[Updated, 3:40 pm ET, see below] The Food and Drug Administration approved 59 new drugs last year, a record for the agency which over the years has swung back and forth between tight control and leniency. We are in the midst of perhaps the agency’s most permissive era ever, thanks to its openness to speed up reviews and to greenlight certain drugs with slim evidence, like those for cancer patients who have run through all other options, or for kids with rare diseases and no available treatments.
The pace appears slower this year, but the agency just green-lighted a new drug for treatment-resistant tuberculosis, and it could approve as many as four more new drugs by early next week, all of them notable for different reasons. One taps into a history of FDA drama. Another is a bellwether for companies hoping to fight off “superbug” infections. A third makes the case for precision cancer treatment, and a fourth is a key part of pharma’s ongoing fight against generic competition. Here’s a thumbnail preview of each.
Duchenne… without the drama?
The FDA made one of its most controversial decisions ever when it granted “accelerated” approval to the Duchenne muscular dystrophy drug eteplirsen (Exondys 51) in 2016 on the slimmest of evidence. Now a follow-on drug, also from Sarepta Therapeutics (NASDAQ: SRPT), is on the agency’s desk. Despite some similarities, there isn’t much controversy expected.
Like Exondys 51, the new medicine golodirsen (Vyondys 53) is an RNA-based drug meant to produce a truncated form of the shock-absorbing protein, dystrophin, that Duchenne patients lack. Exondys is for 13 percent of Duchenne patients with a particular genetic profile; Vyondys 53 is for a different 8 percent of Duchenne patients. Both are weekly infusions given chronically.
Another similarity: The main evidence for both drugs was their ability to help patients produce around 1 percent of normal levels of dystrophin, known as a “surrogate” marker because the studies—which were tiny—did not conclusively show that patients were benefiting from treatment.
With Exondys 51, that evidence still doesn’t exist. The clock is ticking. Under the 2016 approval agreement, Sarepta must show the FDA that Exondys 51 is providing meaningful health benefits to patients by 2021. As STAT reported Thursday, Sarepta is running behind: results are expected in 2024.
When Exondys 51 was under review in 2016, some patient advocates argued at a dramatic advisory meeting that the drug was making a difference, but Sarepta’s studies weren’t showing it. Top drug evaluator Janet Woodcock ultimately supported the drug, and Exondys was approved. (As Xconomy reported here, two advocates started a company, Casimir Trials, to try to better measure the effects of Duchenne drugs and other rare disease medicines in the wake of the Exondys saga.)
Sarepta has a similar surrogate-marker story for Vyondys. Again, there isn’t evidence yet that the drug is improving outcomes. The nonprofit drug pricing watchdog ICER called the results “insufficient” in a recent report on Vyondys and other Duchenne medicines.
Yet there is one important difference with Vyondys: It seems to produce more dystrophin than Exondys. There was no advisory meeting scheduled this time, often a positive sign for a drug’s prospects. Wall Street analysts are bullish on Vyondys’s odds. SVB Leerink analyst Joseph Schwartz, for instance, gave the drug a 90 percent chance of approval.
AbbVie (NYSE: ABBV) agreed to buy Allergan (NYSE: AGN) for $63 billion partly to prepare for generic competition to adalimumab (Humira), the world’s top-selling drug. But one of its ace cards comes from up its own sleeve: the anti-inflammatory drug upadacitinib, which AbbVie has been developing as Humira’s successor and has bested Humira head-to-head.
Upadacitinib’s first indication is rheumatoid arthritis. Even with FDA approval, it will face new competition. A new class of oral medications called JAK inhibitors have wrested some market share away from Humira and other so-called TNF inhibitors, which must be injected. Pfizer brought the first JAK inhibitor for RA, Xeljanz, to market in 2012, and it notched $1.8 billion in sales in 2018. Others are either on the market (Olumiant, from Eli Lilly, approved in June 2018), or in development (filgotinib, from Gilead Sciences).
