Upcoming events – Ascendis and Lilly hope for growth with pivotal data

Welcome to your weekly digest of approaching regulatory and clinical readouts. The failure of Versartis’s long-acting human growth hormone (hGH) somavartan in 2017 prompted the share price of its rival Ascendis Pharma to rise 44%, and the stock has nearly doubled since as investors await the first-quarter readout of phase III trials in paediatric growth hormone deficiency.

Ascendis’s TransCon hGH is in development as a once-weekly therapy administered using an auto-injector that can automatically capture usage data. The Height trial compares the project against daily hGH – Pfizer’s Genotropin – in 161 patients aged between three and 12 who have GH deficiency either alone or as part of a multiple pituitary hormone deficiency.

The two cohorts will be assessed on the measure of annualised height velocity at 52 weeks, meaning that the study has the same endpoint, and the same comparator, as Versartis’s failed trial (Ascendis’s growth spurt comes courtesy of Versartis, September 22, 2017). Non-inferiority is the benchmark; it is not necessary to prove superiority since patients and their parents are doubtless clamouring for something that would do away with daily injections.

Non-inferiority to daily GH was hit in phase II, with annualised mean height velocity for the three TransCon GH doses ranging from 11.9cm to 13.9cm, which was not statistically different from 11.6cm for Genotropin. A dose-response was seen, and adverse events were mild to moderate.

Notably, the phase II trial of Versartis’s failed project did not include a control arm. The previous result with TransCon GH prompted Leerink analysts to write that they did not see “any plausible reasoning why the Height trial might fail”. They said the phase II hit came despite the population being skewed, favouring daily injection, with subjects in that group being younger and shorter at baseline than those given TransCon hGH.  

Success in Height would also likely be seen as a validation of Ascendis’s delivery technology, which is also used in TransCon CNP in achondroplasia and TransCon PTH in hypoparathyroidism. Both are in phase I.

This means that if Height fails the stock could fall sharply. A single-arm phase III trial, Flight, assessing TransCon hGH's tolerability in 146 patients aged between six months and 17 years, is to be reported in the second quarter, but it is the Height readout that will determine the future of the project and Ascendis itself.

Not such a breeze?

In the first half of this year Lilly will report pivotal data with its Jak inhibitor Olumiant in its second indication, atopic dermatitis, also known as eczema.

However, the side-effects that have plagued the drug in its original use, rheumatoid arthritis, could be even more problematic in the skin disease. Olumiant’s label carries a black box warning of serious infections, and also states that the drug should not be given to people prone to infection – a group that includes eczema patients, because of their skin lesions.

The infection rate in the seven phase III studies testing Olumiant in eczema will therefore be closely watched, along with thrombotic events, which have previously been seen with the drug.

The risk of birth defects will be another concern, particularly as eczema patients tend to be younger than those with rheumatoid arthritis, meaning that the treatable population would include women of childbearing age.

These concerns could help explain why Lilly has focused on moderate to severe atopic dermatitis. One of the Breeze studies also looks at patients who are running out of options: those who have failed on or cannot receive the immunosuppressant cyclosporine, which is used in those who have not responded to topical steroids.

The primary endpoint of the Breeze trials is the proportion of participants achieving investigator's global assessment (IGA) of 0 or 1.

Other Jak inhibitor developers are taking a different approach to Lilly. Incyte, for example, is testing a topical version of ruxolitinib, the active ingredient in its marketed drug Jakafi, in eczema. This could have a better safety profile than the oral agents, but perhaps lower efficacy – notably, Incyte is studying the project in mild to moderate patients.

Safety worries do not seem to have put Lilly off trying to expand Olumiant’s uses; as well as atopic dermatitis, it is studying the drug in lupus. But the sellside does not have much hope for either new indication right now: of Olumiant’s $1.3bn 2024 consensus sales forecast, just $144m is attributed to lupus and $93m to atopic dermatitis.