STOP CONGRESS FROM DENYING US COMPOUNDED MEDICINES

Compounded medications have greatly improved the quality of the lives of many people living with HIV. Several of these medications (hormone therapies, wasting therapies, quality of life therapies) are not cover by most insurance or ADAP/Medicare/Medicaid formularies, so patients rely on access through compounding pharmacies. Now, access to these medications is facing a huge threat.

A small but powerful group of senators is on the verge of introducing legislation that would severely restrict and possibly deny access to critical medications that many patients rely on, such as women prescribed bioidentical hormones, hospice care patients and children.

Even if you don't currently rely on compounded medicines yourself, you may need them someday - and you know someone who needs them now. Please join me in contacting Congress to stop this legislation and protect patient access to compounded drugs! Visit www.savemymedicine.org to take action.


This is a copy of the letter that savemymedicine.org sends to your congress people after you input your name and address.

Apr 9, 2007

Senator John Cornyn
United States Senate
517 Hart Senate Office Building
Washington, DC 20510-0001

Dear Senator Cornyn,

I know that you are committed to protecting patients and, as a result,
I hope that you share my concerns about the draft Safe Drug
Compounding Act of 2007 that may soon be introduced by Senators Edward Kennedy, Richard Burr and Pat Roberts.

I rely on compounded medications. Without access to them, I will
suffer.

The Safe Drug Compounding Act would restrict and possibly even deny my access to vital compounded medications, medications that my doctor
has determined I need.

As your constituent, I strongly urge you to oppose this legislation
and look forward to hearing your response.

Sincerely,

Mr. Nelson Vergel

*************************************************************************

WATSON PHARMACEUTICALS ABANDONS AIDS WASTING DRUG

FOR MORE INFORMATION ABOUT THIS GO TO http://watsonboycott.blogspot.com/

April 4, 2007



Allen Chao, PhD

Chairman and CEO

Watson Pharmaceuticals

Corporate Headquarters
311 Bonnie Circle
Corona, California 92880

Dear Dr Chao :





I am writing to ask you to reverse your decision of stopping the manufacture of nandrolone decanoate. I am a national treatment advocate and person living with AIDS who has used your product in the past to reverse wasting syndrome and sustain my lean body mass and quality of life. Several HIV studies have shown that nandrolone prevents and reverses the loss of lean body mass (LBM) that has been linked to increased risk of death in HIV while increasing strength and functional capacity. Your decision to abandon this compound affects me, my work, and thousands of people who needed it to keep living a productive life.



At an average cost of $200 a month for dose of 200 mg a week, nandrolone is a lot more cost effective and more tolerable wasting treatment than recombinant human growth hormone (Serostim) ( cost: $6000 a month). You are the sole supplier of several federal-funded AIDS Drug Assistance and Medicaid programs that have recognized its value and have included nandrolone in their formularies to treat thousands of low income HIV-positive patients nationwide.



I have been told by people in your company that you do not have a source of raw materials anymore. It seems that several raw material suppliers are still available. I certainly hope that your decision has not been originated by the DEA and media frenzy over anabolic steroid use in sports. This negative media exposure completely ignores the important medical uses of this medication. For whatever reason, it is irresponsible for Watson to stop supplying this product without a successor that can guarantee that patients in need get access to this important drug.



Thus, unless you decide to reverse your unfortunate decision of abandoning nandrolone decanoate, our organization and many key stakeholders will start a campaign to boycott Androderm and Watson's other products via press releases, emails and direct mailings to physicians. I certainly hope we do not have to go to these extreme measures and that you show compassion towards people living with HIV.



Please have someone from your medical and legal department call me directly at 713-539-1978 to discuss this matter before the patient and physician communities are activated.



Sincerely,









Nelson R. Vergel



Director







cc:



Mr Jeff Murray- Food and Drug Administration

Ms Karen Tandy- Drug Enforcement Administration
Mr Steve Baragona- HIV Medicine Association (HIVMA)

Mr Rob Banaszak- The American Academy of HIV Medicine (AAHIVM)

Ms. Cathy Olufs- President- The AIDS Treatment Activist Coalition (ATAC)

Free HIV lecture in Houston on April 19, 2007

Title: Latest Update on HIV Research

Seminar date : April 19, Thursday

Time: 6:00 pm til 8:30 pm

Free dinner and door prizes

Speakers: Shannon Schrader MD
Nelson Vergel (powerusa.org)


LOCATION:
United Way of the Texas Gulf Coast
50 Waugh Drive
Houston, Texas 77007

For more information email : nelsonvergel@yahoo.com

Letter to the FDA about ways to improve Expanded Access Programs of Investigational Drugs in HIV

From a meeting held by the Forum of Collaborative HIV Research. The list of participants is at the end of the letter. I certainly hope that the FDA encourages industry to implement these recommendations. Great ideas have died due to lack of action.

