Replies to post #59272 on Biotech Values

[DewDiligence]

NIH Trial Recommends Switching Some Epzicom Patients to Truvada

[Truvada (including use as part of Atripla) has almost cornered the US HIV market for first- and second-line patients (#msg-26915314). The development in this newswire might be the last straw for GSK’s Epzicom, a combination of two older HIV drugs that was already on the verge of irrelevancy in the US and has been rapidly losing share in Europe.]

http://www.reuters.com/article/marketsNews/idUKN2862935220080228

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Thu Feb 28, 2008 6:40pm EST
By Deena Beasley

LOS ANGELES (Reuters) - A safety board has recommended that certain AIDS patients taking part in a study of GlaxoSmithKline Plc's (GSK) Epzicom consider switching to Gilead Sciences Inc's (GILD) Truvada, sending Gilead's shares up about 4 percent on Thursday.

The National Institute of Allergy and Infectious Disease's AIDS Clinical Trials Group, a unit of the National Institutes of Health, is comparing the two drugs in a head-to-head trial involving 1,858 patients.

The unit said on Thursday that an independent Data and Safety Monitoring Board recently found that for patients with high levels of HIV virus, treatment regimens containing Epzicom were less effective at controlling the virus than regimens containing Truvada.

The board also found that patients with high levels of HIV virus treated with Epzicom developed side effects such as body aches and high cholesterol more quickly.

Glaxo said in a statement that the NIH study did not routinely exclude patients at risk for a known reaction with Epzicom, which might have accounted for some adverse events.

The trial recommendation applies to about half the patients being treated with the Glaxo drug and, if translated to real world usage, could mean a 20 percent market share gain for Gilead's Truvada and Atripla, Morgan Stanley analyst Sapna Srivastava said in a research note on Thursday.

Truvada is a pill combining Gilead's Viread and Emtriva, also known as tenofovir and emtricitabine. Atripla is a three-drug pill that also includes Bristol-Myers Squibb Co's Sustiva.

Glaxo's Epzicom combines AIDS drugs Ziagen, or abacavir, and Epivir, also known as lamivudine.

The board said it had no safety concerns regarding Epzicom and recommended that study participants who had lower levels of HIV virus continue their assigned treatment regimen.

"There are an estimated 100,000 patients on Epzicom in the U.S. and Europe, or $1 billion (502,000 pound) opportunity if all patients transition to Truvada," Thomas Weisel analyst Ian Somaiya said in a research note.

Even under a conservative scenario where 20 percent of those patients switched to Truvada by 2010, the analyst said his earnings estimate for Gilead would increase to $3.06 per share from $2.95 per share.

Baird analyst Thomas Russo said the NIH trial recommendation followed an update earlier this month from a Danish observational study that suggested a link between Glaxo's AIDS drugs and increased risk of heart attack.

"These issues could lead doctors to reconsider abacavir-based regimens in favor of regimens based on Gilead's market-leading tenofovir," he said in a research note.

Gilead declined to comment on market share impact. "We think this is an important result ... it reinforces the profile of Truvada," spokeswoman Amy Flood said.

The company's shares gained $1.67, or 3.8 percent, to close at $45.46 on Nasdaq. Shares of Glaxo fell about 1 percent to close at $45.05 on the New York Stock Exchange.
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[DewDiligence]

SGP Initiates Phase-2 Study of Vicriviroc in Treatment-Naïve, R5-Type HIV

[This is the first study of Vicriviroc in the treatment-naïve setting. If it works out, the upside is large (see #msg-28310435 and #msg-26915314), but it will IMO be difficult to show that Vicriviroc+Reyataz is as good as or better than Truvada+Reyataz, which is one of the most common and most effective first-line HIV regimens.]

http://biz.yahoo.com/prnews/080415/nytu004.html

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Tuesday April 15, 8:30 am ET

Novel Nucleoside-Sparing Regimen Designed to Avoid Risk of Toxicity Associated with Nucleoside Class of HIV Drugs

