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Roche's Actemra Misses Primary Endpoint In COVACTA Trial

Roche Holding AG/Chugai Pharmaceutical Co., Ltd.’s Actemra/RoActemra (tocilizumab) has missed its primary endpoint of improved clinical status in hospitalized adult patients with severe COVID-19-associated pneumonia in the Phase III COVACTA study.

The anti-IL-6 receptor antibody, an established treatment for rheumatoid arthritis and other inflammatory conditions, has been seen as a likely candidate for repurposing against the most critically ill COVID-19 patients. This is based on its ability to target the runaway 'cytokine storm' inflammatory reaction, with the hypothesis that this plays a key role in many coronavirus deaths.

However the failure of COVACTA has undermined this theory, and the hope of Actemra or other IL-6 therapies proving valuable against COVID-19 is diminishing, with Sanofi and Regeneron's Kevzara (sarilumab) also recently failing to show benefits. (Also see "Coronavirus Update: Moderna Hold Up, Sanofi and Regeneron's Kevzara Fails In Phase III" - Scrip, 3 Jul, 2020.)

Roche undertook the Phase III trial to produce robust data which it hoped would back up earlier encouraging results from single arm studies undertaken on the coronavirus frontline, but the COVACTA trial has failed to produce any significant benefits.

The endpoint was measured by a seven-category ordinal scale which tracked status based on the need for intensive care and/or ventilator use, as well as supplemental oxygen requirements.

The companies said the difference at week four was not statistically significant (p=0.36; odds ratio [95% CI] = 1.19 [0.81, 1.76]) - a statistically significant odds ratio greater than 1 would have favored the biologic.

Key secondary endpoints, which included the difference in patient mortality at week four, were also not met, although there was a positive trend in time to hospital discharge in patients treated with tocilizumab.

Roche and Chugai said they were "disappointed", but noted that further analysis of the results would be needed to fully understand the data and that the study would be submitted for publication in a peer-reviewed journal.

Dr. Levi Garraway, Chief Medical Officer and Head of Global Product Development, Roche and GenentechROCHE'S LEVI GARRAWAY

“We will continue to generate evidence to provide a more complete understanding of Actemra/RoActemra in COVID-19 associated pneumonia,” stressed Levi Garraway, Roche’s chief medical officer and head of global product development.

Hope in Actemra had been based on a small single-arm trial in China, patients treated with tocilizumab experienced reduced fevers and had 75% less need for supplemental oxygen within days of receiving the drug.

In addition to COVACTA, Roche has several other ongoing studies investigating tocilizumab for patients with COVID-19-associated pneumonia, including two Phase III clinical trials, REMDACTA (plus the antiviral remdesivir) and EMPACTA (in minority populations), as well as the Phase II MARIPOSA trial. There are also a number of independent trials underway exploring efficacy and safety in the COVID-19 setting, and China's National Health Commission has included the drug in the updated diagnosis and treatment plan for the coronavirus-caused disease.

The COVACTA trial was conducted at sites in North America and Europe with the Biomedical Advanced Research and Development Authority under the US Department of Health and Human Services, and looked at intravenous tocilizumab added to standard-of-care treatment, compared to placebo plus standard of care.

For the secondary endpoints, there was no difference between tocilizumab and placebo in percentage of patients that died by week four. Time to hospital discharge or ready to discharge was shorter in patients treated with the antibody than in those given placebo, (20 days versus 28 days). However, the companies noted the difference cannot be considered statistically significant as the primary endpoint was not met, as was the case in measurements of ventilator-free days and rates of infection comparisons between tocilizumab and placebo.

The news is a blow for the field of COVID-19 therapy, where only two drugs - dexamethasone and Gilead's remdesivir have shown significant efficacy. One other promising development is from the UK's small pharma company Synairgen plc, which produced encouraging results earlier this month with its inhaled interferon beta candidate SNG001.  (Also see "Synairgen Stock Soars 420% On Promise Of Inhaled COVID-19 Drug" - Scrip, 20 Jul, 2020.)

Indian Favipiravir Market Buzzing With Activity

The Indian market for favipiravir is heating up with several new entrants expected to vie for a share of the pie, notwithstanding polarized views of physicians around the data thus far for the antiviral as a potential treatment for COVID-19. (Also see "Coronavirus Update: Favipiravir Scores In Phase III Trial" - Scrip, 24 Jul, 2020.)

