Bristol Advancing Two New Mechanisms In HIV, With Focus On Treatment-Experienced Patients

An attachment inhibitor entering Phase III may offer a new option for patients who have outlived the utility of other antiretrovirals. Bristol also is advancing a second-generation maturation inhibitor of HIV into Phase IIb studies, hoping to succeed where other candidates failed to address viral mutation.

Advancement of antiretroviral therapies for HIV has become a double-edged sword for some patients, as patients living longer and better with the virus can outlast the utility of various drugs and combination regimens that once suppressed the virus. Bristol-Myers Squibb Co. is hoping to provide new options for such patients with a pair of HIV candidates offering new mechanisms of action.

The company believes it is positioned to succeed where earlier attempts failed years ago, with development of a drug to inhibit HIV’s maturation process. It also just advanced an attachment inhibitor, part of a larger class of experimental “entry inhibitors” of the virus, into Phase III. Bristol detailed up-to-date trial findings on the two candidates at the 2015 Conference on Retroviruses and Opportunistic Infections Feb. 25-26 in Seattle.

At the same meeting, the company also outlined its plans to target another tough-to-treat population, those co-infected with HIV and hepatitis C. It will follow up resubmission of its NS5A inhibitor daclatasvir for HCV with a supplemental NDA based on data presented at CROI on daclatasvir plus Sovaldi (sofosbuvir) in the co-infected subpopulation (Also see "Bristol Already Preparing Daclatasvir Supplemental Filings In HCV" - Pink Sheet, 27 Feb, 2015.).

Bristol’s attachment inhibitor, BMS-663068, began a Phase III trial in late February in heavily treatment-experienced HIV patients, who, due to drug resistance, past intolerabilities and/or drug contraindications, are not able to be treated with a viable three-drug regimen to suppress the virus. The drug is designed to bind directly to the HIV gp120 protein, preventing viral attachment to the host CD4-positive T-cell and entry into the host immune cell, Bristol said.

The maturation inhibitor BMS-955176 is slated to begin Phase II dose-finding studies during the second quarter, with parallel Phase IIb studies in treatment-naïve and treatment-experienced patients, Max Lataillade, Bristol’s global HIV development lead, explained in an interview.

Resistance to existing HIV drugs varies greatly depending upon geography and other factors, he noted. “Depending on where you are globally, whether you are in the U.S. or in the EU or in Latin America, the incidence of drug resistance in HIV is going to be different,” he said. “Where we used to have maybe 20%-25% failing first-line [therapy] with resistance to NRTIs [nucleoside reverse transcriptase inhibitors], now we see … that patients are being transmitted drug resistance. If you’re in New York or a big city, the rate of transmitted drug resistance … may be up to 17%-18%.”

Replacement Or Complementary Therapy

Bristol hopes ‘663068 may be able to offer replacement therapy for such patients, or even to make other existing therapies effective again.

“In heavily treatment-experienced patients, you are trying to optimize whatever they are using now and are failing with,” Lataillade said. “But if they have enough options remaining, it’s going to be a replacement. We’re going to say ‘we’re going to give you this new drug now and back it up with one or two more drugs that you are susceptible to to make it as effective as possible.’ Because those patients don’t have a lot of options left, so you want to maximize that regimen.”

At CROI, Bristol reported that ‘663068 provided similar virologic response rates after 48 weeks of treatment as a comparator arm consisting of the company’s protease inhibitor Reyataz (atazanavir) boosted with ritonavir. Between 61% and 82% of patients in the study-drug arm had HIV-1 RNA levels indicating virus replication was undetectable, compared to 71% for the control arm.

The Phase III, however, will not be structured as a comparison trial, Lataillade explained.

“If you’re comparing your [candidate] with a drug, you cannot use that drug to support the one you are developing, so it’s not going to be a comparative trial,” he said. “It’s going to a trial where people who are failing with very few options are going to be given the attachment inhibitor for seven days versus placebo, and on day eight we’ll get viral loads and then whatever antiretroviral works, the physicians will plug in those drugs to support the attachment inhibitor for 24 weeks.”

In order to obtain virologic-response data from 300 patients, Bristol plans to enroll roughly 412 patients, to allow for treatment failures and discontinuations, he said. The company would like to file an NDA by 2018, with potential launch in early 2019, he added. Earlier it had hoped to launch by 2018, but determined that the trial population might be challenging to enroll.

“HIV maturation is truly crucial because it is the step where the virus changes structure and becomes infectious.” – Max Lataillade, Bristol’s global HIV development lead

While BMS-955176 would be a first-in-class as a maturation inhibitor for HIV, Bristol is building upon past work by companies such as Panacos Pharmaceuticals Inc. and Myriad Pharmaceuticals. Panacos advanced bevirimet (PA-457), a maturation inhibitor, into Phase II before selling off the program, including all related intellectual property, to Myriad Pharma, then a division of Utah-based diagnostics specialist Myriad Genetics Inc. (Also see "Myriad Gets Phase IIb HIV Maturation Inhibitor From Panacos For $7M" - Pink Sheet, 21 Jan, 2009.). Myriad had two other maturation inhibitors in development, including Vivecon (MPC-9055) in Phase I and a preclinical candidate MPI-461359, but shelved the entire program in June 2010 to focus on oncology.

Most Advanced Member Of The Class

Other companies are working on maturation inhibitor candidates, but Lataillade said Bristol is the most advanced with its compound moving into Phase IIb. BioMedTracker lists two other members of this class currently in development, GlaxoSmithKline PLC’s GSK2838232, now in Phase I, and an immunotherapy called DermaVir Patch, in Phase II at Genetic Immunity Inc.

Inhibiting maturation of HIV virus is one of the remaining untapped approaches to fighting the virus, Lataillade explained.

“We have been able to successfully inhibit several steps of the HIV lifecycle; we can prevent attachment, entry, prevent the virus from going from RNA to DNA, [and inhibit] integrase and protease,” he said. “But that left steps in the HIV lifecycle that are very important, [such as] when the virus buds off the cell, assembly of the particle, release into plasma and maturation. HIV maturation is truly crucial because it is the step where the virus changes structure and becomes infectious.”

A maturation inhibitor of HIV works by binding to the gag polyprotein, an enzyme with multiple proteins attached to it.

“They do this because the gag polyprotein is orchestrating those late stages – assembly, budding and maturation,” Lataillade said. “These drugs block a key protease cleavage event, thereby blocking maturation. … [It] inhibits a key protease cleavage event between two different proteins and … prevents the virus from condensing to form a capsid core. Without a capsid core, the virus cannot go on and progress through the lifecycle. Therefore, it does not become infectious to other cells.”

The first generation of maturation inhibitors failed because while they were effective against wild-type gag polyproteins, which did not mutate, about 55% of HIV infections have baseline gag polymorphisms, which mutate constantly, the exec explained. BMS-955176 is showing signs of succeeding where bevirimet and others did not because it is more specific, more potent and less protein-bound, he said.

“Less protein-bound means more drug in the serum, so you can use a lower dose,” Lataillade said. “The drug so far has been well tolerated and works very well against those key gag polymorphisms.”

In a Phase IIa trial of 60 patients in Germany, Bristol found that a 40 mg dose of ‘955176 produced a two-fold reduction in viral load over 10 days compared with placebo. Testing with 80 mg and 120 mg doses suggested a plateauing of virologic effect, but the Phase IIb studies will be dose-finding in preparation for Phase III. The two parallel studies are slated to begin in April.