SciQuest.org

A vaginal microbicide that incorporates an antiretroviral (ARV) drug normally used to treat people with HIV is safe for sexually active HIV-negative women to use every day over an extended period, suggest results of a clinical trial of tenofovir topical gel. Moreover, most of the women who participated in the study conducted in India and the United States adhered to a regimen involving either daily or sex-dependent use of the gel, report researchers from the U.S. National Institutes of Health-funded Microbicide Trials Network (MTN) at Microbicides 2008, an international meeting taking place Feb. 24-26 at the Hotel Ashok in New Delhi.

The findings, presented for the first time, are a significant boost to HIV prevention efforts focused on the potential of “next-generation” microbicides to curb infection rates in women. Globally, nearly half of those living with HIV/AIDS are women, and between 70 and 90 percent of all HIV infections in women are due to heterosexual intercourse. In India and many other parts of the world, even married women and women with steady partners are at risk.

In this Phase II study, called HPTN 059, researchers wanted to understand if tenofovir was safe to use every day for six months compared to its use prior to each act of sex, and if women were able to adhere, or follow, each regimen. Researchers found both approaches equally safe and women’s adherence to product use similar. Interestingly, most participants also said they would be willing to apply gel, including daily, if one were found effective to prevent against getting HIV from their sexual partners.

Microbicides are products designed to prevent the sexual transmission of HIV when applied topically on the inside of the vagina or rectum. Tenofovir gel is among a newer class of candidate microbicides that differ from early types because they have specific action against HIV. In addition, because tenofovir gel and similar products are longer acting, their use may not be required before each act of sex, which is not always practical or desirable for some women.

“Finding that daily use is both safe and feasible is important because we believe a daily approach may provide more sustainable protection against the virus in women who can’t always predict when they will have sex. Based on what we have learned we can proceed with greater confidence on a path that will answer whether tenofovir gel and other gels with HIV-specific compounds will be able to prevent sexual transmission of HIV in women when other approaches have failed to do so. It is a critical time for all of us engaged in HIV prevention, and I truly believe we are turning a corner,” said Sharon L. Hillier, Ph.D., professor and vice chair for faculty affairs, and director of reproductive infectious disease research in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh School of Medicine, who is MTN principal investigator and led the study.

According to UNAIDS, women represent nearly half, or 46 percent, of the 33.2 million people living with HIV/AIDS worldwide, and they are more than twice as likely as men to acquire HIV through sexual intercourse, due to both biological and cultural factors. Although correct and consistent use of male condoms has been shown to prevent HIV infection, women often cannot successfully negotiate condom use with their male partners.

HPTN 059 involved 200 sexually active HIV-negative women: 52 were enrolled at the University of Alabama at Birmingham (UAB) in Birmingham, Alabama; 48 at Bronx-Lebanon Hospital Center, Bronx, New York; and 100 women entered the study at the National AIDS Research Institute in Pune, India. The mean age was 32 and 64 percent of the women were married. All but one of the women at the Indian site were married compared to 28 percent of the women at the two U.S. sites.

Once enrolled, women were randomly assigned to one of four groups: tenofovir gel applied daily; tenofovir gel applied up to two hours before sex; placebo gel (without an active drug) used every day; or placebo gel applied prior to sex. Because the tenofovir and placebo gels look the same, neither researchers nor participants knew who had been assigned to use which gel during the six-month study period. Women were assessed at one month, three months and six months. Throughout the study, participants received free condoms and HIV risk-reduction counseling as well as routine testing and treatment for sexually transmitted infections.

The study found no differences in liver, blood and kidney function between the groups of women using either regimen of tenofovir gel and the groups assigned to use placebo, nor were there differences in these safety measures between groups using daily gel and groups using gel with sex. Likewise, researchers report no statistical differences in the development of genital symptoms such as itching and burning, which are considered minor. One woman became pregnant and stopped gel use. No participants acquired HIV during the study.

Adherence to treatment was also similar. According to structured interviews, 80 percent of the women instructed to use gel within two hours of having sex said they complied with the regimen. Of the women in the daily-use groups, an average of 83 percent reported study gel use in the past week. The two most cited reasons women gave for not using gel was menstruation (41 percent) and forgetting (23 percent).