Hetero Drugs Ltd.and Cipla Limited are now the latest frontline Indian firm to have received regulatory approval for launch of their favipiravir 200mg versions on the market. Hetero’s product (available as Favivir), marketed and distributed by Hetero Healthcare Limited, is available starting 29 July at all retail medical outlets and hospital pharmacies across the country and will be sold only on prescription, the firm said. 

Cipla’s favipiravir (to be sold as Ciplenza), in expected in the first week of August though indications are that a handful of other firms including Sun Pharmaceutical Industries Ltd. could also debut their versions shortly setting the stage for an interesting tug-of-war for a therapy that has yet to be fully endorsed by physicians as an effective treatment option in COVID-19 . Glenmark Pharmaceuticals Limited’s FabiFlu (favipiravir) led the pack hitting the Indian market in June. (Also see "Flutter Over Debut Of Glenmark's Favipiravir For COVID-19 In India" - Scrip, 22 Jun, 2020.)

Cipla, however, said that in order to ensure “fair and equitable” distribution of the drug, supplies of its product will be undertaken predominantly through hospital channels and via “open channels”, prioritized for regions with a high burden of COVID-19 cases.   Cipla’s favipriavir has been jointly developed with the CSIR-Indian Institute of Chemical Technology (IICT). (Also see "India COVID-19 Update: Antivirals, Eyes On HCQ-Azithromycin Data" - Scrip, 22 Mar, 2020.)As part of this partnership, CSIR-IICT developed a convenient and cost-effective synthetic process for favipiravir and the entire process and active pharmaceutical ingredient of the drug has been transferred to Cipla to manufacture and market the drug at scale. Specifics on the early trial data for Cipla-IICT ‘s favipiravir were not immediately provided.

Favipiravir has received restricted emergency use authorization in India under the accelerated approval process aimed at meeting the urgent and unmet medical need for COVID-19 treatment options.

Pricing Dynamics

Significantly, both Hetero’s Favivir with a price tag of INR59 ($0.79) per tablet and Cipla’s Ciplenza at Rs 68 per tablet, are less expensive than FabiFlu’s recently pared maximum retail price of INR75 per tablet, down 27% from its launch price of INR103. (Also see "Coronavirus Update: 'Positive News' Imminent From Oxford and AstraZeneca Vaccine" - Scrip, 16 Jul, 2020.)

But pricing dynamics are likely just beginning to play out.  The Mumbai-based Jenburkt Pharmceuticals launched its favipiravir 200mg (Favivent) at INR39 per tablet, undercutting existing players, while others in the fray including Brinton Pharmaceuticals also launched its favipiravir (Faviton) at INR59 per tablet. Earlier the Hyderabad-based Biophore India Pharmaceuticals had received a license from the Drugs Controller General of India to manufacture favipiravir API and also clearance for exports, while Strides has exported the product to Gulf Cooperation Council countries.

But all eyes will likely be on the impending arrival of the favipiravir version from India’s top ranked drug firm Sun Pharma, though the antiviral, sources say, is expected to be manufactured by BDR Pharma. BDR Pharma is also a manufacturing partner of Cipla for remdesivir, the antiviral also being used as part of the COVID-19 treatment arsenal and licensed by Gilead Sciences, Inc.to a several generic firms including Hetero, Cipla, Mylan N.V.Dr. Reddy's Laboratories Ltd..and Zydus Cadila. (Also see "India Remdesivir Black Market: Supply Gap May Normalize Soon, But No End To Greed" - Scrip, 20 Jul, 2020.) (Also see "Hetero, Cipla's Remdesivirs Hit India Market, 'Surplus' Envisaged By August" - Scrip, 22 Jun, 2020.)

It will be interesting to see how favipravir originator, Fujifilm Toyama Chemical Co. Ltd.., and its partners view the goings on in the Indian market. The Japanese firm recently struck a wide-ranging deal with Dr Reddy's and Global Response Aid (GRA), a provider of medical supplies and pharmaceuticals, opening up a new front to accelerate the development and global supply of the antiviral.

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