KENILWORTH, N.J., April 15 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP ) today announced that it has initiated a Phase II clinical study with vicriviroc, its investigational CCR5 antagonist, for use in first-line therapy of adult treatment-naive HIV-infected patients with R5-type virus only. Vicriviroc is a next-generation HIV entry inhibitor designed to prevent the virus from infecting CD4 cells by blocking its predominant entry route, the CCR5 co-receptor. Approximately 80-90 percent of treatment-naive patients have virus that uses the CCR5 co-receptor. Vicriviroc also is being studied in two large Phase III clinical studies in treatment-experienced HIV patients, which are ongoing and currently enrolling patients.

The study in treatment-naive patients evaluates the virologic benefit of vicriviroc, administered once-daily as a single 30 mg tablet, in combination with ritonavir-boosted atazanavir, compared to a control group receiving Truvada (emtricitabine and tenofovir disoproxil fumarate) plus ritonavir-boosted atazanavir, which is a currently recommended option for first-line therapy. Atazanavir is a product in the protease inhibitor (PI) class of HIV medications. Truvada is a combination product in the nucleoside reverse transcriptase inhibitor (NRTI) class.

"A nucleoside-sparing vicriviroc regimen for initial treatment may have the added strategic benefit of preserving most products used to create a highly active antiretroviral therapy "cocktail" for later use in patients, while also avoiding the risk of toxicity known to be associated with the nucleoside class," said Joseph C. Gathe, Jr., M.D., F.A.C.P., clinical instructor, department of internal medicine, Baylor College of Medicine, Houston, and lead investigator for the study. "This treatment strategy could also prove beneficial for the growing number of patients who already have primary resistance to NRTIs prior to any treatment."

In previous studies in treatment-experienced HIV-infected patients, vicriviroc in combination with an optimized ritonavir-boosted PI-containing regimen demonstrated potent and sustained viral suppression through 48 weeks of treatment.

The standard of care for treatment-naive HIV-infected individuals is to combine three drugs from two classes to initiate antiretroviral therapy. The combinations characteristically use two NRTIs with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted PI.(6) While these combinations have been demonstrated to be highly effective, long-term tolerance may be limited by the toxicity specifically associated with nucleosides, which can include neuropathy, myopathy, renal toxicity, hepatic steatosis, lactic acidosis, bone marrow suppression, fat atrophy and, with certain agents, increased risk of myocardial infarction.(7-9)

"As a next-generation HIV entry inhibitor, vicriviroc has the potential to benefit a broad range of patients by offering potent and sustained viral suppression, and a single once-daily dose for use in combination with other antiretroviral agents," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "CCR5 antagonists such as vicriviroc have a novel mechanism of action in fighting HIV, and may play a unique role as physicians seek to construct new regimens to meet the specific needs of their patients, whether they are starting treatment or have been treated with several different combinations over a period of time."

About the Phase II Naive Study

This randomized, controlled, open-label study is projected to enroll approximately 200 treatment-naive HIV-infected adult patients at more than 20 sites in North America, Central America, Europe and South Africa. Patients coinfected with hepatitis B or C may be included in the study.

The primary efficacy endpoint of the study is the mean change from baseline in viral load (log10 HIV RNA) at week 48 of treatment. A key secondary efficacy endpoint is the proportion of patients with plasma HIV RNA less than 50 copies/mL at week 48 of treatment.

The study will be conducted in two stages. In the first stage, 80 patients will be randomized (40 per treatment arm) into the study. When the 80 subjects from the first stage have completed 24 weeks of treatment, a formal interim analysis will be conducted and the results presented to an independent Data Safety Monitoring Board (DSMB) to assure the safety of the study participants. The study will be extended to stage 2 based on the results of the 24-week interim analysis; at which time an additional 120 patients (60 per treatment arm) will be enrolled. The final analysis will be conducted at week 48 of treatment for all patients.