Overall, 41 percent of the women indicated there was nothing they disliked about using the gel and 39 percent said it was easy to use. Other attributes of the gel women identified included its potential for protecting against HIV (19 percent), its smell and appearance (14 percent) and that it made sex more pleasurable (12 percent). Thirty-two percent didn’t like that the gel was messy, but none of the women said sex was made less pleasurable because of the gel.

Importantly, when asked if they would use the gel if it were found to help prevent people from getting HIV, 90 percent of the women who had been assigned to use the gel at the time of sex and 96 percent of the women who had been asked to use gel daily said yes.

“Women are definitely willing to use a gel to protect against sexual transmission of HIV. That’s very encouraging,” Dr. Hillier commented.

HPTN 059 also evaluated how the active ingredient in the gel was absorbed from the vagina into the blood and vaginal tissue; and looked at the effects of prolonged use on vaginal flora, the vagina’s naturally protective population of microorganisms; and whether the activity of certain immune system molecules called cytokines could serve as a useful measure, or marker, for assessing the safety of microbicides. Results of these evaluations are not yet available.

HPTN 059 was conducted by the Microbicide Trials Network (MTN), a clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health (NIH). Prior to the establishment of the MTN, HPTN 059 study was led by the NIAID-funded HIV Prevention Trials Network (HPTN), from which the study gets its name.

At the site level, HPTN 059 was led by Smita Joshi, MBBS, in Pune, India; Jessica Justman, M.D., at Bronx-Lebanon Hospital; and Craig Hoesley, M.D., UAB.

In its pill form, tenofovir is a mainstay of one of the most widely used regimens for treating HIV. The active ingredient in tenofovir gel belongs to a class of anti-retroviral drugs called nucleotide reverse transcriptase inhibitors, which act against HIV by targeting a key enzyme the virus needs to copy itself before taking over a host cell. The topical gel form of tenofovir was not developed as treatment for HIV but as an approach to prevent the sexual transmission of HIV. Both oral and topical formulations were developed by Gilead Sciences, Inc., of Foster City, California, which assigned a royalty-free license for the topical gel to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, of Arlington, Virginia, in December 2006.

MTN will launch a series of other trials that will further evaluate the safety and adherence of tenofovir gel as well as look at its effectiveness for preventing HIV. Researchers will soon begin enrolling participants into MTN-002, the first trial of a candidate microbicide in pregnant women that seeks to understand the extent of drug absorption during pregnancy and the degree to which the active ingredient in tenofovir gel can be transferred to the fetus. Another trial, MTN-001, will be the first direct comparison of oral and vaginal gel preparations of tenofovir - looking at differences in drug absorption (systemically and locally) and adherence and acceptability of each approach separately and in combination. Finally, the VOICE Study (Vaginal and Oral Interventions to Control the Epidemic) will be the first effectiveness trial of a microbicide that women use every day instead of at the time of sexual intercourse. Moreover, VOICE will be the only trial evaluating two promising HIV prevention approaches in the same study: tenofovir gel and pre-exposure prophylaxis, or PrEP, an HIV prevention approach that involves daily use of oral anti-retrovirals.

Currently, tenofovir gel is being evaluated in a Phase IIb study being conducted at the Centre for the AIDS Programme of Research in South Africa (CAPRISA) in Durban. The study, known as CAPRISA 004, will enroll 980 women. Unlike VOICE, researchers are evaluating a dosing strategy timed around sexual intercourse.

Other microbicide products have been or are currently being tested in clinical trials, although none is yet approved or available for use by women.

The FDA budget for oversight of direct-to-consumer prescription drug advertisements in fiscal year 2008 is “larger than the past five years combined,” but “whether that level of funding will be sustained and continue to come from taxpayers — or will be raised from drug makers through new user fees — is likely to be battled out in Congress,” USA Today reports.

In FY 2008, FDA received $6.1 million to determine the fairness and accuracy of DTC ads, compared with $2.2 million in FY 2007 and $1 million in FY 2006. FDA officials said that the agency plans to hire additional employees to review more DTC ads. FDA, which currently has 13 employees who review DTC ads, received materials for 12,616 ads last year.

