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HIV Drug Pipeline at CROI
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--for patients with extensive drug resistance a little is ongoing.......
Reported by Jules Levin
CROI 2009 Feb 8-12 Montreal
For early-line therapy there are several new twists. For patients with pan-class HIV drug resistance as I see there are a few but limited promising new developments, there is GSK's 2 integrase inhibitors, if they are active against raltegravir resistance, which in vitro they appear to be but this has to be tested in patients, so these integrase inhibitors could also be for early therapy, perhaps firstline. There is the Tanox drug which is an infusion, there is PRO140 which is in reality a CCR5 inhibitor which may be active against CCR5 drug maraviroc resistance which I don't think has been tested yet in patients but still PRO140 is an infusion even if perhaps subcutaneous; there are the 2 Ardea NNRTIs, in the poster it says RDEA427 retains activity against "many of the recently identified etravirine mutations" which is a key question so they will have to prove this in patients. There is also the Idenix NNRTI which was bought recently by GSK, and again a key question is can they prove it's activity against etravirine resistance mutations. There is CMX 157 which is merely a new perhaps improved of tenofovir, yet to be proven. There is the Merck RNase program which displayed its first poster at a major conference, see link below, but is in preclinical and in very early development; as they identified a series of compounds with HIV activity in cell culture, I don't know how close this could be. Then there are the maturation inhibitors, Panacos' bevirimat now at Myriad and the back up maturation inhibitors at Myriad and at Panacos. Bevirimat appears to be a reasonable candidate but whether it can be used by a patient appears to require a lab test to see if a patient has certain polymotphism mutations, so the drug will be active for about 50% of patients. Myriad has an additional maturation inhibitor program that includes MPC-9055 which is early clinical development and Myriad said they plan to start a new bevirimat study and develop MPC-9055 as well. In sum, there are several possibilities for patients with extensive HIV drug resistance and with pan-class resistance. The most promise at this time studies for the near future may be the GSK integrase inhibitors, they have 2 in early clinical patient studies, if it will be active against raltegravir resistance. And if they prove the new NNRTIs from Idenix/GSK and Ardea are active against etravirine mutations in patients with etravirine resistance these are promising. There still is CCR5 maraviroc and soon vicriviroc, for CCR5-tropic patients. If the maturation inhibitors work out that would provide helpful therapy but bevirimat has limited promise, for 50% of patients, if it gets developed. The Myriad maturation inhibitors are further behind and perhaps that will work out. Panacos has a second generation maturation inhibitor program and an oral fusion inhibitor, but as you know the company is almost bankrupt and looking to sell its assets. Several years ago we had an exciting and explosive new drug development situation for pan-resistant patients with several very good drugs in development-- darunavir, etravirine, raltegravir, maraviroc and prior to that T-20 and tipranavir. Don't lose these drugs, adherence is the key. Right now future options appears limited for bright and novel developments. The only new class in clinical development is maturation inhibitors. Why? Coming up with new ideas is not easy. It's much harder to develop new drugs, it's expensive and the field of available drugs is very crowded, so there is limited opportunity to make much profit. J&J and Tibotec displayed guts, a big commitment to HIV, and were fortunate to be able to develop their new drugs including TMC278 out of the Belgium labs co-founded by Rudi Pauwels and Paul Stoffels in the 1990s, where J&J got these drugs, thank them all for their foresight and skills. Both Virco & Tibotec co-founded by Pauwels & Stoffels in the 1994/1995 were acquired by J&J in 2002. John Erickson was key to the invention of darunavir at Tibotec. He was also instrumental in inventing ritonavir, so he has played a key role in protease inhibitor and HAART development. Erickson has gone on to be the Founder of Sequoia, where they are working on developing new HIV protease inhibitors for patients with extensive resistance to protease