Atazanavir boosted by ritonavir was selected for use in this study because it is recommended as an option for first-line therapy in both the International AIDS Society and Department of Health and Human Services guidelines for antiretroviral therapy. Additionally, it has been shown to have a more favorable lipid profile than other drugs in the PI class.

The study is being sponsored by Schering-Plough with support from Bristol-Myers Squibb.

About Vicriviroc Ongoing Phase III Studies in Treatment-Experienced Patients

Schering-Plough is currently enrolling patients in two large global Phase III clinical studies with vicriviroc in adult treatment-experienced HIV-infected patients with R5-type virus only.

The two studies, known as VICTOR-E3 and VICTOR-E4 (Vicriviroc in Combination Treatment with an Optimized Antiretroviral Therapy Regimen in HIV-Infected Treatment-Experienced Subjects), evaluate the virologic benefit of adding vicriviroc 30 mg once daily to an optimized ritonavir-boosted PI-containing background therapy compared to a control group receiving new optimized background therapy alone. The optimized background therapy must include at least two drugs to which the patient's HIV is susceptible. Patients coinfected with hepatitis B or C may be included in these studies and there are no exclusions of commonly prescribed drugs or need for dose adjustments based on the known vicriviroc drug-drug interaction profile. The two studies are currently enrolling approximately 375 patients each at more than 160 sites in North America, Latin America, Europe, Australia and South Africa.
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[DewDiligence]

Notes on US HIV Market from GILD CC

Total US patients on therapy:
530K

Proportion of total on Viread in some form:
68% (up from 64% one year ago)

Proportion of total on Truvada in some form:
31%

Proportion of total on Atripla:
28%

Note: the above figures are for all treatment settings, while the pie chart in #msg-26915314 is for the first-line setting only.

[DewDiligence]

Roche Pulls Out of the HIV Drug-Discovery Arena

[I must sound like a broken record in saying this again, but the immense commercial success of GILD’s Atripla and Truvada (#msg-26915314) have made HIV an indication where few other companies will be able to succeed. Congrats to Roche for recognizing this and cutting their losses.]

http://www.reuters.com/article/marketsNews/idINN1135940720080711

›Fri Jul 11, 2008 6:15pm EDT
By Deepa Seetharaman

NEW YORK (Reuters) - Swiss pharmaceutical company Roche Holding AG will suspend its HIV research because none of its pending medicines represent significant improvement over existing drugs, a company spokeswoman said on Friday.

"Research scientists currently working in HIV will be reassigned to other activities," Linda Dyson, a spokeswoman in Roche's U.S. office in New Jersey, said in an e-mail.

Dyson confirmed an e-mail sent on Wednesday to some activists informing them of the decision. In that e-mail, the company said it "decided to refocus our resources within virology on diseases in which we can deliver substantial improvements over existing medications."

Dyson declined to specify how much Roche has been investing in HIV research.

She also said she could not specify how many employees worked in the HIV research division. Roche employs 5,000 people in the U.S. and 3,000 in its New Jersey office.

The company said in the e-mail to some activists that it initially had been excited about the potential for drugs in pre-clinical testing, but it has "concluded that none would provide a true incremental benefit for patients compared to medicines currently on the market."

Roche said it would continue to support its molecular diagnostic tests and drugs already on the market, including the fusion-inhibitor Fuzeon.

Roche has partnered with Morrisville, North Carolina-based biotech Trimeris Inc to sell Fuzeon, which netted $266.8 million in sales last year.

But the drug struggled because of its cost -- $25,000 for a year's supply -- exceeding the cost of other HIV drugs on the market, said Peter Staley, founder of AIDSmeds.com, which tracks HIV- related news.

The launch of new drugs and an uptick in HIV cases is set to make AIDS medicine a $10.6 billion market by 2015, according to a study published last year by independent market research firm Datamonitor.

More than 20 separate HIV drugs are available, with several combination pills also available. None can cure the fatal disease, which infects an estimated 33 million people globally and which has killed 25 million.