In his FY 2009 budget request, President Bush seeks $14 million in user fees from the pharmaceutical industry to finance 27 additional FDA employees who review DTC ads. In exchange, FDA would review DTC television ads within 45 days and before the ads begin to air.

The Pharmaceutical Research and Manufacturers of America supports the use of user fees to finance FDA oversight of DTC ads. According to PhRMA, expedited FDA reviews of DTC ads would “help drug makers meet marketing goals and lessen the risk of running ads later cited by the FDA for false or misleading content,” USA Today reports.

However, some Democratic lawmakers — such as House Appropriations Subcommittee on Agriculture, Rural Development, FDA and Related Agencies Chair Rosa DeLauro (D-Conn.) — oppose the use of user fees to finance FDA oversight of DTC ads. “Congress should provide a direct appropriation in order to minimize industry influence in the FDA,” DeLauro said (Schmit, USA Today, 2/25).

FDA Authority Over Imports
In related news, HHS Secretary Mike Leavitt said that the Bush administration supports a proposal that would expand FDA authority over medications and foods manufactured abroad for distribution to the U.S., the Wall Street Journal reports. In a letter to Reps. Joe Barton (R-Texas) and John Shimkus (R-Ill.), Leavitt wrote that, because companies abroad often can “deny U.S. officials access to their facilities without any adverse consequences,” such a proposal “would better enable FDA to address criminal conduct that occurs entirely outside of the United States and threatens the health and safety of consumers within the United States.”

Leavitt sent the letter in response to a request from Barton and Shimkus, who have lobbied for such a proposal since 2000. Barton said, “The secretary’s support is good news. We have to get this right, and we have to get it right soon because the volume, variety and the complexity of products arriving from overseas is increasing every day” (Zhang, Wall Street Journal, 2/23).

Opinion Piece
The “unfolding tragedy” in which hundreds of U.S. residents experienced severe allergic reactions or died after they received injections of “Chinese-made heparin has its roots in a spectacular example of bad government that some federal watchdogs started barking at a decade ago,” but lawmakers “simply did not respond adequately to the warnings,” syndicated columnist Terence Jeffrey writes in the Washington Times.

A 1998 investigation conducted by the Government Accountability Office found that FDA “did not possess a complete and reliable list of the foreign manufacturers producing drugs” and that the system “put Americans at risk,” Jeffrey writes. In November 2007, GAO presented to the House Energy and Commerce Subcommittee on Oversight and Investigations the results of a recent investigation that found FDA “still did not have a complete and reliable list of foreign factories making drugs,” according to Jeffrey.

He concludes, “Will another decade pass before politicians fix the FDA?” (Jeffrey, Washington Times, 2/24).

A “simple approach” to efforts to reduce health care costs that could “save consumers billions of dollars annually” is “stopping pharmaceutical companies from colluding with competitors to keep lower-cost generic alternatives to prescription drugs off the market,” Jon Leibowitz, one of five members of the Federal Trade Commission, writes in a Washington Post opinion piece.

According to Leibowitz, the Hatch-Waxman Act, which Congress passed in 1984, has made “it easier for noninfringing generic drugs to enter the market, while giving brand-name manufacturers the patent protection they need to encourage the lifesaving research that is the hallmark” of the pharmaceutical industry.

However, the “crucial benefit is threatened by … the emergence of ‘pay-for-delay’ settlements” — in which brand-name pharmaceutical companies pay generic pharmaceutical companies to delay market entry of their products — and the “willingness of some federal courts to permit such obviously anticompetitive agreements,” Leibowitz writes. “When these troubling deals first came to light in the late 1990s, the FTC fought them — and stopped them cold” — as “no brand and generic companies entered pay-for-delay deals” between 2000 and 2004, but “that success is under siege,” according to Leibowitz.

He writes that two federal appeals courts recently “have found that a brand-name drug company facing a patent challenge is free to pay any amount to keep a generic producer from entering the market until the patent expires.” Leibowitz adds, “These rulings depart from the spirit of Hatch-Waxman and our nation’s antitrust laws, and they harm consumers by subverting the competition at the heart of our free-market system.”

