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AbbVie’s, Ascletis’ protease inhibitors spark skeptical outlook for repurposed activity in Covid-19

Protease inhibitors like AbbVie’s HIV drug Kaletra (lopinavir/ritonavir) and Ascletis Pharma’s HCV therapy Ganovo (danoprevir) elicit skepticism for their potential in Covid-19. There is a low probability of an inhibitor being effective against two different viruses with different structures, with the negative randomised data so far also adding to reservations.

On 9 March, AbbVie said there were unconfirmed media reports that data from China indicated Kaletra’s efficacy in Covid-19 but that it did not have access to that information. Nonetheless, it was collaborating with select health authorities and institutions globally to determine Kaletra’s potential against SARS-CoV-2. The initial enthusiasm pushed several groups to consider protease inhibitors worth exploring, and several studies around the world, including some large international trials, are evaluating Kaletra or Ganovo.

However, on 18 March, results from a China-based 199-patient study indicated no clinical benefit with Kaletra, sending AbbVie’s stock down 10% during trading hours, with the company closing at 2.7% lower than the previous day. This result, along with the difficulty in finessing a protease inhibitor to work against a different virus, are challenges for protease inhibitors used in HIV and hepatitis C virus (HCV) to work in Covid-19. Nonetheless, in vitro data along with activity in other coronaviruses provided some evidence to test the drugs in different settings.

Kaletra is also sold as Aluvia in some countries. While ritonavir is a protease inhibitor, it is used as a pharmacokinetic enhancer in combination with lopinavir.

AbbVie and Ascletis did not respond to a request for comment.

Viral structure dissimilarity in protease inhibitors leads to apprehension

It is a long shot to expect a drug that was specially tailored to the HIV structure will have enough cross-reactivity to really be effective against SARS-CoV-2, said Dr Jonathan Karn, director, Case Center for AIDS Research, Cleveland, Ohio. While developing drugs for HIV, medicinal chemistry was used extensively to optimise their bioavailability and make them metabolically stable, so for a drug to be used against SARS-CoV-2, the same will need to be done, he added.

Besides Kaletra, it is hard to think protease inhibitors like Johnson & Johnson’s Prezista (darunavir)—administered with the enhancer cobicistat—will be effective, because like other HIV drugs it is targeted toward a specific HIV protease, which does not have much structural similarity to enzymes used by SARS-CoV-2, said Derek Lowe, drug discovery scientist. Johnson & Johnson (J&J) has stated that while anecdotal reports indicated Prezista’s antiviral effect against Covid-19, there was a lack of evidence to support Prezista against SARS-CoV-2. J&J said it would continue to screen its antiviral compounds including Prezista for in vitro efficacy.

In HCV as well, there was a long optimisation pathway for drug candidates, Karn added. Ganovo does not have anything to do with Covid-19, so it is difficult to see why it would have an effect, but clinical data will bear this out, said Dr Raymond Chung, director of hepatology, Massachusetts General Hospital, Boston, and an investigator on Phase II pegylated interferon lambda study in Covid-19. Ganovo development was discontinued because Gilead Sciences’ Sovaldi (sofosbuvir) eventually became the drug of choice for HCV, said Dr Peter Ferenci, professor of medicine, Medical University of Vienna, Austria.

Clinical data furthers reservations but preclinical evidence retains interest

Nonetheless, anecdotal evidence from the use of protease inhibitors in early cases in China, where the pandemic began, provided the impetus to try this drug class in Covid-19. However, it is challenging to interpret early anecdotal reports without a comparator, said Chung. The data to date has not shown any effect, so Kaletra is unlikely to be effective, said Dr Lewis Nelson, chair, Department of Emergency Medicine, Rutgers New Jersey Medical School.

In the China-based 199-patient randomised, open-label Phase II trial (ChiCTR2000029308), Kaletra did not show a statistically significant improvement compared to standard-of-care in its time to clinical improvement primary endpoint (Cao et al; N Engl J Med; 18 March 2020 ePub). While there were initial suggestions that symptomatic patients could benefit from Kaletra, this data indicated that there was no major benefit, said Dr Carlo Giaquinto, professor of Pediatrics, University of Padova, Italy.

However, the patients included in this study were very sick, said Giaquinto. The overall mortality rate in this study was 22.1%, compared to 11‒14.5% observed in initial descriptive studies of hospitalised Covid-19 patients, which indicated the inclusion of severely ill patients, as per the authors. It is important to test any antiviral drug in less sick patients because even if it is shown to reduce the viral load or slow progression of the disease, that could be encouraging, Giaquinto said, adding if a drug can prevent transmission, it would be a major breakthrough.

Kaletra is one of the several treatments like hydroxychloroquine, interferon-beta and remdesivir being explored in large trials, like the 2,000-patient University of Oxford Phase III (EudraCT-2020-001113-21); 3,100-patient Phase III French DisCoVeRy study (NCT04315948); and the WHO Solidarity study under the 440-patient Phase II (NCT04330690) Canadian arm. Additionally, Kaletra is also being evaluated in an 80-patient Ganzhou People’s Hospital 5 study (ChiCTR2000030218), while Ganovo/Norvir (ritonavir) is being studied in the Phase II 60-patient Shanghai Changzheng Hospital trial (ChiCTR2000030259) and the Phase II 40-patient Wuhan Huoshenshan Hospital study (ChiCTR2000031734). While all listed trials do not clarify characteristics of its target patients, the DisCoVeRy study is specifically enrolling patients who have respiratory failure requiring supplemental oxygen or ventilatory support or have a peripheral capillary oxygen saturation (SpO2 ≤94%) on room air.

Trials that include patients in the symptomatic stage of upper respiratory tract infection can assess viral reduction, said Karn. Unfortunately, current tests for SARS-CoV-2 do not accurately measure viral loads and are mostly geared to have a binary positive or negative result, he noted. Until the technology to measure infected cells in a sample improves, it is difficult to do a virological endpoint the way HIV trials are done, he added.

However, while trial confirmation is needed, Kaletra has shown in vitro activity against SARS-CoV-2 (Choy et al; Antiviral Res. 3 April. Epub), noted Dr Daniel Freilich, attending physician, Bassett Healthcare Network, Cooperstown, New York. Also, in the China-based study, there were some positive outcomes among secondary measures, he added. Freilich has started a Phase II/III study (NCT04328012) at the Bassett Clinical Center, New York, to evaluate different treatments, including Kaletra.

Dr Darrell Tan, clinician-scientist, Department of Medicine, St Michaels Hospital, Toronto, also referred to the secondary endpoint data. While the results were not statistically significant, the various secondary measures showed a trend toward Kaletra being efficacious. Kaletra-treated patients had numerically shorter intensive care unit (ICU) stays (6 days vs. 11 days; 95% CI) and duration from randomisation to hospital discharge (12 days vs. 14 days; 95% CI), and the percentage of patients with clinical improvement at day 14 was higher than standard-of-care (45.5% vs. 30.0%; 95% CI)

This spurred Tan’s group to initiate a Phase III Kaletra study (NCT04321174), targeted to enrol 1,220 patients and to specifically evaluate the drug as an intervention for postexposure prophylaxis.

Also, limited clinical data as well as molecular and animal data from other related novel coronaviruses like MERS-CoV acted as an impetus for evaluating Kaletra, said Tan. Both viruses have proteases, and since Kaletra is a protease inhibitor it may work against the proteases of both, he noted.

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