Upadacitinib is the next JAK inhibitor in line. In addition to RA, the drug is being tested in four other mid- or late-stage trials. EvaluatePharma projects that the drug could generate $2.5 billion in yearly sales for AbbVie by 2024, with a majority coming in RA. AbbVie executives have said that upadacitinib and another recently approved drug, risankizumab (Skyrizi), could fill a Humira-sized hole by 2025, bringing in combined more than $10 billion annually. (Drug-sales projections, however, have a history of going off the rails.)
But there are concerns. The FDA slapped a safety warning on Xeljanz last month, meaning two drugs in the class are now tied to potential health problems. That decision highlighted “potential safety risks for the JAK inhibitor class overall,” wrote RBC Capital Markets analyst Brian Abrahams, And that’s why all eyes are on the FDA’s upcoming decision on AbbVie’s drug.
“Our program hasn’t demonstrated that risk,” AbbVie vice chairman and president Michael Severino said on a conference call last week. If the FDA issued a warning about upadacitinib, it would be evidence of “some form of class labeling,” he said.
Despite the growing need for antibiotics to fight drug-resistant superbugs, biotechs in the field have had a rough time. Nabriva Therapeutics (NASDAQ: NBRV) will try to change that trend if the FDA approves its antibiotic lefamulin for bacterial pneumonia.
The odds aren’t in Nabriva’s favor. Achaogen (NASDAQ: AKAO) went bankrupt a year after approval of its antibiotic plazomicin (Zemdri). Tetraphase Pharmaceuticals (NASDAQ: TTPH) restructured shortly after approval of its antibiotic eravacycline (Xerava), noting at the time that selling antibiotics requires “a long runway and unwavering perseverance.” Paratek Pharmaceuticals (NASDAQ: PRTK) is off to a “promising” start with omadacycline (Nuzyra), wrote SVB Leerink analyst Ami Fadia. But shares have been cut in half since Nuzyra’s approval last October.
The problem: Antibiotics are tough to make money with. They don’t get the same pricing power as, say, cancer immunotherapies. And ideally they’re used as little as possible, so bacteria don’t become resistant to them. All that leads to a business that, as this April story from Wired explains, “is broken.” That’s why Big Pharma largely exited the business.
Last week, Seema Verma, who runs the federal Centers for Medicare & Medicaid Services, proposed policy reforms to “stabilize the antibiotic development pipeline” and deal with the superbug threat. (Here’s more on Verma’s proposed policy changes.)
Amid all this uncertainty, here comes Nabriva, and it faces an uphill battle. The biotech’s shares are trading near all-time lows ($2.24) days before potential approval of its antibiotic. It also has less than a year of cash left in the bank.
The FDA has approved two cancer drugs that target a tumor’s genomic signature, no matter where in the body that tumor is found. One of those “tissue agnostic” approvals was for the immunotherapy pembrolizumab (Keytruda), which is already used to treat a slew of cancer types. Larotrectinib (Vitrakvi), from Loxo Oncology, got the second nod, prompting Eli Lilly to buy Loxo for $8 billion, even though rival Bayer held claim to the drug’s commercial rights.
[Updated with approval, price details] The third came on Thursday. Last month entrectinib (Rozlytrek) nabbed the first “tissue agnostic” approval in the history of Japan. On Thursday, the FDA followed suit and approved Rozlytrek, which Roche grabbed when it bought Ignyta for $1.7 billion. Like Viktravi, Rozlytrek is for people whose tumors have an NTRK gene that has abnormally fused to another gene. The FDA approved it for those patients, as well as for non-small cell lung cancer patients with a different fusion called ROS1.
Rozlytrek will cost about $17,050 per month for patients with Ros1-positive lung cancer, in-line with the price of crizotinib (Xalkori), the other approved drug for the disease, according to Genentech spokesperson Meghan Cox. The price for patients with NTRK fusions is based on which dose they get, but the number is “lower than” Vitrakvi, she said. (Genentech is offering support for out-of-pocket costs and free access to Rozlytrek for people who meet certain eligibility criteria, Cox said.)
The field of precision medicine, matching the right drug to the right patient, holds out the promise of less trial-and-error (and ideally, fewer side effects and more lives saved). But the commercial success of both Vitrakvi and Rozlytrek are every bit as important as touchstones for the economic viability of these drugs. Several others are in development, aiming for the same path as Vitrakvi and Rozlytrek.