He writes, “Not surprisingly, after two courts blessed such payoffs, the frequency of these settlements has increased sharply,” adding, “In fiscal 2006, fully half of all pharmaceutical patent settlements (14 of 28) contained such payments.” In response, FTC supports the “bipartisan legislation to ban such agreements that is moving through both houses of Congress” and, “until that law is enacted, we are doing everything in our power to end these unconscionable deals,” Leibowitz concludes (Leibowitz, Washington Post, 2/25).

A new study by researchers in the UK suggests that antidepressants only benefit the very severely depressed and are no more effective than a placebo for everyone else.

The meta-analytical study (ie one that systematically pools the results of other studies) is the work of Dr Irving Kirsch, from the University of Hull, and his colleagues, and is published today, 26th February, in the open access journal PLoS Medicine.

Antidepressants are prescribed for the treatment of clinical depression, and the most widely used are the “new generation” drugs, the SSRIs such as fluoxetine (Prozac) and venlafaxine (Effexor).

Previous meta-analytical studies of antidepressants have already suggested they have only modest benefits over placebos, and the authors pointed out that when data from unpublished trials are included, the benefits are so small they fall below the criteria for clinical significance. What has not been clear in the past however, is whether within this overall result, the effectiveness of antidepressants depends on how severely depressed patients are when they start treatment.

Kirsch and colleagues pooled all the available full data sets from all clinical trials submitted to the US Food and Drug Administration (FDA) for licensing four of the new generation of antidepressants, the SSRIs fluoxetine (Prozac), venlafaxine (Effexor), nefazodone (Serzone), and paroxetine (Seroxat, Paxil). The data came from both published and unpublished trials.

The point of including data from unpublished as well as published trials, is to avoid potential bias arising from the omission of “disappointing” unpublished findings.

SSRI stands for “selective serotonin reuptake inhibitors”. This new type of antidepressant, like the older ones, works by attempting to stabilize chemicals in the brain that influence mood, except that SSRIs specifically target and increase the circulating levels of a brain chemical called serotonin, a neurotransmitter that regulates mood. They do this by inhibiting the reuptake of serotonin so that more of it is available for binding to cell receptors.

Using meta-analytical techniques (a way of pooling data from a range of studies as if they were one big study with broadly the same objectives) the authors assessed the relation between the initial severity of depression and the improvements shown by drug and placebo groups, as well as the relation between initial severity and differences in drug-placebo improvement scores.

The results showed that:

* Drug-placebo differences got bigger as initial severity went up.

* This difference was hardly noticeable at moderate levels of initial depression, went up to a relatively small difference for patients with severe depression, and reached a level that would be classed as clinically significant only in those patients at the extreme end of the very depressed scale.

* The improvement seemed to result from the most severely depressed patients not responding as well to placebo compared to their less depressed counterparts, than because they responded better to the active drug.

Kirsch and colleagues concluded that:

“Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients.”

“The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication,” they added.

In other words, the difference in effect between drug and placebo was only clinically significant in those patients who were very severely depressed at the start of their treatment and this effect was more likely due to a weaker response to the placebo than a stronger response to the drug itself in that group.

This study is important because although licensing authorities like the FDA in the US and NICE (National Institute for Health and Clinical Excellence) in the UK have approved SSRIs for treating depression, there are nagging doubts about how effective they are.

Depression, which affects about 1 in 6 people at some point in their life, is a serious medical condition characterized by imbalances in brain chemicals that regulate mood. The illness, which can last for months and sometimes years, makes a person feel unmotivated, worthless, hopeless, and sometimes even that life is so futile it would be better to be dead. Depression is often a cause of suicide.

Severity of depression is measured using a questionnaire called the Hamilton Rating Scale of Depression (HRSD) which comprises up to 21 items. If the total score comes to 18 or more, the person is classed as severely depressed.

For an antidepressant to receive a license, clinical trials have to show that it can significantly improve the HRSD score compared to a placebo.

Different countries have slightly different clinical criteria for how much the HRSD score has to improve by before the drug can be licensed to treat depression. In the UK, NICE require that the drug show an improvement in the HRSD score of 3.