March 11, 2007





The Forum for Collaborative HIV Research, an independent public/private partnership that includes government agencies, pharmaceutical and diagnostic industries, HIV researchers and clinicians, payers, foundations, and the HIV patient advocacy community organized a roundtable discussion on February 16, 2007 to discuss how current and future HIV antiretroviral expanded access programs (EAPs) might be improved so that they best meet the needs of patients, clinicians, industry sponsors, and regulatory agencies. This roundtable meeting was the first opportunity for all of the relevant parties to talk about improving expanded access programs for antiretroviral agents. As such, it was a valuable opportunity not only to listen to the concerns and perspectives of the various constituencies, but also to realize how much their interests align in support of providing access to therapies for patients with few treatment options.



We submit the following comments and recommendations to the FDA Docket No. 2006N-0062 and RIN 0910-AF14.



Introductory comments:



Expanded access programs were developed in order to make promising treatments available to patients who need them as early in the drug evaluation process as possible. In particular, the goal is to make such drugs available to patients who have exhausted all currently approved therapies. Early in the HIV epidemic, HIV activist organizations challenged the existing drug approval system as too cautious, particularly in the face of a deadly epidemic that was claiming thousands of lives for lack of effective therapies. Their efforts shifted the balance from the strictly protective model with an emphasis on preventing harm to patients toward increasing access to potentially effective therapies for patients who are in need.



The HIV field likely has the most experience with expanded access programs compared to other diseases. Twenty-one drugs have previously been made available through expanded access programs in the United States and an additional three drugs are currently available through expanded access programs for people living with HIV.



At present, the approach to EAPs is to have each company’s program (independent of other companies) precede the release of new antiretrovirals prior to FDA approval. Major concerns to this approach within the HIV scientific, medical and activist communities include the increased risk of drug resistance when adding a single new agent to a failing regimen (or “virtual monotherapy”), potentially leading to a transient response but reduced long-term durability; and the risks associated with using untested combinations of drugs before the potential for drug interactions has been systematically studied.



Key issues in HIV-therapy related EAPs:



The size of the patient population that currently needs access to investigational antiretroviral drugs is difficult to estimate. We recognize that such patients do still exist and that the size of the population is probably decreasing, but convincing data to indicate the number of patients in need of early access is lacking. In addition to the criteria of failing a third regimen, a key factor in the equation is the urgency of the patient’s need for new therapy.
Tension exists between the clinical and research aspects of EAPs. While the primary rationale for EAPs is to provide early access to drugs for patients in need, there are secondary competing interests in terms of the requirements to collect useful safety data on emerging compounds that might identify unknown safety issues and ultimately help guide treatment strategies. However, current data collection practices rarely yield useful information.
EAPs are associated with a heavy administrative burden that limits the ability of some sites to participate and these programs are unfunded or underfunded. This burden appears to be particularly acute in the academic research setting, where intensive IRB approval and oversight combined with the data collection requirements of the protocols has forced some centers to forego participation in EAPs until they can find a way to pay for them. As sites refuse to participate, this limits patient access to the EAP.
EAPs need to be conceived of within the context of clinical strategies overall. As the HIV epidemic and antiretroviral treatment strategies have evolved, it is no longer advisable to give patients new drugs without ensuring other active agents in the regimen. Otherwise patients would effectively be receiving virtual monotherapy and risk the development of drug resistance and subsequent regimen failure.
Geographic limitations continue to impede access for patients in small cities and in rural areas. Ideally, the system should be able to provide access to experimental drugs for all patients who need them and qualify for EAPs regardless of where they live.
Information about the EAPs can be quite difficult to find. Some companies do not list sites participating in their EAP on their own websites or on database websites like clinicaltrials.gov, making it very difficult for patients and their physicians to know where they might access experimental agents outside of clinical trials. Similarly, companies may not adequately advertise the existence of their EAPs. Industry is particularly concerned about the perceived appearance of pre-approval marketing.




