Déjà vu for Zaf­gen: Still fret­ting about lin­ger­ing car­dio con­cerns, FDA clamps a hold on lead obe­si­ty drug -- shares plunge

Two years af­ter Zaf­gen torched its lead obe­si­ty com­pound fol­low­ing an ug­ly crash in late-stage test­ing that cost lives, the FDA is still fret­ting whether the com­pa­ny is con­tin­u­ing to ex­pose more peo­ple to harm.

The biotech re­port­ed to­day that the FDA has slapped a clin­i­cal hold on their MetAP2 drug ZGN-1061, wor­ried that the car­dio threat posed by their first-gem drug be­lo­ranib might still be in play. They plan to fol­low up with a face-to-face meet­ing, but there’s no clar­i­ty on how long their drug could be in lim­bo now.

In­vestors hat­ed the sound of it. Zaf­gen’s shares cratered, plung­ing 46% short­ly af­ter the mar­ket opened Mon­day.

Zaf­gen’s shares $ZFGN — once over $40 — nev­er re­vived af­ter the plunge that oc­curred in the fall of 2015, when man­age­ment ini­tial­ly stonewalled in­vestors clam­or­ing to find out what had prompt­ed the com­pa­ny to abrupt­ly drop out of a promi­nent in­vest­ment con­fer­ence. Back-to-back deaths, though, along with a clin­i­cal hold that led to a list of re­quire­ments for be­lo­ranib’s clin­i­cal de­vel­op­ment that Zaf­gen de­cid­ed had cre­at­ed a hur­dle too steep to clear, killed that ef­fort.

Ac­cord­ing to their state­ment, Zaf­gen got the lat­est hold let­ter some­time last week.

The FDA cit­ed the pos­si­bil­i­ty of car­dio­vas­cu­lar (CV) safe­ty risk based on the Com­pa­ny’s pri­or com­pound and out­lined mul­ti­ple po­ten­tial paths for mov­ing for­ward, in­clud­ing non­clin­i­cal or clin­i­cal op­tions, to ad­dress these con­cerns in the on­go­ing de­vel­op­ment of ZGN-1061. The Com­pa­ny plans to as­sess these op­tions and re­quest a Type A meet­ing with the Agency to dis­cuss next steps with the pro­gram.

Tom Hugh­es

De­spite the reg­u­la­to­ry con­cerns in the US, Zaf­gen says it plans to sol­dier on with a dose-es­ca­lat­ing Phase II study for ZGN-1061 in Eu­rope, which is be­yond the FDA’s reach.

Like their first drug be­lo­ranib, ZGN-1061 has demon­strat­ed an abil­i­ty to knock off a sig­nif­i­cant amount of weight. But the safe­ty bar for a drug now guid­ed to­ward di­a­betes is clear­ly very high.

Leerink’s Joseph Schwartz had this to say af­ter the news hit:

As we pre­vi­ous­ly high­light­ed in de­tail, pre­clin­i­cal da­ta sug­gests that ZGN-1061 has the po­ten­tial to in­duce clot­ting fac­tors if it is not cleared. De­spite a clean safe­ty re­port card to date in a small Ph.2 study, our main con­cerns have stemmed from lack of dis­clo­sure about how the drug is me­tab­o­lized and cleared, and the po­ten­tial for drug-drug in­ter­ac­tions that could de­lay the drug’s clear­ance when test­ed in a larg­er Ph.3 study of T2D pa­tients, which we be­lieve could have played in­to the FDA’s de­ci­sion. How this de­ci­sion will af­fect the over­all time­line for this pro­gram is un­known, but the com­pa­ny plans on defin­ing a path for­ward with reg­u­la­tors.

Over the last few months Zaf­gen has seen a big change at the top, with Tom Hugh­es leav­ing the com­pa­ny af­ter lead­ing it for 9 years — to take the CEO’s job at Nav­i­tor — just ahead of board mem­ber Bruce Booth. 

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

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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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