A previous meta-analysis of published and unpublished trials sent to the FDA for licensing these drugs showed they only have an average benefit of 1.8 HRSD points.

The reason this study was done was to find out if underneath this 1.8 average there might be subgroups of patients for whom the improvement score was significantly higher, perhaps within the range required by NICE.

And indeed, this is what Kirsch and colleagues found: the clinical criteria were only met when the drugs were used to treat the most severely depressed patients, that is ones with an initial HRSD score of 28 or more, at the extreme end of the scale. And perhaps just as important, is the finding that this effect did not arise as a result of responding to the drug, but because of decreased responsiveness to the placebo.

This last, rather surprising finding, provides a new direction for future research.

“Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration.”
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, et al.
PLoS Medicine Vol. 5, No. 2, e45
Published online: February 26, 2008.
doi:10.1371/journal.pmed.0050045

The prices of brand-name medications have continued to increase despite calls from all three major presidential candidates for pharmaceutical companies to make their products more affordable, the Wall Street Journal reports. Wholesale prices for the 50 brand-name medications with the most sales increased by an average of 7.82% in 2007, compared with increases of 6.73% and 6.22% in the previous two years, according to Delta Marketing Dynamics. The overall U.S. economy had an inflation rate of 4.1% in 2007.

In some cases, pharmaceutical companies have increased the prices of brand-name medications scheduled to lose patent protection to prompt patients to switch to similar, newer products that will have patent protection for a number of years. William Little, president of Delta, said, “Companies are under great pressure to deliver revenue, and it’s becoming increasingly difficult to do so as generics displace profitable brands.”

However, such price increases could “backfire politically, pushing policies toward greater government power over price negotiations,” according to the Journal. Presidential candidates Sens. John McCain (R-Ariz.), Barack Obama (D-Ill.) and Hillary Rodham Clinton (D-N.Y.) have criticized pharmaceutical companies over the high prices of the products and have announced proposals to address the issue.

McCain has said that he supports the legalization of prescription drug reimportation from Canada to reduce costs and “keep competition vigorous,” and Obama on his Web site promises to “prevent (drug) companies from abusing their monopoly power through unjustified price increases.” In addition, Clinton and Obama both have said that they support proposals to allow the federal government to negotiate prices directly with pharmaceutical companies under the Medicare prescription drug benefit.

According to some analysts, pharmaceutical companies have increased the prices of brand-name medications to “protect their margins in case the Medicare effort and others like it succeed,” the Journal reports.

Comments
Jeff Nelligan, a spokesperson for CMS, said, “Allowing the government to negotiate drug prices would not generate additional savings” under the Medicare prescription drug benefit because the program “relies on health plans and their related pharmacy benefit managers to negotiate deep discounts with manufacturers.”

Officials for the Pharmaceutical Research and Manufacturers of America said that the prices of brand-name medications “are determined by market transactions, and health plans are able to negotiate for discounts,” adding that Medicare and Medicaid beneficiaries “have benefited from our competitive market approach.”

Raymond James analyst John Ransom said, “Direct negotiations clearly could save the feds money, the concept being that the government makes almost 50% of purchases, and accordingly have almost fiat-like power to set their purchase price wherever they wish” (Won Tesoriero, Wall Street Journal, 2/21).

The National Drugs and Poisons Schedule Committee (NDPSC) considered the scheduling of zolpidem (contained in the medicine Stilnox) at its February 2008 meeting, held this week, because of concerns relating to reports of potential abuse of this substance.

The NDPSC also considered a number of submissions describing personal accounts of adverse events, including bizarre sleep behaviours and their consequences.

While the NDPSC acknowledges the concerns that members of the public have raised regarding these adverse events, members of Committee concluded that the current Schedule 4 (Prescription Only) status of zolpidem remains appropriate.

In reaching this conclusion, the NDPSC agreed that zolpidem does not meet the criteria for a Schedule 8 (Controlled Drug) medicine. Schedule 8 medicines must demonstrate a substantial risk of abuse, dependence or misuse for illegal purposes. There was no compelling evidence presented to the NDPSC that the abuse potential of zolpidem requires it to be rescheduled.