Specific Recommendations:



· Explore the potential for standardization of EAP data collection requirements and safety reporting. This could reduce the redundancy in the current system and simplify participation in multiple simultaneous EAPs.

· Consider further collaboration between regulatory agencies and the pharmaceutical companies in the design of EAPs to include the simultaneous use of multiple investigational agents and to identify creative study designs that will limit the use of virtual monotherapy and address the evolving therapeutic needs of patients.

· Explore standardizing EAP protocols so that some of the administrative work (example being submission to IRBs) can be lessened.

· Explore the potential collaboration between the FDA and other regulatory bodies to standardize and minimize the burden, as much as possible, for the very complex and variable regulatory requirements for EAPs.

· Explore how the pharmaceutical companies can standardize their EAPs in terms of development of case report forms and adverse events reporting.

· Provide guidance to contract research organizations (CROs) on data collection requirements such that the administrative burden for an EAP is reduced compared to a standard clinical trial.

· Apply and take advantage of technological modernization in adverse event reporting. For example, a centralized electronic database could provide access to basic tabulation and analysis of the voluminous serious adverse event reports that in their present form are virtually useless to the individual site investigators and site IRBs.

· Consider a two tiered expanded access approach: one would be an actual research protocol designed to address specific questions leading to approval, and which would be appropriately reimbursed like any other clinical trial. Such a protocol could address the types of issues normally studied in Phase 4 studies. These could be designed to target underrepresented patient populations. The second parallel approach could be a simplified protocol, similar to the current EAP protocols. However, both tiers likely would need reimbursement to participating institutions due to non-recovered costs of participation in the EAP.







A full report from this roundtable discussion will be available on the Forum for Collaborative HIV Research’s website at http://hivforum.org/projects/Expanded%20Access.htm





Forum for Collaborative HIV Research

Rethinking the Approach to Expanded Access Programs

February 16, 2007

Washington, D.C.





Valerianna Amorosa, M.D.

University of Pennsylvania


Christine Balt, M.S., R.N., APRN-BC, AACRN
Indiana University Division of Infectious Diseases

Association of Nurses in AIDS Care



Debra Birnkrant, M.D.

FDA


Rob Camp

ACTG NCAB



Ben Cheng, M.Sc.

Forum for Collaborative HIV Research


Joel Gallant, M.D., M.P.H.

Johns Hopkins University School of Medicine



Roy Gulick, M.D., M.P.H.

Cornell University


Michael Horberg, M.D., M.A.S., F.A.C.P.

Kaiser Permanente



Ernest Igwacho

Forum for Collaborative HIV Research


Daniel Kuritzkes, M.D.

Harvard Medical School



Katherine Laessig, M.D.

FDA


Randi Leavitt, M.D., Ph.D.

Merck & Co., Inc.



Meagan Lyon, M.P.H

Forum for Collaborative HIV Research


Bill Mannion, R.N., B.S.N.

Pfizer, Inc.



Karen Manson

Tibotec BVBA


Kendall Marcus, M.D.

FDA



Scott McCallister, M.D.

Panacos Pharmaceuticals


Marita McDonough, R.N., M.P.A.

Boehringer Ingelheim Pharmaceuticals, Inc.



Luis Mendao

European Aids Treatment Group


Veronica Miller, Ph.D.

Forum for Collaborative HIV Research



Nathalie Morgensztejn

EMEA representative for the HIV Forum


Jeff Murray, M.D., M.P.H.

FDA



Linda Onaga
Forum for Collaborative HIV Research


Frederick Schmid, D.V.M., M.B.A.
Panacos Pharmaceuticals


Kimberly Struble, Pharm.D.
FDA
Pablo Tebas, M.D.
University of Pennsylvania



Randall Tressler, M.D.
Pfizer, Inc.



Nelson Vergel, B.Ch.E., M.B.A

Salvagetherapies.org



Douglas Ward, M.D.

Dupont Circle Physicians Group


Eric Zechman

Medical Writer

Do not do as I did

Please read the article written by Enid Vazquez in the latest Positively Aware, one of the main free HIV magazines distributed around the U.S.


