Ver­tex ex­ecs whip up a cheer from the an­a­lysts af­ter hedg­ing their bet by pick­ing their two top triples for PhI­II

Ver­tex mapped out its late-stage strat­e­gy for a new triple ther­a­py for cys­tic fi­bro­sis on Wednes­day evening, earn­ing con­sid­er­able ap­plause from an ap­pre­cia­tive group of an­a­lysts cov­er­ing the biotech.

Jeff Lei­den

The biotech’s $VRTX ex­ec­u­tive team has stoked block­buster hopes around these com­bi­na­tion stud­ies, key to their plan to broad­en the scope of pa­tients they can cov­er, and they did their best to keep ex­pec­ta­tions high as ri­vals look to carve in­to the mar­ket.

In the end, the team clear­ly likes VX-659 in com­bi­na­tion with teza­caftor and Ka­ly­de­co, not­ing that their Phase II da­ta demon­strat­ed that the high dose im­proved a mea­sure of lung func­tion by 13.3%.

That helped earn a 6% boost in their stock price in af­ter-mar­ket trad­ing.

But with the com­pa­ny’s fu­ture be­ing built on the out­comes of the Phase III stud­ies to come, they al­so want to pur­sue a Phase III tri­al that match­es an­oth­er ex­per­i­men­tal ther­a­py, VX-445, for the triple — though that tri­al will get start­ed af­ter the 659 study gets un­der­way.

Why two Phase II­Is?

“(W)e’re tak­ing two for­ward be­cause that’s one way of mod­i­fy­ing one risk and that’s the risk of some rare off tar­get tox­i­c­i­ty due to the next-gen cor­rec­tor in one of these reg­i­mens and ob­vi­ous­ly by tak­ing two for­ward, we mit­i­gate that risk,” CEO Jeff Lei­den told an­a­lysts dur­ing the quar­ter­ly call.

The 445 triple ac­tu­al­ly just bare­ly edged out 659 for the high-dose re­sponse, with a 13.8% im­prove­ment in FEV1. But the sec­ond high­est dose on­ly came in at a sin­gle-dig­it im­prove­ment rate, with a low­er rate of re­duc­tion for sweat chlo­ride as well as two trou­bling dis­con­tin­u­a­tions in one of the drug arms.

“(A)t the mar­gin, VX-659 looks to be the clean­er and more ef­fec­tive of the two mol­e­cules, al­though the pa­tient num­bers are still small (40-50 pa­tients per tri­al),” not­ed Leerink’s Ge­of­frey Porges Thurs­day morn­ing. “The com­pa­ny ap­pears to be fo­cus­ing on VX-659 as the pre­ferred sec­ond gen­er­a­tion cor­rec­tor com­bi­na­tion part­ner for fur­ther de­vel­op­ment, al­though VX-445 is al­so be­ing ad­vanced in­to piv­otal tri­als. The first triple com­bi­na­tion piv­otal tri­al (VX-659+ Tez/Iva) will be­gin in Q2, pend­ing fi­nal­iz­ing study de­sign with the FDA, and will ini­tial­ly fo­cus on het min pa­tients, al­though piv­otal tri­als in ho­mozy­gous delF508 pa­tients are like­ly to be on­ly a few months be­hind. Ver­tex ex­pects to start a sec­ond piv­otal tri­al pro­gram with VX-445 in mid year, most like­ly in­cor­po­rat­ing VX-561, (deuter­at­ed iva­caftor li­censed from Con­cert) and con­sist­ing of all med­i­cines dosed on a once dai­ly ba­sis.”

“The da­ta an­nounced to­day are re­mark­able and demon­strate the po­ten­tial for sig­nif­i­cant and con­sis­tent clin­i­cal ben­e­fits in pa­tients with one F508del mu­ta­tion and a min­i­mal func­tion mu­ta­tion when treat­ed with a triple com­bi­na­tion reg­i­men con­tain­ing ei­ther VX-659 or VX-445,” not­ed Lei­den.

