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offer a glimpse at Gener8-1, the first Phase 3 study ever of a hemophilia gene therapy. Enrollment should be complete in the second quarter, and shortly thereafter BioMarin may file for a quicker than the norm, “accelerated,” FDA approval while the study is ongoing. If it doesn’t, it’ll say so publicly in 2019, says spokesperson Debra Charlesworth. The trial will wrap up in late 2020.
If successful, the treatment, known as valoctocogene roxaparvovec, or val-rox, could start to reshape the treatment paradigm for hemophilia.
Since the early 1990s, hemophiliacs have been able to treat their disease with chronic infusions of proteins, or factors, that clot their blood and prevent dangerous bleeds. But those drugs are administered frequently and don’t give patients a steady amount of clotting protein, which can lead to “subclinical” bleeds patients aren’t aware of.
The cost of care is prohibitive: $250,000 to $400,000 or more per year for an adult who receives treatment several times a week, experts have told Xconomy. The bills run higher for those who have bleeding episodes or who have immune responses called “inhibitors” that require additional, expensive drugs.
Even without gene therapy, the landscape is changing. The just-approved Roche drug emicizumab (Hemlibra), for hemophilia A, provides a more steady level of clotting protein. Then there’s gene therapy and the potential of a long-lasting, if not permanent boost in clotting protein from a one-time infusion. The price tags could exceed $1 million; insurers will no doubt determine whether that figure could in fact save healthcare costs if factor replacement therapy is no longer necessary.
BioMarin is the first of a group of developers, which also includes UniQure (NASDAQ: QURE), Pfizer (NYSE: PFE), and Spark Therapeutics (NASDAQ: ONCE) advancing gene therapies for hemophilia A and the less common hemophilia B. Gener8-1, a 130-patient single-arm study, is the largest and most advanced Phase 3 program to date.
The FDA has shown openness to approve hemophilia gene therapies on an accelerated basis based on their ability to boost clotting factors to a point that is “reasonably likely to predict clinical benefit.” It’s unclear, however, what that point is. Katherine High, Spark’s chief scientific officer and a gene therapy expert recently told Xconomy that in discussions with the FDA, the agency “has indicated flexibility around accelerated approval” for data that show “eradication of bleeding.” Does that occur at 20 percent of normal clotting protein, a measure many believe may reduce subclinical bleeds? Or is it higher? That’s an important and to date unknown question. When the full Gener8-1 data emerge, the field could learn the answer.
Disease Area: Multiple myeloma
Companies: Celgene/Bluebird Bio; Amgen
Data Expected: TBA (Celgene/Bluebird); 2019 (Amgen)
Why We’re Watching: Immunotherapy has transformed how a number of cancers are treated. Multiple myeloma, a persistent, deadly cancer of the bone marrow, could soon follow, thanks to a slew of experimental cell immunotherapies targeting a protein called BCMA. Several companies are testing CAR-T treatments that go after BCMA, a protein found in abundance on the surface of cancerous B cells in the bone marrow. These treatments involve drawing T cells from patients and engineering them to attack BCMA-bearing cells. The results in early studies have been promising, but questions linger, like how long the treatments will last and whether they’ll be used for more than just patients who have run out of options.
Some of those questions may be answered in 2019. Next year, the most advanced anti-BCMA therapy, bb2121, from Bluebird Bio (NASDAQ: BLUE) and partner Celgene (NASDAQ: CELG), should have data from a single-arm, Phase 2 study called KarMMA. The study is testing bb2121 in 140 multiple myeloma patients whose disease has persisted despite several treatments. Celgene says the study should generate the data needed to support a regulatory approval in 2020.
The pressure is on Celgene and Bluebird to move fast. Rival anti-BCMA CAR-T treatments from Nanjing Legend Biotech and partner Johnson & Johnson (NYSE: JNJ), Poseida Therapeutics, and others may not be far behind. Celgene and Bluebird are even co-developing an improved version of their product, bb21217, part of Celgene’s strategy to stay ahead of the competition. That’s why, on a recent research note, Leerink’s Geoffrey Porges wrote that Celgene “seems the most likely winner of this [BCMA] race in 4-5 years.”