My comments are in the last part in the section called "Don't do as I did"

I want to make sure that people who are applying for TMC 125 expanded access are very careful when assuming that this medication will be represent an "active" agent. No genotype test for EAP drugs is available, so we are in danger of assuming that a new drug is an active drug (this assumption may not be true when starting drugs in existing classes). An active drug is one that is shown in your resistance test (genotype or phenotype) to have a good chance to work in controlling your virus. Another danger with TMC 125 is that it is a NNRTI and we know that prior NNRTI resistance can be archived and not show up in genotype tests. Many patients like myself with extensive NNRTI resistance in the past show activity to that class in our genotype test. If the doctor does not carefully review prior medication history and asks the right questions to the patient, both the doctor and patient will assume that there is no archived prior resistance. So be very careful!

If you are to start a new combo with MK 518 integrase inhibitor, a drug that is showing more promise than most for patients with multidrug resistance, make sure that you start it with Fuzeon (if you are Fuzeon naive) and/or Maraviroc (if you have a R5 tropic virus) unless you can be 100 % certain that TMC 125 will work on your virus. With all the hype surrounding TMC 114, I made the terrible assumption about the activity of TMC 114 (Darunavir, Prezista) when I got that drug via EAP to start it with MK 518 as part of Merck's phase III study. Read more in the link below.


Around 30 % of people who have extensive Kaletra and protease resistance may have pre-existing resistance to Aptivus (Tipranavir) and/or Prezista (Darunavir). No one is talking about this and there are a few conference posters on the subject but not discussed by anyone. Do not fall prey of the hype that is built around new medications, unless they are in a new class that you have never taken before and that show great response. This is the best chance for many of us to attain undetectable virus and hopefully keep it that way for a long time, if you do it right the first time.

http://www.tpan.com/publications/pa/07_02/tales_of_salvage.shtml

How many people are in dire need for new HIV meds in the US in 2007

The number of salvage patients may be calculated with some current data and assumptions:
450,000 under treatment in the US

Assume: aconservative high estimate of 60 % of patients treated have undetectable viral load (under 50 copies per ml)(from 96 week studies of different drugs)

so, 40 % have over 50 copies per ml

out of those, 13 % have three class resistance (from prior studies)

so around 18,540 patients have 3 class resistance

let's assume only half of them are in dire need since
their CD4 cells are under 100

So around 9000 are in dire need for new meds. They are
looking not for one, but for three new active agents
to combine

possibilities:

1- TMC 125+ Fuzeon + MK 518+ NRTIs
2- TMC 275+ Fuzeon+ Maraviroc+ NRTIs- probably not as good as (1)
3- Maraviroc + MK 518 + TMC 125 ( all expanded access)

Many of those patients have Fuzeon resistance in 2007. Some of the Fuzeon resistant patients also have resistance to Prezista and Aptivus.

TMC 125 only got 30 % of people undetectable when combined with Fuzeon in a prior 24 week data, so it may not provide much activity for patients with several NNRTI
resistance mutations

The only drug that will truly help most people is MK 518, the integrase inhibitor from Merck,since it is a new class and it is extremely potent. The
secret to its success will be how to add two more active
agents that wil sustain its work effectiveness. 30 % of patients in the Merck BENCHMRK study failed MK 518 after 48 weeks when combined with a background with no active agents. MK 518's effectiveness increases to about 94% when started with Fuzeon in Fuzeon naive patients. Hopefully, this will be sustained over 96 weeks or more. Resistance to MK 518 will also mean that resistance to the Gilead integrase will be present.

30 % of patients with heavy prior protease resistance
have pre existing resistance to Aptivus and Prezista,
so 30 % of 90000 will be in trouble if they also have
Fuzeon resistance (I am in this group)

Maraviroc will only work for 50% of patients (those
with R5). It is a drug that will help patients in
early stages, not in salvage


So, it is not that simple just to come up with
generalizations about how wonderful it is now to
combine these agents and how there are no patients who need new medications after the Merck integrase is approved.

These assumptions do not include people in Canada, Europe, and the rest of the world.

Comments from Dr Paul Bellman about HIV rescue therapy

Dear Nelson and Friends,

I read with interest the attached excellent review of treatment strategies for PRN Notebook by Dr's Charles Farthing and Athe Tsibris. I believe and feel strongly that two incorrect conclusions might be drawn from the studies presented in article that could adversely effect treatment strategy in individual patients.