The NDPSC noted that zolpidem is only available by prescription under the supervision of a medical practitioner and its use should be carefully monitored by the prescribing doctor. It is only indicated for short-term use and should not be used with alcohol. Zolpidem should be used with caution if taking other central nervous system medications, such as antidepressants, under close medical supervision.

The NDSPSC also noted that the TGA has taken several appropriate regulatory actions and is currently continuing its evaluation of Australian and international data on the safety of zolpidem. The NDPSC will be keeping a watching brief on this matter over the coming months.

In accordance with the NDPSC’s practice and statutory requirements, a record of reasons for this and other scheduling decisions made at the February 2008 meeting will be publicly available on the NDPSC website on 4 April 2008.

The National Drugs and Poisons Schedule Committee

The NDPSC is a statutory committee established under the Therapeutic Goods Act 1989. It is responsible for determining the classification and scheduling of substances for inclusion in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), together with other related functions. The NDPSC has a wide range of expert and professional members, with jurisdictional memberships from the Commonwealth, States and Territories and New Zealand.

The NDPSC is required to publish a notice in the Gazette before and after each meeting, which includes an invitation to the public to make submissions.

Scheduling and voting procedures, and the issues the NDPSC must take into account in reaching a decision, are set out in the Act and its associated regulations.

Decisions of the NDPSC are made by a majority of the members present and voting at a NDPSC meeting and must include a majority of the jurisdictional members present and voting. There are eleven jurisdictional members comprising of the Commonwealth (1), states and territories (8) and New Zealand (2). However, only one New Zealand representative is counted as a jurisdictional member for the purposes of voting.

As part of its statutory obligations, the NDPSC publishes records of reasons for its scheduling decisions. This record is published on the NDPSC website approximately six weeks after each meeting. The record of reasons for the February 2008 NDPSC Meeting will be released around 4 April 2008 and can be found here.

http://www.tga.gov.au

An international research study, published in The Lancet, has thrown into question the current method of treating Crohn’s disease - opening the door to a safer and more effective treatment option for sufferers of the chronic disease.

“Our study clearly demonstrated that this alternative treatment method was more effective at inducing disease remission than the conventional method,” said Dr. Brian Feagan, Director of Robarts Clinical Trials at Robarts Research Institute at The University of Western Ontario. Dr. Feagan coordinated the research trial and is an author on the study. “Not only were patients more likely to get their disease under control, but they were also spared exposure to steroids - the extended use of which is linked with metabolic disease and even increased mortality. It’s simply a safer, more effective treatment method.”

Called a “step-up” approach, the conventional treatment for Crohn’s disease involves first administering steroids in order to control the patient’s symptoms (abdominal pain and bloody diarrhea); the next step involves administering immune-suppressing drugs, which prepare the body to receive the third medication - an antibody that curbs the inflammatory response at the root of the disease.

The alternative strategy, called “top-down” therapy, employs early use of immune-suppressing drugs combined with an antibody in order to address the disease from the start. Symptom-treating steroids may never even be needed.

The two-year study was conducted at research centres in Belgium, Holland, and Germany and involved 129 subjects with active Crohn’s disease. 64 patients received the conventional step-up treatment and 65 the combined immune-suppressing method (top-down). 60% of the top-down subjects were symptom-free by the 26th week of the study, compared to only 36% of the step-up subjects.

“This study is a milestone in the management of Crohn’s disease,” said lead author Dr. Geert D’Haens, of the Imelda GI Clinical Research Centre at the Imelda Hospital in Bonheiden, Belgium. “It does not look at the effects of single drug intervention but at strategies to alter the natural history of this chronic destructive condition. All ‘classic’ paradigms for the management of Crohn’s disease need to be questioned.”

The impact of the study goes beyond Crohn’s disease. “We’ve seen similar results in top-down, step-up studies of rheumatoid arthritis,” said Dr. Feagan, “suggesting that the top-down approach could be the best treatment method for other chronic auto-immune diseases such as ulcerative colitis.”

