Phase 3 results for VX-445 triple combo

[jricci]

Very exciting results announced today for VX-445
Sounds like they'll review more data at end of 24 weeks and decide between VX-659 and VX-445

From Vertex press release on 3/6:
https://investors.vrtx.com/news-rel...lacing-two-phase-3-studies-triple-combination

Two Phase 3 Studies of the Triple Combination of VX-445, Tezacaftor and Ivacaftor Met Primary Endpoint of Improvement in Lung Function (ppFEV1) in People with Cystic Fibrosis

-Mean absolute improvement in ppFEV1 of 13.8 percentage points from baseline at week 4 in people with one F508del mutation and one minimal function mutation (F/MF) compared to placebo (p<0.0001)-

-Mean absolute improvement in ppFEV1 of 10.0 percentage points from baseline at week 4 when VX-445 was added in people with two F508del mutations (F/F) already receiving tezacaftor and ivacaftor compared to control group of placebo added to tezacaftor and ivacaftor (p<0.0001)-

-Safety and efficacy profile reported today supports potential submission of a New Drug Application for the VX-445 triple combination regimen-

-Vertex plans to seek global regulatory approvals for either VX-659 or VX-445 triple combination regimen in both F/F and F/MF patient populations concurrently based on final 24-week data for both regimens expected in the second quarter of 2019-

-U.S. NDA and EU MAA planned for the third and fourth quarters of 2019, respectively-

-Given the similarity of the data for the 4-week primary efficacy endpoint for the VX-659 and VX-445 regimens and the near-term availability of the final 24-week data for both regimens in the second quarter of 2019, Vertex plans to utilize these final 24-week data to choose the best regimen to submit for regulatory approvals globally.

“Both the VX-659 and VX-445 triple combination regimens showed highly consistent and significant improvements in lung function across our Phase 3 programs, underscoring the important clinical benefit that a triple combination regimen may provide to patients with two F508del mutations and to those with one F508del and one minimal function mutation,” said Reshma Kewalramani, M.D., Executive Vice President, Global Medicines Development and Medical Affairs and Chief Medical Officer at Vertex. “We look forward to submitting global regulatory applications for one of these triple combination regimens for both patient populations later this year.”

 

[stephen]

I wonder if this will replace Kalydeco, Orkambi, and Symdeko, the way Symdeko has replaced Kalydeco in most/many cases.

 

[erock77]

Can someone clarify this key bullet:
"-U.S. NDA and EU MAA planned for the third and fourth quarters of 2019, respectively-"

Does that mean they're applying for approval? Or they're expecting approval? I saw similar results published a few months ago and was very excited, maybe it was for a different combination of Vertex drugs, but I've been excited and reading about this stuff for 10 years or so. I wanna take it!

 

[stephen]

Eric,

I think it means they are applying for a New Drug Approval (NDA). Then it takes months for the approval to be granted.

 

[jricci]

I wonder if this will replace Kalydeco, Orkambi, and Symdeko, the way Symdeko has replaced Kalydeco in most/many cases.

I might not have this right, but I’ve been given the impression that Vertex will attempt to get triple combo approved for anyone with at least one df508 mutation, even if their other mutation wasn’t included in the clinical trials of triple combo.

I’m not sure why they didn’t have a separate clinical trial of VX-445 or VX-659 for patients with a residual function mutation who are already approved for Symdeko but don't have df508 on other allele (like you stephen). Just as Symdeko was shown to be more effective than Kalydeco for those with a single copy of one of the select residual function mutations--regardless of their other mutation, it would seem that adding this third drug to Symdeko would further increase the amount of CFTR at the cell surface, and therefore be more effective than Symdeko alone. But maybe in-vitro testing didn’t show this? Seems hard to believe. Sadly, there doesn't seem to be the same sense of urgency for clinical trials of modulators for those with rare mutations.

 

[jricci]

Can someone clarify this key bullet:
"-U.S. NDA and EU MAA planned for the third and fourth quarters of 2019, respectively-"

Does that mean they're applying for approval? Or they're expecting approval? I saw similar results published a few months ago and was very excited, maybe it was for a different combination of Vertex drugs, but I've been excited and reading about this stuff for 10 years or so. I wanna take it!

When they have the 24 week data in, they'll choose which triple they’re going to submit for new drug application. Sounds like it will be sometime in third quarter of 2019. FDA will hopefully accept priority review of application and they’ll set an action date to review. Because it will be a priority review, it has to be reviewed within 6 months of submission, but could be reviewed quicker. Kalydeco was reviewed in only 3 months after submission of NDA. With other Vertex drugs, once approved by FDA, they were available for distribution to pharmacies soon after approval (within a week I think).

 

[stephen]

When Symdeko was approved, my CF center gave their patients who were on Kalydeco the choice of switching to Symdeko. Among the reasons was that it would cost less. This was due to the larger market for the new drug.

I would expect the same may be true for the "triple combination"as long as there are no adverse affects. Kalydeco, Symdeko, and Orkambi may become obsolete.

During my CF center visit, I'll ask if they still have any patients on Kalydeco.

 

[kenna2]

So I think they might keep these older ones around after the triple's come out. The reason is my doctor has told me that some patients can't handle the full dose of the ones that are out now and some are on half doses. There is a good chance the triple combo ones might be too strong for them to handle too. So I think having something that helps is better than having nothing at all. Just my thoughts