1. Firstly, the conclusion is drawn from the tipranavir (Aptivus) and darunavir (Prezista) trials that "Salvage therapy is best undertaken when at least two active drugs are available." Although the data presented from the tipranavir and darunavir trials show that two active drugs are better than one active drug for patients starting a new salvage regimen the results in my mind are pretty poor even when two new actives agents are used. MY CONCLUSION IS THAT 3 not 2 ACTIVE DRUGS SHOULD BE STARTED IF AT ALL POSSIBLE IN A SALVAGE REGIMEN.

Starting just two drugs is not quite as bad as starting one new drug but similarly risks exposing patients to sequential therapy and blowing sometimes the last remaining treatment options. In fact starting two new "active agents" in salvage therapy instead of one active agent risks blowing two drugs which is worse that blowing one active drug.

For example, the clinical trial presented on tipranavir shows that only 34% of pts given tipranavir and enfurvitide (Fuzeon) sustained an undetectable viral load at 96 weeks. That means that 66% of patients probably ended up resistant to Fuzeon and Aptivus and possibly components of their "optimized" background.

So the question needs to be posed when is it worth the risk of failing therapy and using up two active agents instead of waiting for three active agents?. Unfortunately, none of the studies presented provide much help in answering this question.

In the Resist studies with tipranavir the average CD4 cell count at entry was 196 with only 20% of the patients studied starting with less than 50 T cells. Thus easier to treat patients with higher T cells are mixed in with more difficult to treat patients. Although patients with higher CD4 cells may have a lot of resistance they are often viral disconnect patients who maintain stable CD4 cells sometimes for years despite drug resistance. (more on this later)

The consequences of more sequential therapy for these patients is less dire than for more advanced patients with very low CD4 cells whose lives may depend on the success of a salvage regimen using new meds.

Unfortunately the consensus in my profession as reflected in this article and the DHHS treatment guidelines is to start two new drugs. Perhaps this is why Nelson has correctly described patients truly in need of salvage rx as the "invisibles" in an important Wall Street Journal article on the plight of HIV infected patients in need of better therapies.

It seems wrong to me that the standard of care for easier to treat naive patients is to get three fully active drugs in combination when much more difficult to treat patients are told the standard is to get just two new active drugs.


I believe patients with very low CD4 cells and multidrug resistance and who have or at risk of suffering from AIDS complications are in a different category than healthier patients with MDR-HIV who are usually asymptomatic. These patients sometimes desperately need three fully active drugs in their salvage regimen.

In addition as Nelson correctly points out on his website salvagetherapies.org patients are getting exposed to sequential therapy who participate in clinical trials of new drugs where patients are randomized to drug or placebo and less than 3 fully active drugs are given.

There needs to be a pooled treatment registry tracking the outcomes of all salvage patients treated in clinical trials to learn what approaches lead to the best outcomes including what constitutes the best Optimized Background regimen for patients who must start a substandard regimen with only one or two active drugs if the clinical situation dictates an urgent treatment change,

Drug companies like BI, Merck and Tibotec deserve great credit for developing new drugs and bringing them to market. However it is important for the HIV medical community and patient community to realize that the focus of drug companies is to gain accelerated FDA approval based on a multidrug resistance based indication and win market share for their new drug. How to best use their drug with other active agents is often left to private investigators in post approval studies.

In summary Dr's Farthing and Tsibris conclude that "when using tipranavir or darunavir be sure to combine it with at least one new active agent." I believe that this is a mistake and should specify using tipranavir or darunavir with at least 2 active drugs. The current second wave of HAART can make this reality a possibility with two new protease inhibitors, a new non nucleoside, Maraviroc, an integrase inhibitor and Fuzeon. The challenge that we face now is how to treat patients who have already developed resistance to several of these products since their approval or in EAPs and phase III studies.

2. My second point regards what I believe can be a wrong conclusion drawn from a study referenced in the article entitled "Rate of Viral evolution and risk of losing future drug options in heavily pretreated patients remaining on a stable partially suppressive regimen" by H Hatano.

Farthing raises concerns that patients who are stable but elect to continue their meds rather than starting new drugs could lose active drugs due to resistance due to progressive resistance and cross resistance. This supports the notion that patients with viral breakthrough and drug resistance should if possible be put on maximally suppressive regimens to avoid using up future drug options.

While this is a reasonable concern, there is in my mind little evidence in the actual paper supporting this concern. In addition, there is no evidence in the Hatano paper that patient outcomes are compromised by the strategy of maintaining an MDR-HIV patient who has a viral disconnect response.

