Two years after a wrenching setback, Protagonist touts a slice of data and sets sights on pivotal trial in a surprising place: the blood – Endpoints…

In 2018, the floor fell out beneath Protagonist Therapeutics. Months ahead of an expected readout, the companys first major trial, a Phase IIb testing their lead drug in ulcerative colitis, failed a futility analysis. Investors sold off en masse. Protagonist searched for answers.

Two years later, CEO Dinesh Patel maintains the drug had efficacy pointing to a blinded re-read conducted later that year but the company has moved on. Now, armed with the results from a small proof-of-concept, they are readying to put their resources behind a new lead program and another attempt at a pivotal trial in an entirely different disease.

We couldnt have asked for better data, Patel toldEndpoints News.

The drug is an artificial protein called PTG300. Unlike the drug in the 2018 trial or a compound licensed in 2017 to J&J, PTG-300 is designed to treat blood disorders. Since August, the company has been testing it in a series of tiny proof-of-concept trials to see how well it works in different diseases, including beta thalassemia, hereditary hemochromatosis and myelodysplastic syndromes.

The latest study, announced today, is in people with polycythemia vera, a chronic blood cancer in which patients produce an overabundance of red blood cells. Complications can range from itchiness to blood clots. Normally, patients are treated with phlebotomies every few weeks or months. The problem, though, is that their red blood cell counts can rise in-between and continually removing a persons blood is not without consequence. It can lead to weakness and iron deficiency, among other complications.

In the part of the trial that is now evaluable, investigators gave different doses of PTG-300 to 7 different patients who had at least three phlebotomies in the 24 weeks prior. Six patients did not need a phlebotomy over the 4 to 28 weeks they took it. A 7th had an unintended interruption to his dosing, received a single phlebotomy and continued therapy.

Lead investigator Ron Hoffman, called it a potential paradigm shift. Unlike phlebotomies or the other drugs used to treat the disease, it could allow patients to maintain good red blood cell counts over long stretches without severe side effects.

What has been done for 100 years is that patients undergo blood letting essentially, Hoffman told Endpoints. We didnt anticipate using this kind of approach. Its really pretty cool actually, Im excited.

The drug mimics the effect of hepcidin, a natural hormone that regulates iron levels. Because the body needs iron to produce red blood cells, limiting those levels can in theory limit overproduction in these patients.

The results convinced Protagonist to pick their lead indication ahead of schedule, Patel said. They will now expand their current study from a goal of 30 patients to 50 patients and they plan to start a pivotal trial next year. That will move it significantly ahead of their remaining irritable bowel disease asset, PTG-943. Development of that drug has been pushed back significantly during the Covid-19 pandemic; because it targets IL-23, it could make patients more susceptible to infection.

These are immuno-suppressive agents at the end of the day, Patel said of PTG973. Basically, for now the focus is on blood disorders.

Its a marked shift for Patel and Protagonist. The company spent a decade building its peptide-based platform, and its earliest assets were for IBD. They raised investors confidence around PTG100 and quickly brought it into a Phase IIb study. J&J offered $990 million in a deal centered on a second IBD drug, PTG-200. These drugs appealed particularly because they were oral, unlike the injectables that have dominated the inflammatory disorders market.

The J&J drug is still in the clinic, but in March of 2018, Protagonist announced that PTG-100 failed a futility analysis; an independent review board determined it had no chance of beating placebo. The stock fell 58%, from $20.43 to $8.59, roughly where it sits today.

PTG-100 has since been retired, but Patel claimed the review decision was actually wrong. The company noted a high placebo response in the initial assessment and sent it for a blinded review to a third party and CROs subcontractor, who determined some of the initial endoscopes had been initially misread and the trial should have continued.

Within two days we figured out the endoscopy readouts were errant, he said. The outcome should not have been futile.

The company went back to the FDA with the third party review, Patel said, but the FDA said they had to start a new trial. By that point, though, the company had already come up with PTG-943, which they believed worked better and was wiser to advance if they were going to start a new trial.

Now with Covid-19 pushing back IBD further, blood disorders have become the companys main strategy, despite having only a tiny, open-label data set. Patel is confident, though, that it can be a fruitful one. He said there was a clear regulatory path with a 150-person trial, good effects in those patients, and a significant potential market.

It fits all of the three category: strong data, a good regulatory path forward, and a very large commercial opportunity, he said. So thats where Protagonist will be focused.

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Two years after a wrenching setback, Protagonist touts a slice of data and sets sights on pivotal trial in a surprising place: the blood - Endpoints...