MK-5172

MK-5172 is an investigational, once-daily, oral HCV NS3/4A protease inhibitor currently in Phase II development that has demonstrated potent in vitro antiviral activity. Early data on MK-5172 has shown a broad HCV genotypic activity spectrum and in vitro activity against genotype 1a and 1b viral variants that have been associated with resistance to other HCV protease inhibitors, including those in development. Given the clinical experience of MK-5172 to date, including its potentially high barrier to resistance and antiviral activity across HCV genotypes, Merck will evaluate MK-5172 in treatment regimens in a broad spectrum of patients with chronic HCV infection.

Merck's Global Commitment to Advancing Hepatitis Therapy

Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies for our marketed and investigational medicines for the treatment of chronic HCV, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United Statesand Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger

between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

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Liver cirrhosis deaths double in last 15 years

The Irish Times - Friday, November 2, 2012

 

KITTY HOLLAND

 

LEVELS OF mortality from cirrhosis of the liver have doubled in the last 15 years as a “direct result of alcohol consumption”, a leading consultant on gastroenterology has said.

Prof Frank Murray, chairman of the alcohol policy group at the Royal College of Physicians of Ireland, also said women were far less accurate than men in estimating how many units of alcohol they consumed, because so many women drank wine.

He said while most men correctly estimated there were two units of alcohol in a pint of beer and so “know where they stand”, most people thought there were about six units in a bottle of wine.
“In fact, in a 750 ml bottle of wine at 13 per cent [alcohol], there are 10 units. You should be getting 10 glasses from a bottle of wine if there is to be one unit per glass.”

He was addressing a conference calling for a minimum price per gram of alcohol. The event was hosted by Alcohol Action Ireland and backed by 27 charities and medical and community organisations. He said the policy group had been established recently as he and colleagues were “distressed and upset at the damage alcohol is doing to people and families and the huge burden of alcohol to our health and our economy”.

Two things were necessary to address this: increase the price of alcohol and reduce its availability.
The conference also heard from Alex White, Minister of State for Health with responsibility for the Substance Misuse Strategy, who said the strategy would be brought to Cabinet “within weeks . . . absolutely before Christmas”.

Mr White’s predecessor as minister of state, Róisín Shortall, had championed radical measures to address alcohol abuse, including minimum pricing, an end to alcohol sponsorship of sports and other cultural events by 2016 and tough regulations on advertising, which she wanted in the strategy.
Mr White said the issues were “complex” and he was “working hard on this”. He added he had not met the drinks industry and did not expect to.

Prof Murray, a consultant gastroenterologist at Beaumont Hospital in Dublin, said the number of people dying as a result of cirrhosis of the liver had increased from 3.6 per 100,000 people in 1996 to 7.2 per in 2010. “That is as a direct result of alcohol consumption. Mortality due to liver disease has doubled, just as there has been a significant increase in alcohol consumption here,” he said.

He said once a person was hospitalised for liver damage their prognosis was to live for little more than a year to 18 months more. “They are getting younger and the gender imbalance between men and women is disappearing.”

http://www.irishtimes.com/newspaper/ireland/2012/1102/1224326035488.html

Hepatitis C-Why IL28B Genotype Remains Important With DAA Regimens

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Why IL28B Genotype Remains Important With DAA Regimens

Raymond T. Chung MD - 11/1/2012
More from this author

One of the most interesting questions attending the remarkable pace of new therapies for patients with chronic hepatitis C is to what extent  IL28B genotype plays a role in management—both now and in the future.

IL28B: Still Important With PI Therapy
How do I currently use IL28B genotype in my practice? In the era of peginterferon/ribavirin plus protease inhibitor therapy, IL28B can be used to provide an increment of additional data that may assist with decision making. For the patient who needs to be treated (advanced fibrosis) or who really wants to be treated, I will not be deterred from starting therapy, so the test has limited value. On the other hand, for the patient with more limited disease in whom we could justifiably defer therapy, the finding of a CC genotype may persuade the patient toward giving treatment a try, particularly given the high likelihood of being able to abbreviate treatment to 24 weeks. If it’s clear that the patient has no inclination to consider interferon-containing therapy, then again the test has little value.