In fact only 4% of patients followed in this study developed evidence of new resistance to tipranavir which could compromise a future salvage regimen. This is a complicated study but in my opinion after careful review if anything it shows the opposite: that it is reasonably safe to continue a regimen that is maintaining a good immune response despite ongoing viral replication (viral disconnect) from the standpoint of preserving good future treatment options

In fact, a recent study published in JAIDS in September 2004 entitled "Effect of Persistent Moderate Viremia on Disease Progression During HIV Therapy" shows that patients with less than 20,000 copies/ml have similar outcomes as patients with less than 400 copies /ml in patients on treatment when followed up several years later. Presumably some of the patients with ongoing viremia followed in this study also developed some additional resistance mutations which did not impact on outcomes. Of note patients with viral loads >than 20,000 had worse outcomes.

The issue of how to strategically address treatment in healthier patients with drug resistance is a complicated one and requires the careful individualized application of principles of therapy including drug toxicity concerns not just drug resistance concerns. More research is needed in these patients that tracks clinical outcomes.

Its great news that finally new HIV drugs with new mechanisms of action are becoming available to patients. Let's make sure we make the best possible use these new drugs by strategically applying what we have learned about principles of antiviral therapy such as combination therapy with three active drugs (whether treatment naive or experienced) and by tracking actual patient outcomes.

Sincerely,
Dr. Paul Bellman
New York City


Reference:

http://www.prn.org/html/authorized/prnnotebook/index.php?actpage=2006/volume11_3/salvage_sum.php
Surviving Antiretroviral Drug Resistance: Strategies for Optimal Use of Therapeutic Agents

The second wave of HAART: Combining MK 518 plus TMC 125 or Maraviroc

Now, patients with HIV multidrug resistance can start three active drugs in three different expanded access programs! This is the first time this has been possible in the 25 years of the AIDS epidemic. The closest thing to this wonderful time was the 1996-1998 period.

This information was provided by Merck (Feb 20, 2007):

Co-Administration of MK-0518 and TMC125


Merck & Co, Inc and Tibotec Pharmaceuticals Ltd. have jointly reviewed the available pharmacokinetic data on TMC125 and MK-0518 and concluded that co-administration of TMC125 and MK-0518 may be allowed for patients in the MK-0518 expanded access program. This assessment is based upon data collected from a drug-drug interaction pharmacokinetic study in 19 healthy volunteers to evaluate the potential interaction of the two compounds.
Preliminary safety data from the study indicated that co-administration of MK-0518 and TMC125 was generally well tolerated. Preliminary MK-0518 pharmacokinetic data showed a modest effect of TMC125 on MK-0518 pharmacokinetics (mean decrease in AUC of ~10%, in Cmax of ~11%, and C12 hr of ~34%). This overall modest decrease in MK-0518 pharmacokinetic parameter values is not felt to require dose adjustment based on the efficacy demonstrated by MK-0518 doses ranging from 100 to 600 mg in treatment-naïve patients and from 200 mg to 600 mg in treatment-experienced patients. Preliminary TMC125 pharmacokinetic data showed essentially no meaningful effect of MK-0518 on TMC125 pharmacokinetics (~4 to 17% mean increase in TMC125 pharmacokinetic parameter values).

Co-administration of MK-0518 and Maraviroc


Merck & Co, Inc. has reviewed the available pharmacokinetic data on MK-0518 and Maraviroc and concluded that co-administration of MK-0518 and Maraviroc may be allowed for patients in the MK-0518 expanded access program.

Maraviroc is predominantly metabolized by CYP3A4 with renal clearance contributing less than 25% of total clearance. Maraviroc has been shown to have no effect on the major cytochrome P450s in vitro, at clinically relevant concentrations. Maraviroc has also been shown to have no clinically relevant effect on CYP3A4 activity. As such, Maraviroc is not expected to affect the pharmacokinetics of other co-administered drugs metabolized by CYP450. Maraviroc exposure is affected by modulators of CYP3A4 activity.

MK-0518 is primarily cleared by metabolism via glucuronidation (by UGT1A1) with a small renal component. In vitro studies have confirmed it is not a substrate or inhibitor/inducer of cytochrome P450s. A clinical study with MK-0518 showed no effect on midazolam pharmacokinetics.

