Lenacapavir

In the CAPELLA study, 56% of participants (40 out of 72 individuals) had at least one injection site reaction (ISR). Most (70%) were Grade 1 (mild). There were no discontinuations for ISR. For Grade 3 and 4 abnormalities, four individuals (6%) experienced hyperglycemia (high blood sugar); four experienced glycosuria (excess sugar in urine); and eight individuals (11%) experienced low creatinine clearance (eGFR) or high creatinine—signs of kidney toxicity. The hyperglycemia, glycosuria, and creatinine changes observed were related to the individual’s diabetes or was either transient or unconfirmed.  No dose adjustment is anticipated for individuals with mild to moderate hepatic (liver) impairment or mild, moderate, or severe renal impairment.

Based on drug-drug interaction studies, lenacapavir should not be taken with Evotaz or the TB drug rifampin. Use caution with the sedative midazolam (Versed). Okay to take with Prezcobix, the antacid famotidine (Pepcid), the cholesterol drug rosuvastatin (Crestor), tenofovir alafenamide (TAF, found in Descovy and other medications), and the antifungal voriconazole. Other acid-reducing medications can be used, such as the H2 blockers (such as Axid, Tagamet, and Zantac) and proton pump inhibitors (including Nexium, Prevacid, and Prilosec). Clinical trials did not allow the use of atazanavir (Evotaz or Reyataz), efavirenz (Atripla, Sustiva, Symfi, or Symfi Lo), etravirine (Intelence), nevirapine (Viramune), or tipranavir (Aptivus); all other HIV medications were allowed. See prescribing information after approval for more information.

Lenacapavir was expected to be approved by the FDA this year. This long-acting subcutaneous injection —administered just once every six months—is the first in its drug class. It was granted a Breakthrough Therapy Designation by the FDA in 2019. Lenacapavir is a capsid inhibitor, and inhibits HIV replication by interfering with multiple essential steps of the viral lifecycle. Ultimately, it prevents viral RNA from entering the nucleus of human CD4 T cells, halting virus assembly and protein formation, and inhibiting assembly of new viral particles. The approval is anticipated for heavily treatment-experienced (HTE) individuals with resistance to multiple HIV drug classes. Lenacapavir is highly potent at low doses. Drug efficacy was similar across demographic groups (race, sex at birth, age, and geographic region), CD4 cell count and viral load at study entry, and which background HIV medications were used. Lenacapavir was studied as an injection taken every six months and must be used with an optimized background regimen (OBR). It is important that people still take other HIV medications in addition to lenacapavir. As always with HIV therapy, remember that adherence remains important for good results. Adherence may be an issue for some people whose HIV therapy has led to drug resistance—information and support is available. As a first-in-class medication, lenacapavir lacks cross-resistance to other HIV drugs.

Future drug development plans include lenacapavir-containing complete regimens to provide treatment options to individuals and use as a single drug for HIV prevention. HIV prevention studies with injectable lenacapavir taken once every six months for PrEP (pre-exposure prophylaxis) began last year. Pregnant individuals can voluntarily enroll in the Antiretroviral Pregnancy Registry through their provider; go to apregistry.com. There are two other drugs currently approved for HTE individuals, Rukobia (BRIGHT study) and Trogarzo (TMB-301) (see those pages). As a medication for HTE individuals with multiple drug resistance, lenacapavir is a much-needed drug for many people living with HIV who have limited treatment options

Dr. Melanie Thompson:

Lenacapavir, Gilead’s first-in-class capsid inhibitor, was being studied for treatment and prevention via subcutaneous injection every six months. Obviously, it needed a suitable partner for treatment, and islatravir appeared to be an excellent choice. Gilead quickly submitted a New Drug Application for lenacapavir based on promising 26-week results of the phase 2/3 CAPELLA trial in heavily treatment-experienced people with multidrug-resistant virus. As with the pivotal trial of fostemsavir (Rukobia), the primary endpoint was change in HIV RNA after 14 days of functional monotherapy, followed by optimization of the background therapy (OBT) and open label lenacapavir. There was also a separate nonrandomized cohort who started LEN and OBT from Day 1. These data were presented at the July 2021 IAS Conference. The combination of injectable lenacapavir and an injectable version of islatravir was on the horizon until the FDA hold on islatravir stopped the phase 1 trial of the injectable formulation

For an even worse end to 2021, on December 21, Gilead announced that the FDA had placed a clinical hold on injectable lenacapavir in all ongoing studies for treatment and prevention, due to concerns about the safety of the borosilicate glass vials. Both enrollment and dosing were stopped in 10 ongoing trials. If there is good news here, it is that there was no concern expressed about lenacapavir itself, so one hopes that Gilead will quickly solve this problem and continue on with the trials. However, if problems with islatravir are not solved, it will also be a setback for lenacapavir and LEN will be looking for another date to the prom.

Activist Michael Broder:

Lenacapavir is an investigational drug, meaning it is still in clinical trials, and not yet approved for clinical use. Lenacapavir is on track to be the first in a new class of HIV drugs called capsid inhibitors. The genetic material of HIV is packaged inside a cone-shaped structure called a capsid, which is made of a protein also called capsid. Lenacapavir interferes with capsid functions at multiple points in the viral life cycle. Lenacapavir is being evaluated for use by people who have been on a number of previous HIV treatment regimens and have multidrug-resistant virus. Based on promising clinical trial results reported last summer, it is possible that lenacapavir will be approved for this indication in the spring of 2022