Genentech’s Avastin, a drug which is currently used to treat colon and lung cancer, has been approved by the FDA for breast cancer treatment. Earning approximately $2.3 billion in the USA alone in 2007, this new approval is expected to boost Avastin sales by at least $500 million. Experts had expected the Food and Drug Administration (FDA) to either delay or turn down Genentech’s breast cancer application after an Advisory Panel narrowly recommended rejecting breast cancer treatment with Avastin last December.

New positive data was published recently - A Phase III study(E2100) that showed that Avastin in combination with paclitaxel chemotherapy resulted in a 52% reduction in the risk of disease progression or death compared to patients treated with paclitaxel alone and a doubling in progression-free survival (PFS) (based on a hazard ratio of 0.48; p<0.0001).

Roche Holding AG, which is a major holder of Genentech stocks, markets Avastin worldwide outside the USA.

The FDA accelerated approval is for Avastin (bevacizumab), in combination with paclitaxel chemotherapy, for the treatment of patients who have not received chemotherapy for their metastatic HER2-negative breast cancer. Accelerated approval means the FDA approves products for life-threatening diseases based on initial positive clinical data.

Genentech says that it has “shared with the FDA a summary of the results from a second positive Phase III trial (AVADO), and is expecting results from a third Phase III trial (RIBBON I) in first-line metastatic breast cancer in late 2008. A full review of both the AVADO and RIBBON I data by the FDA will be required for the accelerated approval to be converted into a full approval.” Data from three randomized trials that are either planned or ongoing will be submitted to the FDA, the company informs.

In a Genentech news release, Kathy Miller, M.D., Associate Professor of Medical Oncology, Indiana University School of Medicine, Head Researcher on the E2100 trial, said “There is no cure for metastatic breast cancer so it is important to control the disease as early and for as long as possible. Now with Avastin plus paclitaxel, we can increase the time a woman’s cancer is kept under control, and offer a biologic option to women who previously were limited to chemotherapies alone.”

Breast cancer is the second most common cancer for women in the USA; it is the biggest cancer killer of women in the country. Approximately 178,000 women were diagnosed with breast cancer in the United States in 2007. About 40,000 American women died of breast cancer in 2007 (American Cancer Society).

E2100 Trial

E2100 was a multicenter, randomized and controlled clinical trial involving 722 women with previously untreated, locally recurrent or metastatic breast cancer. The women were randomized to receive weekly treatment with paclitaxel every 3 out of 4 weeks, with or without Avastin. Based on an independent, blinded review of patient scans, those treated with Avastin plus paclitaxel experienced median PFS was 11.3 months versus 5.8 months in the paclitaxel alone arm. The independent review showed a similar significance of benefit relative to the initial results presented by the Eastern Cooperative Oncology Group (ECOG) at the American Society of Clinical Oncology annual meeting in 2005. A secondary endpoint of overall survival was 1.7 months longer in the Avastin-containing arm (with a hazard ratio of 0.87), supporting the primary endpoint of PFS. This improvement did not reach statistical significance (p=0.14).

Grade 3/4 adverse events that occurred more often in the Avastin arm included neuropathy (due to longer time on paclitaxel treatment), high blood pressure (hypertension), arterial thromboembolic events and proteinuria. These safety findings were in general consistent with earlier Avastin plus chemotherapy trials and no new safety signals related to Avastin were observed.

A trial to evaluate an anti-HIV microbicide cream for women has found the product is safe, but it was not able to prove it could prevent male to female transmission of the virus during sex. However, researchers said it was a milestone in the fight to prevent the spread of HIV.

The cream is called Carraguard and is made from carrageenan seaweed. The US Food and Drug Administration (FDA) have given it a “Generally Recognized As Safe” go ahead for oral and topical use.

Carraguard is the first product designed to be a microbicide that has completed the final phase of clinical testing. The trial found it to be safe for vaginal use, but it did not show it was effective at stopping the virus passing from a man to a woman during vaginal intercourse.

The randomized, double blind, phase 3 trial involved 6,202 women and was carried out at three South African sites where the HIV epidemic is acute. It started in March 2004 and finished in March 2007.