IL28B With Investigational Therapies
Given the postulated mechanisms of direct-acting agents (DAAs)—offering a stranglehold on virus replication by means of blocking enzymes or proteins that contribute to the replication machinery—the use of DAAs should “level the playing field” by halting replication until it’s extinguished. Under this scenario, we might then expect the contribution of IL28B genotype to be rendered either irrelevant or minimally relevant, given that it was discovered due to its relationship with interferon responsiveness. However, in recent phase II DAA studies, IL28B status still mattered in predicting outcome in genotype 1 patients being treated with interferon-free regimens. I found this to be somewhat unexpected but quite revealing about the role of this polymorphism in dictating outcome.

Contribution of HCV Subtype
How might IL28B be contributing to success under these circumstances? Let’s drill down somewhat deeper. In SOUND-C2, a study of the combination of a protease inhibitor plus nonnucleoside polymerase inhibitor with or without ribavirin, it appeared that in subtype 1b patients, responsiveness was excellent across the board, regardless IL28B status. By contrast, those subtype 1a patients with non-CC IL28B genotypes did poorly compared with those with the CC genotype who performed as well as the 1b subjects. This suggests to me that genotype 1 may need to be cleaved further into 1a/1b subtype distinctions for future clinical trials, and I can envision that DAA regimens may even be tailored to HCV subtype. In current practice, we routinely obtain subtype information with our genotype assays, so no additional information generally needs to be requested. However, subtype has less bearing presently on the decision to treat with current regimens, since overall SVR rates with these regimens are not terrifically different between subtypes.

The findings also suggest that HCV subtype 1a is an inherently more difficult-to-treat virus and that the right innate immune “equipment”—in this case, represented by IL28B genotype—is essential to maximize response for this group of patients. These data further imply to me that IL28B status does matter even in the absence of exogenous interferon. In the case of a virus with a low barrier to resistance development, such as HCV subtype 1a, the strength of the innate response coupled with antiviral therapy becomes critical. This might be reflected in an enhanced ability to respond to locally produced interferon and to minimize breakthrough of resistant viral variants. By contrast, in the case of HCV subtype 1b, where there is a generally higher barrier to virally encoded resistance, the DAA regimen alone may suffice, given the lower hurdle presented to the regimen. 

Of course, these hypotheses are nothing more than that until we understand more precisely how IL28B genotype functionally produces its phenotype. Until then, we are left stratifying for subtype and IL28B in upcoming trials. Of course, the development of regimens that present ever higher barriers to resistance, including those that contain nucleotide polymerase inhibitors, may overcome these concerns at the end of the day. 

Your Thoughts
How about you? Are IL28B testing and HCV subtyping an important part of your practice workup when making decisions about HCV therapy? Do you see this changing in the future?

Raymond T. Chung, MD, is Director of Hepatology, Vice Chief of Gastroenterology, Massachusetts General Hospital and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts. 

Dr. Chung has disclosed that he has received funds for research support from Gilead Sciences, Mass Biological, Pfizer, and Romark.

Topics: HCV

Hepatitis C-Avoiding Missteps When Evaluating New HCV Trial Data

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Avoiding Missteps When Evaluating New HCV Trial Data

Graham R. Foster FRCP, PhD - 10/30/2012 More from this author

For the last 20 years, I have evaluated treatments for chronic hepatitis C by studying results from randomized, controlled clinical trials. I hunt for the “intent-to-treat” (ITT) sustained virologic response (SVR) rates and use these to compare the different regimens. Using this approach, my practice has matured from a fixed-dose, fixed-term regimen for everyone to nuanced therapy based on genotype and early virologic response. Latterly, I have introduced the protease inhibitors for patients with genotype 1 HCV.

