Welcome to your weekly digest of approaching regulatory and clinical readouts. Array Biopharma has become notorious for licensing out early-stage assets that go on to achieve greatness, but the Beacon CRC trial is an attempt to underscore its ability to take drugs through to approval itself (In sticking to the knitting has Array given up too much?, January 31, 2019).
The study tests Array’s Braftovi/Mektovi doublet combined with Erbitux in second/third-line Braf-mutant colorectal cancer, and interim results from its phase III portion are due by the mid-year. The Braf/Mek inhibitor combo is licensed to Pierre Fabre in Europe and Ono in Japan, and is approved in Braf-mutant melanoma, where uptake is said by analysts to be surpassing expectations.
Colorectal cancer represents an important label expansion, accounting for over half of 2024 forecast sales of $1.2bn, according to EvaluatePharma. Hints from a Beacon CRC safety lead-in are promising, showing 15.3 months of overall survival for the triplet.
It is not certain what the interim data might amount to, but at the very least they will disclose overall remission rates, which might be used to back a US accelerated approval filing. Stifel analysts believe that duration of response data would also be needed, noting that this metric amounted to 5.5 months for the triplet in the lead-in.
Mektovi had previously been licensed to Novartis, but the deal was unwound, additionally throwing in Novartis’s own Braftovi, when Array alleged an antitrust breach caused by the Swiss firm’s ownership of the similarly acting Mekinist/Tafinlar combo. Later Mektovi development for Nras-mutated melanoma was abandoned.
Colorectal cancer represents a significant opportunity, and the separate Anchor CRC trial could further expand this into front-line use. First, however, the combo must score in Beacon.
|Study||Line of colorectal cancer therapy||Data due||Trial ID|
|Beacon CRC||2nd/3rd-line||H1 2019||NCT02928224|
Second time lucky for Proteon?
The failure of the first phase III trial of vonapanitase at the end of 2016 wiped 75% off Proteon Therapeutics' share price. Nevertheless the company pushed ahead with a second phase III trial, intended for chronic kidney disease patients undergoing haemodialysis, and topline data from this are due in March.
Haemodialysis patients need a site where blood can be removed, filtered and returned several times a week. It is safer to take blood from veins than from arteries, but vein walls are thin and would be damaged by repeated long-term insertion of needles. An arteriovenous fistula can be created surgically to allow patients to tolerate needles, by joining an artery and a vein in the arm, causing the walls of the vein to thicken owing to the higher arterial blood pressure.
Vonapanitase, a liquid formulation of recombinant human elastase, is intended to be applied to the external surface of the vessel during fistula creation, where it is hoped that it will boost endogenous elastase activity, thereby allowing the fistula to remain open longer.
This does not seem to have been the case in Patency-1. This 313-patient trial missed its primary endpoint of primary unassisted patency – the length of time from fistula creation to the first occurrence of a fistula thrombosis or corrective procedure to restore or maintain blood flow – versus placebo, an identical-looking liquid that did not contain the active ingredient.
It did hit a couple of secondary endpoints: secondary patency – the time from fistula creation to its abandonment – and fistula use for dialysis. Vonapanitase led to a 34% reduction in the risk of secondary patency loss over one year versus placebo, and at the end of one year 74% of vonapanitase-treated patients maintained secondary patency, versus 61% of placebo recipients.
This was not lost on Proteon, which in March 2017 tweaked the endpoints of Patency-2, the second phase III trial of vonapanitase, to make secondary patency and fistula use the co-primaries; primary patency was relegated to secondary status. Enrolment was also boosted from 300 to 500 patients, and subsequently increased to 600.
A US filing is expected in the second half of 2019, and questions over the size of the market will come to the fore at that point. Vonapanitase is currently forecast to sell less than $200m in 2024.
|Proteon's hopes for vonapanitase|
|Annual sales ($m)|
|Phase III||Elastase inhibitor||Chronic kidney disease||-||22||93||199|