Based on these data, Maraviroc and MK-0518 are not expected to interact with each other and may be co-administered in expanded access programs without dose adjustment of either agent.
MK-0518 Protocol 023 Expanded Access Program Amendment

A protocol amendment is in preparation to allow enrollment of patients who have:
-chronic renal insufficiency including patients undergoing dialysis
-failed an NNRTI containing regimen but do not have documented genotypic or phenotypic resistance to NNRTIs.
All other inclusion/exclusion criteria remain unchanged and patients need to have documented phenotypic or genotypic resistance to both NRTIs and PIs.

Prior to approval of the protocol amendment, enrollment of these patients will be permitted as a protocol deviation and it will be necessary to obtain a sponsor consultation Form from Parexel and IRB/ERC approval for each individual patient.

My experience with MK 518 and Prezista..and thoughts about TNX 355

Prior to joining Merck's phase III, my CD4 cells wereon their way down ....from 540 three years ago to 300, then to 200's and finally to 180 in April 2006.My viral load set point was around 15,000-30,000 for years until April 2006 (VL then = 69,000). I have extensive PI , non nuke and nuke resistance and also failed Fuzeon two years ago. I also had preexisting Aptivus resistance, so I never took that drug.

I had an internal conflict abut making the decision of taking a chance or waiting for later to get two active agents started at the same time. I knew the Tibotec DUET study sucked due to the high probabilities of TMC 125 placebo (50%) and 6 month wait period to get open label drug. Merck's integrase inhibitor study was a little more friendly with a lower chance of placebo (33%) and a switch to open label after 16 weeks if you fail.

After the activist community was successful in getting Tibotec and Merck to work together, I decided to apply for TMC 114's (Prezista) expanded access program and at the same time to apply for the last spot on the Merck trial in Texas (in Austin). Getting a drug via expanded access and combining it with another experimental drug in phase III studies had never been done before in HIV.

There was a 33% chance I would get placebo MK518 and go on sequential monotherapy of Prezista with a background of Truvada. My VL dropped to 2000 in a matter of days after I started the study. My Vl dropped to under 50 copies per ml in 3 weeks and stayed there for 24 weeks. I was so happy since I had never had undetectable viral load in 23 years. My CD4 cells went up from 180 to 450 in that period. At week 24, I had what I thought was a blip of 800. Two weeks later it was 20,000. Three months later, I am still at 20,000. My CD 4 cells are now 330 ( a lotbetter than baseline), so I am still benefiting fromthe MK 518+Prezista+ Truvada combo. I also added Reyataz to it in hopes that it would increase the MK518 levels (my VL went down to 2000 after I added Reyataz, but then rebounded a month later)

I have been trying to find out why this happened. I have never had adherence problems at all. But I failed to think about the possibility of Prezista’s preexisting resistance, which may have exposed me to virtual monotherapy of MK 518. With all the hype from Tibotec about their wonder PI, I jumped on their EAP to combine it with MK 518. As you probably know, no resistance test for the study drug is available in EAP's, so you are always taking a chance if you are taking a drug in an existing class to which you have developed resistance. So, I did not know if Prezista had any activity to my virus at entry. After looking at presented isolate data, it seems that some people with heavy Kaletra resistance can also have baseline resistance to Aptivus and/or Prezista even if they have never taken those drugs. After having Monogram run Prezista’s resistance on my baseline vector at study entry (which had no Prezista resistance info then since the drug was not approved yet), I found out the hard way I am in that “weird”group of difficult to treat patients, as Lew from Tibotec would call us.

Now I am hoping that I my virus is R5 tropic so that I can get access to Maraviroc and that TMC 278 is the super non nuke we hope it will be. And I am also keeping my eyes open for gene therapy. In the meanwhile, I am hoping that M K 518 keeps my virus' replicating capacity down so that I can live healthy like I have for 24 years without complete viral suppression. With the Panaco’s drug’s bad news, and now TNX 355’s potential termination, I am a little concerned about the pipeline.



About TNX 355….. Most of the patients in the TANOX study had no access to another active agent. TANOX did not allow Fuzeon use either. So, does anyone think that the data on TNX 355 would not have looked better if better OBT’s had been included in the study?I agree with Marty Delaney that this drug may be a horribly expensive to make. But are we sure of that 100%? Would this drug provide good activity when used withMaraviroc, Fuzeon, MK 518 or TMC 278? Can this drug be available via an orphan drug set up? Should this drug be completely dropped? Can a once every two week drug not compete with Fuzeon? Anyway, I am not sure that we have the full picture about this drug and it would be unfortunate to see it dropped. Of course, I have avery strong bias for having this drug move forward ….

