HTB

Pipeline compounds and new approaches to treatment

Simon Collins, HIV i-Base

There were fewer presentations at this years meeting on either new drugs or comparative studies between existing drugs. While the missing studies were very noticeable, this is probably more due to the recent approval of several new drugs over the last two years.

It may be significant though that most of the notable studies were nearly all included in one oral abstract session. [1]

QUAD, elvitegravir and cobicistat

New clinical data was presented on the integrase inhibitor elvitegravir, in combination with a new pharmacokinetic booster from Gilead called cobicistat (previously GS-9350), both coformulated with tenofovir/FTC in a four-in-one tablet called Quad. [2]

When Quad was compared to Atripla (efavirenz + tenofovir + FTC), over 80% of patients in each group had undetectable viral load (less than 50 copies/mL) after 24 weeks. However, mean  baseline viral load was <40,000 copies/mL, and it was only >100,000 copies/mL in 25% of patients. In this Phase 2 study, patients in the Quad group (n=48) became undetectable more quickly than those on Atripla (n=23), as was seen with raltegravir. For example, after 8 weeks, about 80% people were undetectable with Quad compared to about 50% with Atripla.

While Quad was better tolerated in terms of not having efavirenz-related side effects, a caution due to the impact of cobicistat on reducing estimated glomerular filtration rate (eGFR) – but not actual GFR – suggests that management of renal toxicity may have to be handled differently.

Results from a second Phase 2 study were presented in the same oral presentation, this time comparing the new booster (n=50) to ritonavir (n=29), each in combination with atazanavir, tenofovir and FTC. [2]

No differences were seen in efficacy or tolerability between the two boosters. Unlike ritonavir, cobicistat has no antiretroviral activity.

In summary, results were sufficiently encouraging for both QUAD and cobicistat to be taken into larger Phase 3 studies.

Compounds in earlier development

A dose-finding Phase 1 study of a CCR5-inhibitor in development with Tobira Pharmaceuticals under the compound name TBR-652. The compound has a plasma half-life of 35-40 hours allowing once-daily dosing and although metabolised by CYP and non-CYP pathways is neither and inducer or inhibitor of CYP P450. [3]

These first results in 54 HIV-positive patients produced median viral load reductions of 1.7 log with the 50, 75 and 150mg doses after 10 days monotherapy. Although baseline viral load was lower in the 150mg group (median 4.0 logs, compared to 4.5 and 4.6 logs in the 50mg and 75mg groups), all patients using the 75mg dose had >1.0 log reductions. Patients were treatment-experienced (off treatment for at least 6 weeks), CCR5-naïve and CCR5-postive. No dose-related or serious side effects were reported, though the study was only in about 50 people.

Side effects were mild (none reported at the 75mg dose) and included nausea, diarrhoea, headache and fatigue in greater frequency at the 100 and 150mg – although many of these were reported as being associated with one patient with a concomitant infection.

Very little new information was available for the new integrase inhibitor in development with Shionogi and GSK called S/GSK1349572. [4] Although included in the oral session, this was more a product overview, adding no new in vivo data to that presented at the IAS meeting in Cape Town last year. [5]

Results from a pooled analysis of 721 treatment experienced patients in the unfortunately named Victor-E 3 and 4 Phase studies, presented by Joe Gathe, disappointingly found to too little difference compared to placebo for the troubled CCR5-inhibitor vicriviroc to continue to be taken forward for further development. In a modified ITT analysis the percentage of patients with undetectable viral load (<50 copies/mL) at 48 weeks was 64% and 61% in the vicriviroc and placebo groups respectively (p=0.6). [6]

The presentation suggested this was because of more effective background drugs were available for patients to construct optimum background therapy (approximately 65% had >3 active drugs), for the third agent to show significant advantages. A prespecified sub analysis showed that 70% of people randomised to the vicriviroc arms who had <2 active drugs achieved <50 copies/mL compared to 55% of the placebo group, and an indication that this was significant. As the vicriviroc group had fewer active drugs at baseline, this potentially obscured a difference in activity between the two arms.

While safety was apparently similar, during the questions, we learned that there were 7 vs 0 deaths in the vicriviroc and placebo arms respectively, not apparently significant after adjusting for time on treatment.

Despite the early promise, it looks likely that the development of this compound will now be put on hold. [6]

Preliminary studies looking at a handful of other targets and approaches, including attempts to target latently infected cells were presented as posters.

Frauke Christ and colleagues from University of Leuven, Belgium, detailed potential compounds from a new class of integrase inhibitor, called LEDGINS, that would not bind at the active site, and therefore not be cross-resistance to raltegravir or elvitegravir. These potential molecules, 2-(quinolin-3-yl)acetic acid derivatives, were designed by rational drug design, and identified after screening 200,000 molecules. [7]

Stephen Mason presented preclinical results on two early compounds that could interfere with the assembly and stability of the capsid core, that are in development at Boehringer Ingleheim. These compounds interrupt the process for assembling new virus and were shown to have activity against resistant HIV from other classes.

Many presentations reiterated that eradication with current drugs is not possible, due to the inability to recognise latently infected resting cells. Even after many years of maximally suppressive therapy, it is well established that viral load rapidly rebounds to pretreatment levels, potentially within weeks of discontinuing treatment.

At least five new types of treatment are the focus of research on how to target latently infected cells. These include cellular restriction factors – human proteins that reduce HIV replication and that can help or block infections – such as tetherin, a protein that blocks HIV release, APOBEC3, an immunity gene that has anti-HIV activity, and TRIM5-alpha, a protein that in some monkeys protects against HIV infection, and that gene therapy could perhaps be modified to adapt the related human protein. Zinc finger inhibitors that can knock out CCR5 were included in other presentations, although this potential target that has been on the outer radar of investigative treatment for at least 15 years.

References

Unless stated otherwise, all references are to the Programme and Abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco.

  1. Webcast: Advances in ART. Wednesday 9.30am.
    http://www.retroconference.org/2010/data/files/webcast_2010.htm
  2. Cohen C et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. 17th CROI 2010. Oral abstract 58LB.
    http://www.retroconference.org/2010/Abstracts/39864.htm
  3. Palleja S et al. Safety and efficacy of TBR 652, a CCR5 antagonist, in HIV-1-infected, ART-experienced, CCR5 antagonist-naïve patients. 17th CROI 2010. Oral abstract 53.
    http://www.retroconference.org/2010/Abstracts/37579.htm
  4. Johns B et al. The discovery of S/GSK1349572: a once-daily next generation integrase inhibitor with a superior resistance profile. 17th CROI 2010. Oral abstract 55.
    http://www.retroconference.org/2010/Abstracts/37960.htm
  5. First results of new integrase compound: GSK1349572. HTB October 2009.
    http://i-base.info/htb/5976
  6. Gathe J et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. 17th CROI 2010. Oral abstract 54LB.
    http://www.retroconference.org/2010/Abstracts/39832.htm
  7. Christ F et al. First-in-class inhibitors of LEDGF/p75-integrase interaction and HIV replication. 17th CROI 2010. Oral abstract 49.
    http://www.retroconference.org/2010/Abstracts/37630.htm
  8. Titolo S et al. Discovery of potent HIV-1 capsid assembly inhibitors. 17th CROI 2010. Oral abstract 50.
    http://www.retroconference.org/2010/Abstracts/38238.htm

Links to other websites are current at date of posting but not maintained.