The Big Phar­ma dis­card pile; Lay­offs all around while some biotechs bid farewell; New Roche CEO as­sem­bles top team; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

With earnings seasons in full swing, we’ve listened in on all the calls so you don’t have to. But news is popping up from all corners, so make sure you check out our other updates, too.

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Raymond Stevens, Structure Therapeutics CEO

Be­hind Fri­day's $161M IPO: A star sci­en­tist, GPCR drug dis­cov­ery and a plan to chal­lenge phar­ma in di­a­betes

What does it take to pull off a $161 million biotech IPO these days?

In Structure Therapeutics’ case, it means having a star scientist co-founder paired with the computational drug discovery company Schrödinger, $198 million in private funding from blue-chip investors, almost six years of research work on G protein-coupled receptors and a slate of oral, small-molecule drugs, with an eye on the huge and growing diabetes and weight-loss market.

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Ma­gen­ta halts stem cell work and may sell it­self fol­low­ing pa­tient death, clin­i­cal hold

Magenta Therapeutics said it is halting work on its stem cell transplant drug pipeline and may sell itself, a week after the company reported the death of a patient in an early stage trial of its antibody-drug conjugate.

The Cambridge, MA-based company said it will conduct a “review of strategic alternatives,” and that could include an “acquisition, merger, business combination, or other transaction.”

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Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

Sanofi scraps PhI­II tri­al for Prin­cip­ia drug af­ter re­view­ing com­pe­ti­tion

Months after the FDA placed Phase III trials of Sanofi’s BTK inhibitor on hold, the company is winding down one of the studies.

Sanofi reported in its Q4 earnings that the URSA study “was discontinued after careful evaluation of the emerging competitive treatment landscape in” myasthenia gravis, a rare disease that causes muscle weakness.

The Phase III, placebo-controlled trial was testing tolebrutinib in patients with the moderate-to-severe form of the disease. It started in late 2021, according to records on clinicaltrials.gov, and was originally designed to recruit 154 participants who were receiving the standard of care.

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Af­ter 13 years, Ramy Mah­moud steps in­to CEO seat at Opti­nose; Ru­pert Vessey set to ex­it Bris­tol My­ers in Ju­ly

After 13 years as president and COO at Optinose, Ramy Mahmoud has stepped into a new role as its CEO. He is taking the place of Peter Miller, who stepped down earlier this week, though Miller is still staying with the company as a consultant.

In 2010, the two business partners joined Optinose to take it in a new direction, transforming it from a delivery platform to product company. They previously worked together at Johnson & Johnson, when Miller was president at Janssen and Mahmoud headed medical affairs. Miller said after he learned about Optinose, “I did what I always do, which is find people smarter than me to talk with about the idea. And the first person I called was Ramy … and I said, ‘Hey, Ramy, what do you think of this technology?’”

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How to use ex­ter­nal con­trols: FDA spells out think­ing in new draft guid­ance

The use of real-world evidence to inform the FDA’s decision-making continues apace, with the agency releasing new draft guidance yesterday on how sponsors can compare outcomes of trial participants receiving a test treatment with outcomes in a group of people external to the trial.

The practice of externally controlled trials is common, particularly in oncology or other difficult areas where it’s not ethical or feasible to use internal controls.

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The Big Phar­ma axe: Mer­ck cuts chikun­gun­ya vax, Bris­tol My­ers drops Cy­tomX-part­nered pro­gram, and more

As fourth quarter earnings come in, Big Pharmas are disclosing changes to their pipelines during their investor calls, and sometimes more quietly in presentation appendices.

Merck dropped its chikungunya vaccine candidate, which completed a Phase II study. Merck acquired the vaccine through its purchase of Themis Bioscience in 2020. In developing a vaccine for chikungunya, a mosquito-borne virus, Valneva is the frontrunner, as it submitted its vaccine to the FDA at the end of December.

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