Upcoming events – Novartis and Miragen hope for heartening data

Welcome to your weekly digest of approaching regulatory and clinical readouts. After a slow start Novartis’s heart failure drug Entresto finally became a blockbuster in 2018. And the company reckons the product could sell another $1bn annually if label extension efforts go to plan.

Entresto got the go-ahead in 2015 for heart failure patients with reduced ejection fraction, and Novartis is now taking aim at heart failure with preserved ejection fraction (HFpEF), an arguably less severe subtype of the disease that has nevertheless proved difficult to treat.

Data from the final analysis of the Paragon-HF trial are due in the second half of the year, and should answer the question of whether Entresto can become the first approved therapy for HFpEF. Of the approximately six million people in the US, around half have reduced ejection fraction and half have HFpEF, but incidence of the latter is increasing.

Paragon compares Entresto versus valsartan, an angiotensin II antagonist and one of Entresto’s active ingredients, in 4,800 patients with an ejection fraction of 45% or greater. The primary endpoint is a composite of cardiovascular death and total heart failure hospitalisations, and Entresto must show superiority below p=0.025.

The event-driven study was due an interim analysis last year, but was not stopped for efficacy or futility. This might not be a cause for concern: Novartis had always said the trial would probably proceed to its final analysis (Novartis hopes Entresto can be a Paragon of label expansion, July 31, 2018). 

However, history is not on Novartis’s side. The Paragon investigators have noted that various outcomes trials of drugs acting on the renin-angiotensin-aldosterone system have failed to show a benefit in HFpEF. They hope that by focusing on total hospitalisations, both first and recurrent, Paragon could give a better picture of disease burden – other studies have looked at time to first event.

Novartis has long maintained that Entresto could reach blockbuster status in HFpEF alone, but getting a clinical result here could be a hard task.

Scar tissue

Although an upcoming phase II readout in keloid reduction is not the main event for Miragen’s pipeline, a positive result would be a step along the road to validating the microRNA approach.

In the second half of the year the group expects results from a 14-patient trial of MRG-201 in keloids, which are thick scars that are larger than an original wound and result from build-up of collagen. Although there are existing therapies surgery is not always successful, and many drugs come with serious side effects.

MRG-201 comprises short stranded RNA molecules that control gene expression. MRG-201 has been specifically designed to mimic the activity of miR-29, which decreases the expression of collagen and other proteins involved in scar formation.

Miragen’s trial aims to ascertain whether MRG-201 can prevent keloid formation. Patients with a history of keloid scars have been given two identical, small skin biopsies, which are closed with sutures and treated with either up to six doses of MRG-201 or placebo – meaning that trial participants are acting as their own control. Six months after treatment the scars are assessed for keloid formation.

If there are signs that a keloid is forming at one or both biopsy sites a second two-week treatment cycle can be administered. Subjects will also be followed for a year to assess long-term safety and efficacy.

Given that Miragen’s pivotal Solar trial for its lead candidate, MRG-106, in mycosis fungocides is behind schedule, execution in the keloid study is important. A triumph here could also lead to partnering interest for Miragen.

Still, there could be questions about the cost of microRNA therapies for conditions like keloids, which are generally not life threatening.

Forecasts have been modest in keloids, with EvaluatePharma sellside consensus predicting MRG-201 sales of $22m in 2024. However, limited data on the number of hyper keloid formers, and the high prevalence of the disorder in certain ethnic groups, mean that the opportunity could be larger.