The drugs fall into various classes, each of which interferes with the replication of the virus at a different stage. The human immunodeficiency virus hijacks immune system cells, forcing them to create copies of itself.

Activists said they would not mourn the withdrawal of Roche from the field.

"They're not beloved in the AIDS community," said James Love, Director of Knowledge Ecology International, an advocacy group that focuses on access to medication.

"They are criticized a lot by people in the AIDS field because they are the least willing to give discounts on their AIDS drugs."

The decision reflects "the lack of productivity among the groups that they have working in this area," he said, adding that "a lot of the big pharma companies haven't been very impressive in terms of their big internal pipeline."

Staley said Roche has never come up with an AIDS drug that has sold really well.

"Roche is a big company and they've been trying to get this right for many, many years." Staley said.

"It is disappointing that there is one less big pharmaceutical company in this field. I don't think it's a sign of a serious problem in pharma's commitment."‹

[DewDiligence]

Epzicom Comparable to Truvada in GSK Postmarketing Study

[In the treatment-naïve setting, each drug was added to Kaletra and the differences were inconsequential in terms of safety and efficacy. Nonetheless, it’s doubtful, IMO, that this study will do much to revive the commercial prospects for GSK’s Epzicom (a combination of Ziagen and Lamivudine, two older NRTI’s from GSK), which is getting badly beaten by GILD’s Truvada in the marketplace (#msg-26915314).

From a business standpoint, it would have been more meaningful for the common third drug in this study to be Sustiva or Reyataz—the two drugs most commonly given with Truvada—instead of Kaletra.]

http://biz.yahoo.com/prnews/080807/neth021a.html

›MEXICO CITY, Aug. 7 /PRNewswire-FirstCall/ -- GlaxoSmithKline (NYSE: GSK ) today announced that 96-week data from the HEAT study show that once-daily EPZICOM (abacavir + lamivudine) provides comparable efficacy to once-daily Truvada® (tenofovir DF + emtricitabine) as a first-line option for the treatment of HIV. The data were presented today at the 17th International AIDS Conference in Mexico City, Mexico.

HEAT is the first large, prospective, long-term, head-to-head trial to evaluate the safety and efficacy of EPZICOM and Truvada both combined with a boosted protease inhibitor (Kaletra) administered once-daily in adults who had no previous exposure to HIV medicines. The study involved 688 HIV therapy-naive patients: 343 randomized to treatment with EPZICOM and 345 randomized to treatment with Truvada.

Results of the study found that through 96 weeks efficacy endpoints for EPZICOM were comparable to Truvada, regardless of baseline viral load. At 96 weeks 60% of subjects receiving EPZICOM versus 58% of subjects receiving Truvada achieved a viral load <50 c/mL. Patients receiving EPZICOM also experienced similar median CD4+ cell increases to those patients receiving Truvada, 250 vs. 247. Overall, both regimens were generally well-tolerated with comparable safety profiles and few study discontinuations due to adverse events (6% for both treatment arms). Virologic failure occurred in 14% of patients for both groups.

"The result of the HEAT trial further demonstrates that EPZICOM is an effective first-line option for treatment-naive HIV patients with a well-established safety profile," said John Pottage, M.D., Vice President Global Clinical Development at GlaxoSmithKline. "This study provides the first, head-to-head, completed study comparing these two HIV treatments and demonstrates comparable results between the two."

Additionally, a review of two important inflammatory biomarkers, hs-CRP and IL-6, in the HEAT data set showed that levels of both biomarkers decreased from baseline at 48 weeks and 96 weeks. Further, there were no significant differences between EPZICOM and Truvada at any time points. Elevations of these markers have been associated with increased risk of cardiovascular events but the degree of association is still being evaluated.

HEAT Study Explained

HEAT is a head-to-head prospective, randomized, double-blind, placebo-matched, multicenter study evaluating the safety and efficacy of EPZICOM and Truvada. The study assigned 688 patients to receive either EPZICOM QD (n=343) or Truvada QD (n=345) both in combination with QD lopinavir/ritonavir. The primary efficacy endpoint was to determine the proportion of subjects with a viral load of <50 c/mL at 48 weeks and the primary safety endpoint was to evaluate safety and tolerability of both regimens at 96 weeks.