The women were equally split into a Carraguard group and a placebo group. Both groups received a topical gel and condoms, and neither participants nor their doctors knew who got the Carraguard and who got the placebo (double blind). All participants also received education about HIV, counselling about safe sex and how to reduce risk of sexually transmitted infections, as well as being medically examined, and tested and treated for curable sexually transmitted infections.

The results showed 134 new infections in the group that used Carraguard and 151 in the placebo group. This translates to an incidence rate of 3.3 infections per 100 woman-years compared to 3.7, respectively, a difference that was not found to be statistically significant.

The researchers found no safety related differences between the placebo and the active ingredient group, and adverse events due to gel application were minor and infrequent.

The researchers said this result was important because of what it means to the development of the next generation of microbicides, of which Carraguard is an important ingredient.

President of the Population Council, Peter Donaldson, said:

“We are disappointed that this trial did not show Carraguard to be effective.”

But, he added that the completion of the trial marked a “milestone in HIV prevention research”. It has made a big contribution to knowledge about product development, trial design, and the willingness of women and their partners to use a vaginal gel consistently, said Donaldson. The data will be very useful to other researchers working on microbicides.

Director of the Population Council’s HIV and AIDS program, Naomi Rutenberg, said:

“The Population Council will use these trial results to accelerate the development of effective means for women to protect themselves against HIV.”

In the laboratory, Carraguard was found to be effective at stopping cells from invasion by HIV, and it also stopped mice getting some sexually transmitted infections. Carraguard and similar products based on carrageenan seaweed have been tested widely in trials in the US, Australia, Chile, the Dominican Republic, Finland, South Africa and Thailand, in over 850 men and women.

The US Agency for International Development (USAID) and the Bill & Melinda Gates Foundation funded the trial. Speaking for USAID, their senior science advisor, Jeff Spieler said they always knew it would take a long time to produce a successful microbicide:

“The Population Council has done groundbreaking work in completing this trial, even though we are terribly disappointed that the product was not shown to be effective,” said Spieler.

“Now we all have to redouble our efforts to develop a microbicide that women can use to protect themselves,” he urged.

Developing effective vaginal microbicides is important because it gives women more options for controlling the spread of HIV and other sexually transmitted infections, especially since current strategies are not always possible.

For many patients, the pain and complications associated with sickle cell disease can have a profound impact on their quality of life, ability to work, and long-term health and well-being. Unfortunately, these challenges are often coupled with significant barriers to care. Hydroxyurea is an FDA-approved therapy for adults with certain forms of sickle cell disease, and acts to increase the percentage of non-sickled red blood cells in circulation. However, concerns remain for both physicians and patients. The conference panel will examine these issues in detail at the upcoming conference, resulting in a summary of what we know and what we need to learn about hydroxyurea treatment for sickle cell disease.

What

Experts will describe the available evidence on hydroxyurea treatment for sickle cell disease, including efficacy, effectiveness, harms, barriers to treatment, and future research needs. Following a series of scientific presentations and open public discussions, an impartial, independent panel will issue a statement of its findings on the final day of the conference, and will hold a press conference at 2:00 p.m. on Wednesday, February 27. Convened by the Office of Medical Applications of Research (OMAR) and the National Heart, Lung, and Blood Institute (NHLBI) of the NIH, this conference is free and open to the public and the media.

The conference presentations, open discussions, and the panel’s statement will focus on these questions:

1. What is the efficacy (results from clinical studies) of hydroxyurea treatment for patients who have sickle cell disease in three groups: infants, preadolescents, and adolescents/adults?

2. What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?

3. What are the short- and long-term harms of hydroxyurea treatment?

4. What are the barriers to hydroxyurea treatment for patients who have sickle cell disease and what are the potential solutions?

5. What are the future research needs?

When

Monday, February 25, 2008 - 8:30 am - 5:30 pm
Tuesday, February 26, 2008 - 8:30 am - 12:00 pm
Wednesday, February 27, 2008 - 9:00 am - 11:00 am
Press Conference: Wednesday, February 27, 2:00 p.m.

Where

Natcher Conference Center
NIH Main Campus - Building 45
9000 Rockville Pike
Bethesda, Maryland 20892