Gilead Sciences and Merck & Co. have agreed to jointly develop and commercialize two long-acting drugs for highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection.

For the purposes of the project, Gilead will provide lenacapavir, Merck & Co.’s contribution is formalized by islatravir.

This is a combination drug that will be offered in oral and injectable formulations which will free patients from the day-to-day administration of existing HAART medications. It is possible that the long-acting novel drug, implemented in tablet form, could be prescribed once a week or perhaps a month and in the injectable form once every three months or even six months.

Such a regimen would increase adherence to HAART, which is critical to controlling the spread of HIV and preventing the emergence of mutant strains that are resistant to therapy as well as making treatment less visible to others as the stigmatization of HIV-positive people continues. Again, the entirely new mechanisms of action that lenacapavir and islatravir have will bypass the increasingly common mutations of the virus that render it resistant to current HAART regimens.

If we talk about the timing of the appearance of a fully ready-made drug (of course, in the case of its successful clinical testing), the market launch of the oral version is scheduled for 2025 and the injectable version for 2027.

According to the terms of the deal, Gilead and Merck & Co. will share the costs in the ratio of 60% to 40%. The former will be responsible for commercializing the drug in oral formulations in the U.S. and the latter in the European Union and other distribution territories. Commercialization of the injectable formulation would be the other way around. Sales revenues will be split equally but once sales cross $2.0 billion and $3.5 billion for the oral and injectable versions of the drug, respectively, the ratio will change to 65% to 35%.

Although Gilead and Merck & Co. fought a raging patent battle over chronic viral hepatitis C treatment and the latter still lostnulla salus bello, pacem te poscimus omnes — especially if big profits loom ahead. According to industry forecasts, the global market for HIV therapy is projected to be $30 billion by 2024 and for prevention $10 billion by 2029.

 

Lenacapavir: Capsid Inhibitor

Lenacapavir (GS-6207) is the first member of a new class of antiretroviral capsid inhibitors that inhibits HIV replication by stabilizing and then preventing the functional cleavage of its capsid in infected cells.

The vast majority of existing HAART drugs work by blocking the enzymes of the virus – the proteins that initiate key steps in its life cycle.

The capsid (the envelope around the viral genome), which is necessary for the successful passage of literally every stage of infection, involves a number of interactions between its proteins and a host cell’s many factors. For example, lenacapavir prevents capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6, which mediate viral nuclear import and direct integration into gene-rich chromatin regions.

The capsid inhibitor lenacapavir has activity against HIV-1 of all subtypes and HIV-2, is unlikely to develop drug resistance against it (capsid protein mutations are very rare), interacts synergistically (complementing and enhancing) with major classes of HAART drugs and has no cross-resistance to other antiretroviral drugs, including maturation inhibitors.

Gilead is fully exploring lenacapavir, which is administered by subcutaneous injection once every six months. For example, the CAPELLA (NCT04150068) phase 2/3 clinical trial involving HIV-positive multidrug-resistant patients was successful and confirmed the feasibility of adding lenacapavir to the no longer working HAART regimen. A New Drug Application (NDA) is scheduled to be sent to the regulator in the second half of this year 2021.

The CALIBRATE (NCT04143594) phase 2 clinical trial, which will test the addition of lenacapavir to various HAART regimens among previously untreated HIV patients, will be initiated in the second half of the year.

This year, lenacapavir will be put on the clinical track for its applicability in the pre-exposure prophylaxis (PrEP) task of HIV infection. The experimental drug will be tested among cisgender men, transgender women, transgender men, and non-binary people at high risk for HIV who have sex with men, as well as among adolescent girls and young women who have heterosexual sex.

 

Islatravir: Nucleoside Reverse Transcriptase Translocation Inhibitor

Islatravir (ISL, MK-8591, EFdA) is the first representative of a new class of antiretroviral nucleoside reverse transcriptase translocation inhibitors (NRTTI).

Due to three chemical groups — 4′-ethyl, 3′-hydroxyl, and 2-fluorine — the molecule is characterized by unique pharmacological properties. These are manifested as:

  • close binding to the conserved hydrophobic pocket in the HIV-1 reverse transcriptase with preventing translocation of the elongated DNA primer, which leads to an immediate chain break
  • very high affinity to reverse transcriptase
  • reduced sensitivity to deamination, which, due to the inhibition of islatravir metabolism, promotes its long period of intracellular half-life.

If translocation does occur, islatravir acts as an elongation terminator with a delayed chain break. The active form, represented by islatravir triphosphate, effectively inserts itself into the end of the viral DNA chain but results in erroneously paired primers that are difficult to extend.

Merck & Co. licensed islatravir from Japan Yamasa in July 2012.

Islatravir is undergoing extensive clinical validation for both HIV therapy (oral once daily or once weekly) and PrEP (oral once monthly). A subcutaneous implant with islatravir is particularly interesting, a single insertion of which will give a healthy person reliable protection against HIV infection for a whole year.

 

HAART: Simple and Convenient

A dramatic change in the HAART paradigm began to occur when Gilead established the once-daily oral single-tablet Biktarvy (bictegravir + emtricitabine + tenofovir alafenamide, BIC/FTC/TAF). The new product became an instant blockbuster with $1.18, $4.74, and $7.26 billion in sales in 2018, 2019, and 2020, respectively.

HAART then received a powerful boost from ViiV Healthcare, three-quarters owned by GlaxoSmithKline, and Janssen, owned by Johnson & Johnson. They were the first in the pharmaceutical industry to offer HIV patients an incredibly convenient treatment with a long-acting drug.

Cabenuva (cabotegravir + rilpivirine, CAB/RPV), which is approved in the United States, Canada, and the European Union and is injected intramuscularly, can be prescribed either once a month or once every two months. In other words, people are finally spared tedious courses of daily pill therapy for HIV.

Gilead and Merck & Co., impressed by the ideas of Cabenuva, conceived of doing something similar but already in an oral formulation. At this stage, given the due diligence of the partners, there is no doubt that everything will work out in the best possible way.

 

In the Meantime

In early February 2021, Gilead befriended Gritstone Oncology, hoping to find a way to completely cure HIV. The idea is to develop a therapeutic vaccine that would train the immune system to recognize and destroy cells infected with the virus. This requires redirecting cytotoxic CD8+ T-cells to targets specific to HIV-infected cells. The corresponding vaccine must have a decent capacity to deliver the payload, in this case, represented by as wide a variety of HIV antigens as possible. The partners are piloting a prime-boost immunization strategy: one vaccine is based on self-amplifying mRNA and the other on adenoviral vectors.

In July 2020, Merck & Co. formalized an agreement with Dewpoint Therapeutics intending to cure HIV through beneficial effects on biomolecular condensates. These are membrane-free organelles whose main task is to compartmentalize (surround and contain) reactants (proteins and nucleic acids) for intracellular chemical reactions. Although biomolecular condensates, as dynamically forming (by phase separation) transient liquid-like droplets, have long been known to science, they still remain very mysterious components of cells — mainly because they are difficult to analyze by traditional methods: for example, crystallography, suitable for protein analysis, does not work here. Dewpoint found a way, though.

 

Extras

Merck announces HIV collaboration with Gilead. March 15, 2021. [PDF]

Gilead Sciences. HIV long-acting therapy collaboration with Merck. FAQ. March 15, 2021. [PDF]

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Mark Gubar

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Mark has long been the most closely involved in the entire process of drug approval. His professional interests include phenotypic screening in vitro, sequencing technologies, predictors of clinical relevance, and patient compliance.

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