Results demonstrate that EPZICOM was comparable to Truvada in virologic and immunologic efficacy. At 48 weeks, 68% of subjects receiving EPZICOM versus 67% of subjects receiving Truvada achieved a viral load <50c/mL. At 96 weeks 60% of subjects receiving EPZICOM versus 58% of subjects receiving Truvada achieved a viral load <50c/mL. Of those patients who were able to achieve a viral load <50c/mL (ITT, M=F), both EPZICOM and Truvada saw similar success rates regardless of whether baseline viral load was <100,000c/mL (63% vs. 58%) or greater than or equal to 100,000c/mL (56% vs. 58%). Median CD4+ increase was comparable in both arms at week 96 (250 vs. 247).

Adverse events were similar in both arms. Both treatment arms had 6% of patients prematurely withdraw due to adverse events. In addition, 15% of patients had drug-related Grade 3-4 adverse events in both treatment arms. Patients receiving EPZICOM reported higher rates of suspected abacavir hypersensitivity reaction compared with Truvada (4% vs. <1%). Prospective HLA-B*5701 screening was not employed in this study. One percent of patients receiving Truvada developed proximal renal tubule dysfunction (vs. 0% for EPZICOM). Overall, treatment-limiting adverse events were comparable between the two arms.‹

[DewDiligence]

Glaxo's HIV-Drug Ads Draw Critics

[These ads are a sign of desperation insofar as GILD has eaten GSK’s lunch in the HIV market (#msg-26915314).]

http://online.wsj.com/article/SB121961241070167309.html

›By JEANNE WHALEN
August 25, 2008

GlaxoSmithKline PLC, one of the biggest sellers of drugs to fight the AIDS virus, is drawing criticism over magazine ads in the U.S. that patient-support groups say attempt to scare patients away from trying newer drug regimens.

Bob Huff, antiretroviral project director at Treatment Action Group, an advocacy group in New York, says he complained to Glaxo a few months ago about an ad that shows shark-infested waters with the message: "Don't take a chance -- stick with the HIV medicine that's working for you." Mr. Huff calls the ad offensive and aimed at instilling fear in patients. The ads carry Glaxo's logo but don't promote specific drugs.

In another ad in Poz, a monthly magazine for patients infected with AIDS, Glaxo promotes its protease inhibitor Lexiva and advises patients to ask their doctor, "Will the HIV medicine make my skin or eyes turn yellow?" Other protease inhibitors have been associated with that side effect.

The AIDS Healthcare Foundation, a nonprofit group in Los Angeles that provides health care to patients who test positive for HIV, the human immunodeficiency virus that causes AIDS, says it sent a letter last month to the Department of Health and Human Services complaining about Glaxo's advertisements. The group says it hasn't yet received a response.

A spokesman for HHS said the department hadn't received the letter.

Glaxo says the ads are "educational" and appropriate. "While we acknowledge that some people may find the headline and imagery of the materials to be provocative, GSK stands firmly behind the ads and their underlying message: Patients considering changing HIV therapy ought to consult closely with their physician to fully understand the near and potential long-term health implications of such changes," Marc Meachem, a company spokesman, said in an emailed statement.

The ads are part of a larger trend of drug companies taking aim at rival HIV drugs, hinting at side effects and other drawbacks, experts say.

Among other controversial campaigns, a recent print ad from Bristol-Myers Squibb shows an image of a toilet and says, "Ask your doctor if there are HIV medications with a low risk of diarrhea." That is a side effect associated with the HIV drug Kaletra made by Abbott Laboratories. Bristol-Myers' antiviral drug Reyataz isn't commonly associated with diarrhea. Brian Henry, a spokesman for Bristol-Myers, said the ad is appropriate. Abbott spokeswoman Melissa Brotz said "Kaletra has a well-established side-effect profile and profound and sustained effectiveness in combating HIV."