inhibitors, and Sequoia developed a booster substitute for ritonavir still in early development and presented at CROI. Rudy Pauwells worked in Erick DeClecq's lab in Belgium and it was DeClecq who established the relationship between his lab and Janssen. Janssen was part of J&J. I recall participating in the early scientific meetings in Europe during the 1990s organized by Pauwels and other resistance scientists before they discovered darunavir (TMC114) and etravirine (TMC125), where resistance testing was first discussed. These meetings were in the pre-discovery days of resistance testing, they helped to develop and promote resistance testing. Merck as well displayed guts & determination & a big commitment. The Merck integrase program started at least 10 years ago hit a wall many times over the years appearing to be stalled. The development team at Merck deserves much credit for sticking this out. As well Pfizer and Schering have demonstrated commitment to their CCR5 programs. A full new drug development program is very expensive and in order to make a commitment you need a drug or a new class of drugs with great promise, and it has become much harder to find these.. Patients who still have not used Fuzeon can still use it. We can hope that novel major breakthroughs might occur but right now the future has a few hopeful opportunities for new therapy, but it's not like it was several years ago with the explosion of new potent drugs from Merck & Tibotec. But don't forget Pfizer's CCR5 drug maraviroc and Schering Plough's vicriviroc. For the CCR5-tropic patient this remains a viable treatment option, particularly pan-class resistant.. CCR5 drugs are a new class with no cross-resistance with other HIV drug classes. It was a big discovery and promise for patients. Recently Pfizer reported positive safety data and are following through with their 5-year safety data commitment. As well, Schering will provide similar safety data. Sure you have to take a test, the Tropism assay to see if a patients is CCR5-tropic to see if you can use the drug, but if you need a new drug and you are CCR5-tropic these drugs are potent and maraviroc has demonstrated a good side effects and clean lipids profile in patients in Phase 3. I remember when T-20 was in early development and everyone was very excited to be able to get this drug for patients with resistance. I participated in Roche-community study design planning meetings. Advocates were very excited and anxious for this drug. The same can be said for tipranavir. Just like with T-20 there was a tremendous need for new drugs for patients with drug resistance and after T-20 Boerhinger Ingelheim acquired tipranavir. Again patients and advocates were very excited and anxious for tipranavir. Clearly people forgot those days, but I don't and they shouldn't. Here are links to reports from CROI with more detailed reports forthcoming for Myriad maturation inhibitor and Ardea NNRTI programs. Jules
New HIV Agents - written by Joe Eron, MD, University of North Carolina - (02/25/09)
Weekly and Biweekly Subcutaneous PRO 140 Demonstrates Potent, Sustained Antiviral Activity: 2-week study - (02/26/09)
New HIV Drug Candidates in Pre-Clinical Development - (02/24/09)
TNX-355 survives Tanox: new Phase 2 Dose-Finding StudyStudy
TaiMed Biologics Inc. will conduct clinical trials of TNX-355 -- also known as Ibalizumab -- from a location on the West Loop near the former Tanox ...
www.natap.org/2009/HIV/012809_01.htm
Phase 1, Single Ascending Oral Dose Study of the Safety, Tolerability, and Pharmacokinetics of MPC-9055 a Novel HIV-1 Maturation Inhibitor in HIV Negative Healthy Subjects - (02/27/09)
Anti-viral Characterization in vitro of a Novel Maturation Inhibitor, MPC-9055 - (02/27/09)
RDEA427 and RDEA640 are Novel NNRTIs with Potent Anti-HIV Activity Against NNRTI-Resistant Viruses - (02/27/09)
In Vitro Resistance Selection Study and Favorable Human Pharmacokinetic Properties of RDEA427, a New HIV NNRTI - (02/27/09)
A Single-dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of OBP-601, a Novel NRTI, in Healthy Subjects - (02/24/09)
CMX157 Conjugate of tenofovir, prodrug: Hexadecyloxypropyl Tenofovir Associates Directly with HIV and Subsequently Inhibits Viral Replication in Untreated Cells - (02/24/09)
Inhibitors of the RNase H Activity of Reverse Transcriptase as an Approach to New HIV-1 Antiretroviral Agents: Merck program - (02/24/09)
New HIV Drugs: NNRTI, PRO140, Maturation, 2 New Ardea NNRTIs (02/19/09)
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