Upcoming events – Vertex awaits triplet data and GBT seeks approval for approval

Welcome to your weekly digest of approaching regulatory and clinical readouts. Vertex is facing decision time, awaiting phase III data from the first of its cystic fibrosis triplets, and the results should help determine which of its two combinations it takes to regulators.

Two phase III trials are due to report by the end of this year, both testing VX-659 plus tezacaftor and ivacaftor; the last drug is sold as Kalydeco, and ivacaftor plus tezacaftor is marketed as Symdeko. One of the studies evaluates the triplet in subjects homozygous for the F508del mutation in the CFTR gene, while the other has enrolled patients with one F508del mutation and one minimal function mutation (known as F508del/Min).

There are no therapies for the F508del/Min CF subtype. Vertex is also testing another triplet, VX-445 plus tezacaftor and ivacaftor, with the first phase III data due in the first quarter of 2019. Again the company is looking at F508del homozygous and F508del/Min populations.

Speaking earlier this year to Vantage, Vertex said it would choose one of the two depending on their respective efficacy and safety profiles. The primary endpoint of all the trials is change in percent predicted forced expiratory volume in one second (ppFEV1).

Asked why the company was evaluating its triplets in homozygous patients, who can be treated with existing CF therapies, a spokesperson replied: “We need to both reach new patients who aren’t yet helped today by our existing medicines, but also enhance the benefit of our medicines for everyone, which we believe we can do.”

The victorious triplet will be the subject of an NDA application, due to be submitted by the middle of 2019. This strategy could be risky as the decision will be based on interim results. Only in the second half of 2019 will Vertex disclose additional safety and efficacy data.

The group likely wants to stay well ahead of its closest rival, Abbvie, which recently took over its partner Galapagos’s CF work. Data from the phase I Falcon trial of the Galapagos triplet looked lacklustre, but Abbvie might have a better chance of competing than the smaller company (Abbvie’s low-risk bet could challenge Vertex on price, 25 October 2018).

Another challenger, Proteostasis, expects data on a triplet by the end of the year, after reporting results with its doublet last month.

Good or bad Blood?

With forecast sales of $1.6bn in 2024, a lot is riding on Global Blood Therapeutics’ voxelotor. The FDA will decide by the end of the year whether this sickle cell disease asset qualifies for accelerated approval, and the group has bet big on getting a yes.

Patients with sickle cell have few therapeutic options, so granting voxelotor accelerated approval based on the surrogate endpoint hit in the phase III Hope trial – or more accurately, half of it – is a definite possibility. But if the agency declines GBT’s request the company will be in trouble.

GBT toplined data from part A of Hope in June, revealing that both doses, 1,500mg and 900mg, caused significantly more patients to have an increase in haemoglobin from baseline of more than 1g/dl versus placebo (Global Blood launches bold bid for early sickle cell approval, June 27, 2018). Increased haemoglobin levels correlate with decreased morbidity and mortality among sickle cell patients.

But part A only hinted at an ability to reduce vaso-occlusive crises, with numerically fewer crises in both voxelotor groups than with placebo. GBT ascribed the failure to hit significance to limited patient follow-up. Part B of Hope might have reached more definite conclusions on this record, as well as symptom severity as reported by patients, but GBT shelved plans for it, pinning its accelerated approval hopes on part A alone.

The full Hope dataset is to be presented on December 3 at the Ash meeting in San Diego. If this does not convince the FDA of voxelotor’s bona fides GBT will likely take quite a knock, since it might have to reanimate part B and face a long and expensive wait for harder data. Still, the company's move to license inclacumab from Roche in August, and plan to test this in vaso-occlusive crises, has led to speculation that it might have already given up on voxelotor.

The FDA might well come down on GBT’s side this time; voxelotor’s safety profile was clean, and the agency could well decide that there is little downside to putting it on the fast track, particularly considering its current lenient stance.