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Will Biocon’s COVID-19 anti-inflammatory succeed where IL-6 blockers have failed?

Biocon is ramping up manufacturing of Alzumab as it prepares to start a large study of the drug

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With an Indian EUA for Alzumab, Biocon is now planning to run larger studies and collect real-world data that can demonstrate the CD6 inhibitor can effectively dampen the cytokine storm observed in severe COVID-19 patients, a feat IL-6 inhibitors have yet to demonstrate.

The company also needs to generate additional data beyond those from its 30-patient Phase II trial, which supported the Emergency Use Authorization, to persuade India’s National Task Force on COVID-19 to add the drug to its treatment protocol for the novel coronavirus.

The inflammatory pathology of COVID-19 began to emerge in March as doctors identified a virus-induced hyperinflammatory cytokine storm as one of the leading drivers of acute respiratory distress syndrome (ARDS).

Multiple studies identified IL-6 as a marker that could distinguish severe COVID-19 from milder forms of the disease.

Doctors quickly turned to mAbs that block IL-6 to treat the cytokine storm because of their broad use in dampening a similar reaction in cancer. Cytokine-release syndrome is a common side effect of treatment with CAR T therapies, and IL-6 inhibitors such as Actemra tocilizumab from Roche (SIX:ROG; OTCQX:RHHBY) and its Genentech Inc. unit have been shown to be efficacious in treating CRS.

But so far, Phase III data in COVID-19 have shown that mopping up just the one, albeit prominent, cytokine may not be sufficient.

Two IL-6 inhibitors have failed Phase III trials in the indication this month: Actemra and Kevzara sarilumab from Sanofi (Euronext:SAN; NASDAQ:SNY) and Regeneron Pharmaceuticals Inc. (NASDAQ:RGEN) (see “Finding Immunosuppression Sweet Spot”).

“Itolizumab stops the formation of the cytokine storm, whereas the others mop up the cytokine storm.”

Kiran Mazumdar-Shaw, Biocon

According to Kiran Mazumdar-Shaw, Alzumab itolizumab’s mechanism of action, which is upstream of IL-6 and several other cytokines, could give it an advantage in tamping down the cytokine storm, and enable it to succeed where IL-6 inhibitors have failed. Mazumdar-Shaw is executive chair of Biocon Ltd. (NSE:BIOCON; BSE:532523).

“Itolizumab stops the formation of the cytokine storm, whereas the others mop up the cytokine storm,” Mazumdar-Shaw told BioCentury. “What itolizumab does is it downregulates all the cytokines, not just IL-6 but also TNF-α and many other cytokines.”

Alzumab has been approved to treat psoriasis in India since 2013.

“We had done clinical trials in over 500 patients in the past and have real-world data over seven years with no safety issues,” she said. “We were very confident from a safety point of view there was enough data to show it was safe.”

The most common adverse event is an infusion reaction, Mazumdar-Shaw said, but the company has learned that can be controlled by delivering the drug via a slow infusion and administering antihistamines.

Biocon decided to run a small trial of Alzumab first, given the urgency of finding countermeasures during the pandemic. It enrolled 20 patients on itolizumab plus best standard of care vs. 10 patients in a control arm that received best standard of care alone.

“Very early on we started getting very good data coming out of patients who were very sick,” Mazumdar-Shaw said. “Within 24 hours they were showing a good response, with inflammatory markers coming down and oxygen intake was getting better.”

Biocon said that the Phase II trial met the primary endpoint of a mortality benefit at one month, with all 20 patients in the treatment arm fully recovering, whereas three of the 10 patients in the control arm died. The study enrolled patients who had moderate to severe ARDS not yet on mechanical ventilation.

The Drugs Controller General of India (DCGI) issued an EUA for Alzumab on July 11.

According to Balram Bhargava, the director general of the Indian Council of Medical Research, Alzumab, along with Actemra, has yet to demonstrate mortality reduction in any trial. Bhargava’s remarks came three days after the issuance of the EUA at a Ministry of Health and Family Welfare (MHFW) press briefing.

At an Aug. 4 MHFW press briefing, the agency’s new secretary, Rajesh Bhushan, said the task force needed to see more evidence before including Alzumab in its standard protocol.

A Biocon spokesperson said in response to follow-up questions from BioCentury via email that the company agrees with the need for a larger trial, but added, “We stand by our comment that our Randomized Controlled Phase II Trial met its primary endpoint of mortality at the end of one month.”

The spokesperson added that Biocon plans to submit the Phase II results for peer review after it finalizes its clinical study reports.

The EUA does come with strings attached. Biocon has to provide Alzumab under a risk management plan and conduct a Phase IV trial to confirm the results.

Mazumdar-Shaw said Biocon plans to start a clinical trial registry as soon as possible that will include 200 patients in the Phase IV trial and patients treated off label. A separate registry will launch to capture Alzumab’s real-world use and outcomes in patients prescribed the drug through the EUA.

“We’ll hopefully build up thousands of patients-worth of data,” she said.

In the U.S., Equillium Inc. (NASDAQ:EQ) has rights to Alzumab under a 2017 deal, and the biotech has announced plans to launch a global study of Alzumab for COVID-19, although the timeline for the trial start hasn’t yet been disclosed.

Equillium is already testing the mAb across three indications: asthma, systemic lupus erythematosus (SLE) and acute graft-versus-host disease (GvHD).

In terms of manufacturing capacity, Mazumdar-Shaw said Biocon was caught a bit off guard in terms of how quickly demand for Alzumab would spike.

“As you can imagine our manufacturing capacity was really just addressing the needs of our psoriasis market and Equillium’s needs,” she said. “Now there’s a huge surge in demand that obviously we were not prepared for, so we are rapidly ramping up.”

The company plans to ramp up manufacturing through year-end with a goal of being able to make hundreds of thousands, if not millions, of doses on an annual basis going forward.

In India, the cost for a single dose of Alzumab is about Rs32,000 ($425).

Separately on Friday, Tata Capital Growth Fund invested Rs2.3 billion in Biocon Biologics Ltd., valuing the Biocon subsidiary that is developing Alzumab for COVID-19 at about $3.5 billion.

Targets

IL-6 - Interleukin-6

TNF alpha - Tumor necrosis factor (TNF) alpha

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