ITT vs Per Protocol SVR
I believe that SVR is the most important outcome from therapy, as we know that patients who achieve SVR almost never relapse and have long-term benefits. The ITT analysis is important as it assesses adverse effects and withdrawals as well as the efficacy of the drug. Take, for example, a hypothetical drug that has terrible adverse effects and kills 9 out of 10 patients but cures the other 1. By ITT analysis, its problems are obvious (10% of patients achieve an SVR) but by “per protocol” analysis—where only patients who complete therapy are evaluated—the drug has an efficacy of 100%. Clearly, the per protocol analysis is far from ideal.

Rethinking ITT
As we move to an era of interferon-free potent antivirals, I am beginning to question the value of the ITT analysis. At the forthcoming AASLD meeting, we will see new data on combinations of direct-acting antivirals. I expect exciting data with very high cure rates. I suspect that it will be difficult to compare the various drugs as, for many combinations, the final ITT SVR will be heavily influenced by patient withdrawals. Take, for example, a hypothetical drug where every patient is cured but 10% of the patients fail to attend for their final blood test; by ITT analysis, the drug has a success rate of 90%. Contrast this with a second hypothetical drug that cures 95% of patients but where only reliable patients are enrolled and are then hunted down by an army of private detectives. If the investigators identify all the patients, then this inferior drug has an SVR of 95% and appears the superior molecule.

These issues will become less important as we move into large clinical trials where the numbers of patients are sufficient to dilute out the effects of poor attendance. However, in the current era of small phase II studies, these issues will play a major role.

As a result, I now wonder if we should shift our attention from ITT to per protocol analysis when evaluating early-phase studies. But the dangers of a per protocol analysis are that tolerability issues may be masked—a drug with adverse effects where patients withdraw from therapy can hide those deficiencies behind a non-ITT analysis.

Reading Between the Lines
On balance, I believe that the ITT SVR analysis is still the best way to compare drugs but I will be looking very carefully at the dropout rates and I will be studying with great care the withdrawn for adverse event and the failed to attend rates in studies presented at AASLD. Only when I have considered all 3 metrics will I reach my decision on the promise of the new regimen. For our patients struggling to cope with the deluge of new data, invariably spun into the most promising strands, it will be important to draw their attention to the many factors that determine the outcome of a clinical trial.

Your Thoughts
Tell me your thoughts. Do you put more value in ITT or per protocol analysis when interpreting and comparing results from small clinical trials of direct-acting antivirals? How do you help your patients wade through the data and interpret the results?

Graham R. Foster, FRCP, PhD, is Professor of Hepatology, The Liver Unit, and Consultant Hepatologist, Queen Marys University of London, London, United Kingdom.

Dr. Foster has disclosed that he has received consulting fees, fees for non-CME services, and funds for research support from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, and Roche and has served on the safety board for Idenix.

Topics: HCV

FDA Hepatitis Update - Victrelis (boceprevir) labeling update

FRIDAY, NOVEMBER 2, 2012

FDA Hepatitis Update - Victrelis (boceprevir) labeling update

On November 2, 2012, the Victrelis (boceprevir) package insert and Medication Guide was updated to include postmarketing information about serious acute hypersensitivity reactions observed during boceprevir, peginterferon and ribavirin combination therapy. The following sections of the package insert were updated.

A new contraindication was added to section 4:
Patients with a history of a hypersensitivity reaction to boceprevir

Section 5.4 Hypersensitivity was added to Warnings and Precautions to include the following:

Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted [see Contraindications (4) and Adverse Reactions (6.2)].

Section 6.2 Postmarketing Experience was added to Adverse Reactions to include the following:

The following adverse reactions have been identified during post-approval use of VICTRELIS in combination with peginterferon alfa and ribavirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: mouth ulceration, stomatitis
Skin and Subcutaneous Tissue Disorders: angioedema, urticaria [see Warnings and Precautions (5.4)]; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma

Section 17.4 Hypersensitivity was added to Patient Counseling Information to include the following:

Patients should be informed that serious acute hypersensitivity reactions have been observed during combination therapy with VICTRELIS, peginterferon alfa, and ribavirin therapy [see Contraindications (4) and Warnings and Precautions (5.4)]. If symptoms of acute hypersensitivity reactions (e.g., itching; hives; swelling of the face, eyes, lips, tongue, or throat; trouble breathing or swallowing) occur, patients should seek medical advice promptly.

