Two New Pharmaco-enhancers -- GS 9350 and SPI-452 -- May Rival Ritonavir (Norvir) as a Boosting Agent

By Liz Highleyman

The discovery that a small dose of ritonavir (Norvir) can be used to "boost" plasma levels of other protease inhibitors contributed to a dramatic improvement in the efficacy and convenience of antiretroviral therapy. This is due to the fact that ritonavir interferes with the action of the cytochrome P450 3A (CYP3A) enzyme, which metabolizes many drugs including other protease inhibitors (PIs). When drug clearance is slowed by ritonavir, concentrations in the body remain higher for longer periods.

Ritonavir is not without problems however -- including its association with metabolic side effects such as elevated blood lipids and its control by a single company (Abbott) -- leading researchers to explore new "pharmaco-enhancing" agents that can serve the same function.

Data on 2 such candidates were presented on Monday, February 9, at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009), taking place this week in Montreal.

GS-9350

Brian Kearney from Gilead Sciences presented early data on GS 9350, the result of a development program that sought a pharmaco-enhancing agent that works by the same mechanism as ritonavir, but without anti-HIV activity of its own.

The company wanted a suitable agent to include in coformulations with other drugs, including its investigational integrase inhibitor elvitegravir, which requires boosting to reach optimal therapeutic levels (an in-progress study of elvitegravir is using ritonavir as a booster).

Preclinical Studies

Gilead reported data from pre-clinical and early clinical studies of GS 9350. Antiviral activity was assessed using standard assays. The drug's effects on CP450 enzyme inhibition and metabolism (including lipid and glucose accumulation) were studied in cultured human liver cells.

Results

GS 9350 was shown to slow systemic drug clearance by inhibiting CYP3A.

GS 9350 appeared to be a more specific inhibitor CYP3A than ritonavir, with less effect on other CP450 enzymes.

GS 9350 exhibited no activity against HIV at concentrations up to 90 mcM.

GS 9350 was not associated with lipid accumulation in adipocytes (fat cells) at 30 mcM and only minimally (< 10%) inhibited insulin-stimulated glucose uptake at 10 mcM.

GS 9350 had a favorable pharmacokinetic profile, including high aqueous solubility (about 200 times that of ritonavir), making it suitable for coformulation with other drugs.

Phase 1 Trial

Following these promising laboratory findings, the pharmacokinetics, safety, and boosting activity of GS 9350 were studied in Phase 1 clinical trials.

In Study GS-216-0101, healthy HIV negative volunteers (18 per cohort) were randomly assigned to receive GS 9350 (at doses of 50, 100, or 200 mg once-daily) or 100 mg ritonavir or placebo, both as a single dose and as multiple doses administered over a 14-day period. Investigators used the benzodiazepine midazolam -- a known CYP3A substrate -- as a "probe" to assess how well GS 9350 boosted drug levels.

Results

GS 9350 doses of 100 and 200 mg inhibited midazolam clearance by 92% and 95%, respectively, compared with 95% using ritonavir.

GS 9350 was generally well tolerated, both single and multiple doses.

No drug-related grade 3 or 4 laboratory abnormalities or grade 4 clinical adverse events were observed; the single grade 3 clinical event was a woman who said she could no longer juggle while taking the drug, which was classified as "discoordination").

GS 9350 was reported to have little taste, in contrast to the notoriously bitter ritonavir.

Quad Pill

After this successful proof-of-concept trial, researchers created fixed-dose "quad" coformulations containing GS 9350 plus 150 mg elvitegravir, 300 mg tenofovir, and 200 mg emtricitabine -- a complete once-daily regimen in a single pill smaller than Atripla (efavirenz/tenofovir/emtricitabine, a collaborative effort of Gilead and Bristol-Myers Squibb).

Study GS-236-0101 (also Phase 1) assessed the bioavailability, pharmacokinetics, and safety of the quad pill in 44 healthy HIV negative volunteers. In this open-label trial, participants were assigned to receive a quad pill containing either 100 or 150 mg GS 9350.

The pharmacokinetic profile of elvitegravir administered in the single-tablet coformulation regimen was compared to the profile when the drug was boosted with 100 mg ritonavir and administered with the same doses of tenofovir and emtricitabine (the Truvada combination pill).

Results

Both the 100 mg and 150 mg GS 9350 coformulations boosted plasma concentrations of elvitegravir.

The tablet containing 150 mg GS 9350 produced elvitegravir concentrations previously determined to be therapeutic, including maintenance of an adequate trough concentration (lowest level between doses).

Here again, treatment was generally well tolerated.

There were no drug-related grade 3 or 4 clinical adverse events and no grade 4 laboratory abnormalities; the sole grade 3 lab abnormality was a transient ALT elevation.

Future Plans

Gilead is now planning Phase 2 trials to further evaluate GS 9350, including a head-to-head study comparing the quad coformulation versus Atripla in treatment-naive patients (scheduled to start in the second quarter of 2009) and an ongoing study of GS 9350 as a stand-alone agent as a booster for atazanavir (Reyataz).