Maraviroc, a new entry inhibitor, available via expanded access

First watch this cool video that explains how Maraviroc works
http://www.maraviroceap.com/interested_healthcare_professional/ccr5_tropism_video.aspx


Overview and Registration for the Maraviroc EAP

--------------------------------------------------------------------------------

Overview of the Maraviroc EAP
Welcome to the Maraviroc EAP Website.

Maraviroc is an investigational drug being developed for use in combination with other antiretroviral medications for the treatment of human immunodeficiency virus, type-1 (HIV-1) infected treatment-experienced patients.

Maraviroc uses a new mechanism of action that blocks viral entry into human cells by binding to the chemokine (C-C motif) receptor 5 (CCR5) co-receptor located on the surface of the CD4 cell. It belongs to a new class of drugs known as CCR5 antagonists. The mechanism prevents HIV from entering target cells thereby preventing the initiation of HIV's replication cycle. This is different from currently available oral HIV/AIDS antiretroviral drugs (such as protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors) which work by inhibiting HIV/AIDS replication intracellularly. Maraviroc has also been shown in vitro to be effective against HIV/AIDS strains that are resistant to the current classes of HIV/AIDS antiretroviral agents.

Maraviroc, in combination with other antiretrovirals, is currently under development for the treatment of HIV. The trials, MOTIVATE-1 and 2 (Maraviroc Plus Optimized Therapy In Viremic Antiretroviral Treatment-Experienced Patients), represent 24-week data of Optimized Background Therapy (OBT), with or without maraviroc, in over 1,000 highly treatment-experienced patients with CCR5-tropic HIV-1.

The purpose of the maraviroc EAP is to provide access to maraviroc for patients who have limited or no other treatment options. This study will also permit collection of safety data in a larger and diverse population. It will also evaluate the effectiveness of maraviroc in treatment-experienced patients who are followed according to local medical practice.

The program has the capacity to enroll up to 6000 men and women worldwide.



Maraviroc EAP Patient Entry Criteria


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Following is a list of some of the major inclusion/exclusion criteria for the maraviroc EAP. Please note that this list is not exhaustive. For further information, please call the Toll Free Line @ 1-888-275-4478 and a clinical research assistant will assist you.
INCLUSION CRITERIA

Subjects, male or female, must meet all of the following inclusion criteria to be eligible for enrollment into the trial:

At least 16 years of age (or minimum adult age as determined by local regulatory authorities or as dictated by local law)
Subjects with limited or no approved treatment options available to them due to resistance or intolerance
Have an HIV-1 RNA ≥ 1000 copies/ml
Have only R5 HIV-1
Have negative urine pregnancy test prior to the first dose of study medication for Women of Child Bearing Potential
Agree to use an effective barrier contraception method
Subjects receiving investigational antiretroviral compounds through participation in a Phase 3 or 4 clinical study are eligible to participate in this trial provided:
That the 2 investigational agents are required to offer the patient a regimen with 2 or 3 active antiretroviral drugs (i.e. one or fewer commercially available agent is available to the patient due to prior resistance or intolerance)
Neither protocol prohibits the use of the other antiretroviral agent, AND
The dosing of the two agents when used together is known AND supported by published literature OR a letter from the Pfizer clinical pharmacologists for maraviroc identifying the dose to be used with maraviroc.
EXCLUSION CRITERIA

Subjects presenting with any of the following will not be included in the trial:

Unable to provide consent
Failed prior treatment with any CCR5 antagonist, in any ongoing CCR5 trials or having previously discontinued Maraviroc in trials
Potentially life threatening (Grade 4) laboratory abnormality or medical condition still under investigation unless a diagnosis has been established and felt not to affect risk/benefit assessment or eventual interpretation of safety results
Any condition (including alcohol and drug abuse) which, in the opinion of the investigator, could compromise the subject’s safety or adherence to the study protocol
Pregnant or nursing an infant, or planning to become pregnant
Inability to tolerate oral medication
Subject requires a contraindicated medication
Subjects with known hypersensitivity to maraviroc, excipients or dyes.
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