Such comparison ads are common elsewhere. But the pharmaceutical industry traditionally sold HIV drugs with images of hope and by explaining the benefits of their treatments. The tough new tack has some patient groups unsettled, saying it could scare off patients.

A development fueling the sharp-elbows advertising: The market for HIV medicines has grown crowded, and companies want to protect their market share. [Moreover, the immense success of newer drugs has turned AIDS into a chronic condition, which raises the stakes for brand-switching.]

"Treatments have become so comparable, so [companies] are really trying to split hairs to have a marketing advantage," says Regan Hoffman, editor of Poz, which has a circulation of 150,000. Ads for HIV treatments usually run in magazines that focus on the disease, or sometimes on billboards and street posters.

Glaxo is one of the world's biggest sellers of HIV drugs, but its medicines are relatively old and losing market share. Its share of the $11 billion global market has fallen sharply in recent years, to about 25% today from about 39% in 2004, according to IMS Health. [See the annotations in the prologue to this post.] During that time, Glaxo launched few new HIV treatments.

Some of Glaxo's biggest HIV drugs, including Combivir and Trizivir, have been losing ground to newer treatments such as Truvada from Gilead Sciences Inc. and Atripla from Gilead and Bristol-Myers Squibb Co. AIDS groups say Glaxo's ads appear aimed at stopping patients from abandoning Glaxo drugs for others.

Dan Kuritzkes, a professor at Harvard Medical School who also treats HIV-positive patients at Brigham & Women's Hospital in Boston, says he worries that the shark ads "scare patients into resisting their doctor's advice."

Glaxo's Mr. Meachem says this isn't the case. The advertising is "just as likely to encourage a patient to stay with another medicine as it is one of our own, assuming that the medicine is working for a patient and is well-tolerated," he says.

However, Mr. Meachem says he is aware of the groups' concerns. The shark-themed ad campaign "ends this September, and, as always, we will take all the community feedback we have received into consideration for future campaigns," he says.‹

[DewDiligence]

Teva Challenges US Truvada Patent

[Technically, the challenge is against GILD’s patents on Emtriva, one of the two constituent drugs in Truvada; however, Emtriva is hardly ever used other than as a component in Truvada and hence it makes much more sense for Teva to submit an ANDA for Truvada (as it has done) rather than an ANDA for Emtriva.

The loss of US patent protection for Truvada would be devastating for GILD because Truvada is the leading nucleoside backbone in three-drug HIV cocktails that dominate the early lines of treatment (see data in #msg-32944110 and pie chart in #msg-26915314). Moreover, a loss by GILD in the Truvada patent challenge would put its US Atripla patent at risk.]

http://biz.yahoo.com/bw/081114/20081114005887.html

›Gilead Sciences Announces Notification of ANDA Filing for Truvada

Friday November 14, 4:30 pm ET

FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD ) today announced receipt of a Paragraph IV Certification Notice Letter advising that Teva Pharmaceuticals submitted an Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA) requesting permission to manufacture and market a generic version of Truvada® (emtricitabine and tenofovir disoproxil fumarate).

In the Notice Letter, Teva alleges that two of the patents associated with emtricitabine – U.S. Patent Numbers 6,642,245 and 6,703,396 – owned by Emory University and licensed exclusively to Gilead Sciences are invalid, unenforceable and/or will not be infringed by Teva’s manufacture, use or sale of the product described in its ANDA submission.

Gilead is currently reviewing the Notice Letter and has 45 days from the date of receipt to commence a patent infringement lawsuit against Teva. Such a lawsuit would restrict the FDA from approving Teva’s ANDA for up to 30 months or until a district court decision that is adverse to Gilead, whichever occurs first. Truvada is currently protected by 10 patents, which are listed in the FDA’s Approved Drugs Products List, and all 10 patents would need to be invalidated or expired before a generic version of Truvada could be marketed.‹