But the competition isn’t only coming from CAR-T competitors. Antibody drugs that target BCMA are in the mix too. One called AMG-420, from Amgen (NASDAQ: AMGN), binds to both a protein on T cells and to BCMA. These so-called BiTE molecules are meant to bring tumor-killing T cells to their cancer targets, which CAR-T therapies also do but involve more complicated cell manufacturing work than antibody drugs. Amgen recently announced updated Phase 1 data at the American Society of Hematology’s annual meeting. The data “fall short” of the recent hype that has surrounded Amgen’s program, Porges wrote. Still, as a potential “off-the-shelf” alternative to CAR-T, AMG-420 could muddy the waters if all of these treatments come to market. Further data from AMG-420 are expected in 2019, according to Amgen.
Disease Area: Solid-tumor cancers
Companies: Bristol-Myers Squibb, Nektar Therapeutics
Data Expected: 2019
Why We’re Watching: It’s one of the boldest, most expensive forays into combination cancer immunotherapy yet. In February, Bristol-Myers Squibb (NYSE: BMY) paid Nektar Therapeutics (NASDAQ: NKTR) nearly $2 billion just for partial rights to Nektar’s NKTR-214, including the opportunity to pair it with Bristol’s immunotherapy nivolumab (Opdivo).
Part of a new wave of breakthrough cancer drugs called checkpoint inhibitors, nivolumab is approved for several types of cancer and has earned Bristol nearly $5 billion through the first three quarters of 2018, 37 percent higher than the same period in 2017. But like its checkpoint peers, nivolumab only benefits a minority of patients. The race is on to create combinations to broaden immunotherapy’s reach, but experts warned more than a year ago that companies were moving too fast, and not doing enough underlying basic research to select the best combinations.
This year came the I-told-you-so’s. Attempts to pair checkpoints with so-called IDO inhibitors were a major flop, and calls came again for drug developers to slow down.
All eyes, then, are on Bristol and Nektar, and another high-wire combination act. NKTR-214 stimulates the immune system protein IL-2, an old idea (drugs were approved in the 1990s) now gaining new life through Nektar and several others. It has limits; IL-2 stimulation revs up cancer-killing T and NK cells, which can quickly lead to dangerous side effects. (Nektar says its version, with a chemical adjustment called pegylation, has blunted those effects.)
The first PIVOT-02 data release after the Nektar-Bristol deal came in June. The mixed results, in patients with 13 types and subtypes of solid-tumor cancers, left investors feeling a little wobbly in the knees.
But the argument for moving ahead got even choppier in November, when selected PIVOT-02 data were updated and didn’t look much better than they did before.
More updates from PIVOT-02 are expected next year, and they should help paint a more comprehensive picture of what the nivolumab/NKTR-214 combination can do. The bar is higher than it used to be: Several immunotherapies are approved for melanoma, including Bristol’s own in-house combination of nivolumab and ipilimumab (Yervoy). Bristol will need nivolumab/NKTR-214 to clear that bar not just to solidify its big investment in Nektar but to calm broader worries about finding combination partners to build upon the initial success of checkpoint immunotherapies.
Disease Area: Age-related macular degeneration
Data Expected: 2019
Why We’re Watching: Age-related macular degeneration is one of the most common forms of vision loss in the Western world, affecting 2 million Americans today and an expected 5.5 million by 2050, according to the National Eye Institute. It’s also a huge business for the drug industry.
To deal with the more damaging “wet” form of the disease—which can lead to a distortion of vision that gets worse over time—patients periodically have a drug injected into their eyes. Even with the generic option of off-label bevacizumab (Avastin), the two FDA-approved drugs continue to rack up sales. Each one—ranibizumab (Lucentis) from Roche/Genentech and aflibercept (Eylea) from Regeneron Pharmaceuticals—costs doctors close to $2,000 a dose and, combined, they generate more than $7 billion in annual sales. They also account for a roughly 12 percent chunk of Medicare Part B spending every year.
One way to top these drugs and perhaps lower costs is to … Next Page »