The Medication Guide (MG) was also updated to let patients know they should not take Victrelis if they have had an allergic reaction to boceprevir or any of the ingredients in Victrelis. Also the MG was updated to inform patients that a possible side effect of Victrelis is serious allergic reactions and may become severe requiring treatment in a hospital. If patients experience itching, hives, swelling of face, eyes, lips, tongue or throat or have trouble breathing or swallowing they should tell their healthcare provider immediately.

Victrelis is a protease inhibitor for the treatment of HCV infection and manufactured by Schering Corporation, a subsidiary of Merck & Co.

The complete, revised label will be posted soon at Drugs@FDA
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Posted on 11/02/12, 05:42 pm

India revokes patent on Roche's Pegasys

November 02, 2012

India revokes patent on Roche's Pegasys

Last Updated:November 02, 2012 10:43

India's Intellectual Property Appellate Board (IPAB) revoked a patent Friday on Roche's hepatitis C drug Pegasys (peginterferon alfa-2a) on the grounds that it didn’t demonstrate inventiveness. The patent had been issued in 2006 and was the first to be granted under reforms introduced in the country a year earlier.

The original patent was challenged by patient group Sankalp Rehabilitation Trust in 2007 on the grounds that the pegylation process was known. Both Sankalp Rehabilitation Trust's post-grant opposition challenge and another made by Wockhardt were rejected by the Indian Patent Office, although the patient group appealed the decision.

In its ruling, the IPAB determined that "in the end, the invention is held to be obvious. The appeal is allowed and the grant of Patent No.198952 is set aside." The IPAB added that the technology involved in producing the drug could be easily replicated by anyone skilled in the process.

Pegasys costs around 360 000 rupees ($6700) for six months of treatment. Eldred Tellis, director of Sankalp Rehabilitation Trust, said "we hope that the absence of [a] patent barrier will spur generic competition to bring down the price of this much-needed drug."

This is the second patent setback that Roche has faced in India recently, after the Delhi High Court in September dismissed a patent infringement lawsuit filed by the company against Cipla over a generic version of Tarceva (erlotinib).

Reference Articles
Patent on Roche Hepatitis C drug revoked - (Business Line)
IPAB sets aside Indian patent for Roche's Pegasys - (Business Standard)
Board revokes patent on Roche hepatitis drug - (NDTV)
Intellectual Property Appellate Board revokes patent on Roche's Pegasys; victory for Hepatitis-C patients - (The Times of India)
IPAB invalidates patent on Roche hepatitis C drug Pegasys - (livemint.com)

http://www.firstwordplus.com/Fws.do?src=corp_site&articleid=5886A58FDCB94FB8AEFEC25BA5743EA9

Candidiasis and other oral mucosal lesions during and after interferon therapy for HCV-related chronic liver diseases

Research article

Candidiasis and other oral mucosal lesions during and after interferon therapy for HCV-related chronic liver diseases

Yumiko Nagao, Kouji Hashimoto and Michio Sata

BMC Gastroenterology 2012, 12:155 doi:10.1186/1471-230X-12-155
Published: 2 November 2012

Download complete article available as a provisional PDF

Abstract (provisional)
Background

Oral lichen planus (OLP) is seen frequently in patients with hepatitis C virus (HCV) infection. The aim of this study was to evaluate the occurrence of oral candidiasis, other mucosal lesions, and xerostomia during interferon (IFN) therapy for HCV infection.

Methods

Of 124 patients with HCV-infected liver diseases treated with IFN therapy in our hospital, 14 (mean age 56.00 +/- 12.94 years) who attended to receive administration of IFN once a week were identified and examined for Candida infection and other oral lesions and for the measurement of salivary flow. Serological assays also were carried out.

Results

Cultures of Candida from the tongue surfaces were positive in 7 (50.0%) of the 14 patients with HCV infection at least once during IFN therapy. C. albicans was the most common species isolated. The incidence of Candida during treatment with IFN did not increase above that before treatment. Additional oral mucosal lesions were observed in 50.0% (7/14) of patients: OLP in three (21.4%), angular cheilitis in three (21.4%) and recurrent aphthous stomatitis in one (7.1%). OLP occurred in one patient before treatment with IFN, in one during treatment and in one at the end of treatment. 85.7% of the oral lesions were treated with topical steroids.

