05 noviembre 2020
COVID19 . PharmaMar Making Strides . As WHO findings disappoint, COVID-19 developers stand in Solidarity .
BY RANDY OSBORNE .
Interim data from the Solidarity Therapeutics Trial coordinated by the World Health Organization (WHO) show Foster City, Calif.-based Gilead Sciences Inc.’s remdesivir (branded as Veklury) as well as hydroxychloroquine, lopinavir/ritonavir, and interferon regimens apparently “have little or no effect” on 28-day mortality or the in-hospital course of COVID-19 among patients admitted.
Gilead, about a week ago, pointed to the publication in The New England Journal of Medicine detailing results from the 1,062-patient phase III study of remdesivir led by the National Institute of Allergy and Infectious Diseases. Preliminary data were made known in May, but the final set of data covers about 1,060 hospitalized patients. Those given remdesivir recovered five days faster on average, and in patients with severe disease, seven days faster. The severely ill patients made up 85% of the total study population. Remdesivir reduced the likelihood of patients progressing to more severe stages of the disease where they would require new or additional oxygen support. In the largest group of patients, those on low-flow oxygen, there was a significant reduction in mortality in a post-hoc analysis.
SVB Leerink analyst Geoffrey Porges said in an Oct. 9 report that “the fine print of the results is perhaps less encouraging than the top line. While remdesivir además to accelerate clearance of virus and resolution of symptoms, it did not improve survival at 29 days which is the endpoint of most importance in the end (earlier endpoints are confounded by patients still in the hospital, still on oxygen or ventilation).”
In any case, the Solidarity study paints a different picture of remdesivir and other treatments. Involving more than 30 countries, the experiment checked effects on overall mortality, start of ventilation, and duration of hospital stay. In 405 hospitals, 11,266 adults were randomized, with 2,750 allocated remdesivir, 954 hydroxychloroquine, 1,411 lopinavir/ritonavir, 651 interferon plus lopinavir, 1,412 only interferon, and 4,088 no study drug. Compliance was 94% to 96% midway through treatment, with 2% t 6% crossover. In all, 1,253 deaths were reported (at median day eight, interquartile range 4-14). Kaplan-Meier 28-day mortality turned up at 12% (39% if already ventilated at randomization, 10% otherwise).
The regimens proved unhelpful “as indicated by overall mortality, initiation of ventilation and duration of hospital stay,” Solidarity researchers concluded.
“The mortality findings contain most of the randomized evidence on remdesivir and interferon, and are consistent with meta-analyses of mortality in all major trials.”
Turku, Finland-based Faron Pharmaceuticals Oy is not giving up on interferon beta-1a in COVID-19, delivered by a different route than in Solidarity. Findings from the WHO experiment “support our long-held view that interferon beta-1a is likely to be ineffective when given subcutaneously, CEO Markku Jalkanen said. “The science behind [Faron’s] Traumakine and its potential to prevent multi-organ failure through the upregulation of the key endothelial enzyme CD73 is compelling, and we continue to believe that an intravenous [I.V.] formulation of interferon beta-1a is what patients need to strengthen the body's own interferon beta signaling,” and thereby “provide optimal exposure to the lung vasculature.” Specifically, the I.V. approach achieves more than 150 times higher peak concentration there.
A global trial at more than 200 sites in 19 countries is testing Traumakine and other treatments for community-acquired pneumonia, including in COVID-19 patients. Faron is also supporting a potential phase II/III U.S. effort to probe the potential of the drug against COVID-19. To be conducted at Harvard Medical School’s Beth Israel Deaconess Medical Center, the effort awaits finalized funding arrangements and regulatory approval. It will focus on intensive-care patients with acute respiratory distress syndrome caused by viral infections that include COVID-19 and influenza. Traumakine will be tested against placebo and dexamethasone.
Another company keeping the interferon faith is Southampton, U.K.-based Synairgen plc, with an inhaled version known as SNG-001. The company disclosed positive results this summer from its double-blind, placebo-controlled phase II trial in hospitalized patients, and the study, called SG016, was extended to include 120 more patients with confirmed COVID-19 in the home environment. CEO Richard Marsden, responding to the Solidary results, told BioWorld that his firm’s “feeling was that if it was going to work in injection it was going to work through a more subtle boost to the immune system, but the results today suggest this isn’t the case.” With SNG-001, Synairgen is “rolling straight into a phase III trial in 900 COVID-19 patients globally,” working with partners “to manufacture enough drug to run the trial and, more importantly, to put drug on the shelf so that it can get to patients quickly if the trial is successful.’
The company said its Aplicov-PC1,2 trial with EF1A blocker Aplidin (plitidepsin) for hospitalized patients met primary safety and secondary efficacy endpoints.
Three patient cohorts, with three Aplidin dose levels (1.5 mg, 2.0 mg, and 2.5 mg), were evaluated.
The patients' viral load was evaluated quantitatively at the same center at the beginning of treatment and on days four, seven, 15 and 30.
The drug yielded a substantial reduction of the viral load in patients between days four and seven, with the average drop on day seven at 50% and on day 15, 70%.
More than 90% of the patients included in the phase I trial had medium or high viral loads at the start.
Pharmamar said 80.7% were discharged on or before the 15th day of hospitalization, and 38.2% before the 8th day.
Protocol required that patients stay in the hospital for a minimum of a week.
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