"These data represent the first major step forward in Gilead's clinical development of a new integrase-based, single tablet, once-daily regimen for HIV," said Gilead's Chief Science Officer Norbert Bischofberger, PhD, in a press release issued by the company. "Results also indicate that GS 9350 holds promise as a stand-alone alternative to ritonavir for patients receiving boosted HIV protease inhibitor-based treatment regimens."

SPI-452

In the second conference presentation, Robert Guttendorf from Sequoia Pharmaceuticals reported preclinical and Phase 1 clinical data on the company's novel pharmaco-enhancer, SPI-452. Like Gilead, Sequoia sought a boosting agent with activity similar to that of ritonavir, but with no anti-HIV activity and better tolerability.

Preclinical Studies

The preclinical pharmacology of SPI-452 was evaluated in vitro in human liver cells. Its ability to boost levels of the PIs saquinavir (Invirase), lopinavir (a component of Kaletra), and atazanavir was evaluated in rats and dogs.

Results

In vitro, SPI-452 inhibited metabolism of all HIV PIs.

It also slowed metabolism of the investigational HCV protease inhibtor boceprevir.

SPI-452 demonstrated no inherent antiviral activity.

In animals, SPI-452 potently inhibited CYP3A, boosting levels of saquinavir, lopinavir, and atazanavir.

First Human Trial

In Study 0452-001 -- the first human clinical trial evaluating the safety, tolerability, and pharmacokinetics of SPI-452 -- 58 healthy HIV negative volunteers first received single ascending doses of SPI-452 (25, 50, 100, 200, 400, or 600 mg); in part 2, they were assigned to receive either 50 mg or 200 mg SPI-452 plus 1000 mg saquinavir, or saquinavir alone, or placebo alone.

Results

SPI-452 pharmacokinetics was described as "unremarkable" and "fairly well behaved."

SPI-452 increased mean levels of saquinavir, demonstrating its boosting effect.

SPI-452 was generally safe and well tolerated in single ascending doses of 25 to 600 mg, and in combination with saquinavir.

Adverse events were typically mild, with no severe events reported.

The most commonly reported adverse events were headache and pharyngitis (sore throat).

Proof-of-concept

Finally, the pharmacokinetic profile of multiple doses of SPI-452 and the drug's boosting ability were assessed in a Phase 1 proof-of-concept trial. A total of 67 healthy HIV negative volunteers first received single doses of 600 mg darunavir (Prezista) or 300 mg atazanavir or placebo, in order to establish PI plasma concentrations.

Then, after a 7 day washout period, participants were randomly assigned to receive 25, 50, or 200 mg once-daily SPI-452 or placebo for 15 days. On day 15, they also received darunavir, atazanavir, or placebo co-administered with the final dose of SPI-452. On day 16, they received darunavir, atazanavir, or placebo only.

Results

SPI-452 drug levels reached a steady state by day 14.

Co-administration of SPI-452 significantly increased minimum plasma concentrations (Cmin) of the PIs at 12 and 24 hours:

Darunavir: up to 37-fold increase;

Atazanavir: up to 13-fold increase.

The boosting effect was durable through day 16 (the day after the last dose).

SPI-452 was generally safe and well tolerated at doses of up to 200 mg for 15 days.

Again, most adverse events were mild and no serious events were reported.

The most common adverse event was headache, followed by nausea/vomiting and diarrhea.

No significant changes were observed in laboratory parameters -- including liver function tests -- or ECGs.

Participants taking SPI-452 experienced no significant changes from baseline in LDL ("bad") cholesterol or triglycerides.

The researchers concluded that SPI-452 is a potent CYP3A inhibitor that was well tolerated and safe when administered at doses of up to 200 mg once-daily for 15 days.

Speaking at a press conference following his presentation, Guttendorf said the Sequoia believes SPI-452 has "great potential." The company now plans to move forward with further clinical trials looking at SPI-452 both as a stand-alone agent and as a component of fixed-dose coformulations.

In addition to pursuing SPI-452 as a booster for HIV PIs, he added, Sequoia is exploring its use in treatment of hepatitis C, and it -- as well as other pharmaco-enhancer drugs in the pipeline, including those targeting other CP450 enzymes -- might be used for other, non-viral diseases.

2/10/09

References

A Mathias, M Lee, C Callebaut, and others. GS-9350: A Pharmaco-enhancer without Anti-HIV Activity. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 40.

S Gulnik, M Eissenstat, E Afonina, and others. Preclinical and Early Clinical Evaluation of SPI-452, a New Pharmacokinetic Enhancer. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 41.

Other sources

Gilead sciences. Gilead Announces Data Demonstrating Pharmacokinetic Boosting Activity of GS 9350. Press release. February 9, 2009.

Sequoia Pharmaceuticals. Sequoia Pharmaceuticals Presents Proof of Clinical Concept of SPI-452, a Novel Pharmacokinetic Enhancer. Press release. February 9, 2009.