We compared the characteristics of the 7 patients in whom Candida was detected at least once during IFN therapy (group 1) and the 7 patients in whom Candida was not detected during IFN therapy (group 2). The prevalence of oral mucosal lesions (P=0.0075) and incidence of external use of steroids (P=0.0308) in group 1 were significantly higher than in group 2.

The average body weight of group 1 decreased significantly compared to group 2 (P=0.0088). Salivary flow decreased in all subjects throughout the course of IFN treatment and returned at 6th months after the end of treatment. In group 1, the level of albumin at the beginning of the 6th month of IFN administration was lower than in group 2 (P=0.0550). According to multivariate analysis, one factor, the presence of oral mucosal lesions, was associated with the detection of Candida. The adjusted odds ratio for the factor was 36.00 (95% confidence interval 2.68-1485.94).

Conclusion

We should pay more attention to oral candidiasis as well as other oral mucosal lesions, in patients with weight loss during IFN treatment.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Hepatitis C - Vertex sinks as Incivek sales decline further

AP News

Vertex sinks as Incivek sales decline further

NEW YORK (AP) — Shares of Vertex Pharmaceuticals Inc. slumped Friday after the company said sales of its hepatitis C pill Incivek continued to decline in the third quarter.

THE SPARK: Vertex reported its third-quarter results after the markets closed on Thursday. They fell far short of Wall Street expectations, as Vertex said it lost $57.5 million, or 27 cents per share. Excluding a variety of one-time costs, the company said net income totaled 13 cents per share. Revenue fell 49 percent, to $336 million.

Analysts expected net income of 20 cents per share and revenue of $375.7 million, according to FactSet.

Vertex reported $254 million in U.S. sales of Incivek and $49 million in sales of its cystic fibrosis drug Kalydeco. It also reported $20 million in royalty payments from European sales of Incivek by its partner Johnson & Johnson.

A year ago the company received a $200 million payment after European Union regulators approved Incivek and Johnson & Johnson began selling the drug.

THE BIG PICTURE: The Food and Drug Administration approved Incivek in May 2011, making it one of the first new hepatitis C drugs to reach the market in decades. Analysts expected annual sales of the pill to be in the billions of dollars. However revenue has stalled, partly because research into hepatitis C drugs has accelerated so quickly that patients are holding off on starting treatment as they wait for newer products to be approved.

Incivek is approved in combination with two standard drugs: ribavirin, which is a pill, and Interferon, which is given by injection. Several companies are studying hepatitis C regimens that don't include Interferon. Interferon has been a staple of hepatitis C therapy for years, but it can cause flu-like symptoms that last for months.

Compared to a year ago, Incivek sales dropped 39 percent. Quarterly sales peaked at $456.8 million in the fourth quarter of 2011, and then declined to $356.9 million in the first quarter of 2012, $327.7 million in the second quarter and $254.3 million in the latest quarter.

In July the Cambridge, Mass., company lowered its annual revenue forecast for Incivek to a range of $1.1 billion to $1.25 billion from $1.5 billion to $1.7 billion. Vertex maintained that forecast on Wednesday. That estimate suggests the company expects fourth-quarter sales will be anywhere from $161.1 million to $311.1 million.

THE ANALYSIS: Cowen & Co. analyst Phil Nadeau said sales of Incivek and Kalydeco were both well below Wall Street estimates, as analysts expected about $267 million in Incivek revenue and $57 million from Kalydeco. Nadeau said Vertex will need to successfully develop an all-oral hepatitis C regimen to stay competitive.

SHARE ACTION: Shares of Vertex lost $5.47, or 10.8 percent, to close at $45.01. The stock is down 24.3 percent since Oct. 5.

http://www.businessweek.com/ap/2012-11-02/vertex-sinks-as-incivek-sales-decline-further